CADTH Reimbursement Review

Upadacitinib (Rinvoq)

Sponsor: AbbVie Corporation

Therapeutic area: Psoriatic arthritis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

ACE

Arthritis Consumer Experts

ACR

American College of Rheumatology

ACR20

20% improvement in the American College of Rheumatology criteria

ACR50

50% improvement in the American College of Rheumatology criteria

ACR70

70% improvement in the American College of Rheumatology criteria

AE

adverse event

BASDAI

Bath Ankylosing Spondylitis Disease Activity Index

bDMARD

biologic disease-modifying antirheumatic drug

BSA

body surface area

CAPA

Canadian Arthritis Patient Alliance

CAPP

Canadian Association of Psoriasis Patients

CI

confidence interval

CPK

creatine phosphokinase

CPN

Canadian Psoriasis Network

CrI

credible interval

CSA

Canadian Spondylitis Association

csDMARD

conventional synthetic disease-modifying antirheumatic drug

DMARD

disease-modifying antirheumatic drug

EQ-5D-5L

EuroQol 5-Dimensions 5-Levels

FACIT-F

Functional Assessment of Chronic Illness Therapy–Fatigue

FAS

full analysis set

HAQ-DI

Health Assessment Questionnaire–Disability Index

HRQoL

health-related quality of life

hs-CRP

high-sensitivity C-reactive protein

IL

interleukin

ITC

indirect treatment comparison

JAK

Janus kinase

LDI

Leeds Dactylitis Index

LEI

Leeds Enthesitis Index

LS

least squares

MACE

major adverse cardiovascular event

MCS

mental component summary

MDA

minimal disease activity

MID

minimal important difference

MMRM

mixed model for repeated measures

NMA

network meta-analysis

NRI

nonresponder imputation

NRS

numerical rating scale

NSAID

nonsteroidal anti-inflammatory drug

PASI

Psoriasis Area and Severity Index

PASI 50

50% reduction in Psoriasis Area Severity Index

PASI 75

75% reduction in Psoriasis Area Severity Index

PASI 90

90% reduction in Psoriasis Area Severity Index

PASI 100

100% reduction in Psoriasis Area Severity Index

PCS

physical component summary

PDE4

phosphodiesterase type 4

PPS

per-protocol set

PsA

psoriatic arthritis

PY

patient-year

RCT

randomized controlled trial

SAE

serious adverse event

SAPS

Self-Assessment of Psoriasis Symptoms

SC

subcutaneous

SD

standard deviation

SF-36

Short Form (36) Health Survey

SHS

Sharp/van der Heijde Score

sIGA

Self-Assessment of Psoriasis Symptoms

SJC

swollen joint count

SJC66

swollen joint count based on 66 joints

TEAE

treatment-emergent adverse event

TJC

tender joint count

TJC68

tender joint count based on 68 joints

TNF

tumour necrosis factor

tsDMARD

targeted synthetic disease-modifying antirheumatic drug

ULN

upper limit of normal

VAS

visual analogue scale

WDAE

withdrawal due to adverse event

WPAI

Work Productivity and Activity Impairment

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

Item

Description

Drug product

Upadacitinib (Rinvoq) 15-mg extended-release oral tablets

Indication

For the treatment of adults with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other DMARDs; Rinvoq (upadacitinib) may be used as monotherapy or in combination with methotrexate

Reimbursement request

As per indication

Health Canada approval status

NOC

Health Canada review pathway

Standard

NOC date

June 3, 2021

Sponsor

AbbVie Corporation

DMARD = disease-modifying antirheumatic drug; NOC = Notice of Compliance.

Introduction

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease with a heterogenous presentation and disease course. While it is associated with psoriasis, PsA also presents with variable clinical features involving multiple domains, including peripheral arthritis, enthesitis, dactylitis, and axial disease.1,2 Patients with PsA also present with psoriatic skin lesions and are usually seronegative for rheumatoid factor (95%).2,3 Pain and stiffness of the affected joints are the most predominant presenting symptoms, with fatigue also occurring in many patients.1 The prevalence of PsA varies, depending on the case definition and geography, and is estimated to be 1 to 2 per 1,000 in the general population.1 A population-based Canadian study estimated that the age- and sex-standardized cumulative prevalence of PsA in Ontario ranged from 0.09% in 2008 to 0.15% in 2015. The same study estimated the age- and sex-standardized incidence in 2015 was 14 per 100,000.4 These figures may vary; for example, in another reference, the estimated annual incidence of PsA was reported to be 6 per 100,000 per year.1 Over time, PsA can lead to deformities and joint damage.2 This can lead to significant functional impairment, which in turn can affect work productivity and reduce health-related quality of life (HRQoL).2,3

Several drug classes are employed in the pharmacologic treatment of PsA, including nonsteroidal anti-inflammatory drugs (NSAIDs); conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, sulfasalazine, and leflunomide; biologic disease-modifying antirheumatic drugs (bDMARDs) such as tumour necrosis factor (TNF) inhibitors; interleukin (IL)-23, IL-12/23, and IL-17 inhibitors; and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) that inhibit phosphodiesterase type 4 (PDE4) such as apremilast or Janus kinases (JAKs) (tofacitinib).5 In the treatment of PsA, csDMARDs, typically methotrexate, are recommended as first-line therapy or after a short course of NSAIDs in patients with polyarthritis. Some guidelines also recommend first-line treatment with a TNF inhibitor, particularly in patients with severe PsA or psoriasis.6,7 In patients with an inadequate response to at least 1 csDMARD, a bDMARD may be started. In the case of biologic drug treatment failure, due to either lack of efficacy or adverse events (AEs), treatment guidelines recommend switching to an alternative biologic drug within a drug class, or to a drug with a different mode of action.5-7 Specific treatment recommendations are also available for other scenarios, such as for patients with unequivocal enthesitis or predominantly axial disease. Treatment choice is individualized based on numerous factors, including severity and manifestations of disease, contraindications, concomitant conditions (e.g., active inflammatory bowel disease), and patient preference (e.g., route of administration or dosing frequency).7

Upadacitinib is an oral JAK inhibitor that is selective for JAK1. By inhibiting JAKs, upadacitinib modulates intracellular signalling pathways of cytokines and growth factors involved in a broad range of cellular processes, such as inflammatory responses, hematopoiesis, and immune surveillance.8 It is approved for the treatment of adults with active PsA who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). The recommended dosage of upadacitinib for treatment of PsA is 15 mg orally once a day, used as monotherapy or in combination with methotrexate.8

The objective of this CADTH Drug Reimbursement Review, as established before the granting of the Notice of Compliance, is to perform a systematic review of the beneficial and harmful effects of upadacitinib 15 mg oral extended-release tablets as monotherapy or in combination with non-bDMARDs for the treatment of active PsA in adult patients who have responded inadequately or who are intolerant to 1 or more DMARDs.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

Four inputs were submitted for this review from 6 different patient groups: Arthritis Consumer Experts (ACE), the Canadian Spondylitis Association (CSA), the Canadian Association of Psoriasis Patients (CAPP) in partnership with the Canadian Psoriasis Network (CPN), and the Canadian Arthritis Patient Alliance (CAPA) in partnership with the Arthritis Society. Five of these patient organizations (the Arthritis Society, CSA, CAPP, CPN, and CAPA) collaboratively developed a survey that was shared with their respective memberships or patient communities. Overall, the survey drew 94 responses. The CSA also conducted a telephone interview with a patient on upadacitinib. Arthritis Consumer Experts gathered its own data from 5 patients who completed a patient input survey.

Respondents to the surveys emphasized pain, stiffness, lack of mobility, and fatigue, all of which affect activities associated with daily living and family life, and their ability to work and maintain certain hobbies. Other impacts included embarrassment and self-consciousness from symptoms caused by PsA. Respondents reported difficulties contributing and participating at school or work due to their symptoms. The impact of PsA extends to others within a person’s support circle, including caregivers such as spouses, partners, or children who may have to take on additional roles or tasks to support the person living with PsA.

The patient input noted that those living with psoriatic disease often try a succession of treatments throughout their lives. Patients’ responses to medication can vary significantly, and treatments that are initially effective can become less effective over time. As a result, patients need several treatment options to effectively manage their disease. Outcomes that were identified as important to patients with PsA include the route of drug administration (oral versus infusion versus self-injection), a reduction in pain and fatigue, treatments that are effective for psoriasis as well as PsA, increased mobility, ability to work and be productive at work, ability to carry out activities of daily living, ability to effectively carry out parenting tasks and other important social roles, reduced infection rates, affordability of the medication, and improved HRQoL. According to the input from the CSA, new treatment options and different classes of medications fill a void in the unmet needs of patients and prescribers; the oral formulation of upadacitinib provides another option for administration and may help lead to improved adherence and ultimately better outcomes.

Clinician Input

Input from Clinical Experts Consulted by CADTH

The clinical expert consulted by CADTH for this review identified an unmet need in the treatment of psoriatic disease as some patients may not respond to any treatment, and only a minority achieve minimal disease activity (MDA). In the treatment of PsA, numerous domains of disease activity that might not be accomplished by a single drug need to be addressed. In patients who do not respond or become refractory to treatment, a switch to treatment with a different mechanism of action will be necessary.

The clinical expert indicated that any patient with peripheral joint and skin disease that does not respond to csDMARDs would be eligible for upadacitinib, barring contraindications. Tumour necrosis factor inhibitors and IL-17 inhibitors will generally be prescribed before upadacitinib. However, the clinical expert noted that upadacitinib may become a first-line treatment for PsA as clinicians become more experienced with upadacitinib and long-term safety is confirmed. The caveat with this assumption is that longer-term observation in patients on upadacitinib will be needed to confirm the durability of benefit and safety. The clinical expert also identified the oral route of upadacitinib as an advantage, with the improved convenience over subcutaneous injections or IV infusions expected to enhance treatment adherence. It is also expected that a benefit from a JAK inhibitor will become apparent sooner than from TNF inhibitors, and a lack of response and/or side effects will result in the discontinuation of treatment.

According to the clinical expert, the swollen joint count (SJC) is the most likely measure used in clinical practice to assess response, with a reduction in joint count reflecting a meaningful response. Other clinically meaningful responses may be measured using achievement of MDA or patient-reported outcomes.

Clinician Group Input

No clinician group input was received for this reimbursement review.

Drug Program Input

Input was obtained from the jurisdictions participating in CADTH reimbursement reviews. The following were identified as key factors that could impact the implementation:

The clinical expert consulted by CADTH provided responses that can be found in the Drug Program Input section.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Two multi-centre, phase III, randomized, double-blind, placebo-controlled trials, SELECT-PsA1 and SELECT-PsA2, met the inclusion criteria for this review. Both SELECT studies enrolled adult patients with an established diagnosis of moderately to severely active PsA who had been previously treated with a DMARD. SELECT-PsA1 was conducted in patients who had an insufficient response or were intolerant to a non-bDMARD, whereas PsA2 included patients who had an insufficient response or were intolerant to a bDMARD. Both trials investigated 2 dosages of oral upadacitinib: 15 mg once daily and 30 mg once daily; however, to align with the Health Canada–recommended dosage, only results for upadacitinib 15 mg once daily are presented in this review.

Efficacy and safety of upadacitinib were compared with placebo in both studies; SELECT-PsA1 also included adalimumab as an active comparator. Both studies consisted of 2 periods, and at the end of week 24 in period 1, all patients on placebo were switched to upadacitinib. In SELECT-PsA1, period 1 was 56 weeks in duration and included a 24-week double-blind placebo and active comparator–controlled period followed by 32 weeks of blinded active comparator–controlled treatment. SELECT-PsA2 also consisted of period 1, which was 56 weeks in duration and included 24 weeks of a double-blinded placebo-controlled phase followed by a 32-week non-comparative treatment phase. Period 2 is an ongoing, open-label, long-term treatment extension of up to approximately 5 years for PsA1 and 3 years for PsA2.

In SELECT-PsA1 (N = 1,705), eligible participants were randomized at a 2:2:2:1:1 ratio to 1 of 5 treatment groups: upadacitinib 15 mg once daily, upadacitinib 30 mg once daily, adalimumab 40 mg subcutaneous every other week, and placebo followed by upadacitinib 15 mg once daily or placebo followed by upadacitinib 30 mg once daily. Randomization was stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of enthesitis. Patients enrolled in SELECT-PsA2 (N = 642) were randomized in a 2:2:1:1 ratio to 1 of 4 treatment groups similar to SELECT-PsA1, but without the adalimumab treatment group: upadacitinib 15 mg once daily, upadacitinib 30 mg once daily, and placebo followed by either upadacitinib 15 mg once daily or upadacitinib 30 mg once daily. Randomization was stratified by extent of psoriasis, current use of at least 1 DMARD, and number of prior failed bDMARDs (1 versus > 1). Patients were permitted to continue their stable background non-bDMARD therapy. Both studies had an appropriate randomization strategy, and treatment groups within each study were generally well balanced. Compared to patients in SELECT-PsA1, those in SELECT-PsA-2 had PsA for longer with more significant disease.

The primary end point for both SELECT-PsA1 and SELECT-PsA2 was the proportion of patients who achieved at least a 20% improvement in American College of Rheumatology response criteria (ACR20) at week 12. The primary and major secondary efficacy outcomes were assessed using a hierarchical testing procedure to control the overall type I error rate. The multiplicity-adjusted testing hierarchy included the primary end point plus 14 ranked key secondary end points in SELECT-PsA1, and 7 ranked key secondary end points in SELECT-PsA2. Several additional end points that were not part of the multiplicity-adjusted analyses but were identified in the CADTH systematic review protocol are also discussed in this report.

Efficacy Results

Efficacy results are summarized in Table 2. Results of the primary outcome, key secondary efficacy outcomes, outcomes identified in the review protocol (Table 5), and those considered important by patient groups are reported. Results of efficacy outcomes that were not included in the multiplicity-controlled analyses are described; however, they are considered inconclusive because of the potential for inflated type I error.

In the SELECT-PsA1 trial, upadacitinib 15 mg did not demonstrate superiority over adalimumab in ACR20 response at week 12. As such, statistically significant differences in the key secondary end points lower in the testing hierarchy were not tested because of the multiplicity control strategy.

Clinical Responses in Psoriatic Arthritis Symptoms

Clinical response in PsA symptoms or overall disease activity were measured using ACR20, MDA, and modified Psoriatic Arthritis Response Criteria (PsARC). In SELECT-PsA1, 70.6% and 36.2% of patients treated with upadacitinib 15 mg and placebo, respectively, achieved an ACR20 response, and the difference between the upadacitinib 15 mg group and placebo treatment group was 34.5% (95% confidence interval [CI], 28.2 to 40.7; P < 0.0001), which was clinically relevant and statistically significant in favour of upadacitinib 15 mg. In SELECT-PsA2, 56.9% and 24.1% of patients treated with upadacitinib 15 mg and placebo, respectively, achieved an ACR20 response; the difference between the upadacitinib 15 mg group and the placebo treatment group was 32.8% (95% CI, 24.0 to 41.6; P < 0.0001), which was clinically relevant and statistically significant in favour of upadacitinib 15 mg. Results of the pre-specified subgroup analyses by current use of non-bDMARD, number of prior non-bDMARD (SELECT-PsA1) and number of prior failed bDMARDs (SELECT-PsA2) were consistent with results from the overall population for the primary end point of an ACR20 at week 12; however, these analyses were not included in the hierarchical statistical analysis and should be interpreted with caution because of the potential for inflated type I error. The clinical expert consulted for this review noted that the differences in ACR20 responses compared with placebo were clinically meaningful.

In SELECT-PsA1, the proportion of patients achieving an ACR20 at week 12 with upadacitinib treatment compared to adalimumab was tested for noninferiority and superiority as key secondary end points. An ACR20 response was achieved by 70.6% of the upadacitinib 15 mg group and by 65.0% of patients in the adalimumab group. The difference between the upadacitinib 15 mg group and the adalimumab treatment group was 5.6% (95% CI, −0.6 to 11.8). The adalimumab effect preservation, calculated by (upadacitinib – placebo)/(adalimumab – placebo), was 119.4% (95% CI, 98.0 to 147.9); the lower bound of the 95% CI exceeded the pre-specified noninferiority ratio of at least 50% of the placebo-subtracted adalimumab effect, indicating that upadacitinib 15 mg daily was noninferior to adalimumab 40 mg every other week. In the subsequent testing of superiority, upadacitinib 15 mg was not found to be superior compared to adalimumab 40 mg, as it did not meet the statistical significance for superiority.

For clinical responses measured with the MDA criteria, patients treated with upadacitinib 15 mg had higher response rates compared to placebo at week 24 in both SELECT-PsA1 (36.6% for upadacitinib 15 mg and 12.3% for placebo) and SELECT-PsA2 (25.1% for upadacitinib 15 mg and 2.8% for placebo). The between-group differences were 24.3% (95% CI, 18.8 to 29.8; P = 0.0004) in the SELECT-PsA1 trial and 22.3% (95% CI, 16.0 to 28.6; P < 0.0001) in SELECT-PsA2. In both trials, the between-group differences were statistically significant in favour of upadacitinib 15 mg.

For modified PsARC response at week 24, a higher proportion of patients treated with upadacitinib achieved a response compared to patients randomized to adalimumab or placebo in both studies (SELECT-PsA1: 83.7% for upadacitinib 15 mg, 76.6% for adalimumab 40 mg, and 59.3% for placebo; SELECT-PsA2: 68.2% for upadacitinib 15 mg and 36.3% for placebo). In SELECT-PsA1, the response-rate difference between the upadacitinib and adalimumab groups was 7.0% (95% CI, 1.7 to 12.3), whereas the difference between upadacitinib and placebo was 24.3% (95% CI, 18.5 to 30.2). In SELECT-PsA2 the difference between upadacitinib and placebo was 31.9 (95% CI, 22.9 to 40.9). These analyses were not included in the hierarchical statistical analysis.

Measurement of Function and Disability

The improvement in physical function at week 12 as measured by the Health Assessment Questionnaire–Disability Index (HAQ-DI) was statistically significant. The change in scores from baseline in upadacitinib 15 mg and placebo were −0.42 and −0.14, respectively, in SELECT-PsA1, and −0.30 and −0.10, respectively, in SELECT-PsA2. The differences in change from baseline between upadacitinib 15 mg and placebo were −0.28 (95% CI, −0.35 to −0.22; P < 0.0001) in SELECT-PsA1 and −0.21 (95% CI, −0.30 to −0.12; P < 0.0001) in SELECT-PsA2. While in both studies, the between-group differences in the improvement of the HAQ-DI scores did not exceed the estimated minimal important difference (MID) of 0.35 found in the literature, the proportions of patients who achieved a clinically meaningful improvement in HAQ-DI at week 12 in the SELECT-PsA1 study were 33.4%, 47.2%, and 57.9% in the placebo, adalimumab 40 mg, and upadacitinib 15 mg treatment groups, respectively, while the proportions of patients who achieved a clinically meaningful improvement in HAQ-DI at week 12 in SELECT-PsA2 were 27.2% and 44.6% in the placebo and upadacitinib 15 mg treatment groups, respectively.

Work productivity was measured by the Work Productivity and Activity Impairment (WPAI) questionnaire in a portion of study participants in both studies. Numerically greater reductions in work or activity impairment due to disease were observed for the upadacitinib 15 mg group compared to placebo at week 24. Although it appears the suggested MID was achieved by SELECT-PsA1 patients in the upadacitinib group for improvement in presenteeism (≥ 20%) and activity impairment (≥ 20%), the between-group differences in change from baseline compared to placebo or adalimumab did not exceed this threshold. The least squares (LS) mean difference in the change in scores between upadacitinib and adalimumab was −2.5 (95% CI, −6.2 to 1.2), whereas the LS mean differences between upadacitinib and placebo were −13.4 (95% CI, −17.1 to −9.7) in SELECT-PsA1 and −12.2 (95% CI, −18.8 to −5.6) in SELECT-PsA2. With a smaller number of patients included in the analysis, and the lack of a confirmed MID for the WPAI instrument, it remains unclear whether the differences were clinically meaningful. This was identified as an important outcome by the patient groups, but as it was an exploratory variable in both SELECT-PsA1 and SELECT-PsA2 it was not included in the multiplicity-controlled analyses.

Measurement of PsA Symptoms

Symptoms of PsA such as fatigue and pain were reported in both studies. A statistically greater improvement in fatigue from baseline, measured using the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), was seen at week 12 with upadacitinib 15 mg compared to placebo in both studies. The mean changes from baseline were 6.3 for upadacitinib 15 mg and 2.8 for placebo in SELECT-PsA1 (between-group difference of 3.5; 95% CI, 2.4 to 4.7; P = 0.0004) and 5.0 for upadacitinib 15 mg and 1.3 for placebo in SELECT-PsA2 (between-group difference of 3.7; 95% CI, 2.0 to 5.4; P < 0.0001). The between-group difference in the improvement in FACIT-F score at week 12 exceeded the estimated MID (3.1 points) in both studies. The impact of upadacitinib on pain is uncertain as this end point was not part of the hierarchical analysis, and no MID was identified for the patient’s assessment of pain numeric rating scale (NRS) in patients with PsA.

Health-Related Quality of Life

Health-related quality of life was measured by the Short Form (36) Health Survey (SF-36) and EuroQol 5-Dimensions 5-Levels questionnaire (EQ-5D-5L) in SELECT-PsA1 and PsA2. Only the physical component summary (PCS) of the SF-36 was part of the multiplicity-adjusted testing hierarchy in the SELECT studies, and the differences between the 2 groups were statistically significant. In SELECT-PsA1, the difference in mean change from baseline for upadacitinib 15 mg versus placebo was 4.67 (95% CI, 3.67 to 5.67; P = 0.0004) in favour of upadacitinib 15 mg; in SELECT-PsA2 the difference in mean change from baseline for upadacitinib 15 mg versus placebo was 3.52 (95% CI, 2.07 to 4.98; P < 0.0001) in favour of upadacitinib 15 mg. For the mental component summary (MCS), a numerically greater improvement from baseline was seen for upadacitinib compared to placebo in both trials; the difference in mean change from baseline between the 2 treatment groups was 1.70 (95% CI, 0.58 to 2.82) in SELECT-PsA1 and 2.98 (95% CI, 1.44 to 4.52) in SELECT-PsA2. The results from the EQ-5D-5L suggest that there were greater improvements in the utility index and the Visual Analogue Scale (VAS) scores from baseline to week 24 in the upadacitinib treatment group compared to patients randomized to placebo in both studies, as well as adalimumab in PsA1. For the utility index, the difference in mean change from baseline between upadacitinib and adalimumab was 0.03 (95% CI, 0.00 to 0.05), whereas the difference in mean change from baseline between upadacitinib and placebo was 0.09 (95% CI, 0.06 to 0.11) in SELECT-PsA1 and 0.10 (95% CI, 0.06 to 0.14) in SELECT-PsA2. For the VAS, the difference in mean change from baseline between upadacitinib and adalimumab was 2.8 (95% CI, 0.0 to 5.6), whereas the difference in mean change from baseline between upadacitinib and placebo was 10.9 (95% CI, 8.0 to 13.7) in SELECT-PsA1 and 6.8 (95% CI, 2.5 to 11.1) in SELECT-PsA2. For the comparison of upadacitinib to placebo in both studies, the mean between-group differences in the EQ-5D-5L utility index reached the MID threshold identified in the literature for the general Canadian population (summarized mean of 0.056; standard deviation [SD] = 0.011). These results suggest that treatment with upadacitinib 15 mg was associated with improved HRQoL. Although patient groups identified HRQoL as an important outcome, the EQ-5D-5L and the MCS of the SF-36 were not part of the hierarchical analysis plan and were not adjusted for multiple comparisons; therefore, the results should be interpreted with caution due to the risk of inflated type I error.

Measurement of Skin Disease

Extent and severity of skin disease was measured in both studies using the PASI, sIGA, and SAPS. Only patients with psoriasis involving a 3% or greater BSA baseline had a PASI assessment. In SELECT-PsA1, the proportion of patients achieving a PASI response of 75 in the upadacitinib 15 mg treatment group was 62.6% compared to 21.3% in the placebo group, and the difference between the upadacitinib 15 mg and placebo groups was 41.3% (95% CI, 32.8 to 49.8; P < 0.0001), which was statistically significant in favour of upadacitinib 15 mg. In PsA2, the proportion of patients achieving a 75% reduction in PASI score (PASI 75) in the upadacitinib treatment group was 52.3% compared to 16.0% in the placebo group, and the difference between the upadacitinib 15 mg group and placebo group was 36.3% (95% CI, 25.6 to 46.9; P < 0.001), which was statistically significant in favour of upadacitinib 15 mg. The clinical expert consulted for this review indicated that the between-group differences in PASI 75 were considered clinically relevant, although the true effect should be derived from separate studies that are specifically designed for patients with skin disease.

Only patients with an sIGA score of 2 or greater at baseline, and an improvement of at least 2 points from baseline at week 16 were included in the assessment. In both SELECT-PsA1 and SELECT-PsA2, a statistically significant difference was seen in the proportion of patients achieving a response (an sIGA of psoriasis score of 0 or 1) in favour of upadacitinib. At week 16, the proportions of responders were 41.9% for upadacitinib 15 mg and 10.9% for placebo (between-group difference of 31.1%; 95% CI, 24.7 to 37.5; P < 0.0001) in SELECT-PsA1, and 36.8% for upadacitinib 15 mg and 9.2% for placebo (between-group difference of 27.6%; 95% CI, 19.2 to 36.1; P < 0.0001) in SELECT-PsA2.

A greater reduction in SAPS score from baseline was reported for patients in the upadacitinib group compared to placebo at week 16. In PsA1, the difference in LS mean change from baseline between upadacitinib and placebo was −17.1 (95% CI, −19.6 to −14.6) for upadacitinib 15 mg versus placebo. Testing for superiority of upadacitinib compared to placebo was part of the multiplicity-adjusted analyses in PsA1; however, because it was ranked after the point at which the hierarchical analysis failed and was stopped, no appropriate statistical comparisons can be made. In SELECT-PsA2, the difference between groups in the LS mean change from baseline in SAPS scores was statistically significant, favouring upadacitinib compared to placebo (−22.9; 95% CI, −27.4 to −18.4; P < 0.0001).

Measurement of Other Musculoskeletal Disease

Impact of treatment on musculoskeletal disease was assessed by measuring the resolution of enthesitis with the Leeds Enthesitis Index (LEI), resolution of dactylitis with the Leeds Dactylitis Index (LDI), and change in axial disease using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). For SELECT-PsA1 patients with enthesitis at baseline, resolution of enthesitis (LEI = 0) was achieved by a statistically significantly higher proportion of patients in the upadacitinib 15 mg treatment group (53.7%) compared to placebo (32.4%) at week 24 (between-group difference of 21.3%; 95% CI, 13.0 to 29.7; P = 0.0004). In SELECT-PsA2, a numerically higher proportion of patients in the upadacitinib 15 mg treatment group achieved resolution of enthesitis at week 24 compared to patients in the placebo group, with a difference of 27.6% (95% CI, 17.3 to 37.8); however, this end point was not part of the multiplicity-controlled analyses in PsA2. As there is a risk of inflated type I error, no appropriate statistical comparisons can be made. Resolution of dactylitis (LDI = 0) was achieved by a numerically higher proportion of patients in the upadacitinib group compared to the placebo group at week 24 in both trials. The differences between the 2 treatment groups were 36.8% (95% CI, 25.7 to 47.9) in SELECT-PsA1 and 30.1% (95% CI, 13.0 to 47.1) in SELECT-PsA2. In SELECT-PsA1, this end point was included in the hierarchical statistical analysis; however, it was ranked after the point at which the hierarchical analysis failed and was stopped. In SELECT-PsA2, this end point was not part of the multiplicity-controlled analyses. Results for this end point are therefore considered exploratory in both trials.

Change in axial disease was assessed in patients with the presence of psoriatic spondylitis at baseline. The improvement in BASDAI score from baseline to week 24 numerically favoured the upadacitinib 15 mg treatment group compared to the placebo group in both studies and compared to the adalimumab group in SELECT-PsA1. In SELECT-PsA1, the difference in the LS mean change in scores from baseline between upadacitinib and adalimumab was −0.57 (95% CI, −1.09 to −0.05), and between upadacitinib and placebo it was −1.42 (95% CI, −1.94 to −0.90). In PsA2, the difference between upadacitinib and placebo was −1.85 (95% CI, −2.55 to −1.15). However, this outcome assessment was not included in the hierarchical statistical analysis and should be considered inconclusive because of the potential for inflated type I error.

Radiographic Changes

Radiographic change was assessed only in SELECT-PsA1 using the Sharp/van der Heijde Score (SHS). At week 24, the differences in LS mean change from baseline in SHS was statistically significant, favouring the upadacitinib 15 mg treatment group over placebo (−0.29; 95% CI, −0.44 to −0.14; P = 0.0004). According to the clinical expert consulted for this review, these numerically small changes are unlikely to be clinically meaningful to patients over a period of only 24 weeks and it is difficult to extrapolate the significance of these changes over the lifetime of a patient with PsA. In particular, it is uncertain whether the radiographic changes seen in SELECT-PsA1 correlate with a direct and meaningful improvement in a patient’s physical function, quality of life, or permanent disability. However, the observations satisfy the regulatory requirement that upadacitinib can inhibit radiographic progression.

Harms Results

Safety data are summarized in Table 2. By week 24, the proportion of patients in SELECT-PsA1 who experienced a treatment-emergent adverse event (TEAE) was higher in the upadacitinib 15 mg and adalimumab treatment groups compared to the placebo group. In PsA2, the proportion of patients who experienced a TEAE was similar between the upadacitinib and placebo groups. Generally, the majority of AEs were mild or moderate in severity, and the most frequently reported AE in both studies was an upper respiratory tract infection. The frequency of serious adverse events (SAEs) and withdrawals due to adverse events (WDAEs) were low across all treatment groups and generally below 5%, with the exception of the upadacitinib 15 mg treatment group of SELECT-PsA2, which had the highest proportion of patients experiencing an SAE (5.7%) or WDAE (7.1%) across both studies. None of the specific SAEs were reported by more than 2 patients. Two treatment-emergent deaths were reported by week 24, both in the placebo group. One non–treatment-emergent death (i.e., occurring more than 30 days after the last dose) was reported in the upadacitinib 15 mg group.

Table 2: Summary of Key Results From Pivotal and Protocol-Selected Studies

Outcome

SELECT-PsA1

SELECT-PsA2

PBO

ADA 40 mg every other week

UPA 15 mg daily

PBO

UPA 15 mg daily

Efficacy

ACR20 response rate at week 12 (NRI, FAS)

Total N

423

429

429

212

211

Responder n (%)

153 (36.2)

279 (65.0)

303 (70.6)

51 (24.1)

120 (56.9)

Response rate (95% CI)a

36.2 (31.6 to 40.7)

65.0 (60.5 to 69.5)

70.6 (66.3 to 74.9)

24.1 (18.3 to 29.8)

56.9 (50.2 to 63.6)

Difference vs. control (95% CI)b

34.5 (28.2 to 40.7) UPA vs. placebo

5.6 (−0.6 to 11.8) UPA vs. ADA

32.8 (24.0 to 41.6)

P valuec

< 0.0001 UPA vs. placebo

0.0004 (noninferiority, UPA vs. ADA)d

0.0815 (superiority, UPA vs. ADA)

< 0.0001

MDA at week 24 (NRI,e FAS)

Total N

423

429

429

212

211

Responder n (%)

52 (12.3)

143 (33.3)

157 (36.6)

6 (2.8)

53 (25.1)

Response rate (95% CI)a

12.3 (9.2 to 15.4)

33.3 (28.9 to 37.8)

36.6 (32.0 to 41.2)

2.8 (0.6 to 5.1)

25.1 (19.3 to 31.0)

Difference vs. PBO (95% CI)b

24.3 (18.8 to 29.8)

22.3 (16.0 to 28.6)

P valuec

0.0004

< 0.0001

HAQ-DI at week 12 (MMRM,f FAS)

Total N

392

406

404

180

199

Baseline mean

1.11

1.11

1.15

1.23

1.08

LS mean change from baseline (95% CI)

−0.14

(−0.18 to −0.09)

−0.34

(−0.38 to −0.29)

−0.42

(−0.47 to −0.37)

−0.10

(−0.16 to −0.03)

−0.30

(−0.37 to −0.24)

LS mean difference vs. PBO (95% CI)

−0.28 (−0.35 to −0.22)

−0.21 (−0.30 to −0.12)

P valueg

< 0.0001

< 0.0001

FACIT-F at week 12 (MMRM,f FAS)

Total N

394

410

404

184

201

Baseline mean

30.3

29.8

29.0

26.4

27.9

LS mean change from baseline (95% CI)

2.8 (1.9 to 3.7)

5.7 (4.8 to 6.6)

6.3 (5.4 to 7.2)

1.3 (0.1 to 2.5)

5.0 (3.8 to 6.1)

LS mean difference vs. PBO (95% CI)

3.5 (2.4 to 4.7)

3.7 (2.0 to 5.4)

P valueg

0.0004

< 0.0001

SF-36 PCS at week 12 (MMRM,f FAS)

Total N

394

410

405

185

201

Baseline mean

35.19

35.91

34.71

34.33

35.08

LS mean change from baseline (95% CI)

3.19 (2.41 to 3.96)

6.82 (6.07 to 7.58)

7.86 (7.09 to 8.63)

1.62 (0.58 to 2.67)

5.15 (4.14 to 6.15)

LS mean difference vs. PBO (95% CI)

4.67 (3.67 to 5.67)

3.52 (2.07 to 4.98)

P valueg

0.0004

< 0.0001

PASI 75 at week 16 (NRI, FAS)

Total N

211

211

214

131

130

Responder n (%)

45 (21.3)

112 (53.1)

134 (62.6)

21 (16.0)

68 (52.3)

Response rate (95% CI)a

21.3 (15.8 to 26.9)

53.1 (46.3 to 59.8)

62.6 (56.1 to 69.1)

16.0 (9.7 to 22.3)

52.3 (43.7 to 60.9)

Difference vs. PBO (95% CI)b

41.3 (32.8 to 49.8)

36.3 (25.6 to 46.9)

P valuec

< 0.0001

< 0.0001

sIGA at week 16 (NRI, FAS)

Total N

313

330

322

163

171

Responder n (%)

34 (10.9)

127 (38.5)

135 (41.9)

15 (9.2)

63 (36.8)

Response rate (95% CI)a

10.9 (7.4 to 14.3)

38.5 (33.2 to 43.7)

41.9 (36.5 to 47.3)

9.2 (4.8 to 13.6)

36.8 (29.6 to 44.1)

Difference vs. PBO (95% CI)b

31.1 (24.7 to 37.5)

27.6 (19.2 to 36.1)

P valuec

< 0.0001

< 0.0001

SAPS at week 16 (MMRM,f FAS)

Total N

388

407

396

182

191

Baseline mean

44.0

43.0

44.0

52.6

49.5

LS mean change from baseline (95% CI)

−8.2

(−10.2 to −6.3)

−22.7

(−24.7 to −20.8)

−25.3

(−27.3 to −23.4)

−1.5

(−4.7 to 1.8)

−24.4

(−27.5 to −21.2)

LS mean difference vs. PBO (95% CI)

−17.1 (−19.6 to −14.6)

−22.9 (−27.4 to −18.4)

P valueg

NAh

< 0.0001

Enthesitis resolution (LEI = 0) at week 24 (NRI,e FAS)

Total N

241

265

270

144

133

Responder n (%)

78 (32.4)

125 (47.2)

145 (53.7)

22 (15.3)

57 (42.9)

Response rate (95% CI)a

32.4 (26.5 to 38.3)

47.2 (41.2 to 53.2)

53.7 (47.8 to 59.7)

15.3 (9.4 to 21.2)

42.9 (34.4 to 51.3)

Difference vs. PBO (95% CI)b

21.3 (13.0 to 29.7)

27.6 (17.3 to 37.8)

P valuec

0.0004

NAe

SHS at week 24 (ANCOVA,i FAS)

Total N

372

384

391

NR

NR

Baseline mean

13.05

14.89

13.44

NR

NR

LS mean change from baseline (95% CI)

0.25

(0.13 to 0.36)

0.01

(−0.11 to 0.13)

−0.04

(−0.16 to 0.07)

NR

NR

LS mean difference vs. PBO (95% CI)

−0.29 (−0.44 to −0.14)

NR

NR

P valueg

0.0004

NR

NR

Safety

Harms at end of double-blind period (up to week 24): Safety population

Patients with ≥ 1 AE, n (%)

252 (59.6)

278 (64.8)

287 (66.9)

139 (65.6)

135 (64.0)

Patients with ≥ 1 SAE, n (%)

13 (3.1)

16 (3.7)

14 (3.3)

4 (1.9)

12 (5.7)

Patients with ≥ 1 WDAE, n (%)

13 (3.1)

22 (5.1)

13 (3.0)

11 (5.2)

15 (7.1)

Deathj

1 (0.2)

0

0

1 (0.5)

0

Notable harms, n (%): Safety population

Serious infection

4 (0.9)

3 (0.7)

5 (1.2)

1 (0.5)

1 (0.5)

Serious pneumonia

2 (0.5)

1 (0.2)

1 (0.2)

0

1 (0.5)

Herpes zoster

3 (0.7)

0

4 (0.9)

2 (0.9)

3 (1.4)

Anemia

4 (0.9)

1 (0.2)

3 (0.7)

2 (0.9)

4 (1.9)

Neutropenia

1 (0.2)

10 (2.3)

4 (0.9)

1 (0.5)

2 (0.9)

Malignancy (any)

1 (0.2)

3 (0.7)

1 (0.2)

0

3 (1.4)

VTEk (fatal and non-fatal)

1 (0.2)

2 (0.5)

0

0

1 (0.5)

Arterial thrombosisl

0

1 (0.2)

0

0

0

GI perforation

0

0

0

0

0

CPK elevation

6 (1.4)

24 (5.6)

38 (8.9)

4 (1.9)

4 (1.9)

Hepatic disorder

16 (3.8)

67 (15.6)

39 (9.1)

3 (1.4)

4 (1.9)

MACEm

1 (0.2)

2 (0.5)

0

0

1 (0.5)

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ADA = adalimumab; AE = adverse event; ANCOVA = analysis of covariance; BSA = body surface area; CI = confidence interval; CPK = creatine phosphokinase; DMARD = disease-modifying antirheumatic drug; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; FAS = full analysis set; GI = gastrointestinal; HAQ-DI = Health Assessment Questionnaire–Disability Index; LEI = Leeds Enthesitis Index; LS = least squares; MACE = major adverse cardiovascular event; MDA = minimal disease activity; MMRM = mixed model for repeated measures; NR = not reported; NRI = nonresponder imputation; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PBO = placebo; PCS = physical component summary; SAE = serious adverse event; SAPS = Self-Assessment of Psoriasis Symptoms; SF-36 = Short Form (36) Health Survey; SHS = Sharp/van der Heijde Score; sIGA = static Investigator Global Assessment; UPA = upadacitinib; vs. = versus ; VTE = venous thromboembolic event; WDAE = withdrawal due to adverse event.

Note: Analysis of PASI 75 was performed only in patients with psoriasis covering at least 3% of BSA at baseline; analysis of sIGA was performed for patients who achieved a score of 0 or 1 and an improvement of at least 2 points from baseline, and only in patients with baseline sIGA of at least 2%; analysis of resolution of enthesitis and resolution of dactylitis were performed only in patients with baseline LEI greater than 0 and LDI greater than 0, respectively.

a95% CIs for response rate were calculated based on normal approximation to the binominal distribution.

b95% CIs for response-rate difference were calculated based on normal approximation.

cThe P value was constructed using Cochran-Mantel-Haenszel test adjusted for the main stratification factor of current DMARD use (yes/no). In PsA1, the P value was statistically significant at the 0.025 level for ACR20 (for UPA vs. PBO; and for noninferiority of UPA vs. ADA), MDA, PASI 75, sIGA, and resolution of enthesitis; and at the 0.05 level for ACR20 and superiority of UPA vs. ADA. In PsA2, the P value was significant at the 0.0125 level for MDA, and at 0.025 for ACR20, sIGA, and PASI 75.

dThe noninferiority test of UPA vs. ADA was based on 3-arm noninferiority testing aiming for UPA, preserving at least 50% of the placebo-subtracted ADA effect. The percent of ADA effect preservation is the point estimate of 3-arm noninferiority analysis, which is calculated by (UPA − PBO)/(ADA − PBO) × 100. The confidence interval of the ratio is calculated using Fieller’s method.

eNonresponder imputation with additional rescue handling was used, with patients rescued at week 16 imputed as nonresponders.

fWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an MMRM analysis with an unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current DMARD use (yes/no) as fixed factors, and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 12 (or week 16 for SAPS) before premature discontinuation of the study drug.

gIn PsA, the P value statistically was significant at the 0.0125 level for FACIT-F and SF-36 PCS; and the 0.025 level for HAQ-DI and SHS. In PsA2, the P value was significant at the 0.0125 level for FACIT-F, SF-36 PCS, SAPS; and at the 0.025 level for HAQ-DI.

hIn SELECT-PsA1, because the change from baseline in SAPS at week 16 was ranked below the point at which the hierarchical analysis failed (i.e., after testing had stopped due to failure to show superiority of UPA 15 mg vs. ADA), the P value is not presented in this table.

iResults for SHS were based on an ANCOVA with linear extrapolation for missing data and rescue handling. Within-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an ANCOVA model including treatment and the stratification factor of current DMARD use (yes/no) as fixed factors and the baseline value as a covariate.

jTreatment-emergent deaths were captured for deaths occurring up to 30 days after last dose (or ≤ 70 days for patients in the adalimumab group). In SELECT-PsA1, from week 24 to the data cut-off, 1 additional death in the upadacitinib 15 mg treatment group was reported, occurring more than 30 days after the last dose of the study drug (participant had withdrawn consent).

kIncludes fatal and non-fatal deep-vein thrombosis and pulmonary embolism. None of the patients experience a fatal VTE.

lIncludes non-cardiac, non-neurologic, and non-fatal events.

mDefined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Critical Appraisal

A few major limitations and sources of bias are described in this section. Further details for each point, as well as a complete list of limitations and sources of bias, are available in the Critical Appraisal subsection of the Clinical Evidence – Results section.

Indirect Comparisons

Description of Studies

Other than the inclusion of upadacitinib in SELECT-PsA1 and SELECT-PsA2, there are no studies in which upadacitinib is compared directly to other bDMARDs or tsDMARDs. Therefore, the sponsor conducted an indirect comparison that comprised a network meta-analysis (NMA) that compared the efficacy of upadacitinib to that of TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab), IL-17 inhibitors (secukinumab and ixekizumab), an IL-12/23 inhibitor (ustekinumab), an IL-23 inhibitor (guselkumab), cytotoxic T lymphocyte–associated antigen-4 immunoglobulin (abatacept), a JAK inhibitor (tofacitinib), and a PDE4 inhibitor (apremilast). Results from the indirect treatment comparison (ITC) are summarized in this section only for relevant comparators identified in the CADTH systematic review. Efficacy was compared at 12 and 24 weeks, and the ITC reported results for bDMARD-naive and bDMARD-experienced patients separately.

Efficacy Results

Overall, in biologic-naive patients, the NMA suggests that upadacitinib 15 mg is more efficacious for an ACR20 at week 12 compared to some comparators, specifically an IL-17 inhibitor (secukinumab 15 mg), IL-12/23 inhibitor (ustekinumab 45 mg), and IL-23 inhibitor (guselkumab), but this advantage was only seen for the IL-12/23 inhibitor at 24 weeks. Upadacitinib was also shown to be more efficacious than etanercept at both weeks 12 and 24 for a PASI response; however, this was not seen with other TNF inhibitors. The IL-17 inhibitors (secukinumab 300 mg and ixekizumab) and IL-23 inhibitor (guselkumab) appear to be more efficacious than upadacitinib for PASI responses at week 12, although only the IL-23 inhibitor was favoured over upadacitinib at week 24. For PsARC, upadacitinib was more efficacious than tofacitinib but only at week 12; this was not seen at week 24. For HAQ-DI measured in PsARC responders at week 12, etanercept was more efficacious than upadacitinib; this benefit was not seen with other TNF inhibitors. At week 24, adalimumab appeared to be more efficacious than upadacitinib. The number of comparators included in some analyses (i.e., HAQ-DI at 24 weeks) was limited. Because no difference was seen between upadacitinib and the relevant comparators in other analyses, no consistent benefit of upadacitinib over bDMARDs or tsDMARDs was demonstrated across all measured end points (weeks 12 and 24).

In biologic-experienced patients, upadacitinib 15 mg was favoured only when compared to tofacitinib (a JAK inhibitor) in PASI response at week 12; this comparison was not performed at week 24. No difference in treatment effect was demonstrated in all other comparisons between upadacitinib and the included IL inhibitors. Not all IL inhibitors were included in every analyses, and the IL-23 inhibitor was absent from many comparisons. Furthermore, TNF inhibitors were not included in any of the NMA analyses as there were insufficient eligible data in the bDMARD-experienced patient population, and therefore no conclusions can be drawn on the comparative efficacy of upadacitinib in these patients. Also, because JAK inhibitors were not included in any of the week 24 analyses, the long-term comparative efficacy of upadacitinib compared to tofacitinib is unknown.

Harms Results

The sponsor’s submitted ITC did not report safety outcomes.

Critical Appraisal

Several limitations increase the uncertainty of the results of the ITC discussed in this review. The included studies were highly heterogeneous in terms of inclusion criteria and patient characteristics. Significant differences were noted in potential effect modifiers, such as duration of disease, use of prior DMARDs, and disease severity. Although these factors are heightened due to the variation in inclusion and exclusion criteria across included studies, no sensitivity analysis or subgroup analysis was conducted to assess the impact of these potential effect modifiers on the comparison of upadacitinib and other biologics. The ITC also did not include any analyses of other clinically meaningful outcomes, such as PsA symptoms (e.g., pain and fatigue), HRQoL, or safety.

Overall, there is uncertainty due to the inherent heterogeneity across trials in the networks. The robustness of the comparative efficacy was further compromised by the lack of precision in the findings, and results from the sponsor-submitted ITC must therefore be interpreted with caution.

Other Relevant Evidence

Description of Studies

Each of the SELECT studies included 2 study periods. At the time of this review, data up to the end of period 1 (week 56) was available. Period 1 for SELECT-PsA1 included 24 weeks of randomized, double-blind, placebo- and active comparator–controlled treatment followed by an additional 32 weeks of blinded active comparator–controlled treatment. Period 1 for SELECT-PsA2 included 24 weeks of randomized, double-blind, placebo-controlled treatment followed by an additional 32 weeks of upadacitinib treatment. In both studies, all patients assigned to placebo were switched to pre-assigned upadacitinib 15 mg or 30 mg daily in a 1:1 ratio at week 24.11 Data reported at week 56 used the as-observed dataset, and no adjustments for multiple testing were employed.

Efficacy Results

In both studies, results from the end of period 1 (week 56 data) suggest that the improvements in clinical and patient-reported outcomes observed at week 24 in patients who received upadacitinib 15 mg once daily starting at day 1 were maintained throughout the 56-week blinded treatment period. Patients who switched from placebo to upadacitinib 15 mg once daily at week 24 also showed improvements in clinical and patient-reported outcomes at week 56; the trajectory for achievement of response or improvement in end points after starting upadacitinib was similar to those observed in patients who started upadacitinib on day 1 of both studies. Numerically greater improvement with upadacitinib compared to adalimumab was also demonstrated for several end points in SELECT-PsA1. For example, the difference in the ACR20 response rate between the upadacitinib 15 mg treatment group (including those switched to upadacitinib 15 mg from placebo), and adalimumab was 6.3% (95% CI, 0.3 to 12.2), and the difference in the proportion of patients achieving MDA was 7.6% (95% CI, 0.4 to 14.8).

Harms Results

The safety profile of oral upadacitinib 15 mg once daily over 56 weeks was consistent with that observed during the 24-week double-blind period in both SELECT-PsA1 and PsA2, with no unexpected safety signals reported. Harms for the analysis at week 56 were presented as exposure-adjusted event rates and were also pooled such that data reported for the upadacitinib exposure combined the upadacitinib 15 mg and placebo-switched-to-upadacitinib 15 mg groups. In SELECT-PsA1, 1 or more AEs were reported at an exposure-adjusted incidence of 265.9 events per 100 patient-years (PYs) in the adalimumab group and 281.1 events per 100 PY in the upadacitinib group. In SELECT-PsA2, 1 or more AEs were reported at a rate of 260.6 events per 100 PY (pooled upadacitinib group). With longer exposure to treatment, a greater proportion of patients treated with upadacitinib compared to adalimumab experienced infectious AEs, including the following, which are presented as events per 100 PY: urinary tract infections (3.6 for adalimumab and 6.7 for upadacitinib in SELECT-PsA1, and 9.8 for upadacitinib in SELECT-PsA2), bronchitis (2.9 for adalimumab and 5.7 for upadacitinib in SELECT-PsA1, and 8.8 for upadacitinib in SELECT-PsA2), hypertension (2.7 for adalimumab and 5.6 for upadacitinib in SELECT-PsA1, and 5.7 for upadacitinib in SELECT-PsA2), and influenza (0.8 for adalimumab and 3.2 for upadacitinib in SELECT-PsA1, and 5.2 for upadacitinib in SELECT-PsA2). Herpes zoster was also reported in a higher proportion of patients treated with upadacitinib across both studies (3.9 per 100 PY and 3.8 per 100 PY in SELECT-PsA1 and SELECT-PsA2, respectively), compared to those treated with adalimumab (0.5 per 100 PY). Other notable AEs that showed an imbalance in groups include elevated creatine phosphokinase (CPK) levels and hepatic disorder, which were reported at a higher incidence by both upadacitinib and adalimumab treatment groups in SELECT-PsA1 compared to SELECT-PsA2. Elevated CPK levels were reported at an incidence rate of 7.3 per 100 PY for adalimumab, 11.9 for upadacitinib in SELECT-PsA1, and 5.2 for upadacitinib in SELECT-PsA2. Hepatic disorder was reported in a higher proportion of patients treated with adalimumab (24.9 per 100 PY for adalimumab and 19.1 per 100 PY for upadacitinib in SELECT-PsA1, and 4.8 per 100 PY for upadacitinib in SELECT-PsA2), although this may be confounded overall by the higher usage of concomitant methotrexate treatment in SELECT-PsA1 patients. Withdrawal of treatment due to AEs was reported at an incidence of 7.4 per 100 PY for adalimumab, and 4.6 per 100 PY and 10.0 per 100 PY for upadacitinib in SELECT-PsA1 and SELECT-PsA2, respectively. In total, 5 deaths occurred in the relevant treatment groups by the end of period 1, inclusive of those counted under week 24 data. These include both treatment-emergent deaths (occurring within 30 days of last dose for upadacitinib or 70 days for adalimumab) and non–treatment-emergent deaths. One treatment-emergent death occurred in the adalimumab group, and 2 non-treatment-emergent deaths occurred in the upadacitinib 15 mg treatment group. The remaining 2 deaths occurred in the placebo groups.

Critical Appraisal

Interpretation of the long-term efficacy and safety outcomes at week 56 is limited by the lack of a placebo control in both SELECT-PsA1 and SELECT-PsA2, as well as the lack of a comparator in SELECT-PsA2. Also, because background therapies were allowed to be modified, it is difficult to disentangle the drug effect from the changes in the background therapies on the reported outcomes. Furthermore, given that all patients were aware that they were receiving an active treatment (upadacitinib or adalimumab), results for patient-reported outcomes may be subject to bias. Because no adjustment was made for multiplicity to evaluate long-term data, and given the large number of analyses performed, there is a risk of inflated type I error. As such, the week 56 data should be interpreted with caution.

Conclusions

Psoriatic arthritis is a complex disease due to the numerous domains of disease activity that need to be addressed with treatment. Based on the double-blind portion of both phase III randomized controlled trials (RCTs) (SELECT-PsA1 and SELECT-PsA2), treatment with oral upadacitinib 15 mg once daily is associated with statistically significant and clinically meaningful improvement compared to placebo in the clinical response of PsA symptoms, as measured by the primary efficacy outcome of an ACR20 response at week 12. In bDMARD-naive patients (SELECT-PsA1), upadacitinib 15 mg orally once daily was no worse than (i.e., noninferior to) adalimumab 40 mg administered subcutaneously every other week in achievement of an ACR20 at week 12. The efficacy of upadacitinib compared to adalimumab in bDMARD-experienced patients is unknown.

Additionally, an overall consistent effect of upadacitinib 15 mg compared to placebo was demonstrated for numerous clinically relevant manifestations of PsA, including function and disability, PsA symptoms (pain and fatigue), HRQoL or patient-reported health outcomes, skin disease or psoriasis, musculoskeletal symptoms (enthesitis, dactylitis, and spinal symptoms), and other measures of clinical response or disease control such as MDA. Improvement in these measures of treatment response with upadacitinib 15 mg compared to placebo was demonstrated across both studies in patients with inadequate response or intolerance to non-bDMARDs (SELECT-PsA1) and bDMARDs (SELECT-PsA2). Efficacy of upadacitinib in radiographic changes was only studied in bDMARD-naive patients, and the clinical meaningfulness of the small improvement seen versus placebo over this short duration is uncertain. Furthermore, an estimated MID for many of the measures used to assess continuous end points was not identified for patients with PsA, making the clinical significance of the numerical improvements seen in some end points, notably the patient’s assessment of pain NRS, uncertain.

Findings from the end of period 1 of SELECT-PsA1 and SELECT-PsA2 suggest that the improvements in outcomes observed at week 24 in the upadacitinib 15 mg treatment group were maintained throughout the 56-week extension.

By week 24, the proportion of patients who experienced a TEAE with upadacitinib in SELECT-PsA1 was comparable to the proportion treated with adalimumab but higher relative to the placebo group. In SELECT-PsA2, the proportion of patients who experienced a TEAE was similar between the upadacitinib and placebo groups. Upper respiratory tract infection was most commonly reported in both studies. The safety profile of upadacitinib 15 mg once daily over 56 weeks was consistent with that observed during the 24-week double-blind period, with no unexpected safety signals reported. However, long-term data from the ongoing extension phase of both SELECT-PsA1 (up to 5 years) and SELECT-PsA2 (up to 3 years) will help better characterize the efficacy and safety of upadacitinib in the treatment of this chronic condition.

No direct comparative evidence for upadacitinib 15 mg versus bDMARDs or tsDMARDs other than adalimumab was identified. A sponsor-submitted ITC comparing upadacitinib 15 mg to bDMARDs or tsDMARDs suggested that in both bDMARD-naive and DMARD-experienced patients, upadacitinib does not show either a consistent or distinct difference in efficacy as measured by ACR20, PASI, PsARC, or HAQ-DI when compared to bDMARDs or tsDMARDs. The value of the ITC results is uncertain due to the inherent heterogeneity across trials in the networks. Moreover, no information was obtained regarding safety compared to other bDMARDs or tsDMARDs. In addition, no conclusion could be drawn on the HRQoL outcomes.

Introduction

Disease Background

Psoriatic arthritis is an inflammatory musculoskeletal disease with a heterogenous presentation and disease course. While it is associated with psoriasis, PsA also presents with variable clinical features involving multiple domains, including peripheral arthritis, enthesitis, dactylitis, and axial disease.1,2 Diagnosis of PsA can be a challenge, as there is no gold-standard diagnostic test; diagnoses are typically based on clinical findings and imaging features that evaluate specific patterns of joint inflammation or involvement of the different domains. Patients with PsA also present with psoriatic skin lesions and most (95%) are usually seronegative for rheumatoid factor.2,3 Pain and stiffness of the affected joints are the most predominant presenting symptoms, with fatigue also occurring in many patients.1

The prevalence of PsA varies, depending on the case definition and geography, and is estimated to be 1 to 2 per 1,000 in the general population.1 A population-based Canadian study estimated that the age- and sex-standardized cumulative prevalence of PsA in Ontario ranged from 0.09% in 2008 to 0.15% in 2015. The same study estimated the age- and sex-standardized incidence in 2015 to be 14 per 100,000.4 These figures may vary. For example, another study found the estimated annual incidence of PsA was 6 per 100,000 per year.1

About 30% of patients with psoriasis develop PsA; skin disease usually precedes manifestations of PsA by several years (10 years on average), although both can occur simultaneously in some individuals or PsA may occur before the onset of psoriasis.2 A Canadian prospective cohort study estimated the annual incidence of PsA was 2.7 cases per 100 psoriasis patients.12 Over time, PsA can lead to deformities and joint damage.2 This can lead to significant functional impairment, which in turn can affect work productivity and reduce HRQoL.2,3

Standards of Therapy

Treatment goals for patients with PsA include achieving the lowest possible level of disease activity in all domains of disease; optimizing functional status, improving quality of life and well‐being; preventing structural damage to the greatest extent possible; and avoiding or minimizing complications, both from untreated active disease and from therapy. Because this disease affects more than just the joints of the patient, treatment is individualized based on various factors, including disease activity, structural damage, comorbid conditions, and previous therapies.6 Accordingly, treatment effects need to be evaluated in different domains involving the musculoskeletal system (e.g., in dactylitis, enthesitis, and axial disease) as well as extra-articular manifestations (e.g., nails, skin, eyes, and the gastrointestinal tract). Several drug classes are employed in the pharmacologic treatment of PsA, including NSAIDs, csDMARDs (methotrexate, sulfasalazine, and leflunomide), bDMARDs (TNF inhibitors, IL-23 inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors), and tsDMARDs (apremilast or tofacitinib).5

In the treatment of PsA, NSAIDs are generally used for symptomatic treatment. Despite the lack of evidence from RCTs, guidelines often recommend using csDMARDs, typically methotrexate, as the primary treatment in first-line therapy or after a short course of NSAIDs in patients with polyarthritis.5,6 These recommendations were based on data from primarily observational studies, the low costs and universal access associated with csDMARDs, and the lack of evidence that a short time delay in the introduction of more effective therapies would affect long-term function and quality of life.6 Some guidelines also recommend first-line treatment with a TNF inhibitor, particularly in patients with severe PsA or psoriasis.6,7 In patients with an inadequate response to at least 1 csDMARD, the European League Against Rheumatism recommends starting a bDMARD. The latest recommendations do not distinguish among TNF inhibitors, IL-17 inhibitors, and IL-12/23 inhibitors, and the choice is individualized based on numerous factors, including cost. However, an IL-17 or IL-12/23 inhibitor may be preferred in patients with relevant skin involvement.5

In the case of biologic drug treatment failure due to either lack of efficacy or AEs, switching to an alternative biologic drug within a class or with a different mode of action was recommended in treatment guidelines.5-7 Tofacitinib (a pan-JAK inhibitor) may be considered in patients who have an inadequate response or intolerance to at least 1 csDMARD and at least 1 bDMARD, or when a bDMARD is not appropriate.5 It is given in combination with methotrexate or another csDMARD.13 Thereafter, European League Against Rheumatism recommendations suggest considering apremilast (a PDE4 inhibitor) in patients with mild disease and an inadequate response to at least 1 csDMARD, and for whom neither a bDMARD nor a JAK inhibitor is appropriate. Abatacept, a cytotoxic T lymphocyte–associated antigen-4 immunoglobulin co-stimulation modulator, is another potential option in the treatment of PsA; however, its use is generally limited due to its relatively low efficacy, and it is also not funded by public drug plans.5 Specific treatment recommendations are also available for other scenarios; for example, in patients with unequivocal enthesitis or predominantly axial disease, for whom bDMARDs are generally considered after insufficient response to NSAIDs.5 In addition to the severity and manifestations of disease, treatment choice may vary depending on contraindications, concomitant conditions (e.g., active inflammatory bowel disease), and patient preference (e.g., route of administration or dosing frequency).7

Although there is no specific Canadian treatment guideline for the management of PsA, the Canadian Rheumatology Association/Spondyloarthritis Research Consortium of Canada Treatment Recommendations for the Management of Spondyloarthritis from 2014 include the following recommendations: (1) methotrexate, sulfasalazine, and leflunomide may be considered in patients with peripheral arthritis, however these treatments have only minimal to moderate evidence of efficacy (on peripheral joints and no efficacy on the spine); (2) combination therapy with DMARDs should be considered in peripheral arthritis, particularly in patients with moderate to high disease activity, poor prognostic features, and in patients with recent-onset disease, and combination therapy should also be considered in patients with inadequate response to monotherapy; (3) TNF inhibitors should be offered to those with persistent inflammation despite a trial of NSAID and 1 csDMARD in patients with predominantly peripheral arthritis; and (4) TNF inhibitors should be offered to patients with refractory enthesitis or dactylitis accompanied by persistent inflammation. The recommendations on the use of csDMARDs and TNF inhibitors in peripheral arthritis were based on PsA data.14

Currently, a single JAK inhibitor is available in Canada. Tofacitinib, a pan-JAK inhibitor, is indicated for the treatment of adult patients with active PsA when the response to previous DMARD therapy has been inadequate.13 However, it has not undergone review by CADTH and is not publicly funded in Canada. Some safety signals have been identified for tofacitinib. Most recently, preliminary results for a post-marketing safety trial comparing tofacitinib to TNF inhibitors identified an increased risk of major adverse cardiovascular events (MACEs). The trial enrolled patients with rheumatoid arthritis who were 50 years of age or older and had at least 1 additional cardiovascular risk factor. Results suggest that risks are associated with dosages of both 5 mg twice daily and 10 mg twice daily.15

The input received from the clinical expert consulted by CADTH for this review is consistent with the guidelines. According to the clinical expert, treatment of PsA is directed at fundamental disease mechanisms, and is complex because decisions are based on managing the diverse domains of psoriatic disease (i.e., arthritis, spondylitis, enthesitis, dactylitis, and skin and nail dysfunction). Treatment decisions are further influenced by the number of swollen peripheral joints (oligoarthritis versus polyarthritis), by the magnitude of skin disease, and by the presence of associated conditions, such as inflammatory bowel disease and uveitis. For treatment goals in PsA, the clinical expert noted that a treat-to-target strategy is advocated. The recommended target for arthritis is MDA, a high-level end point of almost no disease activity. Targets involving peripheral joint activity may also be acceptable. Control of musculoskeletal disease is expected to prevent joint damage and deformity. In turn, control of articular disease would be expected to improve quality of life, restore functional capacity, and enhance work attendance and productivity. The clinical expert indicated that the current treatment plan in Canada for patients with PsA begins with a DMARD. Trials of at least 2 csDMARDs as monotherapy (methotrexate, leflunomide, or sulfasalazine) lasting 3 to 4 months. In patients with inadequate responses to csDMARDs, treatment is escalated to a TNF inhibitor. Patients with inadequate response to TNF inhibitors would be treated with an IL-17 inhibitor or IL-12/23 inhibitor next, and the oral JAK inhibitor tofacitinib is currently considered as last-line therapy. Oral apremilast, a PDE4 inhibitor, is considered in a minority of patients, typically those with less joint and skin disease; however, it is not reimbursed by public drug plans. The clinical expert noted that patients with spinal disease are treated first with NSAIDs, followed by biologics when NSAIDs fail. Oral and IV steroids are not indicated in patients with spondylitis and used only with caution and at low doses for patients with peripheral arthritis. Intra-articular steroid injections can be used in patients with oligoarthritis and dactylitis.

Drug

Upadacitinib is an oral JAK inhibitor that has greater inhibitory potency on JAK1 proteins relative to JAK2, JAK3, and TYK2. By inhibiting JAKs, upadacitinib modulates the intracellular signalling pathways of cytokines or growth factors involved in a broad range of cellular processes, such as inflammatory responses, hematopoiesis, and immune surveillance. Specifically, upadacitinib prevents the phosphorylation and activation of signal transducers and activators of transcription by JAKs, blocking intracellular activity, including gene expression. Upadacitinib is available as 15 mg extended-release tablets.8

The recommended dosage of upadacitinib for treatment of PsA is 15 mg orally once a day. Upadacitinib may be used as monotherapy or in combination with methotrexate.8

Upadacitinib is approved by Health Canada for the treatment of adults with active PsA who have had an inadequate response or are intolerant to methotrexate or other DMARDs. The requested reimbursement criteria align overall with the Health Canada indication. AbbVie Inc., the sponsor, is requesting reimbursement for the treatment of active PsA in adult patients who have responded inadequately or who are intolerant to 1 or more DMARDs. The approved indication states that upadacitinib may be used as monotherapy or in combination with methotrexate. The European Commission has also granted marketing authorization for upadacitinib for the same indication.16

Upadacitinib has been previously reviewed by CADTH for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate.17

In addition to upadacitinib, various treatments for PsA are currently approved in Canada (Table 3).

Table 3: Key Characteristics of Select Agents Used in the Treatment of Psoriatic Arthritis

Agents

Characteristics

Mechanisms of action

Indicationa

Route of administration

Recommended dosage

Serious side effects and safety issues

Upadacitinib

JAK inhibitor; greater inhibitory potency at JAK1 relative to JAK2, JAK3, and TYK2

Treatment of adults with active psoriatic arthritis who have had an inadequate response or are intolerant to methotrexate or other DMARDs; may be used as monotherapy or in combination with methotrexate

PO

15 mg once daily

Serious infections (TB, invasive fungal infections, opportunistic infections), malignancies, thrombosis, liver enzyme elevation

Tofacitinib

JAK inhibitor; pan-JAK inhibitor

Reducing the signs and symptoms of PsA in adult patients with active PsA when the response to previous DMARD therapy has been inadequate; can be used in combination with MTX or another conventional synthetic DMARD

PO

5 mg twice a day

Serious infections (TB, invasive fungal infections, opportunistic infections), malignancies, thrombosis, liver enzyme elevation

Ixekizumab

Humanized IgG4 monoclonal antibody that selectively binds and neutralizes the pro-inflammatory cytokine IL-17A

Treatment of adult patients with active PsA who have responded inadequately or are intolerant to 1 or more DMARDs; can be used alone or in combination with a conventional DMARD, e.g., MTX

SC

For PsA or PsA with coexistent mild PP: 160 mg at week 0,

followed by 80 mg every 4 weeks

For PsA with coexistent moderate to severe

PP: 160 mg at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks

Infections (TB and serious infection in particular), hypersensitivity reactions and inflammatory bowel disease (exacerbations or new onset)

Secukinumab

Fully human IgG1k monoclonal antibody that selectively binds and neutralizes the pro-inflammatory cytokine IL-17A

Treatment of adult patients with active PsA when the response to previous DMARD therapy has been inadequate; can be used alone or in combination with MTX

SC

150 mg at weeks 0, 1, 2, 3, and 4 followed by monthly maintenance dosing

For PsA patients with coexistent moderate to severe PP: 300 mg at weeks 0, 1, 2, 3, and 4 followed by monthly maintenance dosing

Patients with PsA who are anti–TNF-alpha inadequate responders or who continue to have active PsA: 300 mg dose should be considered

Infections (TB and serious infection in particular), hypersensitivity reactions and inflammatory bowel disease (exacerbations or new onset)

Ustekinumab

Fully human IgG1k monoclonal antibody that inhibits the bioactivity of IL-12 and IL-23

Treatment of adult patients with active PsA; can be used alone or in combination with MTX

SC

45 mg at weeks 0 and 4, then every 12 weeks thereafter

Alternately, 90 mg may be used in patients with a body weight > 100 kg

Infections and reactivation of latent infections (TB and serious infections), hypersensitivity reactions, malignancies, RPLS

Adalimumab

TNF inhibitor; recombinant human IgG1 monoclonal antibody

Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult PsA patients; can be used in combination with MTX in patients who do not respond adequately to methotrexate alone

SC

40 mg every other week

Serious infections (bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic infections), malignancies, hypersensitivity reactions (allergic reactions and injection site reactions), neurologic events (e.g., demyelinating disease), congestive heart failure

Certolizumab pegol

TNF inhibitor; recombinant, humanized antibody Fabʹ fragment

Reducing signs and symptoms and inhibiting the progression of structural damage as assessed by X-rays in adult patients with moderately to severely active PsA who have failed 1 or more DMARDs; can be used alone or in combination with MTX

SC

Loading dose of 400 mg initially (week 0) and at weeks 2 and 4 followed by a maintenance dose of 200 mg every 2 weeks or 400 mg every 4 weeks

Serious infections (bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic infections), malignancies, hypersensitivity reactions (allergic reactions and injection site reactions), neurologic events (e.g., demyelinating disease), congestive heart failure

Etanercept

TNF inhibitor; recombinant human TNF receptor: fusion protein

Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in adult patients with PsA; can be used in combination with MTX in adult patients who do not respond adequately to MTX alone

SV

50 mg once a week

Can be given as a single 50 mg injection,

or 2 × 25 mg injections given on the same day once weekly or 3 or 4 days apart

Serious infections (bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic infections), malignancies, hypersensitivity reactions (allergic reactions and injection site reactions), neurologic events (e.g., demyelinating disease), congestive heart failure

Golimumab

TNF inhibitor; recombinant human IgG1k monoclonal antibody

Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active PsA; can be used in combination with MTX in patients who do not respond adequately to MTX alone

SC

50 mg once a month on the same date each month

Serious infections (bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic infections), malignancies, hypersensitivity reactions (allergic reactions and injection site reactions), neurologic events (e.g., demyelinating disease), congestive heart failure

Infliximab

TNF inhibitor; recombinant chimeric IgG1k monoclonal antibody

Reduction of signs and symptoms, induction of major clinical response, and inhibition of the progression of structural damage of active arthritis, and improvement in physical function in patients with PsA; can be used with or without MTX

IV

5 mg/kg given as an IV infusion followed with additional similar doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter

Serious infections (bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic infections), malignancies, hypersensitivity reactions (allergic reactions and injection site reactions), neurologic events (e.g., demyelinating disease), congestive heart failure

DMARD = disease-modifying antirheumatic drug; IgG1 = immunoglobin G1; IgG1k = immunoglobin G1k; IgG4 = immunoglobin G4; IL = interleukin; JAK = Janus kinase; MTX = methotrexate; PP = plaque psoriasis; PsA = psoriatic arthritis; PO = oral; RPLS = reversible posterior leukoencephalopathy syndrome; SC = subcutaneous injection; TB = tuberculosis; TNF = tumour necrosis factor.

Note: Only biologic DMARDs and targeted synthetic DMARDs identified as relevant comparators in the CADTH systematic review are included in this table. Comparators are agents used in the treatment of PsA that are publicly funded. Although tofacitinib is currently not reimbursed by public drug programs in Canada, it was deemed to be a relevant comparator to upadacitinib by the clinical expert consulted for this review.

aHealth Canada–approved indication for condition under review, according to product monographs.

Sources: Health Canada product monographs8,13,18-25 and sponsor’s submission.26

Stakeholder Perspectives

Summary of Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

About the Patient Group(s) and Information Gathered

Four inputs were submitted for this review from 6 different patient groups: ACE, the CSA, the CAPP in partnership with the CPN, and the CAPA in partnership with the Arthritis Society.

Canada’s largest and longest-running national arthritis patient organization, ACE is headquartered in Vancouver, British Columbia, and has 50,000 members from coast to coast. It provides free, science-based information and education programs to people with arthritis and those who care for and support them.

The CSA is a national not-for-profit organization federally registered in Canada. Its mission is to be the leading voice for the spondyloarthritis community in Canada, raise awareness, and provide support, education and advocacy for patients, caregivers, and health professionals.

The CAPP is a national not-for-profit organization formed to better serve the needs of psoriasis patients across the country. Its mission is to be a resource and advocate for psoriatic patients and their families to improve patient care and quality of life.

The CPN is a national, not-for-profit organization dedicated to improving the quality of life of people in Canada who live with psoriasis and PsA. The CPN does this by providing current information on research and treatment options and by working with others to build awareness and advocacy about the complexities of these conditions.

The CAPA is a grassroots, patient-driven and managed, independent, national education and advocacy organization with members and supporters across Canada. It creates links between Canadians with arthritis, helps them become more effective advocates, and seeks to improve the quality of life of all people living with the disease.

The Arthritis Society is dedicated to a vision of living in a world in which people are free from the devastating effects of arthritis. The Arthritis Society is Canada’s principal health charity, providing education, programs, and support to the more than 6 million Canadians living with arthritis.

Five patient organizations collaborated by collectively developing survey questions using SurveyMonkey for the submitted inputs. The survey was launched by the Arthritis Society and the raw data were shared with all collaborating organizations. Each organization shared the surveys with its respective memberships or patient communities via newsletters, social media channels, and websites. The CSA conducted a telephone interview with 1 patient on upadacitinib (Rinvoq). Notes from this interview were shared with the CAPP, CPN, CAPA, and Arthritis Society.

The survey was translated into French to reach a broader national audience. The surveys were available from December 15, 2020, to January 18, 2021. Overall, there were 85 responses to the English survey and 9 responses to the French survey. Of those who provided their demographic information, 10 respondents were from British Columbia (10.8%), 6 from Alberta (6.5%), 3 from Saskatchewan (3.2%), 17 from Manitoba (19.3%), 30 from Ontario (32.3%), 13 from Quebec (14.0%), 3 from New Brunswick (3.2%), 5 from Nova Scotia (5.4%), and 4 from Newfoundland and Labrador (4.3%). Only 1 response was from someone outside Canada. In addition to PsA, 90.7% of 54 respondents (n = 49) across the 2 surveys indicated they live with psoriasis, 16.7% (n = 9) live with another inflammatory condition, 35.2% (n = 19) also live with another type of arthritis, and 33.3% (n = 18) live with at least 1 other condition, including fibromyalgia, borderline personality disorder, eczema, Raynaud’s syndrome, scoliosis, hypothyroidism, allergies, asthma, high blood pressure, or bladder conditions. Fifty-four respondents provided information about their age across the English and French surveys. These respondents ranged in age from 26 to 80 years old.

In addition, ACE gathered data from 5 patients who completed a patient input survey through SurveyMonkey from December 18, 2020, to January 26, 2021.

Disease Experience

Psoriatic arthritis is an inflammatory disease that causes swelling and pain in multiple joints and can sometimes result in permanent and debilitating joint damage. It is also a systemic disease affecting other parts of the body, including the eyes and heart, and can vary in severity from mild to very severe. There is currently no cure for PsA. Respondents to the survey emphasized pain, stiffness, lack of mobility, and fatigue, which affect their daily living activities, their family lives, and their ability to work and maintain certain hobbies. People can live in constant pain without remission.

When asked about the most significant impacts of PsA on their daily quality of life, respondents from the collaborative input expressed that PsA interfered with social connections (78%), self-esteem (69%), family life (66%), mental health (66%), work (60%), friendships (50%), intimacy (44%), and parenting (15%). Other impacts included embarrassment and self-consciousness from symptoms caused by PsA. Respondents reported difficulty contributing and participating at school or work due to the fatigue, pain, and other symptoms of PsA. The following quotes from respondents illustrate how living with PsA, and its symptoms, affects their lives:

EXTREMELY painful joints. To the point that walking, climbing stairs (to the 2nd floor where the master bedroom was located), etc. was a challenge. Pain killers and NSAIDs were a minimal daily requirement just to get out of bed and make it through the day... Sometimes not being able to go to work because of the pain. When I was first diagnosed with PsA, my son had just been born. I was not even able to do what many fathers do, and take for granted, and that was hold my son up over my head with my arms, smiling up to him as he would be laughing down to me... That was almost 30 years ago. My son passed in March of 2019 and to this day, I still regret not being able to do that simple thing, that “[rite] of passage”... Holding my infant so up in the air. PsA took that from me...

People living with the disease are also at risk of comorbidities, such as depression and mental health issues, diabetes, and cardiovascular disease. For some people, flares can be incapacitating. Due to their unpredictability, flares must be dealt with reactively. According to the joint input from CAPA and the Arthritis Society, the unpredictable nature of PsA may often make it feel like a person is not in control of their disease and can affect their ability to carry out day-to-day activities and life roles, such as contributing to the workplace. The following respondent quote indicates how chronic fatigue influences daily activities:

Chronic fatigue — daily. Worse in the winter than summer months. Energy levels decline dramatically starting 4pm. I am unable to do much socializing after 6pm due to lack of energy. Dinners out are a rare occurrence. Enthesitis — in my wrists, elbows,—. My hands are now weak (I'm 50) that carrying grocery bags is uncomfortable. I take a rolling cart whenever I have to carry more than 5l lbs. Flares — occur when there is hot weather or I have over-exerted myself exercising. This causes the enthesitis to become painful and I experience extreme body aches and fatigue. Like the flu. This lasts 1 to 3 days. Gluten and dairy flares me — so I avoid them in my diet. I normally have to pack food when travelling as it's difficult to find gf [gluten-free] options.

The impact of PsA extends to others within a person’s support circle, including caregivers such as spouses/partners and children. The CAPA and the Arthritis Society note that these people often take on additional chores or tasks such as cooking, cleaning, and shopping to support the person living with PsA, and family roles change as spouses and partners take on more tasks, such as supporting their partners in getting to and from medical appointments. The following are respondent quotes indicating how PsA affects their caregivers: “I'm sick of the Pain and Fatigue!! I feel like a Burden to my Husband!” and “I had struggled with severe pain for 30 plus years, was very hard to do everyday tasks, my son thank god for him was always there to help me as opening a simple bottle of water was at times very hard to even open.”

Patients who submitted input to ACE’s patient survey spoke to the following disease experiences, and certain aspects of the disease that are more important to control than others:

Experiences With Currently Available Treatments

Patients living with psoriatic disease often try a succession of treatments throughout their lives. Due to the inflammatory nature of the diseases, treatments that are initially effective can become less effective over time. It is important to note that many people who live with PsA also live with psoriasis. As some drugs are indicated for both diseases, it is not uncommon for people with psoriasis to have some experience taking a treatment indicated for PsA and vice versa. For patients who take treatments for psoriasis, these same treatments can but do not always adequately manage their PsA.

Effective treatments mean that people with PsA do not need to live with the permanent damage, high medical costs (e.g., surgery, mobility aids, and accessible housing), and disability. Early intervention is critical to allow people with PsA the opportunity to fully participate in all aspects of life. Although numerous medication options exist, patients’ responses to medication can vary significantly. As a result, patients need a number of medication options to effectively manage their disease throughout their lives. There are also no specific tests that identify which medication will be effective for a person living with PsA. This means that a person with the disease will need to take 1 or more medications on a trial-and-error basis to find an effective medication. It is also an anxious and stressful experience if medications are not effective and cost thousands of dollars out of pocket. Oftentimes, people with PsA need to make difficult financial choices to pay for their medications.

Of individuals who had taken the treatment and responded to the question from the collaborative input, biologics had the highest proportion of patients, with 50% (18 of 36) indicating the treatment was “very effective” and 22% (n = 8) “mildly effective.” Non-bDMARDs were mildly effective for 36% (16 of 44 respondents) and very effective for 11% (n = 5). For 36% (n = 16) of respondents, DMARDs were either very or mildly ineffective. Nonsteroidal anti-inflammatory drugs were mildly effective for 36% (19 of 53 of respondents) but ineffective for 38% (n = 20), and for 19% (n = 10) there was no difference in symptoms. Forty percent (6 of 15) of those taking leflunomide reported it to be very ineffective, with no respondents reporting it was very effective. Apremilast was very ineffective for 55% of patients (6 of 11 respondents) and mildly effective for 27% (3 of 11 respondents). Tofacitinib was very ineffective for 71% (5 of 7 respondents), with no respondents reporting it to be very or mildly effective.

Many patients have experience with DMARDs. Fifty-four respondents had experience with non-bDMARDs, including combinations containing methotrexate: apremilast (18.5%; n = 10), methotrexate (74.1%, n = 40), azathioprine (0.02%, n = 1), cyclosporine (13.0%, n = 7), hydroxychloroquine (13.0%, n = 7), leflunomide (14.8%, n = 8), sulfasalazine (22.2%, n = 12), and Salazopyrin (0.04%, n = 2). Several respondents had experience with methotrexate and noted a variety of side effects, including nausea, raised liver enzyme levels, headaches, and a sore mouth. Patient experiences with methotrexate include “worsening my brain fog” and “feeling ‘worse’ on it in other ways” are reflected in the following statement:

I've only tried methotrexate and am currently on it. It manages my PsA quite well but I'm still susceptible to joint injuries and cuts and abrasions can still lead to new psoriatic lesions. The side effects I get are poor sleep, nausea, poor balance, mental fog, runny stool, flatulence, and some GI discomfort. The needs not being met by methotrexate are that it doesn't completely put my arthritis into remission and it doesn't completely eliminate my psoriatic lesions. Wishful thinking, I know.

The side effects of sulfasalazine were noted by several respondents. One reported, “I had fever, chills, a horrible hot tingling rash and fatigue, ended up going off all medications including my anti-inflammatory. So I spent 2 weeks [with] no medications and my pain increased more and more each day till I was able to resume my anti-inflammatory…. My PsA remains uncontrolled.” Another noted that “sulphasalazine almost cost me my marriage due to mood swings.”

Cyclosporine was also noted to affect other organs: “When I took cyclosporine my kidney function became a problem. I have not been able to achieve comfort with any treatment.” Some respondents noted that apremilast (Otezla) helped their psoriasis but did not improve their PsA, and came with challenging side effects, including increased heart rate, nausea, diarrhea, depression, and moodiness.

Several respondents also had experience with different biologics, but the benefits do not last forever: “The biologics do a good job until they fail. Then the search is on for the next one that will work” and “on my 5th biologic since 2007.”

According to the input from CSA, new treatment options and different classes of medications fill unmet needs of patients and prescriber. The Rinvoq oral formulation is an exciting option for patients. It provides another option for administration and may help lead to improved adherence and ultimately better outcomes.

The input from CAPA and the Arthritis Society stated that patients may also pursue medical cannabis and/or non-pharmacological approaches to manage PsA symptoms, such as physiotherapy, occupational therapy, massage therapy, counselling, or acupuncture. These approaches can often help address the symptoms of the disease, such as pain and fatigue. However, the patient groups noted that there are significant unmet patient needs in terms of accessing non-pharmacological treatments, often because they are not reimbursed through provincial health care systems, the treatment options are simply not offered, or there are lengthy waits.

Patients identified a number of issues in accessing treatment options. Expense, travel, and time required for treatment were all cited as being prohibitive. Some patients also identified a lack of access to specialists and general practitioners, and/or restrictions associated with the coronavirus disease 2019 pandemic.

One patient who filled out ACE’s patient survey spoke to experiences taking infliximab (Remicade) as an infusion every 7 weeks combined with a weekly dose of methotrexate. They experienced nausea for a couple of days after taking methotrexate and higher levels of fatigue. When asked if there are any needs that are not met by current therapy, this patient stated: “Not for me to say – but many friends and relatives have asked about my treatments and their inability to access them or their acceptance of arthritis/pain as part of getting old.” While this patient had no hardships in accessing current therapies, they added: “But I have private coverage for Remicade, which is roughly $3K every 7 weeks – roughly $21-25,000.”

Improved Outcomes

Through their joint input, the CAPA and the Arthritis Society identified several outcomes that are important to patients with PsA and that should be considered when evaluating new therapies. These include the route of drug administration (oral versus infusion versus self-injections), reduction in pain and fatigue, effectiveness for psoriasis symptoms as well as PsA symptoms, increased mobility, ability to work and be productive at work, ability to carry out activities of daily living, ability to effectively carry out parenting tasks and other important social roles, reduced infection rates, affordability of the medication, and increased quality of life.

People living with PsA shared the following experiences:

Experience With Drug Under Review

Of those surveyed in the joint patient survey, 6 respondents indicated that they have experience taking upadacitinib for PsA. Four of these respondents were from Manitoba and 2 were from Quebec. Five indicated that they live with psoriasis. Five of the 6 respondents who have experience with upadacitinib indicated that they have used DMARDs. No patients from ACE’s survey had experience with upadacitinib. When asked about their positive and negative experiences with upadacitinib, 1 of these respondents noted: “[The] only negative [side effect] as mention[ed] before is a feeling of being cold all the time. I have had 80-90% relief of pain.” Another reported that “It has helped a lot with my pain and joint swelling, I really haven’t noticed any side effects. It’s definitely better than the injections I take, I hope that taking this now will prevent worsening problems on my joints as I age. It makes day to day easier and less painful.” A third reported, “Getting up every morning with pain is a challenge! In contrast, with upadacitinib, pain lasts less when you wake up. The look of others, when I had psoriasis on hands was a challenge, now I have beautiful nails and beautiful hands. Maintain[ing] clean[lines] is much easier. Besides, shortness of breath is the only side effect I have observed.”

When asked about the impact of upadacitinib (Rinvoq) on caregivers and their family and their day-to-day activities, these respondents answered with: “Yes. I am able to move more freely and exercise more often,” “I have more energy to do activities with my partner. I had support from my partner, he does the shopping. The support of the research centre team was very important to me, [to address] my anxieties and my fears about the disease,” and “Greater self-esteem and easier to get around.”

The CSA conducted 1 interview with a female patient who has lived with PsA for 30 years, has had severe psoriasis her entire life, and who also had experience with upadacitinib through a clinical trial. Her PsA caused pain and reduced her mobility to the point that she had to retire from her job. Her past medication history included methotrexate, “every topical under the sun,” and 2 biologics that she injected but that were not effective for her. Her experience with upadacitinib was positive: within 2 weeks of beginning treatment, she was able to walk around her home without walking aids and her pain was significantly better. Her skin was almost entirely clear, with the exception of a couple of small spots. She noted no side effects, despite previously being very prone to them and unable to tolerate other medications. She has been able to return to work part-time. She commented that for her, this drug is life-altering, has given her freedom, and she can’t believe how much she can move around and not be in pain all the time.

Additional Information

According to the joint input from CAPP and CPN, PsA is a disease that often “falls through the cracks.” Some patients are seen by a dermatologist while others are seen by rheumatologists. Joint pain is not always discussed with a dermatologist and plaques on the skin are not always discussed with rheumatologists. These challenges often lead to delays in diagnosis and consequently severe and irreversible damage to the joints. Roughly 30% of people with psoriasis will develop PsA. Most (80%) of the time, psoriasis comes first, but it remains difficult to predict whether a person living with psoriasis will later develop PsA, despite research advances that have identified a number of biomarkers associated with PsA and led to predictive screening tools.

The patient input from the CSA states that effective treatments give Canadians the opportunity to regain self-confidence and re-integrate into society and personal relationships. The input from this group noted that, for those yet to find relief, it can be a life of darkness, isolation, and desperation, leaving people spiralling into further depression and anxiousness and robbing them of life. The input emphasized it is important for CADTH take into consideration that many patients over the course of their journey have tried several, and in some cases all, the options currently available.

Clinician Input

Input from Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of PsA.

Unmet Needs

There are unmet needs in the treatment of psoriatic disease because some patients may not respond to any treatment, and only a minority achieve MDA. The treatment of PsA involves numerous domains of disease activity, not all of which are likely to be addressed by a single agent. Further durability of any therapy is limited and switching to treatment with a different mechanism of action will be necessary when a patient becomes refractory to current treatment.

Place in Therapy

Most rheumatologists will generally use TNF inhibitors and IL-17 inhibitors before upadacitinib. However, as experience is accrued with upadacitinib, and when safety has been confirmed (i.e., when data show a lack of association with AEs of special interest, such as bowel perforations, venous thromboembolic events, MACEs, and malignancy), it is anticipated that upadacitinib could become a first-line treatment for PsA. The caveat with this assumption is that longer-term observation of patients on upadacitinib will be needed to confirm the durability of efficacy and safety.

In general, oral agents are considered more convenient than therapies administered intravenously or subcutaneously and are expected to demonstrate enhanced adherence to treatment. Upadacitinib would have the advantage of oral administration, which adds further support to its appeal.

Patient Population

Any patient with peripheral joint and skin disease who has not responded to conventional synthetic DMARDs would be eligible for upadacitinib. Studies in spondylitis will address its use in this domain. Currently, some rheumatologists may not prescribe upadacitinib to patients with a recent history of thromboembolic disease, and patients with active infection would also not be treated with this drug. Additional data may reveal other contraindications to therapy.

Assessing Response to Treatment

In clinical practice, the SJC is the most likely measure of response, with a reduction in joint count reflecting a meaningful response. Some rheumatologists may use the achievement of MDA as a meaningful response. Other clinically meaningful responses to treatment may involve patient-reported outcomes such as a health assessment questionnaire, patient’s global assessment, and patient’s assessment of pain; however, these outcomes are subjective and prone to bias. Outcome measures of RCTs are seldom used in clinical practice.

It is expected that benefit from a JAK inhibitor will be readily apparent by week 12, and most rheumatologists will decide whether to continue with therapy at that point.

Discontinuing Treatment

Lack of response and/or side effects will result in a decision to discontinue treatment. Blood tests will be monitored every 1 to 3 months.

Prescribing Conditions

Upadacitinib should be prescribed by specialists who treat PsA. Diagnosis, prescribing of treatment, and continued patient monitoring should be performed by specialists such as rheumatologists who treat PsA.

Clinician Group Input

No registered clinician group input was received for this reimbursement review.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

Drug program implementation questions

Clinical expert response

Would upadacitinib be initiated in patients who have failed previous treatment with a biologic?

There may be a desire to switch from biologic therapies to upadacitinib due to the oral route of administration. Would patients who have been successfully treated with a biologic be switched to upadacitinib?

The clinical expert consulted by CADTH for this review indicated that in clinical practice upadacitinib would be initiated in patients who have failed previous treatment with a biologic. However, patients who are successfully treated with biologic therapy should not be switched to upadacitinib.

Tofacitinib (Xeljanz) is currently not reimbursed for PsA; however, would patients who fail tofacitinib treatment or who were previously treated with tofacitinib be switched to upadacitinib? How are these patients expected to respond?

The clinical expert indicated that patients who are successfully treated with tofacitinib should not switch treatment to upadacitinib. However, patients who fail tofacitinib treatment or who were previously treated with tofacitinib can be treated with upadacitinib; this opinion is based on evidence for patients with rheumatoid arthritis who switched treatment from tofacitinib to baricitinib.27 However, no such evidence is available for patients with PsA, and it is unknown how patients with PsA would respond if they switched from treatment tofacitinib to upadacitinib.

How would upadacitinib fit into the current treatment paradigm? Would the place in therapy of upadacitinib be the same as that of the biologic DMARDs?

The clinical expert indicated that the place in therapy of upadacitinib would be the same as that of the biologic DMARDs. Due to the ease of use of upadacitinib, upadacitinib might be used as first-line treatment after failing previous treatment with DMARDs.

Should upadacitinib be prescribed in consultation with a rheumatologist and/or specialist?

The clinical expert indicated that upadacitinib should be prescribed by rheumatologists or non-rheumatologist clinical physicians who have experience treating patients with PsA.

According to the product monograph, Rinvoq (upadacitinib) has been associated with increases in lipid parameters. The effect of lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. What is the significance of this side effect, particularly in patients being treated for PsA?

The clinical expert does not expect that upadacitinib would have an impact on cardiovascular morbidity and mortality; patients should be treated for their lipid abnormalities according to their risk and the standard of care; however, the full effect of upadacitinib on cardiovascular morbidity and mortality still need to be assessed.

Should a potential dose escalation beyond 15 mg per day be expected in the indication under review?

Due to safety concerns of serious infection and zoster which increased with the upadacitinib 30 mg dose in comparison with the upadacitinib 15 mg dose, the clinical expert indicated that clinicians would be cautious about dose escalation. The clinical expert also stated that it is not expected that dose escalation beyond 15 mg of upadacitinib once daily would happen in the clinical practice.

DMARD = disease-modifying antirheumatic drug; PsA = psoriatic arthritis.

Clinical Evidence Selection

The clinical evidence included in the review of upadacitinib is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of upadacitinib 15 mg oral extended-release tablets as monotherapy or in combination with non-bDMARDs for the treatment of active PsA in adult patients who have responded inadequately or who are intolerant to 1 or more DMARDs.

Methods

Studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered important by patients, clinicians, and drug plans.

The systematic review protocol was established before the granting of a Notice of Compliance from Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

Criteria

Description

Patient population

Adult patients with active PsA, who have responded inadequately to, or are intolerant to, 1 or more DMARDs.

Subgroups of interest:

  • Disease severity at baseline

  • Previous exposure to biologic DMARDs (treatment-naive vs. -experienced)

  • Concomitant treatment with non-biologic DMARD

Intervention

Upadacitinib 15 mg orally once daily

As monotherapy or in combination with non-biologic DMARDs

Comparators

bDMARDs

  • TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab)

  • IL-17 inhibitors (ixekizumab, secukinumab)

  • IL-12/23 inhibitors (ustekinumab)

tsDMARDs

  • JAK inhibitor (tofacitiniba)

  • csDMARDs (e.g., methotrexate) alone or in combination with bDMARDs

Outcomes

Efficacy outcomes

  • Clinical response in PsA symptoms (e.g., ACR20, ACR50, ACR70, DAS28, PsARC, and MDA)

  • Measure of function and disability (e.g., HAQ-DI and work productivity)

  • Measure of PsA symptoms (e.g., pain and fatigue)

  • Health-related quality of life (e.g., SF-36 and PsAQoL)

  • Measure of skin disease (e.g., PASI 75 or PASI 90)

  • Measure of other musculoskeletal disease (e.g., dactylitis, enthesitis, and axial arthritis)

  • Radiographic changes

Harms outcomes

  • AEs, SAEs, WDAEs, mortality

  • AEs of special interest (e.g., serious infections [including herpes zoster, TB, and pneumonia], anemia, neutropenia, lymphopenia, malignancies, thrombosis [including VTE, PE, and arterial thrombosis], gastrointestinal perforations, elevated CPK, elevated liver enzymes/hepatic disorders, hyperlipidemia, MACE)

Study design

Published and unpublished phase III and IV RCTs

ACR = American College of Rheumatology; ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; AE = adverse events; bDMARD = biologic disease-modifying antirheumatic drug; CPK = creatine phosphokinase; csDMARD = conventional synthetic disease-modifying antirheumatic drug; DAS28 = Disease Activity Score 28; DMARD = disease-modifying antirheumatic drug; HAQ-DI = Health Assessment Questionnaire–Disability Index; IL = interleukin; JAK = Janus kinase; MACE = major adverse cardiovascular events; MDA = minimal disease activity; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PE = pulmonary embolism; PsA = psoriatic arthritis; PsAQoL = Psoriatic Arthritis Quality of Life; PsARC = Psoriatic Arthritis Response Criteria; RCT = randomized controlled trial; SAE = serious adverse events; SF-36 = Short Form (36) Health Survey; TB = tuberculosis; TNF = tumour necrosis factor; VTE = venous thromboembolism; WDAE = withdrawal due to adverse events.

aTofacitinib is currently not reimbursed by public drug programs in Canada; however, it was deemed to be a relevant comparator to upadacitinib by the clinical expert(s) consulted for this review.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the Peer Review of Electronic Search Strategies checklist (https://www.cadth.ca/resources/finding-evidence/press).28

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid and Embase (1974‒) via Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was upadacitinib (Rinvoq). Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides detailed search strategies.

The initial search was completed on February 1, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on June 16, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.29 Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy. These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

A focused literature search for NMAs dealing with PsA was run in MEDLINE All (1946–) on February 1, 2021.

Findings From the Literature

A total of 2 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

A total of 180 citations were identified, 169 of which were excluded. Another 5 potentially relevant electronic literature full-text reports were retrieved for scrutiny. In total, 6 reports were included in the review.

Table 6: Details of Included Studies

Detail

SELECT-PsA1

SELECT-PsA2

Designs and populations

Study design

Phase III, double-blind, multi-centre, active and placebo-controlled RCT

Phase III, double-blind, multi-centre, placebo-controlled RCT

Locations

281 sites in 44 countries across Canada, US, South America, Europe, Asia, and Australasia

6 Canadian sites (39 Canadian patients) participated in this trial

123 sites in 16 countries across and including Canada, US, South America, Europe, Japan, and New Zealand

5 Canadian sites (17 Canadian patients) participated in this trial

Patient randomization dates

April 27, 2017, to June 28, 2019

May 1, 2017, to April 24, 2019

Randomized (N)

1,705

642

Inclusion criteria

  • ≥ 18 years of age

  • Diagnosis of PsA with symptom onset ≥ 6 months and fulfills CASPAR criteria

  • Active disease at baseline: ≥ 3/68 tender joints and ≥ 3/66 swollen joints

  • Presence of either ≥ 1 erosion on X-ray as determined by central imaging review or hs-CRP > ULN

  • Active or documented history of plaque psoriasis

  • Inadequate response to previous or current treatment with at least 1 non-bDMARD, or intolerance to or contraindication for DMARDsa

  • Patients on current treatment with concomitant non-biologic DMARDs at study entry must be on ≤ 2 non-biologic DMARDs up to specified maximum dosesb for ≥ 12 weeks and at stable dose for ≥ 4 weeks before the baseline visit

  • No other DMARDs permitted during the study

  • ≥ 18 years of age

  • Diagnosis of PsA with symptom onset ≥ 6 months and fulfills CASPAR criteria

  • Active disease at baseline: ≥ 3/68 tender joints and ≥ 3/66 swollen joints

  • Active or documented history of plaque psoriasis

  • Inadequate response (lack of efficacy after a minimum 12 weeks of therapy) or intolerance to treatment with at least 1 bDMARDc

  • Patients on current treatment with concomitant non-bDMARDs at study entry must be on ≤ 2 non-bDMARDs up to specified maximum dosesb for ≥ 12 weeks and at stable dose for ≥ 4 weeks before the baseline visit

  • No other DMARDs permitted during the study

Exclusion criteria

• Prior exposure to biologic immunomodulators

• Prior exposure JAK inhibitor

• Current treatment with > 2 non-biologic DMARDs or use of DMARDs other than MTX, SSZ, LEF, apremilast, HCQ, bucillamine, or iguratimod, or use of MTX in combination with LEF

• History of fibromyalgia, any arthritis with onset before age 17 years, or current diagnosis of inflammatory joint disease other than PsAd

• Extra-articular manifestations of PsA (e.g., psoriasis, uveitis, IBD) not clinically stable for ≥ 30 days

• Current or past history of infectione

• History of cardiovascular conditions (NYHA class III or IV CHF; recent CVA, myocardial infarction or coronary stent; uncontrolled hypertension)

• History of GI perforation or diverticulitis

• History of malignancyf

• History of demyelinating disease (e.g., MS)

• Use of concomitant psoriasis treatmentg

• Prior exposure JAK inhibitor

• Current treatment with > 2 non-biologic DMARDs or use of DMARDs other than MTX, SSZ, LEF, apremilast, HCQ, bucillamine or iguratimod, or use of MTX in combination with LEF

• History of fibromyalgia, any arthritis with onset before age 17 years, or current diagnosis of inflammatory joint disease other than PsAd

• Extra-articular manifestations of PsA (e.g., psoriasis, uveitis, IBD) not clinically stable for ≥ 30 days

• Current or past history of infectione

• History of cardiovascular conditions (NYHA class III or IV CHF; recent CVA, myocardial infarction or coronary stent; uncontrolled hypertension)

• History of GI perforation or diverticulitis

• History of malignancyf

• Use of concomitant psoriasis treatmentg

Drugs

Intervention

  • Upadacitinib 15 mg PO once daily (Health Canada–approved dose)

  • Upadacitinib 30 mg PO once daily

  • Upadacitinib 15 mg PO once daily (Health Canada–approved dose)

  • Upadacitinib 30 mg PO once daily

Comparator(s)

  • Adalimumab 40 mg SC every 2 weeks

  • Matching placebo, SC or PO, followed by upadacitinib 15 mg PO once daily after week 24

  • Matching placebo, SC or PO, followed by upadacitinib 30 mg PO once daily after week 24

  • Matching placebo PO followed by upadacitinib 15 mg PO once daily after week 24

  • Matching placebo PO followed by upadacitinib 30 mg PO once daily after week 24

Duration

Phase

Screening

35 days

35 days

Blinded period

56 weeks (double-blind for 24 weeks)

56 weeks (double-blinded for 24 weeks)

Long-term extension

Up to 5 years

Up to 3 years

Follow-up

At 30 days (call or visit) and 70 days (call)

At 30 days (call or visit)

Outcomes

Primary end point

Proportion of patients achieving ACR20 at week 12

Proportion of patients achieving ACR20 at week 12

Secondary and exploratory end points

Key secondary end points

  • Week 2

    • ACR20

    • Week 12

    • Change from baseline in: HAQ-DI, SF-36 PCS, FACIT-F, patient’s assessment of pain NRS

    • ACR20, ACR50, or ACR70

  • Week 16

    • Change from baseline in SAPS

    • Proportion of patients achieving an sIGA of psoriasis of 0 or 1 and at least a 2-point improvement from baseline

    • PASI 75 response (for patients with ≥ 3% BSA psoriasis at baseline)

  • Week 24

    • Change from baseline in SHS

    • Proportion of patients achieving MDA

    • Proportion of patients with resolution of enthesitis (LEI = 0) or dactylitis (LDI = 0)

Key secondary end points

• Week 2

          o ACR20

  • Week 12

    • Change from baseline in HAQ-DI, SF-36 PCS, FACIT-F

    • ACR50 or ACR70

  • Week 16

    • Change from baseline in SAPS

    • Proportion of patients achieving an sIGA of psoriasis of 0 or 1 and at least a 2-point improvement from baseline

    • PASI 75 response (for patents with ≥ 3% BSA psoriasis at baseline)

  • Week 24

    • Proportion of patients achieving MDA

Additional end points

  • Change from baseline in:

    • Joint space narrowing score and joint erosion score

    • Individual components of ACR response

    • LDI

    • Dactylitis count

    • LEI

    • SPARCC Enthesitis Index

    • Total enthesitis count

    • DAS28 (ESR)

    • PASDAS

    • DAPSA score

    • SF-36

    • FACIT- F

    • EQ-5D-5L

    • WPAI questionnaire

    • SAPS

    • BASDAI

    • Morning stiffness (mean of BASDAI questions 5 and 6)

    • ASDAS

    • DAS28 (CRP)

  • Change from baseline in:

    • Individual components of ACR response

    • LDI

    • Dactylitis count

    • LEI

    • SPARCC Enthesitis Index

    • Total enthesitis count

    • DAS28 (ESR)

    • PASDAS

    • DAPSA score

    • SF-36

    • FACIT-F

    • EQ-5D-5L

    • WPAI questionnaire

    • SAPS

    • BASDAI

    • Morning stiffness (mean of BASDAI questions 5 and 6)

    • ASDAS

    • DAS28 (CRP)

Additional end points

  • Proportion of patients achieving:

    • No radiographic progression (change from baseline in SHS = 0)

    • Resolution of dactylitis

    • Resolution of enthesitis sites included in the LEI=

    • Resolution of enthesitis sites included in the SPARCC Enthesitis Index

    • Resolution of enthesitis

    • sIGA of psoriasis score of 0 or 1 and at least a 2-point improvement from baseline

    • MDA

    • ASDAS inactive disease

    • ASDAS major improvement

    • ASDAS clinically important improvement

    • Clinically meaningful improvement in HAQ-DI (≥ 0.35)

  • Response rates for:

    • ACR20, ACR50, and ACR70

    • PASI 75, PASI 90, and PASI 100 (for patients with ≥ 3% BSA psoriasis at baseline)

    • PsARC

    • BASDAI 50

  • Others

    • BSA-PsO

    • HRU

  • Proportion of patients achieving:

    • Resolution of dactylitis

    • Resolution of enthesitis sites included in the LEI

    • Resolution of enthesitis sites included in the SPARCC Enthesitis Index

    • Resolution of enthesitis

    • sIGA score of 0 or 1 and at least a 2-point improvement from baseline

    • MDA

    • ASDAS inactive disease

    • ASDAS major improvement

    • ASDAS clinically important improvement

    • Clinically meaningful improvement in HAQ-DI (≥ 0.35)

    • Response rates for:

    • ACR20, ACR50, and ACR70

    • PASI 75, PASI 90, and PASI 100 (for patients with ≥ 3% BSA psoriasis at baseline)

    • PsARC

    • BASDAI 50

    • Others

    • BSA psoriasis

    • HRU

Notes

Publications

McInnes et al. (2021)30

Mease et al. (2020)31 and Mease et al. (2021)32

ACR = American College of Rheumatology; ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; ASDAS = Ankylosing Spondylitis Disease Activity Score; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; bDMARD = biologic disease-modifying antirheumatic drug; BSA = body surface area; CASPAR = Classification Criteria for Psoriatic Arthritis; CHF = congestive heart failure; CRP = C-reactive protein; CVA = cerebrovascular accident; DAPSA = Disease Activity Index for Psoriatic Arthritis; DAS28 = Disease Activity Score 28; DMARD = disease-modifying antirheumatic drug; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; ESR = erythrocyte sedimentation rate; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; GI = gastrointestinal; HAQ-DI = Health Assessment Questionnaire–Disability Index; HCQ = hydroxychloroquine; HRU = Health Resource Utilization; hs-CRP = high-sensitivity C-reactive protein; IBD = inflammatory bowel disease; JAK = Janus kinase; LDI = Leeds Dactylitis Index; LEF = leflunomide; LEI = Leeds Enthesitis Index; MDA = minimal disease activity; MS = multiple sclerosis; MTX = methotrexate; NRS = Numerical Rating Scale; NYHA = New York Heart Association; PASDAS = Psoriasis Disease Activity Score; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PASI 100 = 100% reduction in Psoriasis Area Severity Index score PCS = physical component summary; PO = orally; PsA = psoriatic arthritis; PsARC = Psoriatic Arthritis Response Criteria; RCT = randomized controlled trial; SAPS = Self-Assessment of Psoriasis Symptoms; SC = subcutaneously; SF-36 = Short Form (36) Health Survey; SHS = Sharp/van der Heijde Score; sIGA = static Investigator Global Assessment; SPARCC = Spondyloarthritis Research Consortium of Canada; SSZ = sulfasalazine; ULN = upper limit of normal; WPAI = Work Productivity and Activity Impairment.

Note: Four additional reports were included from the sponsor’s submission package (SELECT-PsA1: Clinical Study Report for week 249 and week 5633; SELECT-PsA2: Clinical Study Report for week 2410 and week 5611).

aInadequate response defined as lack of efficacy after a minimum of 12 weeks of therapy, with prior non-bDMARD given at the maximally tolerated dosage, or up to the following dosages: MTX (≤ 25 mg weekly), SSZ (≤ 3,000 mg daily), LEF (≤ 20 mg daily), apremilast (≤ 60 mg daily), HCQ (≤ 400 mg daily), bucillamine (≤ 300 mg daily), and iguratimod (≤ 50 mg daily). Inadequate response to MTX is defined as between 15 mg per week and ≤ 25 mg per week; or at least 10 mg per week in patients who are intolerant of MTX at dosages greater than or equal to 12.5 mg per week after complete titration. For patients in China, Korea, Malaysia, Singapore, Hong Kong (China), Taiwan, and Japan, inadequate response to MTX is defined as at least 7.5 mg per week.

bMaximum dosages defined as: MTX (≤ 25 mg per week), SSZ (≤ 3,000 mg daily), leflunomide (LEF) (≤ 20 mg daily), apremilast (≤ 60 mg daily), HCQ (≤ 400 mg daily), bucillamine (≤ 300 mg daily), and iguratimod (≤ 50 mg daily). In the SELECT-PsA1 trial, no more than approximately 15% of patients with concomitant use of HCQ, sulfasalazine, bucillamine, or iguratimod were enrolled. The use of MTX in combination with LEF was not allowed.

cIn SELECT-PsA2, no more than approximately 40% of patients with less than 3% BSA extent of psoriasis, and no more than approximately 30% of patients with prior failure of more than 1 bDMARD were enrolled.

dInflammatory joint disease included, but was not limited to, rheumatoid arthritis, gout, overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, and systemic lupus erythematosus. Prior history of reactive arthritis or axial spondyloarthritis, including ankylosing spondylitis and non-radiographic axial spondyloarthritis, was permitted if documentation of change in diagnosis to PsA or additional diagnosis of PsA was made.

eIncludes recurrent or disseminated (even a single episode) of herpes zoster, disseminated (even a single episode) of herpes simplex, active tuberculosis, or active infection(s) requiring parenteral anti-infectives within 30 days or oral anti-infectives within 14 days before baseline visit.

fExcept for successfully treated non-melanoma skin cancer or localized carcinoma in situ of the cervix.

gIncludes oral retinoids within 4 weeks of baseline visit; topical treatments within 2 weeks of baseline visit (except low-potency topical corticosteroids on palms, soles, face, inframammary area, and groin only).

Source: SELECT-PsA1 Clinical Study Report,9 SELECT-PsA2 Clinical Study Report,10 SELECT-PsA2 Week 56 Clinical Study Report,11 and sponsor’s response to additional information request.34,35

Description of Studies

Two phase III, multi-centre, double-blind RCTs met the inclusion criteria for this systematic review.9,10 The study designs of SELECT-PsA1 and SELECT-PsA2 are shown in Figure 2 and Figure 3. Both SELECT-PsA1 and PsA2 were funded by AbbVie, Inc.

Both SELECT studies enrolled adults with moderate to severely active PsA who had been previously treated with a DMARD; however, patients enrolled in PsA1 were bDMARD-naive. A screening period running 35 days before randomization was used to assess patients’ eligibility, during which their medical history, treatment history, and current medical condition were assessed, and relevant laboratory tests including tuberculosis skin tests and radiographic examinations were performed. Both studies consisted of 2 periods, and at the end of period 1, all patients on placebo were switched to upadacitinib. In SELECT-PsA1, period 1 lasted for 56 weeks and included a 24-week double-blind placebo and active comparator–controlled period followed by 32 weeks of blinded active comparator–controlled treatment. In SELECT-PsA2, period 1 was also 56 weeks in duration and included 24 weeks of a double-blinded placebo-controlled phase, followed by 32 weeks of a non-comparative treatment phase. Period 2 is an ongoing open-label long-term extension for up to approximately 5 years in PsA1 and 3 years in PsA2.

The primary objective of period 1 in SELECT-PsA1 was to compare the efficacy of upadacitinib versus placebo and versus adalimumab for the treatment of signs and symptoms of moderately to severely active PsA in patients who have an inadequate response or are intolerant to at least 1 non-bDMARD. Prevention of structural progression and safety were secondary objectives. The objective for period 1 in SELECT-PsA2 was to compare the efficacy and safety of upadacitinib versus placebo for the treatment of signs and symptoms of moderately to severely active PsA in patients who had an inadequate response or are intolerant to at least 1 bDMARD. The objective of period 2 in both SELECT studies was to evaluate the long-term safety, tolerability, and efficacy of upadacitinib in patients who completed period 1. In both studies, period 1 was designed to test the superiority of upadacitinib versus placebo in achieving the primary end point (ACR20 at week 12) and other efficacy parameters at week 12 to 24. In addition, period 1 in PsA1 was designed to test the noninferiority of upadacitinib versus adalimumab (ACR20 at week 12). Results from both studies were presented using interim analyses, with a data cut-off of December 13, 2019, for PsA1 and October 9, 2019, for PsA2. At data cut-off, all patients had completed week 24 of period 1 or had discontinued from the study. Both studies are ongoing.

In SELECT-PsA1 (N = 1,705), eligible participants were randomized after the screening phase in a 2:2:2:1:1 ratio to 1 of 5 treatment groups: upadacitinib 15 mg orally once daily, upadacitinib 30 mg orally once daily, adalimumab 40 mg subcutaneous every other week, and placebo followed by either upadacitinib 15 mg daily or upadacitinib 30 mg daily (Figure 2). Randomization was performed through a centralized interactive voice response system and stratified by extent of psoriasis (≥ 3% BSA or < 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of enthesitis. The exception was for patients from China or Japan, where randomization was stratified only by the extent of psoriasis.

In SELECT-PsA2 (N = 642), eligible participants were randomized after the screening phase in a 2:2:1:1 ratio to 1 of 4 treatment groups: upadacitinib 15 mg orally once daily, upadacitinib 30 mg orally once daily, and placebo followed by either upadacitinib 15 mg daily or upadacitinib 30 mg daily (Figure 3). Randomization was performed through a centralized interactive voice response system and stratified by extent of psoriasis (≥ 3% or < 3% BSA), current use of at least 1 DMARD, and number of prior failed (i.e., inadequate response to) bDMARDs (1 versus > 1). The exception was for patients from China or Japan, where randomization was stratified only by the extent of psoriasis.

In both SELECT-PsA1 and SELECT-PsA2, at week 24, patients randomized to placebo at the start of the study were switched to pre-assigned upadacitinib 15 mg or 30 mg daily in a 1:1 ratio, regardless of response. Patients, study-site personnel, the investigator, and the sponsor study team were blinded to study drug assignment, until all patients completed the week 24 visit. Thereafter, an unblinded analysis was conducted by the sponsor but the individual investigators, study sites, and patients remained blinded. When the last patient completed the last visit of period 1 (week 56), the study drug assignments were unblinded and treatment was continued in an open-label manner until the end of period 2.

Starting at week 36 in both studies, patients who did not show an improvement of at least 20% from baseline in either or both TJC and SJC at 2 consecutive visits were discontinued from study treatment but had the option of continuing to participate in the study for continued follow-up.

The primary end point for both SELECT-PsA1 and SELECT-PsA2 was the proportion of patients who achieve an ACR20 at week 12. The Health Canada–approved indication is for upadacitinib 15 mg once daily. Data from the SELECT studies for the 30 mg dose are not presented in this review.

Figure 2: Study Design for SELECT-PsA1

The screening period for SELECT-PsA1 was up to 35 days. Eligible participants were randomized after the screening phase in a 2:2:2:1:1 ratio to 1 of 5 treatment groups: upadacitinib 15 mg orally once daily, upadacitinib 30 mg orally once daily, adalimumab 40 mg subcutaneous every other week, and placebo followed by either upadacitinib 15 mg daily or upadacitinib 30 mg daily at week 24. When the final patient completed the last visit of period 1 (week 56), the study drug assignments were unblinded and treatment was continued in an open-label manner until the end of period 2.

ABT-494 = upadacitinib; ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; BL = baseline; e.o.w. = every other week; PBO = placebo; QD = once daily; vs = versus; Wk = week.

Note: Sample sizes represent the actual number of patients randomized to each treatment sequence.

a All patients received X-rays of hands and feet at screening, week 24, week 56, week 104, week 152, and at premature discontinuation.

b At week 16, rescue therapy was offered to patients classified as nonresponders (defined as not achieving an improvement of at least 20% in either or both tender joint count and swollen joint count at both week 12 and week 16).

c At week 24, all placebo patients were switched to upadacitinib 15 mg once daily or 30 mg once daily (1:1 ratio) regardless of response.

Source: SELECT-PsA1 Clinical Study Report.9

Figure 3: Study Design for SELECT-PsA2

The screening period for SELECT-PsA2 was up to 35 days. Eligible participants were randomized after the screening phase in a 2:2:1:1 ratio to 1 of 4 treatment groups: upadacitinib 15 mg orally once daily, upadacitinib 30 mg orally once daily, and placebo followed by either upadacitinib 15 mg daily or upadacitinib 30 mg daily at week 24. When the last patient completed the last visit of period 1 (week 56), the study drug assignments were unblinded and treatment was continued in an open-label manner until the end of period 2.

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; BL = baseline; PBO = placebo; QD = once daily; vs = versus; Wk = week.

a At week 16, rescue therapy was offered to patients classified as nonresponders (defined as not achieving an improvement of at least 20% in either or both tender joint count and swollen joint count at both week 12 and week 16).

b At week 24, all placebo patients switched to upadacitinib 15 mg once daily or 30 mg once daily (1:1 ratio) regardless of response.

Source: SELECT-PsA2 Clinical Study Report.10

Populations

Inclusion and Exclusion Criteria

To be eligible for both SELECT-PsA1 and SELECT-PsA2, patients were required to be at least 18 years of age and have an established diagnosis of PsA with at least 3 tender joints and 3 swollen joints. The patients were required to have active or a documented history of plaque psoriasis. Patients enrolled in SELECT-PsA1 were also required to exhibit either 1 or more examples of erosion on X-ray, or hs-CRP levels greater than the ULN. Patients in PsA1 were bDMARD-naive but had been previously treated with at least 1 non-bDMARD. Patients in PsA2 were all bDMARD-experienced.

Patients were excluded if they had prior exposure to a JAK inhibitor, were on concomitant treatment for psoriasis, or were receiving more than 2 concurrent non-bDMARDs at baseline. Patients on concomitant non-biologic treatment must have been on a stable dose for at least 4 weeks. The use of methotrexate in combination with leflunomide was also not permitted. Patients with extra-articular manifestation of PsA who were not clinically stable for 30 days or longer were excluded. In SELECT-PsA1, patients were also excluded if they had prior exposure to biologic immunomodulators or a history of demyelinating disease.

Baseline Characteristics

Across both studies, in the treatment groups of interest to this review, the mean age ranged from 50 to 54 years, and the majority of patients were White. The mean duration of PsA diagnosis was shorter in the SELECT-PsA1 trial and ranged from 5.9 to 6.2 years in SELECT-PsA1 and from 9.6 to 11.0 years in SELECT-PsA2. The mean TJCs were 20 in SELECT-PsA1 and 25 in SELECT-PsA2. The mean SJC was between 11 and 12 in both SELECT-PsA1 and SELECT-PsA2. The proportion of patients with psoriasis affecting 3% or more of their BSA was lower in SELECT-PsA1 (50%) than in SELECT-PsA2 (61%). Enthesitis at baseline was reported in 77% of patients in SELECT-PsA1 and 82% of patients in SELECT-PsA2, while dactylitis at baseline was reported in 30% to 32% of patients in SELECT-PsA1 and ranged from 26% to 30% of patients in SELECT-PsA2. Patients in SELECT-PsA1 had a lower mean LDI baseline score, ranging from 88 to 99, compared to patents in SELECT-PsA2, who had a baseline score of between 96 and 124. In SELECT-PsA1, more than 99% of patients had received a prior non-bDMARD compared to 74% to 81% of patients in SELECT-PsA2, and most patients had received methotrexate. In SELECT-PsA1, most patients (91%) were enrolled due to inadequate response to prior non-bDMARDs (including patients who had lack of efficacy as well as those who had both a lack of efficacy and intolerance), whereas 7% were enrolled due to an intolerance or contraindication to non-bDMARDs.35 As per protocol, 100% of patients in SELECT-PsA2 had received a prior bDMARD; most (62%) had failed 1 prior biologic treatment, whereas 8% were enrolled due to an intolerance to a bDMARD. At baseline, more patients in SELECT-PsA1 were concurrently using a non-bDMARD (81% to 82%) compared to patients enrolled in SELECT-PsA2 (46 to 47%).

The baseline demographic and disease characteristics were generally similar across the treatment groups within SELECT-PsA1 and SELECT-PsA2. There were some minor imbalances between the treatment groups in PsA2; for example, the placebo group had a slightly higher mean LDI (124.19 versus 96.27 for the upadacitinib 15 mg group) and sIGA score of 0 (8.0% versus 4.3% for upadacitinib 15 mg), and a larger share of patients who had received no prior non-bDMARD (25.9% versus 19.4% for upadacitinib 15 mg). A slightly higher proportion of patients in the upadacitinib 15 mg group had a baseline sIGA score of 2 compared to patients in the placebo group (27.8% versus 38.9% upadacitinib 15 mg group).

Table 7: Summary of Baseline Characteristics — Full Analysis Set

Characteristic

SELECT-PsA1

SELECT-PsA2

PBO

(n = 423)

ADA 40 mg

(n = 429)

UPA 15 mg

(n = 429)

PBO

(n = 212)

UPA 15 mg

(n = 211)

Age (years), mean (SD)

50.4 (12.21)

51.4 (12.04)

51.6 (12.19)

54.1 (11.53)

53.0 (12.02)

Male, n (%)

212 (50.1)

207 (48.3)

191 (44.5)

92 (43.4)

98 (46.4)

Race

  White

377 (89.1)

375 (87.4)

386 (90.0)

186 (87.7)

183 (86.7)

  Black or African American

3 (0.7)

2 (0.5)

1 (0.2)

7 (3.3)

5 (2.4)

  American Indian/Alaska Native

2 (0.5)

2 (0.5)

0

0

3 (1.4)

  Native Hawaiian or other Pacific Islander

1 (0.2)

2 (0.5)

0

1 (0.5)

1 (0.5)

  Asian

37 (8.7)

41 (9.6)

37 (8.6)

17 (8.0)

19 (9.0)

  Multiple

3 (0.7)

7 (1.6)

5 (1.2)

1 (0.5)

0

Weight (kg), mean (SD)

87.4 (21.36)

87.8 (21.90)

84.8 (18.89)

90.0 (23.02)

89.3 (23.56)

BMI (kg/m2), mean (SD)

30.4 (6.79)

30.7 (7.24)

30.1 (6.40)

31.8 (7.47)

31.5 (7.37)

Duration of PsA diagnosis (years), mean (SD)

6.2 (7.01)

5.9 (7.06)

6.2 (7.41)

11.0 (10.33)

9.6 (8.36)

Joint counts, mean (SD)

  Tender join count 68

20.0 (14.34)

20.1 (13.82)

20.4 (14.72)

25.3 (17.62)

24.9 (17.27)

  Swollen joint count 66

11.0 (8.16)

11.6 (8.75)

11.6 (9.31)

12.0 (8.85)

11.3 (8.19)

Presence of ≥ 1 erosion, n (%)

  Yes

161 (38.1)

183 (42.7)

165 (38.5)

NR

NR

  No

227 (53.7)

218 (50.8)

241 (56.2)

NR

NR

  Missing

35 (8.3)

28 (6.5)

23 (5.4)

NR

NR

hs-CRP > ULN,a n (%)

324 (76.6)

308 (71.8)

324 (75.5)

121 (57.1)

126 (59.7)

hs-CRP (mg/L), mean (SD)

11.48 (15.80)

10.91 (15.46)

11.00 (14.91)

10.40 (18.46)

11.16 (18.55)

BSA psoriasis

  < 3%

212 (50.1)

218 (50.8)

215 (50.1)

81 (38.2)

81 (38.4)

  ≥ 3%

211 (49.9)

211 (49.2)

214 (49.9)

131 (61.8)

130 (61.6)

PASDAS, n

421

428

425

209

207

  Mean (SD)

6.18 (1.06)

6.15 (1.03)

6.31 (1.05)

6.38 (1.22)

6.26 (1.07)

DAS28 (CRP)

421

428

425

209

208

  Mean (SD)

4.90 (1.01)

4.88 (1.06)

4.94 (1.05)

5.15 (1.03)

5.14 (0.99)

Patient's assessment of pain NRS, n

421

428

425

209

208

  Mean (SD)

6.1 (2.14)

6.0 (2.08)

6.2 (2.07)

6.6 (2.12)

6.4 (2.13)

HAQ-DI, n

421

428

425

209

208

  Mean (SD)

1.12 (0.64)

1.12 (0.63)

1.15 (0.65)

1.23 (0.69)

1.10 (0.61)

PASI (for baseline BSA psoriasis ≥ 3%), n

211

211

214

131

130

  Mean (SD)

11.21 (11.43)

9.42 (8.54)

9.78 (9.95)

11.68 (11.43)

10.13 (9.20)

SHS, n

388

401

406

NR

NR

  Mean (SD)

13.32 (31.21)

14.97 (38.87)

13.14 (42.45)

NR

NR

BASDAI (patients with psoriatic spondylitis), n

130

125

138

74

75

  Mean (SD)

5.81 (1.86)

5.69 (2.19)

5.94 (2.03)

6.54 (1.88)

5.90 (2.14)

Presence of dactylitis (LDI > 0), n (%)

126 (29.8)

127 (29.6)

136 (31.7)

64 (30.2)

55 (26.1)

LDI (for baseline LDI > 0), n

126

127

136

64

55

  Mean (SD)

87.65 (114.76)

99.00 (163.11)

88.99 (106.50)

124.19 (178.76)

96.27 (97.87)

Presence of enthesitis (total count > 0), n (%)b

322 (76.1)

330 (76.9)

333 (77.6)

173 (81.6)

173 (82.0)

LEI (for baseline LEI > 0), n

241

265

270

144

133

  Mean (SD)

2.7 (1.52)

2.5 (1.42)

2.6 (1.55)

3.3 (1.70)

3.0 (1.64)

sIGA of psoriasis score, n (%)

  0

24 (5.7)

34 (7.9)

34 (7.9)

17 (8.0)

9 (4.3)

  1

86 (20.3)

65 (15.2)

73 (17.0)

32 (15.1)

31 (14.7)

  2

167 (39.5)

181 (42.2)

170 (39.6)

59 (27.8)

82 (38.9)

  3

119 (28.1)

132 (30.8)

133 (31.0)

88 (41.5)

78 (37.0)

  4

27 (6.4)

17 (4.0)

19 (4.4)

16 (7.5)

11 (5.2)

Any prior non-bDMARD use, n (%)

423 (100)

427 (99.5)

428 (99.8)

157 (74.1)

170 (80.6)

Number of prior non-bDMARDs, n (%)

26 (6.1)

27 (6.3)

31 (7.2)

NR

NR

  0

0

2 (0.5)

1 (0.2)

55 (25.9)

41 (19.4)

  1

274 (64.8)

286 (66.7)

274 (63.9)

103 (48.6)

109 (51.7)

  2

105 (24.8)

112 (26.1)

112 (26.1)

40 (18.9)

45 (21.3)

  ≥ 3

44 (10.4)

29 (6.8)

42 (9.8)

14 (6.6)

16 (7.6)

Intolerant to prior non-bDMARD

26 (6.1)

27 (6.3)

31 (7.2)

NR

NR

Any prior bDMARD use, n (%)

NR

NR

NR

212 (100)

211 (100)

Number of prior bDMARDs, n (%)

  0

NR

NR

NR

0

0

  1

NR

NR

NR

133 (62.7)

118 (55.9)

  2

NR

NR

NR

39 (18.4)

44 (20.9)

  ≥ 3

NR

NR

NR

40 (18.9)

49 (23.2)

Number of prior anti-TNFs, n (%)

  0

NR

NR

NR

45 (21.2)

50 (23.7)

  1

NR

NR

NR

106 (50.0)

92 (43.6)

  2

NR

NR

NR

42 (19.8)

41 (19.4)

  ≥ 3

NR

NR

NR

19 (9.0)

28 (13.3)

Number of prior bDMARDs other than anti-TNF, n (%)

  0

NR

NR

NR

124 (58.5)

109 (51.7)

  1

NR

NR

NR

79 (37.3)

92 (43.6)

  2

NR

NR

NR

7 (3.3)

7 (3.3)

  ≥ 3

NR

NR

NR

2 (0.9)

3 (1.4)

Number of prior failed bDMARDs, n (%)

  0

NR

NR

NR

18 (8.5)

16 (7.6)

  1

NR

NR

NR

135 (63.7)

126 (59.7)

  2

NR

NR

NR

35 (16.5)

35 (16.6)

  ≥ 3

NR

NR

NR

24 (11.3)

34 (16.1)

Use of ≥ 1 non-bDMARD at baseline, n (%)

347 (82.0)

347 (80.9)

353 (82.3)

100 (47.2)

98 (46.4)

Use of non-bDMARD at baseline, n (%)

  MTX alone

267 (63.1)

270 (62.9)

279 (65.0)

75 (35.4)

74 (35.1)

  MTX + other non-bDMARD

26 (6.1)

16 (3.7)

20 (4.7)

7 (3.3)

6 (2.8)

  Non-bDMARD other than MTX

54 (12.8)

61 (14.2)

54 (12.6)

18 (8.5)

18 (8.5)

  None

76 (18.0)

82 (19.1)

76 (17.7)

112 (52.8)

113 (53.6)

Use of NSAID at baseline, n (%)

275 (65.0)

279 (65.0)

263 (61.3)

125 (59.0)

124 (58.8)

Use of corticosteroid at baseline, n (%)

70 (16.5)

72 (16.8)

73 (17.0)

24 (11.3)

22 (10.4)

ADA = adalimumab; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; bDMARD = biologic disease-modifying antirheumatic drug; BMI = body mass index; BSA = body surface area; CRP = C-reactive protein; DAS28 = Disease Activity Score 28; DMARD = disease-modifying antirheumatic drug; HAQ-DI = Health Assessment Questionnaire–Disability Index; hs-CRP = high-sensitivity C-reactive protein; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MTX = methotrexate; NR = not reported; NRS = Numerical Rating Scale; NSAID = nonsteroidal anti-inflammatory drug; PASDAS = Psoriatic Arthritis Disease Activity Score; PASI = Psoriasis Area Severity Index; PBO = placebo; PsA = psoriatic arthritis; SD = standard deviation; SHS = Sharp/van der Heijde Score; sIGA = static Investigator Global Assessment; TNF = tumour necrosis factor; ULN = upper limit of normal; UPA = upadacitinib.

aFor hs-CRP, the ULN = 2.87 mg/L.

bThe total enthesitis count is calculated by taking the sum of the tenderness scores from all 18 sites derived from the Spondyloarthritis Research Consortium of Canada Enthesitis Index and LEI.

Source: SELECT-PsA1 Clinical Study Report,9 SELECT-PsA2 Clinical Study Report,10 and sponsor’s response to additional information request.34

Interventions

While both included studies randomized patients to 15 mg oral upadacitinib or placebo once daily, the SELECT-PsA1 study also included an active comparator arm (adalimumab 40 mg subcutaneous every other week). Both studies also randomized patients to a 30 mg upadacitinib arm; however, further description of the 30 mg upadacitinib group is not included in this systematic review as it is higher than the dose approved by Health Canada. All patients in the SELECT-PsA1 study received matching placebo injections or tablets. In this double-dummy design, patients received both the oral study drug (upadacitinib or matching placebo) once daily and the subcutaneous study drug (adalimumab or matching placebo) every other week. Adalimumab injections were administered by medical staff or, after training, self-administered or administered by a designee, including a friend or family member. In both SELECT-PsA1 and SELECT-PsA2, all patients randomized to placebo were switched to upadacitinib 15 mg or 30 mg once daily (1:1 ratio) at week 24. No background non-bDMARD therapy was required for participation in either trial, but patients were permitted to continue their stable background non-bDMARD. Patients taking methotrexate were to also take oral folic acid supplements.

In both trials, starting at week 16, rescue therapy was offered to nonresponders, defined as patients who did not achieve an improvement of at least 20% in both TJC and SJC at both week 12 and week 16. Rescue therapy included addition or dose modification of non-bDMARDs, NSAIDs, acetaminophen, low-potency opioids, or oral corticosteroids. Alternatively, 1 intra-articular, trigger point or tender point, intra-bursa, or intra-tendon-sheath corticosteroid injection was permitted to the corresponding affected location. After week 36, patients were permitted to start or change background PsA medications (i.e., NSAIDs, acetaminophen, low-potency opiates), and non-bDMARDs (concomitant use of up to 2 non-bDMARDs except the combination of methotrexate and leflunomide). Any treatment for psoriasis, except non-bDMARDs, was also permitted to start after week 16; initiation or change in dose of non-bDMARD was permitted at week 36.

Prohibited therapies in both studies included treatment with any bDMARD therapy for PsA or non-bDMARD other than methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or apremilast. The combination of methotrexate with leflunomide was not permitted, nor was the concomitant use of more than 2 non-bDMARDs.

Outcomes

Details of outcome measures are provided in Appendix 4. Only the efficacy outcomes identified in the review protocol included in the multiplicity-controlled analyses (primary and major secondary efficacy outcomes) and those indicated as important outcomes by patient groups are presented in Table 5. In both SELECT-PsA1 and PsA2, the following assessments were performed by an independent and blinded assessor if possible: PASI, BSA, sIGA, TJC and SJC assessments, dactylitis, and enthesitis. In total, 20 end points in 7 categories are discussed in this review and summarized in Table 8.

Table 8: Summary of Outcomes in SELECT-PsA1 and SELECT-PsA2

End point

SELECT-PsA1

SELECT-PsA2

Clinical response in psoriatic arthritis symptoms

Proportion of patients achieving ACR20 at week 12

Primary

Primary

ACR20 response rate at week 12 (noninferiority of UPA vs. ADA)

Key secondary

Not measured

ACR20 response rate at week 12 (superiority of UPA vs. ADA)

Key secondary

Not measured

Proportion of patients achieving MDA at week 24

Key secondary

Key secondary

Modified PsARC response rate

Exploratory

Exploratory

Measure of function and disability

Change from baseline in HAQ-DI at week 12

Key secondary

Key secondary

Change from baseline in HAQ-DI at week 12 (superiority of UPA vs. ADA)

Key secondary

Not measured

Change from baseline in WPAI questionnaire

Exploratory

Exploratory

Measure of PsA symptoms

Change from baseline in patient’s assessment of pain NRS at week 12

Exploratory

Exploratory

Change from baseline in patient’s assessment of pain NRS at week 12 (superiority of UPA vs. ADA)

Key secondary

Not measured

Change from baseline in FACIT-F at week 12

Key secondary

Key secondary

Health-related quality of life

Change from baseline in SF-36 PCS at week 12

Key secondary

Key secondary

Change from baseline in EQ-5D-5L and Visual Analogue Scale score

Exploratory

Exploratory

Measure of skin disease

PASI 75 at week 16 (for patients with ≥ 3% BSA psoriasis at baseline)

Key secondary

Key secondary

Proportion of patents achieving a sIGA of psoriasis of 0 or 1 and at least a 2-point improvement from baseline (sIGA 0/1) at week 16

Key secondary

Key secondary

Change from baseline in SAPS at week 16

Key secondary

Key secondary

Measure of other musculoskeletal disease

Proportion of patients with resolution of enthesitis (LEI = 0) at week 24

Key secondary

Exploratory

Proportion of patients with resolution of dactylitis (LDI = 0) at week 24

Key secondary

Exploratory

Change from baseline in BASDAI

Exploratory

Exploratory

Radiographic changes

Change from baseline in modified psoriatic arthritis SHS at week 24

Key secondary

Not measured

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ADA = adalimumab; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; HAQ-DI = Health Assessment Questionnaire–Disability Index; LDI = Leeds Dactylitis Instrument; LEI = Leeds Enthesitis Index; MDA = Minimal Disease Activity; NRS = Numerical Rating Scale; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PCS = physical component summary; PsARC = Psoriatic Arthritis Response Criteria; SAPS = Self-Assessment of Psoriasis Symptoms; SF-36 = Short Form (36) Health Survey; SHS = Sharp/van der Heijde Score; sIGA = static Investigator Global Assessment; UPA = upadacitinib; WPAI = Work Productivity and Activity Impairment.

Note: Efficacy was tested for upadacitinib vs. placebo unless otherwise specified. Key secondary end points refer to those included in the hierarchical testing of multiplicity-controlled analyses. End points included in this table are not listed in the order in which they were included in the statistical testing hierarchy (see the Statistical Analysis section).

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

American College of Rheumatology Measures

The American College of Rheumatology (ACR) criteria for assessing joint status provide a composite measure of 20%, 50%, or 70% improvement from baseline in both SJCs and TJCs and at least 3 of 5 additional core set disease criteria including: patient global assessment of disease activity, physician global assessment of disease activity, patient’s assessment of pain, patient assessment of physical function (e.g., HAQ-DI score), and acute-phase reactant (e.g., hs-CRP). The ACR20 is generally accepted as an indicator reflecting important difference in response to treatment, while the American College of Rheumatology 50% improvement in rheumatoid arthritis (ACR50) and American College of Rheumatology 70% improvement in rheumatoid arthritis (ACR70) more likely reflect truly important change in the long term management of arthropathy. As an example, if a study reported a 50% ACR20, this means that half of the study patients achieved a minimal 20% improvement in TJCs and SJCs and a 20% improvement in at least 3 of the other 5 criteria. This a general measure of clinical response of peripheral joint disease and does not include assessment of enthesitis, dactylitis, the spine, or the skin. The proportion of patients achieving an ACR20 at week 12 was the primary outcome in both SELECT-PsA1 and SELECT-PsA2 and tested in the multiplicity-controlled analyses. Responses of 50% and 70% at week 12 were secondary end points in SELECT-PsA1 and SELECT-PsA2, but they were not included in the multiplicity-controlled analyses.

In both studies, the sponsor noted that a “joint evaluator” assessed whether a particular joint was “tender or painful.” Total TJC was based on 68 joints (TJC68), and the total SJC was based on 66 joints (SJC66). Aspects related to the patient evaluation (e.g., pain and global assessment) was completed by the patient, while a physician’s global assessment was completed by the physician. Global assessments took into consideration both arthritis and psoriasis activity. The patient and physician’s global assessment of disease activity on the NRS as well as patient’s assessment of pain NRS were measured on a scale of 0 to 10, with higher scores indicating greater disease activity. No specific measures beyond the established allocation concealment described earlier were taken to maintain blinding in the ACR-related outcomes assessments.

Minimal Disease Activity

Minimal disease activity is a composite outcome measure that was developed as a target of treatment for patients with PsA that encompasses different aspects of disease domains. In SELECT-PsA1 and SELECT-PsA2, a patient was classified as a responder, or as achieving MDA when 5 out of the following 7 outcome measures were fulfilled: a TJC68 of no more than 1, SJC66 of no more than 1, PASI less than or equal to 1, BSA psoriasis of 3% or less, patient’s assessment of pain of no more than 1.5 (0 to 10 NRS), patient’s global assessment of disease activity of 2 or less (0 to 10 NRS), HAQ-DI score of up to 0.5, and LEI of no more than 1. Patients who did not meet at least 3 of the 7 criteria were considered nonresponders. The proportion of patients achieving MDA at week 24 was a major secondary end point in both studies and was therefore included in the multiplicity-controlled analyses.

Psoriatic Arthritis Response Criteria

The PsARC is a composite responder index that measures signs and symptoms of PsA assessed by TJC and/or SJC, physician’s global assessment (0 to 5 Likert scale), and patient’s global assessment (0 to 5 Likert scale). A patient was classified as a responder if 2 of 4 measures was achieved, 1 of which is TJC68 or SJC66, and no worsening of any of the measures. In the SELECT studies, the specific components were at least a 30% reduction in TJC68, at least a 30% reduction in SJC66, improvement in patient’s global assessment of disease activity, or improvement in physician’s global assessment of disease activity. In both studies, the PsARC response was modified by using the physician’s global assessment and the patient’s global assessment on a NRS instead of a 5-point Likert scale in the original criteria. The PsARC has been shown to be a responsive and discriminate outcome instrument in RCTs of PsA. The PsARC does not account for psoriasis severity and is only a general assessment of clinical status. The MID for PsARC is unknown. This was an additional outcome in SELECT-PsA1 and SELECT-PsA2 and was not included in the multiplicity-controlled analyses.

Health Assessment Questionnaire–Disability Index

The HAQ-DI was developed to assess physical disability and pain in rheumatoid arthritis and has been used extensively in arthritis RCTs, including PsA trials. Through a self-assessed questionnaire of 8 functional areas (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and errands/chores), patients’ difficulty in performing these activities over the past week is scored from 0 (without any difficulty) to 3 (unable to do). The maximum score for all questions in each category is considered as the score for the respective category, and the overall HAQ-DI is calculated as the mean score from all the categories, with higher scores reflecting greater disability. Mease et al.36 estimated that the MID for the HAQ-DI in PsA patients using anchor-based methods is 0.35, while the MID was estimated to be 0.131 in PsA patients using an anchor-based approach (equal bidirectional magnitudes for improvement and worsening) by Kwok and Pope.37 Discrepancies in the MID estimates may partly be explained by differences in the HAQ-DI score of the patients studied at baseline.38 In Mease et al.,36 patients had a mean HAQ-DI score at baseline of 1.16, corresponding to moderate functional impairment. In contrast, patients in the study by Kwok and Pope had less functional impairment at baseline, with a mean HAQ-DI score of 0.732.37 In the SELECT studies, the HAQ-DI score ranged from 1.10 to 1.23. The MID of 0.35 estimated by Mease et al.36 was used for this review. The SELECT studies also considered the MID to be 0.35. As change from baseline in the HAQ-DI score at week 12 was a key secondary end point in SELECT-PsA1 and SELECT-PsA2, it was included in the multiplicity-controlled analyses. In SELECT-PsA1, this end point was also hierarchically tested for superiority of upadacitinib versus adalimumab.

Work Productivity and Activity Impairment

Work productivity was measured by the WPAI questionnaire for PsA, version 2.0. This is a patient-administered instrument used to measure overall health and specific impacts on productivity at work and outside of work. The WPAI consists of 6 questions to determine employment status, missed work due to PsA, impaired work due to PsA, and daily activity impairment due to PsA. Four main impairment scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), overall percentage of work impairment that combines absenteeism and presenteeism, and percentage of impairment in activities performed outside of work. Higher scores indicate greater impairment, and a lower WPAI score indicates an improvement. It has been suggested that improvements of 20% in presenteeism, 15% in work productivity loss, and 20% in activity impairment represent clinically meaningful improvements in patients with active PsA.39 Absenteeism, presenteeism, and work impairment were measured only in patients who were employed. Change from baseline in the WPAI questionnaire up to week 24 was an additional outcome in both SELECT-PsA1 and SELECT-PsA2 and therefore was not included in the multiplicity-controlled analyses.

Patient’s Assessment of Pain Numerical Rating Scale

The patient’s assessment of pain NRS is 1 of the 5 ACR core set criteria. Pain severity was scored on a 0 to 10 scale, with a score of 0 indicating “no pain” and 10 indicating “worst possible pain.” No reported MID was identified for patients with PsA. In SELECT-PsA1, superiority of upadacitinib versus adalimumab in the change from baseline in the patient’s assessment of pain NRS at week 12 was a key secondary multiplicity-adjusted end point. In PsA2, change from baseline in the patient’s assessment of pain NRS was measured as an individual component of ACR response at week 12, and was not included in the multiplicity-controlled analysis.

FACIT-F

The FACIT-F questionnaire is a 13-item tool that measures an individual's level of fatigue during usual daily activities over the past week. The instrument measures physical fatigue (e.g., “I feel tired”), functional fatigue (e.g., trouble finishing things), emotional fatigue (e.g., frustration), and social consequences of fatigue (e.g., limits social activity). Level of fatigue is measured on a 4-point scale, with 4 indicating “not at all fatigued” and 0 indicating “very much fatigued.” The overall score ranges from 0 to 52, with higher scores indicating less fatigue. An MID for the FACIT-F total score has been estimated as 3.1 points. As change from baseline in the FACIT-F at week 12 was a key secondary end point in SELECT-PsA1 and SELECT-PsA2, it was included in the multiplicity-controlled analyses.

Short Form (36) Health Survey

Version 2 of the SF-36 is a 36-item, generic health status instrument that has been used extensively in clinical trials in many disease areas.9,10 It consists of 8 health sub-domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The sub-domains are aggregated to create 2 component summaries: the PCS and the MCS. The PCS constitutes the domains of physical functioning, role physical, bodily pain, and general health and vitality, and has a normative mean value of 50. The scores for each domain range from 0 to 100, with higher scores indicating better health status or HRQoL. The MID for either the PCS or MCS of the SF-36 for the change from baseline is typically between 2.5 and 5 points.40-42 Leung and colleagues reported MIDs of change scores of 3.74 and 1.77 in PsA patients treated with TNF inhibitors for PCS and MCS, respectively.43 Although the SF-36 was conducted, only the change from baseline in PCS at week 12 was a key secondary end point in SELECT-PsA1 and SELECT-PsA2; it was therefore included in the multiplicity-controlled analyses.

EuroQol 5-Dimensions 5-Levels Questionnaire

The EQ-5D-5L is a generic instrument for HRQoL evaluation. It has been validated in a diverse patient population; however, no studies specifically validating EQ-5D-5L in patients with PsA were identified. It may be applied to a wide range of health conditions and treatments. The 5-level version consists of a 5-dimensional descriptive system and the EuroQol VAS. The descriptive system comprises the following 5 dimensions of health status: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, each with 5 levels. A level 1 response represents “no problems” and level 5 “extreme problems” or “unable to perform.” Results from the EQ-5D-5L descriptive system can be converted into a single index score. A score of 0 represents the health state of “dead” and 1.0 reflects “perfect health.” Negative scores are also possible for those health states that society (not the individual patient) considers to be “worse than dead.” The EuroQol VAS records the respondent’s self-rated health on a vertical line on which the end points are labelled 0 (“the worst health you can imagine”) and 100 (“the best health you can imagine”). The EQ-5D-5L index and VAS scores can be summarized and analyzed as continuous data. In the SELECT-PsA1 and SELECT-PsA2 studies, the UK scoring algorithm was used, with the patient’s preference for the current health state estimated through the index score from published algorithms. The range is between –0.285 and 1, with higher scores indicating better health.9,10 The MID estimates for the index score in a Canadian population have a summarized mean of 0.056 (SD = 0.011).44 The change from baseline in the EQ-5D-5L index value and VAS up to week 24 was an additional outcome in both PsA1 and PsA2 and therefore was not included in the multiplicity-controlled analyses.

Psoriasis Area Severity Index

A widely used instrument in psoriasis trials, the PASI assesses and grades the severity of psoriatic lesions and the patient’s response to treatment. Severity of psoriasis is measured at 4 anatomic sites (head, upper extremities, trunk, and lower extremities) and each is assessed for erythema, induration, and desquamation using a 5-point scale. Scores for each site range from 0 (no symptoms) to 4 (very marketed symptoms). The extent of lesions in a given anatomic site is also ranked from 0 (no involvement) to 6 (90% to 100% involvement). The PASI produces a numeric score ranging from 0 to 72, with the highest score representing complete erythroderma of the most severe degree possible. In general, a PASI score of 3 or less represents mild disease, scores above 3 and up to 15 represent moderate disease, and scores above 15 are considered indicative of severe disease.

A PASI 75 response is the current benchmark for most clinical trials in psoriasis and the criterion for efficacy of new psoriasis treatments approved by the FDA.45 The proportion of patients achieving a PASI 75 response at week 16 (restricted to patients with baseline psoriatic lesions involving ≥ 3% BSA) was a key secondary end point in both SELECT-PsA1 and SELECT-PsA2; it was therefore included in the multiplicity-controlled analyses. At week 24, a 75% reduction in Psoriasis Area Severity Index score (PASI 75), 90% reduction in Psoriasis Area Severity Index score (PASI 90), or 100% reduction in Psoriasis Area Severity Index score (PASI 100) from baseline was an additional outcome and was not included in the multiplicity-controlled analyses.

Static Investigator Global Assessment

The sIGA evaluates the severity of psoriasis. It is a 5-point score ranging from 0 (clear) to 4 (severe), based on the investigator’s assessment of the average elevation, erythema, and scaling of all psoriatic lesions. As a static assessment, the patient’s disease state at the time of assessment is not compared to any of the previous measures. A lower score indicates less-severe psoriasis (i.e., less body coverage).

In both SELECT studies, the proportion of patients achieving an sIGA score of 0 or 1 and an improvement of at least 2 points from baseline at week 16 was a key multiplicity-adjusted secondary end point, and was calculated in patients with baseline sIGA scores of 2 or higher.

Self-Assessment of Psoriasis Symptoms

The SAPS questionnaire contains 11 symptom-focused items. Patients self-assess symptoms of psoriasis including pain, itching, redness, scaling, flaking, bleeding, burning, stinging, tenderness, pain due to skin cracking, and joint pain. Each item is scored from 0 (least severe) to 10 (most severe), with the sum of scores forming a total score that ranges from 0 to 110. No reported MID was identified for patients with PsA. As change from baseline in the SAPS questionnaire at week 16 was a key secondary end point in SELECT-PsA1 and SELECT-PsA2, it was included in the multiplicity-controlled analyses.

Leeds Enthesitis Index

The LEI was developed specifically for PsA diagnoses. It measures enthesitis at 6 sites: lateral epicondyle, left and right; medial femoral condyle, left and right; and Achilles tendon insertion, left and right. Tenderness on examination at each site was assigned a score of 0 (absent) or 1 (present); the results from each site were then added to produce an overall score ranging from 0 to 6. Resolution of enthesitis sites was defined as an LEI of 0. An MID was not identified from the literature. The proportion of patients achieving resolution of enthesitis at week 24 (measured in patients with baseline LEI > 0) was a key secondary outcome in SELECT-PsA1 and was therefore included in the multiplicity-controlled analyses. However, in SELECT-PsA2, this end point was considered additional and was not included in the multiplicity-controlled analyses.

Leeds Dactylitis Index

Presence of dactylitis in all 20 digits was assessed using the LDI. Tenderness and circumference of digits were measured with a dactylometer, with presence of a dactylitic digit defined as at least 1 affected and tender digit with a circumference increase of at least 10% over the reference digit. The reference circumference is either the unaffected contralateral digit or derived from a reference table. A digit score is calculated for each of the 20 digits (hands and feet), with a score of 0 representing an unaffected digit. The sum of scores over all 20 digits forms the LDI. Resolution of dactylitis was defined as an LDI of 0. An MID was not identified from the literature. The proportion of patients achieving resolution of dactylitis at week 24 (measured in patients with a baseline LDI > 0) was a key secondary outcome in SELECT-PsA1 and was therefore included in the multiplicity-controlled analyses. However, in SELECT-PsA2, this end point was considered additional and was not included in the multiplicity-controlled analyses.

Bath Ankylosing Spondylitis Disease Activity Index

The BASDAI contains 6 questions pertaining to the 5 major symptoms (domains) of axial disease activity: fatigue, spinal pain, joint pain and/or swelling, areas of localized tenderness, and morning stiffness. A continuous NRS of 0 to 10 is used to measure these disease activities, with 0 indicating no problem and 10 indicating the worst problem. A BASDAI score from 0 to 10 is then calculated. Scores of 4 or greater suggest suboptimal control of disease. The MID for the BASDAI has been determined as a change of −1.96 on the 10-point BASDAI scale.46 The change in BASDAI from baseline up to week 24 (in patients who had psoriatic spondylitis at baseline) was assessed as an additional efficacy outcome in both SELECT trials. This outcome was not included in the multiplicity-controlled analyses.

Sharp/van der Heijde Score

The Sharp method as modified by van der Heijde for PsA was used to assess and score radiographic outcomes. The SHS allows for the assessment of 2 different aspects of joint damage in PsA: articular erosions and joint space narrowing in the hands and feet. A total SHS score is obtained by adding together scores for erosions and joint space narrowing in both hands and feet.

Erosions were assessed in 20 locations in each hand (graded from 0 to 5), and 6 joints in each foot (graded from 0 to 10). Joint space narrowing was assessed in 20 joints in each hand and in 6 joints in each foot (graded 0 to 4). A score of 0 denoted no erosion or narrowing. The range of scores is 0 to 320 for erosions, and 0 to 208 for joint space narrowing. The total score ranges from 0 to 528. A higher score indicates greater radiographic damage. Radiographic images were assessed and scored centrally by 2 independent reviewers who were blinded to patient details and treatment allocation, with the SHS calculated using the score of the 2 closest reads. An MID for SHS is unknown in patients with PsA. Only SELECT-PsA1 assessed change from baseline in SHS at week 24. As this was a key secondary efficacy outcome in PsA1, it was included in the multiplicity-controlled analyses.

Safety

Adverse events, SAEs, severe adverse events (≥ grade 3), AEs of special interest, and WDAEs were recorded in in SELECT-PsA1 and SELECT-PsA2. Two sets of safety analyses were planned, the first by week 24, and a long-term safety analysis.

Unless otherwise noted, all AEs presented were treatment-emergent. The definition of TEAEs and treatment-emergent deaths were those with an onset on or after the first dose of the study drug but no more than 30 days after the last dose of upadacitinib or placebo (oral and subcutaneous) and no more than 70 days after the last dose of adalimumab. Reported AEs did not necessarily have a causal relationship with treatment. Several AEs of special interest were specified in the protocol: serious infections, opportunistic infections, malignancy, hepatic disorders, gastrointestinal perforations, anemia, neutropenia, lymphopenia, herpes zoster, creatine phosphokinase elevation, renal dysfunction, tuberculosis, MACEs, and thrombotic and embolic events.

Statistical Analysis

An unblinded analysis was conducted by an independent data monitoring committee after all patients completed week 24. A final analysis is planned after all patients have completed the last visit of the study (period 2). In SELECT-PsA1, an interim utility analysis of unblinded efficacy data was also performed by the committee after 600 patients completed week 12.

Power analysis in SELECT-PsA1 indicated that 1,640 patients randomized 2:2:2:1:1 to upadacitinib 15 mg, upadacitinib 30 mg, adalimumab 40 mg, and placebo would provide at least 90% power to detect a 20% difference in ACR20 response rates at week 12 versus placebo, assuming a 30% placebo response rate, a 10% dropout, and a 2-sided significance level of 0.025. This sample size also provided at least 85% power to test the noninferiority of upadacitinib versus adalimumab, assuming 50% ACR20 response rates for adalimumab and upadacitinib, and 30% ACR20 response rates for placebo. At least 90% power was also to be provided for the majority of key secondary end points. In SELECT-PsA2, a sample size of 630 was thought to provide at least 90% power to detect a 20% difference in ACR20 response rates, with an assumption of a 20% response rate in the placebo group, at a 2-sided alpha of 0.025, and accounting for a 10% dropout rate. This sample size also provided at least 90% power for the majority of key secondary end points. It was not clear what the basis was for the assumed ACR20 responses in either intervention or placebo groups. No rationale was provided regarding the assumption for the sample size.

Treatment comparisons of categorical efficacy outcomes (e.g., ACR20, ACR50, and ACR70) were reported as point estimates and 95% CIs using normal approximations for response rates of each randomized treatment group. In both trials, treatment comparisons were made between each upadacitinib dose and the combined placebo group using the Cochran-Mantel-Haenszel test, adjusting for the main stratification factor of current DMARD use (yes/no); P values were also constructed using the Cochran-Mantel-Haenszel test. The primary analyses for all continuous efficacy outcomes (e.g., HAQ-DI scores) at the specified time points included in the multiplicity-adjustment plan were based on the mixed model for repeated measures (MMRM). The model included treatment, visit, treatment-by-visit interaction, and the stratification factor of current DMARD use (yes/no) as fixed factors, and the continuous baseline measurements as covariates. The LS mean and 95% CI for each randomized treatment group, the LS mean treatment difference (with associated 95% CI), and the P value between each upadacitinib dose group and the combined placebo group were provided. In SELECT-PsA1, superiority of upadacitinib versus adalimumab in change from baseline in patient’s assessment of pain NRS and change from baseline in HAQ-DI at week 12, were also tested using the same MMRM model. In SELECT-PsA1, change from baseline in SHS at week 24 was also assessed using the analysis of covariance model with treatment and the stratification factor of current DMARD use (yes/no) as the fixed factors and the corresponding baseline values as the covariates.

For SELECT-PsA1 and SELECT-PsA2, all efficacy analyses were conducted in the full analysis set (FAS) population. For the primary end point measuring the proportion of patients with ACR20 at week 12 and other binary end points, nonresponder imputation (NRI) was used for missing values. For the NRI approach, patients who were missing binary response data at a time point of interest were considered as nonresponders for that visit, and patients who had discontinued the study drug before the time point of interest were defined as nonresponders for all subsequent visits. For MDA at week 24 in both trials, resolution of enthesitis at week 24, and resolution of dactylitis at week 24 in SELECT-PsA1, in addition to the NRI data handling, patients who met the rescue criteria (i.e., those not achieving an improvement of at least 20% in either or both TJC and SJC at both week 12 and week 16) were also treated as nonresponders. In both studies, continuous data were analyzed through an MMRM approach that included observed data at all visits. Data collected after premature discontinuation of the study drug were excluded. The parameter estimations for the mixed model assumed that data were missing at random and used the method of restrictive maximum likelihood. Missing data in the radiographic outcome of SHS in SELECT-PsA1 were based on linear extrapolation, with the missing X-ray at the time point of interest after rescue or premature discontinuation imputed by assuming a linear relationship across visits. As-observed handling of missing data was used for supplementary analysis of binary and continuous end points. In such analyses, all observed data regardless of premature discontinuation of the study drug or use of rescue medication were included, and values for missing evaluations were excluded from the analysis for the particular visit. An additional tipping-point analysis was performed for ACR20 and HAQ-DI using multiple imputations to explore various missing data assumptions, including missing not at random.

In SELECT-PsA1, noninferiority of upadacitinib versus adalimumab was assessed for ACR20 at week 12. This was performed using the Koch 3-arm test statistic to demonstrate that upadacitinib preserves at least 50% of the placebo-subtracted adalimumab effect. That is, noninferiority was claimed if the multiplicity-adjusted lower confidence limit for the ratio of placebo-subtracted upadacitinib ACR20 rate compared to the placebo-subtracted adalimumab ACR20 rate was at least 50%. No clear justification for the noninferiority margin was provided in the Clinical Study Report. The noninferiority margin was changed in Protocol Amendment 2; the previous noninferiority margin of 15% was derived from prior data (e.g., a meta-analysis of placebo-subtracted effect of anti-TNF biologics in ACR20 among patients who had inadequate response to csDMARDs). In SELECT-PsA1, superiority of upadacitinib versus adalimumab was also planned and hierarchically tested for ACR20 at week 12, as well as change from baseline in patient’s assessment of pain NRS and HAQ-DI at week 12.

In SELECT-PsA1, the overall type I error rate of the primary and 14 ranked key secondary end points was strongly controlled using a 2-part, sequential, graphical multiple-testing procedure. The testing used the end-point sequence of the primary end point followed by the ranked key secondary end points in the order outlined in the Outcomes section and began with testing the primary end point using alpha/2 (where alpha = 0.0499) for each dose. For the interim futility analysis, an alpha of 0.0001 was spent, and the final analysis at week 24 database lock was performed at the 0.0499 level. Continued testing followed a pre-specified alpha transfer path that included downstream transfer along the end-point sequence within each dose as well as cross-dose transfer between the low (15 mg) and high (30 mg) upadacitinib doses. A superiority-testing sequence at level alpha was subsequently performed if all previous end points were significant. The ranked key secondary end points compared upadacitinib versus placebo, unless specified (e.g., superiority testing versus adalimumab). Adjusted P values were provided for the primary and ranked key secondary end points based on the testing procedure.

In SELECT-PsA2, the overall type I error rate of the primary and 7 ranked key secondary end points was also strongly controlled using a graphical multiple-testing procedure. The testing used the end-point sequence of primary end point followed by the ranked key secondary end points in the order outlined in the Outcomes section, and began with testing the primary end point using an alpha of 0.025 for each dose. Continued testing followed a pre-specified alpha transfer path that included downstream transfer along the end-point sequence within each dose as well as cross-dose transfer between the low (15 mg) and high (30 mg) upadacitinib doses. Sequential noninferiority or superiority testing was not performed in SELECT-PsA2. Adjusted P values were provided for the primary and ranked key secondary end points based on the testing procedure.

In both studies, subgroup analysis was planned for the primary efficacy outcome for age, sex, body mass index, race, geographic region, duration of PsA diagnosis, baseline hs-CRP, and current use of non-bDMARDs. SELECT-PsA1 also included a subgroup factor for number of prior non-bDMARDs (≤ 1, > 1) whereas SELECT-PsA2 included a subgroup factor for the number of prior failed bDMARDs ( = 1, > 1). Subgroup analyses were not adjusted for multiple testing. The CADTH systematic review protocol included subgroups by PsA disease severity at baseline, previous exposure to bDMARDs (treatment-naive versus -experienced), and concomitant treatment with a non-bDMARD. Inclusion criteria for SELECT-PsA1 and SELECT-PsA2 allowed examination of treatment effects separately for biologic-naive (SELECT-PsA1) and biologic-experienced (SELECT-PsA2). Neither study provided subgroup data based on disease severity at baseline.

Analysis Populations

The analysis populations were defined in the same way in both studies.

The FAS consisted of all randomized patients who received at least 1 dose of study medication. The FAS was used for all efficacy and baseline analyses.

The per-protocol set (PPS) consisted of patients in the FAS who did not have any major protocol deviations that could have had an impact on the primary efficacy end point up to week 12 in period 1 of the study. The PPS was used in the additional analysis of the primary efficacy end point to evaluate the impact of major protocol deviations.

The safety analysis set consisted of all patients who received at least 1 dose of study drug. Patients were analyzed “as treated,” regardless of the treatment group to which they were randomized. Specifically, patients were analyzed according to the treatment received during the majority of their drug exposure time during the analysis period.

Results

Patient Disposition

Patient disposition is summarized in Table 9. In SELECT-PsA1, a total of 1,282 patients were randomized to upadacitinib 15 mg, adalimumab 40 mg, or placebo at baseline. In SELECT-PsA2, a total of 423 patients were randomized to upadacitinib 15 mg or placebo at baseline.

Overall, the number of premature discontinuations at week 24 was higher in the placebo groups (10.4% and 20.3% in SELECT-PsA1 and SELECT-PsA2, respectively) than in the upadacitinib 15 mg group (7.2% and 12.3% in SELECT-PsA1 and SELECT-PsA2, respectively), and adalimumab 40 mg every other week (8.4%). Adverse events and patient decisions to withdraw were reported most frequently as the primary reason to discontinue treatment, although lack of efficacy was the most frequent reason in the SELECT-PsA2 placebo group.

Table 9: Patient Disposition up to Week 24

Disposition

SELECT-PsA1

SELECT-PsA2

PBO

ADA 40 mg

UPA 15 mg

PBO

UPA 15 mg

Screened, Na

2,480

751

Randomized, N

423

429

430

212

211

Completed week 12 on study drug, N (%)

399 (94.3)

410 (95.6)

412 (95.8)

183 (86.3)

202 (95.7)

Discontinued study drug by week 12, N (%)

24 (5.7)

19 (4.4)

18 (4.2)

29 (13.7)

9 (4.3)

Primary reason for discontinuation, N (%)

  Adverse event

9 (2.1)

8 (1.9)

5 (1.2)

6 (2.8)

4 (1.9)

  Withdrawal by patient

9 (2.1)

7 (1.6)

7 (1.6)

12 (5.7)

0

  Lost to follow-up

2 (0.5)

1 (0.2)

4 (0.9)

4 (1.9)

3 (1.4)

  Lack of efficacy

1 (0.2)

2 (0.5)

0

7 (3.3)

0

  Other

3 (0.7)

1 (0.2)

2 (0.5)

0

2 (0.9)

Completed week 24 on study drug, N (%)

377 (89.1)

388 (90.4)

395 (91.9)

169 (79.7)

185 (87.7)

Temporary drug interruption

2 (0.5)

4 (0.9)

2 (0.5)

NA

NA

Discontinued study drug by week 24, N (%)

44 (10.4)

36 (8.4)

31 (7.2)

43 (20.3)

26 (12.3)

Primary reason for discontinuation, N (%)

  Adverse event

11 (2.6)

18 (4.2)

10 (2.3)

9 (4.2)

15 (7.1)

  Withdrawal by patient

19 (4.5)

10 (2.3)

10 (2.3)

13 (6.1)

0

  Lost to follow-up

3 (0.7)

3 (0.7)

5 (1.2)

5 (2.4)

4 (1.9)

  Lack of efficacy

7 (1.7)

3 (0.7)

1 (0.2)

14 (6.6)

5 (2.4)

  Other

4 (0.9)

2 (0.5)

5 (1.2)

2 (0.9)

2 (0.9)

Study discontinuation by week 24

39 (9.2)

24 (5.6)

21 (4.9)

38 (17.9)

19 (9.0)

FAS, N

423

429

429

212

211

PP, N

413

424

402

203

192

Safety, N

423

429

429

212

211

ADA = adalimumab; FAS = full analysis set; NA = not applicable; PBO = placebo; PP = per protocol; UPA = upadacitinib.

aIn SELECT-PsA1, of 2,480 patients screened, 774 patients were ineligible for enrolment; in SELECT-PsA2, of 751 patients screened, 109 patients were ineligible for enrolment. The upadacitinib 30 mg oral once daily treatment group is not shown (n = 423 in SELECT-PsA1; n = 219 in SELECT-PsA2).

Source: SELECT-PsA1 Clinical Study Report,9 SELECT-PsA2 Clinical Study Report,10 and sponsor’s response to additional information request.34

Exposure to Study Treatments

In SELECT-PsA1, the mean duration of exposure during the double-blind treatment period (up to week 24) was similar in all groups: 161.7 days (SD = 28.57) for upadacitinib, 161.4 days (SD = 28.24) for adalimumab, and 158.5 days (SD = 32.22) for placebo. Treatment compliance was high (mean > 98%) across all treatment groups. In SELECT-PsA2, the mean duration of exposure during the double-blind treatment period (week 24) was longer in the upadacitinib 15 mg daily group (159.1; SD = 29.10) compared to the placebo group (146.7; SD = 48.24). Treatment compliance was also high (mean > 98%) in both treatment groups. Overall, a higher proportion of patients in the SELECT-PsA1 trial received concomitant treatment with a non-bDMARD compared to patients enrolled in SELECT-PsA2.

Table 10: Treatment Exposure and Concomitant Therapies up to Week 24

Exposure

SELECT-PsA1

SELECT-PsA2

PBO

(n = 423)

ADA 40 mg

(n = 429)

UPA 15 mg

(n = 429)

PBO

(n = 212)

UPA 15 mg

(n = 211)

Extent of exposure to study drug, SAS

Mean days (SD)

158.5 (32.22)

161.4 (28.24)

161.7 (28.57)

146.7 (48.24)

159.1 (29.10)

Treatment compliance, FAS

Mean % (SD)

98.8 (6.16)

98.3 (5.36)

99.4 (13.57)a

116.7 (234.29)

98.7 (7.97)

Concomitant treatment, FAS

Any non-biologic DMARDs, n (%)

354 (83.7)

348 (81.1)

355 (82.8)

113 (53.3)

101 (47.9)

Methotrexate, n (%)

296 (70.0)

286 (66.7)

299 (69.7)

92 (43.4)

82 (38.9)

Any systemic corticosteroid, n (%)

94 (22.2)

82 (19.1)

84 (19.6)

42 (19.8)

33 (15.6)

Any NSAID, n (%)

290 (68.6)

286 (66.7)

277 (64.6)

130 (61.3)

127 (60.2)

ADA = adalimumab; DMARD = disease-modifying antirheumatic drug; FAS = full analysis set; NSAID = nonsteroidal anti-inflammatory drug; PBO = placebo; SAS = safety analysis set; SD = standard deviation; UPA = upadacitinib.

aThis analysis excludes 2 outliers that resulted in an artificially inflated compliance rate. The original analysis included 2 outlier patients who had discontinued the study drug but did not return any tablets, resulting in a compliance of 3,500% and 1,750% and a mean compliance exceeding 100% (103.3%; SD = 80.83%).

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Efficacy

Numerous end points were measured at various time points across both SELECT studies. In this review, a total of 20 end points were presented from PsA1, and 15 end points were presented from PsA2. Only the efficacy outcomes identified in the review protocol (Table 5) and those indicated as important by patient groups are reported below. Data tables are only presented for end points that were included in the multiplicity-controlled analyses (primary and major secondary efficacy outcomes); data tables for end points that were not part of the statistical testing hierarchy are presented in Appendix 3, as indicated in the respective sections. In the data tables, P values are presented only for end points that were part of the multiplicity-adjusted testing hierarchy; P values are not reported for end points that fell below failure of the hierarchical analysis. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

In the multiplicity-controlled analyses of SELECT-PsA1, statistically significant differences for the comparisons between upadacitinib 15 mg once daily and placebo were observed for the primary end point of ACR20 at week 12 and most key secondary end points. Upadacitinib 15 mg once daily did not demonstrate statistically significant superiority over adalimumab in ACR20 at week 12. As such, statistically significant differences in the key secondary end points lower in the testing hierarchy were not tested because of the multiplicity control strategy. The affected end points were the proportion of patients achieving resolution of dactylitis at week 24 (versus placebo), change from baseline in patient’s assessment of pain NRS at week 12 (versus adalimumab), change from baseline in HAQ-DI at week 12 (versus adalimumab), and change from baseline in SAPS at week 16 (versus placebo).

In the multiplicity-controlled analyses of SELECT-PsA2, statistically significant differences for the comparisons between upadacitinib 15 mg and placebo were observed for the primary end point of ACR20 at week 12 and all major secondary end points.

Clinical Responses in Psoriatic Arthritis Symptoms
ACR Responses of 20%, 50%, and 70%

The proportion of patients achieving ACR20 at week 12 was the primary end point in both SELECT-PsA1 and SELECT-PsA2. In SELECT-PsA1, a statistically significantly greater proportion of bDMARD-naive patients in the upadacitinib treatment group achieved ACR20 at week 12 compared with placebo (70.6% for upadacitinib 15 mg versus 36.2% for placebo; P < 0.0001). In SELECT-PsA2, a statistically significantly greater proportion of bDMARD-experienced patients in the upadacitinib treatment group achieved an ACR20 at week 12 compared with placebo (56.9% for upadacitinib 15 mg daily versus 24.1% for placebo; P < 0.0001) (Table 11).

Supplemental analyses using as-observed handling of missing data on the FAS and NRI on the PPS were consistent with the primary analysis. Subgroup analysis by current use of non-bDMARDs, number of prior non-bDMARDs for SELECT-PsA1, and number of failed bDMARDs for SELECT-PsA2 were also consistent with the primary analysis. However, these analyses were not included in the hierarchical statistical analysis approach and should be considered inconclusive because of the potential for inflated type I error.

In SELECT-PsA1, the proportion of patients achieving an ACR20 at week 12 with upadacitinib treatment compared to adalimumab was tested for noninferiority and superiority as key secondary end points. A greater proportion of patients in the upadacitinib treatment group achieved an ACR20 response at week 12 compared with adalimumab (70.6% for upadacitinib 15 mg once daily versus 65.0% for adalimumab 40 mg every other week; between-group difference of 5.6%; 95% CI, −0.6 to 11.8). In the noninferiority analysis, upadacitinib 15 mg daily was noninferior to adalimumab 40 mg every other week. The percentages of adalimumab effect preservation, as calculated by (upadacitinib − placebo)/(adalimumab − placebo), was 119.4% (95% CI, 98.0 to 147.9); the lower bound of the 95% CI exceeded the pre-specified noninferiority ratio of at least 50% of the placebo-subtracted adalimumab effect. The analysis of the PPS showed consistent results for both response-rate difference and adalimumab effect preservation. In the subsequent testing of superiority, upadacitinib 15 mg once daily was not found to be superior to adalimumab 40 mg every other week as it did not meet statistical significance for superiority.

In both SELECT-PsA1 and PsA2, additional exploratory end points showed that, numerically, a greater proportion of patients treated with upadacitinib achieved an ACR50 or ACR70 at week 12 compared to patients who were treated with placebo. In PsA1, the response rates were numerically similar between upadacitinib and adalimumab treatment groups. Furthermore, ACR responses of 20%, 50%, and 70% at week 24 were maintained, with a numerically higher proportion of patients treated with upadacitinib 15 mg achieving a response compared to patients who received placebo (PsA1 and PsA2) or adalimumab (PsA1). As these end points were not part of the multiplicity-controlled analyses, no statistical comparisons can be made.

According to the clinical expert consulted for this review, the between-group differences in ACR20 in the FAS population in SELECT-PsA1 and PsA2 are considered clinically important.

Table 11: Clinical Response (ACR20, ACR50, and ACR70) at Week 12 or Week 24

Treatment group

Total N

Responders,

n (%)

Response rate %

(95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

Primary end point

ACR20 response rate at week 12 (NRI, FAS)

SELECT-PsA1

Placebo

423

153 (36.2)

36.2 (31.6 to 40.7)

34.5 (28.2 to 40.7) UPA vs. placebo

< 0.0001

ADA 40 mg e.o.w.

429

279 (65.0)

65.0 (60.5 to 69.5)

UPA 15 mg q.d.

429

303 (70.6)

70.6 (66.3 to 74.9)

SELECT-PsA2

Placebo

212

51 (24.1)

24.1 (18.3 to 29.8)

32.8 (24.0 to 41.6)

< 0.0001

UPA 15 mg q.d.

211

120 (56.9)

56.9 (50.2 to 63.6)

Key secondary end points

ACR20 response rate at week 12 – noninferiority of UPA vs. ADA; superiority of UPA vs. ADA

SELECT-PsA1 (NRI, FAS)

Placebo

423

153 (36.2)

36.2 (31.6 to 40.7)

5.6 (−0.6 to 11.8) noninferiority, UPA vs. ADAd

0.0004

ADA 40 mg e.o.w.

429

279 (65.0)

65.0 (60.5 to 69.5)

UPA 15 mg q.d.

429

303 (70.6)

70.6 (66.3 to 74.9)

SELECT-PsA1 (NRI, PPS)

Placebo

413

150 (36.3)

36.3 (31.7 to 41.0)

4.8 (−1.5 to 11.2) noninferiority, UPA vs. ADAd

NAe

ADA 40 mg e.o.w.

424

279 (65.8)

65.8 (61.3 to 70.3)

UPA 15 mg q.d.

402

284 (70.6)

70.6 (66.2 to 75.1)

SELECT-PsA1 (NRI, FAS)

Placebo

423

153 (36.2)

36.2 (31.6 to 40.7)

5.6 (−0.6 to 11.8) superiority, UPA vs. ADA

0.0815

ADA 40 mg e.o.w.

429

279 (65.0)

65.0 (60.5 to 69.5)

UPA 15 mg q.d.

429

303 (70.6)

70.6 (66.3 to 74.9)

ACR50 response rate at week 12 (NRI, FAS)

SELECT-PsA1

Placebo

423

56 (13.2)

13.2 (10.0 to 16.5)

24.3 (18.7 to 29.9) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

429

161 (37.5)

37.5 (32.9 to 42.1)

0.0 (−6.5 to 6.5) UPA vs. ADA

UPA 15 mg q.d.

429

161 (37.5)

37.5 (32.9 to 42.1)

Reference

SELECT-PsA2

Placebo

212

10 (4.7)

4.7 (1.9 to 7.6)

27.0 (20.1 to 33.9)

NAe

UPA 15 mg q.d

211

67 (31.8)

31.8 (25.5 to 38.0)

ACR70 response rate at week 12 (NRI, FAS)

SELECT-PsA1

Placebo

423

10 (2.4)

2.4 (0.9 to 3.8)

13.3 (9.5 to 17.0) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

429

59 (13.8)

13.8 (10.5 to 17.0)

1.9 (−2.9 to 6.6) UPA vs. ADA

UPA 15 mg q.d.

429

67 (15.6)

15.6 (12.2 to 19.1)

Reference

SELECT-PsA2

Placebo

212

1 (0.5)

0.5 (0.0 to 1.4)

8.1 (4.2 to 11.9)

NAe

UPA 15 mg q.d.

211

18 (8.5)

8.5 (4.8 to 12.3)

ACR20 response rate at week 24 (NRI, FAS)

SELECT-PsA1

Placebo

423

191 (45.2)

45.2 (40.4 to 49.9)

28.3 (22.0 to 34.6) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

429

288 (67.1)

67.1 (62.7 to 71.6)

6.3 (0.2 to 12.4) UPA vs. ADA

UPA 15 mg q.d.

429

315 (73.4)

73.4 (69.2 to 77.6)

Reference

SELECT-PsA2

Placebo

212

43 (20.3)

20.3 (14.9 to 25.7)

39.0 (30.4 to 47.5)

NAe

UPA 15 mg q.d.

211

125 (59.2)

59.2 (52.6 to 65.9)

ACR50 response rate at week 24 (NRI, FAS)

SELECT-PsA1

Placebo

423

80 (18.9)

18.9 (15.2 to 22.6)

33.5 (27.5 to 39.6) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

429

190 (44.3)

44.3 (39.6 to 49.0)

8.2 (1.5 to 14.8) UPA vs. ADA

UPA 15 mg q.d.

429

225 (52.4)

52.4 (47.7 to 57.2)

Reference

SELECT-PsA2

Placebo

212

20 (9.4)

9.4 (5.5 to 13.4)

29.0 (21.3 to 36.6)

NAe

UPA 15 mg q.d.

211

81 (38.4)

38.4 (31.8, 45.0)

ACR70 response rate at week 24 (NRI, FAS)

SELECT-PsA1

Placebo

423

22 (5.2)

5.2 (3.1 to 7.3)

23.5 (18.7 to 28.2) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

429

97 (22.6)

22.6 (18.7 to 26.6)

6.1 (0.2 to 11.9) UPA vs. ADA

UPA 15 mg q.d.

429

123 (28.7)

28.7 (24.4 to 33.0)

Reference

SELECT-PsA2

Placebo

212

2 (0.9)

0.9 (0.0 to 2.2)

18.5 (13.0 to 24.0)

NAe

UPA 15 mg q.d.

211

41 (19.4)

19.4 (14.1 to 24.8)

Subgroup analyses: ACR20 response rate at week 12 (NRI, FAS)

SELECT-PsA1, Current use of non-biologic DMARD

Yes

Placebo

347

130 (37.5)

37.5 (32.4 to 42.6)

34.8 (27.9 to 41.7) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

347

223 (64.3)

64.3 (59.2 to 69.3)

UPA 15 mg q.d.

353

255 (72.2)

72.2 (67.6 to 76.9)

No

Placebo

76

23 (30.3)

30.3 (19.9 to 40.6)

32.9 (17.9 to 47.9) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

82

56 (68.3)

68.3 (58.2 to 78.4)

UPA 15 mg q.d.

76

48 (63.2)

63.2 (52.3 to 74.0)

SELECT-PsA2, current use of non-biologic DMARD

Yes

Placebo

100

27 (27.0)

27.0 (18.3 to 35.7)

31.2 (18.1 to 44.2)

NAe

UPA 15 mg q.d.

98

57 (58.2)

58.2 (48.4 to 67.9)

No

Placebo

112

24 (21.4)

21.4 (13.8 to 29.0)

34.3 (22.4 to 46.2)

NAe

UPA 15 mg q.d.

113

63 (55.8)

55.8 (46.6 to 64.9)

SELECT-PsA1, number of prior non-biologic DMARDs

≤ 1

Placebo

274

99 (36.1)

36.1 (30.4 to 41.8)

34.8 (27.0 to 42.6) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

288

184 (63.9)

63.9 (58.3 to 69.4)

UPA 15 mg q.d.

275

195 (70.9)

70.9 (65.5 to 76.3)

1

Placebo

149

54 (36.2)

36.2 (28.5 to 44.0)

33.9 (23.3 to 44.5) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

141

95 (67.4)

67.4 (59.6 to 75.1)

UPA 15 mg q.d.

154

108 (70.1)

70.1 (62.9 to 77.4)

SELECT-PsA2, number of prior failed biologic DMARDs

1

Placebo

135

32 (23.7)

23.7 (16.5 to 30.9)

37.4 (26.3 to 48.5)

NAe

UPA 15 mg q.d.

126

77 (61.1)

61.1 (52.6 to 69.6)

1

Placebo

59

12 (20.3)

20.3 (10.1 to 30.6)

24.6 (9.0 to 40.2)

NAe

UPA 15 mg q.d.

69

31 (44.9)

44.9 (33.2 to 56.7)

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; ADA = adalimumab; CI = confidence interval; DMARD = disease-modifying antirheumatic drug; e.o.w. = every other week; FAS = full analysis set; NA = not applicable; NRI = nonresponder imputation; PPS = per-protocol set; q.d. = every day; UPA = upadacitinib; vs. = versus .

a95% CIs for response rate were calculated based on normal approximation to the binominal distribution.

b95% CIs for response rate difference were calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusted for the main stratification factor of current DMARD use (yes/no). In PsA1, the P value was statistically significant at the 0.025 level for ACR20 (UPA vs. placebo; and noninferiority of UPA vs. ADA) and the P value was significant at the 0.05 level for ACR20, superiority of UPA vs. ADA. In PsA2, the P value was significant at 0.025 for ACR20 (UPA vs. placebo).

dFAS effect preservation ratio = 119.381 (95% CI, 97.987 to 147.942); 3-arm noninferiority z statistic = 7.301. PPS effect preservation ratio = 116.433 (95% CI, 95.409 to 144.051); 3-arm noninferiority z statistic = 6.975. Noninferiority test of UPA vs. ADA was based on 3-arm noninferiority testing aiming for UPA preserving at least 50% of the placebo-subtracted ADA effect. The percent of ADA effect preservation is the point estimate of 3-arm noninferiority analysis, which is calculated by (UPA − PBO)/(ADA − PBO) × 100. The confidence interval of the ratio is calculated using Fieller’s method.

eThe P value is not presented, as the end point was not part of the multiplicity-adjusted testing hierarchy and therefore was not controlled for type I error rate.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Minimal Disease Activity

In both SELECT-PsA1 and SELECT-PsA2, a responder or MDA achievement was met when 5 out of 7 outcome measures (involving TJC68, SJC66, PASI, or BSA psoriasis, patient’s assessment of pain, patient’s global assessment of disease activity, HAQ-DI, and LEI) were fulfilled. In SELECT-PsA1, a statistically significantly higher proportion of patients in the upadacitinib treatment group achieved MDA at week 24 compared with placebo: 36.6% for upadacitinib 15 mg and 12.3% for placebo (between-group difference of 24.3%; 95% CI, 18.8 to 29.8; P = 0.0004). Similarly, in SELECT-PsA2 at week 24, a statistically significantly higher proportion of patients in the upadacitinib treatment groups achieved an MDA compared with placebo: 25.1% for upadacitinib 15 mg and 2.8% for placebo (between-group difference of 22.3%; 95% CI, 16.0 to 28.6; P < 0.0001) (Table 12).

Table 12: Proportion of Patients Achieving Minimal Disease Activity at Week 24

Treatment group

Total N

Responders, n (%)

Response rate

(95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

Minimal disease activity at week 24 (NRI,d FAS)

SELECT-PsA1

Placebo

423

52 (12.3)

12.3 (9.2 to 15.4)

24.3 (18.8 to 29.8) UPA vs. placebo

0.0004

ADA 40 mg e.o.w.

429

143 (33.3)

33.3 (28.9 to 37.8)

UPA 15 mg q.d.

429

157 (36.6)

36.6 (32.0 to 41.2)

SELECT-PsA2

Placebo

212

6 (2.8)

2.8 (0.6 to 5.1)

22.3 (16.0 to 28.6)

< 0.0001

UPA 15 mg q.d.

211

53 (25.1)

25.1 (19.3 to 31.0)

ADA = adalimumab; CI = confidence interval; e.o.w = every other week; FAS = full analysis set; NRI = nonresponder Imputation; q.d. = every day; UPA = upadacitinib; vs. = versus

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response-rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). The P value was statistically significant at the 0.025 level for SELECT-PsA1 and the 0.0125 level for SELECT-PsA2.

dNonresponder imputation with additional rescue handling was used, with patients rescued at week 16 imputed as nonresponders.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Modified Psoriatic Arthritis Response Criteria

In SELECT-PsA1, a higher proportion of patients treated with upadacitinib achieved a modified PsARC response at week 24 compared to patients randomized to adalimumab or placebo: 83.7% for upadacitinib 15 mg, 76.6% for adalimumab 40 mg, and 59.3% for placebo (Appendix 3,Table 48). Similarly, in SELECT-PsA2, a higher proportion of patients treated with upadacitinib 15 mg achieved a modified PsARC response at week 24 compared with placebo: 68.2% for upadacitinib 15 mg and 36.3% for placebo. This end point was not part of the multiplicity-controlled statistical analyses.

Measure of Function and Disability
Health Assessment Questionnaire–Disability Index

In SELECT-PsA1, a statistically significantly greater reduction from baseline in the HAQ-DI score was achieved in biologic-naive patients in the upadacitinib treatment groups compared with the placebo group at week 12 (Table 13). The differences in change from baseline between upadacitinib 15 mg and placebo was −0.28 (95% CI, −0.35 to −0.22; P < 0.0001). Similarly, in SELECT-PsA2, a statistically significantly greater reduction from baseline in the HAQ-DI score was achieved in bDMARD-experienced patients in the upadacitinib treatment groups compared with placebo at week 12. The differences in change from baseline between upadacitinib 15 mg and placebo was −0.21 (95% CI, −0.30 to −0.12; P < 0.0001). While in both studies, the between-group differences comparing upadacitinib and placebo in the improvement of the HAQ-DI score did not exceed the MID for the HAQ-DI (estimated in the literature at 0.35), the proportions of patients in the SELECT-PsA1 study who achieved a clinically meaningful improvement in HAQ-DI at week 12 were 33.4%, 47.2%, and 57.9% in the placebo, adalimumab 40 mg, and upadacitinib 15 mg treatment groups, respectively. In SELECT-PsA2, the proportions of patients who achieved a clinically meaningful improvement in HAQ-DI at week 12 were 27.2% and 44.6% in the placebo and upadacitinib 15 mg treatment groups, respectively. The clinical expert consulted for this review indicated that the between-group differences in the change from baseline in HAQ-DI were clinically relevant.

Table 13: Change From Baseline in Health Assessment Questionnaire–Disability Index at Week 12

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)

P valuea

HAQ-DI at week 12 (MMRM,b FAS)

SELECT-PsA1

Placebo

392

1.11

0.98

−0.14 (−0.18 to −0.09)

−0.28 (−0.35 to −0.22) UPA vs. placebo

< 0.0001

ADA 40 mg e.o.w.

406

1.11

0.78

−0.34 (−0.38 to −0.29)

−0.08 (−0.15 to −0.01) superiority, UPA vs. ADA

NAc

UPA 15 mg q.d.

404

1.15

0.72

−0.42 (−0.47 to −0.37)

Reference

SELECT-PsA2

Placebo

180

1.23

1.12

−0.10 (−0.16 to −0.03)

−0.21 (−0.30 to −0.12)

< 0.0001

UPA 15 mg q.d.

199

1.08

0.79

−0.30 (−0.37 to −0.24)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; HAQ-DI = Health Assessment Questionnaire–Disability Index; LS = least squares; MMRM = mixed model for repeated measures; NA = not applicable; q.d. = every day; UPA = upadacitinib; vs. = versus .

aStatistically significant at the 0.025 level.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors, and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 12 before premature discontinuation of the study drug.

cIn SELECT-PsA1, testing for superiority in the change from baseline in HAQ-DI at week 12 was ranked below the point at which the hierarchical analysis failed (i.e., after testing had stopped due to failure to show superiority of UPA 15 mg vs. ADA); the P value is therefore not presented in this table.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Work Productivity

In SELECT-PsA1 and PsA2, numerically greater reductions in work or activity impairment due to disease as measured by the WPAI questionnaire were observed for the upadacitinib group compared with placebo or adalimumab (in SELECT-PsA1) at week 24 (Appendix 3, Table 49). The between-group differences in change from baseline with upadacitinib compared to placebo or adalimumab did not exceed the estimated MID threshold of an improvement of at least 20% for presenteeism and at least 20% for activity impairment. Not all randomized patients participated in this evaluation; absenteeism, presenteeism, and work impairment were measured only in patients who were employed. For these 3 scores, the number of patients evaluated in each treatment group ranged from 42% to 48% in SELECT-PsA1 and 31% to 44% in SELECT-PsA2. More patients were included in the assessment of activity impairment (87% to 90% of patients in each SELECT-PsA1 treatment group; 79% to 87% of patients in each SELECT-PsA2 treatment group). Also, without a confirmed MID for the WPAI instrument, it remains unclear whether differences were clinically meaningful. This was an exploratory variable in both studies and was not included in the multiplicity-controlled statistical analyses.

Measurement of Psoriatic Arthritis Symptoms
Pain

In SELECT-PsA1 and SELECT-PsA2, the mean change in patient’s assessment of pain NRS scores decreased (improved) from baseline to week 12 for all treatment arms (Table 14), and the LS mean reduction in score was the same for upadacitinib and adalimumab in SELECT-PsA1. Specifically, the between-group comparison favoured upadacitinib numerically compared to placebo in both studies, with an LS mean difference of −1.3 (95% CI, −1.6 to −1.0) in SELECT-PsA1 and −1.4 (95% CI, −1.9 to −1.0) in SELECT-PsA2. However, neither treatment was favoured when upadacitinib was compared to adalimumab in SELECT-PsA1 (LS mean difference of 0.0; 95% CI, −0.3 to 0.3). In both trials, the comparison between upadacitinib and placebo was not included in the hierarchical statistical analysis. In SELECT-PsA1, the end point exploring comparisons of upadacitinib and adalimumab was ranked after the point at which the hierarchical analysis failed and was stopped, and no statistical comparisons can be made. An MID was not identified for patients with PsA.

Table 14: Change From Baseline in Patient’s Assessment of Pain at Week 12

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)

P value

Pain NRS at week 12 (MMRM, FAS)

SELECT-PsA1a

Placebo

392

6.1

5.1

−0.9 (−1.2 to −0.7)

−1.3 (−1.6 to −1.0) UPA vs. placebo

NAb

ADA 40 mg e.o.w.

406

5.9

3.6

−2.3 (−2.5 to −2.1)

0.0 (−0.3 to 0.3) superiority, UPA vs. ADA

NAc

UPA 15 mg q.d.

404

6.2

3.8

−2.3 (−2.5 to −2.0)

Reference

SELECT-PsA2d

Placebo

180

6.6

6.0

−0.5 (−0.8 to −0.2)

−1.4 (−1.9 to −1.0)

NAd

UPA 15 mg q.d.

199

6.3

4.4

−1.9 (−2.2 to −1.6)

ADA = adalimumab; CI = confidence interval; e.o.w = every other week; FAS = full analysis set; LS = least squares; MMRM = mixed model for repeated measures; NA = not applicable; NRS = numerical rating scale; q.d. = every day; UPA = upadacitinib; vs. = versus .

aWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 12 before premature discontinuation of the study drug.

bIn SELECT-PsA1 and SELECT-PsA2, patient’s assessment of pain NRS (comparing UPA vs. placebo) was collected as a component of American College of Rheumatology response and was not included in the hierarchical statistical analysis; the P value is therefore not presented.

cIn SELECT-PsA1, change from baseline in patient’s assessment of pain at week 12 (comparing UPA vs. ADA) was ranked below the points at which the hierarchical analysis failed (i.e., after testing had stopped due to failure to show the superiority of UPA 15 mg vs. ADA); the P value is not presented in this table.

dWithin-group LS mean and 95% CI, and between-group LS mean, 95% CI and P value were based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and prior biologic disease-modifying antirheumatic drug use as fixed factors and the baseline value as covariate.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Fatigue

In SELECT-PsA1, a statistically significantly greater improvement from baseline in the FACIT-F score was seen in biologic-naive patients in the upadacitinib treatment groups compared with placebo at week 12 (Table 15). The differences in change from baseline between upadacitinib 15 mg and placebo was 3.5 (95% CI, 2.4 to 4.7; P = 0.0004). Similarly, in SELECT-PsA2, a statistically significantly greater improvement from baseline in the FACIT-F score was seen in bDMARD-experienced patients in the upadacitinib treatment groups compared with placebo at week 12. The differences in change from baseline between upadacitinib 15 mg and placebo was 3.7 (95% CI, 2.0 to 5.4; P < 0.0001). The between-group differences in the improvement in FACIT-F score at week 12 exceeded the estimated MID (3.1 points) in both studies.

Table 15: Change From Baseline in Functional Assessment of Chronic Illness Therapy — Fatigue at Week 12

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference

(95% CI)

P valuea

FACIT-F at week 12 (MMRM,b FAS)

SELECT-PsA1

Placebo

394

30.3

32.8

2.8 (1.9 to 3.7)

3.5 (2.4 to 4.7) UPA vs. placebo

0.0004

ADA 40 mg e.o.w.

410

29.8

35.3

5.7 (4.8 to 6.6)

UPA 15 mg q.d.

404

29.0

35.5

6.3 (5.4 to 7.2)

SELECT-PsA2

Placebo

184

26.4

28.1

1.3 (0.1 to 2.5)

3.7 (2.0 to 5.4)

< 0.0001

UPA 15 mg q.d.

201

27.9

32.8

5.0 (3.8 to 6.1)

ADA = adalimumab; CI = confidence interval; e.o.w = every other week; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; FAS = full analysis set; LS = least squares; MMRM = mixed model for repeated measures; q.d. = every day; UPA = upadacitinib; vs. = versus .

aStatistically significant at the 0.0125 level.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 12 before premature discontinuation of study drug.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Health-Related Quality of Life
Short Form (36) Health Survey

In SELECT-PsA1 at week 12, patients in the upadacitinib group reported higher PCS scores compared with placebo on the SF-36 (Table 16). The LS mean difference for the change in scores from baseline was 4.67 for upadacitinib 15 mg versus placebo (95% CI, 3.67 to 5.67; P = 0.0004). Similarly, in SELECT-PsA2 at week 12, patients in the upadacitinib treatment reported higher PCS scores compared with placebo on the SF-36. The LS mean difference was 3.52 for upadacitinib 15 mg versus placebo (95% CI, 2.07 to 4.98; P < 0.0001). In both studies, the difference versus placebo was more modest for the MCS than for the PCS, with an LS mean difference for upadacitinib 15 mg versus placebo of 1.70 (95% CI, 0.58 to 2.82) in SELECT-PsA1 and 2.98 (95% CI, 1.44 to 4.5) in SELECT-PsA2. The between-group differences achieved the estimated MID (typically between 2.5 and 5 points) for the PCS component in both studies, but the MCS component was only met in PsA2. As reported by Leung et al.,43 when using the MID of 3.74 (for PCS) and 1.77 (for MCS) in patients treated with TNF inhibitors, the between-group differences in patients enrolled in SELECT-PsA2 met the threshold only for the MCS component. Only the PCS component of SF-36 was part of the multiplicity-controlled statistical analyses.

Table 16: Change From Baseline in Short Form (36) Health Survey at Week 12

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within-group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)

P valuea

Physical component summary at week 12 (MMRM,b FAS)

SELECT-PsA1

Placebo

394

35.19

38.44

3.19 (2.41 to 3.96)

4.67 (3.67 to 5.67) UPA vs. placebo

0.0004

ADA 40 mg e.o.w.

410

35.91

42.54

6.82 (6.07 to 7.58)

UPA 15 mg q.d.

405

34.71

42.81

7.86 (7.09 to 8.63)

SELECT-PsA2

Placebo

185

34.33

36.07

1.62 (0.58 to 2.67)

3.52 (2.07 to 4.98)

< 0.0001

UPA 15 mg q.d.

201

35.08

40.11

5.15 (4.14 to 6.15)

Mental component summary at week 12 (MMRM,b FAS)

SELECT-PsA1

Placebo

394

45.65

47.51

2.21 (1.35 to 3.06)

1.70 (0.58 to 2.82) UPA vs. placebo

NAc

ADA 40 mg e.o.w.

410

45.13

48.67

3.59 (2.76 to 4.42)

UPA 15 mg q.d.

405

44.75

48.72

3.91 (3.06 to 4.75)

SELECT-PsA2

Placebo

185

43.70

43.97

−0.13 (−1.25 to 0.98)

2.98 (1.44 to 4.52)

NAc

UPA 15 mg q.d.

201

44.75

47.68

2.84 (1.78 to 3.91)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; LS = least squares; MMRM = mixed model for repeated measures; NA = not applicable; q.d. = every day; SF-36 = Short Form (36) Health Survey; UPA = upadacitinib; vs. = versus .

aStatistically significant at the 0.0125 level.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 12 before premature discontinuation of the study drug.

cThe P value is not presented as the mental component summary was not included in the ranked (multiplicity-adjusted) secondary end points and was therefore not controlled for type I error rate.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

EuroQol 5-Dimensions 5-Levels Questionnaire

In SELECT-PsA1, there were greater improvements in the EQ-5D-5L utility index and VAS scores from baseline to week 24 in the upadacitinib treatment group compared to patients randomized to adalimumab treatment or placebo. The LS mean differences in the utility index were 0.09 (95% CI, 0.06 to 0.11) for upadacitinib 15 mg versus placebo and 0.03 (95% CI, 0.00 to 0.05) for upadacitinib 15 mg versus adalimumab 40 mg. The LS mean differences in the VAS score were 10.9 (95% CI, 8.0 to 13.7) for upadacitinib 15 mg versus placebo and 2.8 (95% CI, 0.0 to 5.6) for upadacitinib 15 mg versus adalimumab 40 mg (Appendix 3, Table 50).

In SELECT-PsA2, there were greater improvements in the EQ-5D-5L utility index and VAS scores from baseline to week 24 in the upadacitinib treatment group compared to the placebo group. The LS mean differences in the utility index was 0.10 (95% CI, 0.06 to 0.14) for upadacitinib 15 mg versus placebo. The LS mean differences in the VAS score was 6.8 (95% CI, 2.5 to 11.1) for upadacitinib 15 mg versus placebo (Appendix 3, Table 50).

For the comparison of upadacitinib to placebo in both SELECT-PSA1 and SELECT-PsA2, the LS mean between-group differences in the EQ-5D-5L utility index reached the MID threshold identified in the literature for the general Canadian population (summarized mean of 0.056; SD = 0.011). This end point was not included in the multiplicity-controlled testing hierarchy.

Measurement of Skin Disease
Psoriasis Area and Severity Index

Patients considered to be PASI 75 responders were those with a 75% improvement from baseline scores. Only patients with a BSA involvement of at least 3% at baseline had a PASI assessment.

In SELECT-PsA1, the proportion of patients achieving a PASI 75 response in the upadacitinib treatment group compared to the placebo group at week 16 was statistically significantly higher: 62.6% for upadacitinib 15 mg and 21.3% for placebo (41.3% difference; 95% CI, 32.8 to 49.8; P < 0.0001). In SELECT-PsA2, the proportion of patients achieving a PASI 75 response in the upadacitinib treatment group compared to placebo at week 16 was also statistically significantly higher: 52.3% for upadacitinib 15 mg and 16.0% for placebo (36.3% difference; 95% CI, 25.6 to 46.9; P < 0.001) (Table 17).

In both SELECT-PsA1 and SELECT-PsA2, additional exploratory end points showed that, numerically, a greater proportion of patients treated with upadacitinib achieved a PASI 75, PASI 90, or PASI 100 score at week 24 compared to patients who were treated with placebo. In SELECT-PsA1, the response rates were numerically similar between upadacitinib and adalimumab treatment groups, although a slightly higher proportion of patients in the adalimumab group achieved PASI 90 or PASI 100 at week 24 (Appendix 3, Table 51).

The clinical expert consulted for this review indicated that the between-group differences in PASI 75 were clinically relevant.

Table 17: Proportion of Patients Achieving PASI 75 at Week 16

Treatment group

Total N

Responders,

n (%)

Response rate (95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

PASI 75 at week 16 (NRI, FAS)

SELECT-PsA1

Placebo

211

45 (21.3)

21.3 (15.8 to 26.9)

41.3 (32.8 to 49.8) UPA vs. placebo

< 0.0001

ADA 40 mg e.o.w.

211

112 (53.1)

53.1 (46.3 to 59.8)

UPA 15 mg q.d.

214

134 (62.6)

62.6 (56.1 to 69.1)

SELECT-PsA2

Placebo

131

21 (16.0)

16.0 (9.7 to 22.3)

36.3 (25.6 to 46.9)

< 0.0001

UPA 15 mg q.d.

130

68 (52.3)

52.3 (43.7 to 60.9)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; NRI = nonresponder imputation; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; q.d. = every day; UPA = upadacitinib; vs. = versus .

Note: Analysis of PASI 75 was performed only in patients with BSA psoriasis of at least 3% at baseline.

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response-rate difference are calculated based on normal approximation.

cP value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). The P value was statistically significant at the 0.025 level.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Static Investigator Global Assessment of Psoriasis

Only patients with an sIGA score of at least 2 at baseline, and an improvement of at least 2 points from baseline at week 16 were assessed (Table 18).

In SELECT-PsA1, the proportion of patients achieving a response (an sIGA of psoriasis score of 0 or 1 and an improvement of at least 2 points from baseline) in the upadacitinib treatment group compared to placebo was statistically significantly higher at week 16: 41.9% for upadacitinib 15 mg and 10.9% for placebo (between-group difference 31.1%; 95% CI 24.7 to 37.5; P < 0.0001). In SELECT-PsA2, the proportion of patients achieving response in the upadacitinib treatment group compared to placebo was also statistically significantly higher at week 16: 36.8% for upadacitinib 15 mg and 9.2% for placebo (between-group difference 27.6%; 95% CI, 19.2 to 36.1; P < 0.0001).

Table 18: Proportion of Patients Achieving an sIGA of Psoriasis Score of 0 or 1 at Week 16

Treatment group

Total N

Responders, n (%)

Response rate

(95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

sIGA at week 16 (NRI, FAS)

SELECT-PsA1

Placebo

313

34 (10.9)

10.9 (7.4 to 14.3)

31.1 (24.7 to 37.5) UPA vs. placebo

< 0.0001

ADA 40 mg e.o.w.

330

127 (38.5)

38.5 (33.2 to 43.7)

UPA 15 mg q.d.

322

135 (41.9)

41.9 (36.5 to 47.3)

SELECT-PsA2

Placebo

163

15 (9.2)

9.2 (4.8 to 13.6)

27.6 (19.2 to 36.1)

< 0.0001

UPA 15 mg q.d.

171

63 (36.8)

36.8 (29.6 to 44.1)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; NRI = nonresponder imputation; q.d. = every day; sIGA = static Investigator Global Assessment; UPA = upadacitinib; vs. = versus .

Note: Analysis was performed for patients who achieved score of 0 or 1 and an improvement of at least 2 points from baseline, and only in patients with baseline sIGA of at least 2%.

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). The P value was statistically significant at the 0.025 level.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Self-Assessment of Psoriasis Symptoms

In SELECT-PsA1 at week 16, patients in the upadacitinib group reported greater reductions in SAPS score compared with placebo (Table 19). The LS mean difference was −17.1 (95% CI, −19.6 to −14.6) for upadacitinib 15 mg versus placebo. Testing for superiority of upadacitinib compared to placebo was part of the multiplicity-adjusted analyses in SELECT-PsA1; however, it was ranked after the point at which the hierarchical analysis failed and was stopped, and no statistical comparisons can be made. In SELECT-PsA2 at week 16, patients in the upadacitinib treatment reported greater reductions in SAPS scores compared to placebo. The LS mean difference was −22.9 for upadacitinib 15 mg versus placebo (95% CI, −27.4 to −18.4; P < 0.0001).

Table 19: Change From Baseline in Self-Assessment of Psoriasis Symptoms at Week 16

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference

(95% CI)

P valuea

SAPS at week 16 (MMRM,b FAS)

SELECT-PsA1

Placebo

388

44.0

34.6

−8.2 (−10.2 to −6.3)

−17.1 (−19.6 to −14.6) UPA vs. placebo

NAc

ADA 40 mg e.o.w.

407

43.0

19.8

−22.7 (−24.7 to −20.8)

UPA 15 mg q.d.

396

44.0

17.5

−25.3 (−27.3 to −23.4)

SELECT-PsA2

Placebo

182

52.6

49.5

−1.5 (−4.7 to 1.8)

−22.9 (−27.4 to −18.4)

< 0.0001

UPA 15 mg q.d.

191

49.5

25.3

−24.4 (−27.5 to −21.2)

ADA = adalimumab; CI = confidence interval; e.o.w = every other week; FAS = full analysis set; LS = least squares; MMRM = mixed model for repeated measures; NA = not applicable; q.d. = every day; SAPS = Self-Assessment of Psoriasis Symptoms; UPA = upadacitinib; vs. = versus .

aStatistically significant at the 0.05 level in SELECT-PSA1 and at the 0.0125 level in SELECT-PsA2.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 16 prior premature discontinuation of the study drug.

cIn SELECT-PsA1, change from baseline in SAPS at week 16 was ranked below the point at which the hierarchical analysis failed (i.e., after testing had stopped due to failure of showing superiority of UPA 15 mg vs. ADA); the P value is therefore not presented in this table.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Measurement of Other Musculoskeletal Disease
Enthesitis

The resolution of enthesitis, defined as an LEI score of 0, was included in the hierarchical statistical analysis only in SELECT-PsA1, and was measured in patients who had a baseline LEI greater than 0 (Table 20). Using multiplicity-controlled analyses, the proportion of patients in SELECT-PsA1 achieving resolution of enthesitis was statistically significantly higher at week 24 in the upadacitinib treatment group compared to placebo: 53.7% for upadacitinib 15 mg and 32.4% for placebo (between-group difference 21.3%; 95% CI, 13.0 to 29.7; P = 0.0004). In SELECT-PsA2, a numerically higher proportion of patients in the upadacitinib treatment group achieved resolution of enthesitis at week 24 compared to patients in the placebo group: 42.9% for the upadacitinib 15 mg group, 15.3% for placebo (between-group difference 27.6%; 95% CI, 17.3 to 37.8). This end point was not part of the multiplicity-controlled statistical analyses in PsA2.

Table 20: Proportion of Patients Achieving Enthesitis Resolution at Week 24

Treatment group

Total N

Responders, n (%)

Response rate (95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

LEI = 0 at week 24 (NRI,d FAS)

SELECT-PsA1

Placebo

241

78 (32.4)

32.4 (26.5 to 38.3)

21.3 (13.0 to 29.7) UPA vs. placebo

0.0004

ADA 40 mg e.o.w.

265

125 (47.2)

47.2 (41.2 to 53.2)

UPA 15 mg q.d.

270

145 (53.7)

53.7 (47.8 to 59.7)

SELECT-PsA2

Placebo

144

22 (15.3)

15.3 (9.4 to 21.2)

27.6 (17.3 to 37.8)

NAe

UPA 15 mg q.d.

133

57 (42.9)

42.9 (34.4 to 51.3)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; LEI = Leeds Enthesitis Index; NA = not applicable; NRI = nonresponder imputation; q.d. = every day; UPA = upadacitinib; vs. = versus .

Note: Resolution was defined as an LEI score of 0; analysis was performed for patients who had a baseline LEI greater than 0.

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). The P value was statistically significant at the 0.025 level.

dNonresponder imputation with additional rescue handling was used, with patients rescued at week 16 imputed as nonresponders.

eIn SELECT-PsA2, resolution of LEI was not included in the ranked (multiplicity-adjusted) secondary end points and therefore was not controlled for type I error rate. The P value is not presented.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Dactylitis

The resolution of dactylitis, defined as an LDI of 0, was included in the hierarchical statistical analysis in SELECT-PsA1 only, and was measured in patients who had a baseline LDI of greater than 0 (Table 21). In SELECT-PsA1, the proportion of patients achieving resolution of dactylitis, defined as an LDI of 0, was numerically higher at week 24 in the upadacitinib treatment group compared to placebo: 76.5% for upadacitinib 15 mg and 39.7% for placebo (between-group difference 36.8%; 95% CI, 25.7 to 47.9). This end point was included in the hierarchical statistical analysis in SELECT-PsA1; however, because it was ranked after the point at which the hierarchical analysis failed and was stopped, no statistical comparisons can be made. In SELECT-PsA2, a numerically higher proportion of patients in the upadacitinib treatment group achieved resolution of dactylitis at week 24 compared to patients in the placebo group: 58.2% for upadacitinib 15 mg and 28.1% placebo (between-group difference 30.1%; 95% CI; 13.0 to 47.1). This end point was not part of the multiplicity-controlled statistical analyses in PsA2.

Table 21: Proportion of Patients Achieving Dactylitis Resolution at Week 24

Treatment group

Total N

Responders, n (%)

Response rate (95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

LDI = 0 at week 24 (NRI,d FAS)

SELECT-PsA1

Placebo

126

50 (39.7)

39.7 (31.1 to 48.2)

36.8 (25.7 to 47.9) UPA vs. placebo

NAe

ADA 40 mg e.o.w.

127

94 (74.0)

74.0 (66.4 to 81.6)

UPA 15 mg q.d.

136

104 (76.5)

76.5 (69.3 to 83.6)

SELECT-PsA2

Placebo

64

18 (28.1)

28.1 (17.1 to 39.1)

30.1 (13.0 to 47.1)

NAf

UPA 15 mg q.d.

55

32 (58.2)

58.2 (45.1 to 71.2)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; LDI = Leeds Dactylitis Index; NA = not applicable; NRI = nonresponder imputation; q.d. = every day; UPA = upadacitinib; vs. = versus .

Note: Resolution was defined as an LDI of 0; analysis was performed for patients who had a baseline LDI greater than 0.

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response-rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no).

dNonresponder imputation with additional rescue handling was used, with patients rescued at week 16 imputed as nonresponders.

eIn SELECT-PsA1, resolution of dactylitis at week 24 was ranked below the point at which the hierarchical analysis failed (i.e., after testing had stopped due to failure of showing superiority of UPA 15 mg vs. ADA); the P value is therefore not presented in this table.

fIn SELECT-PsA2, resolution of LDI was not included in the ranked (multiplicity-adjusted) secondary end points and was not controlled for type I error rate; the P value is therefore not presented.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Axial Arthritis

In SELECT-PsA1 and SELECT-PsA2, change in axial disease was assessed in patients with psoriatic spondylitis at baseline. The number of patients included in this assessment was approximately 30% of those randomized into each treatment group in SELECT-PsA1, and approximately 35% in patients randomized to each treatment in SELECT-PsA2 (Appendix 3, Table 52). In SELECT-PsA1, greater improvement in BASDAI score from baseline to week 24 was observed in the upadacitinib treatment group compared to adalimumab or placebo. The LS mean difference between upadacitinib and placebo in the change in scores was −1.42 (95% CI, −1.94 to −0.90), whereas the LS mean difference between upadacitinib and adalimumab was −0.57 (95% CI, −1.09 to −0.05). In PsA2, greater improvement in the BASDAI score from baseline to week 24 was observed in the upadacitinib 15 mg group compared to the placebo group. The LS mean difference between upadacitinib and placebo in PsA2 was −1.85 (95% CI, −2.55 to −1.15). The difference between treatment groups in the change in scores from baseline did not achieve the MID identified in the literature (a change of −1.96). However, the change in scores from baseline within each active treatment group (upadacitinib and adalimumab) achieved the estimated MID. This end point was not part of the multiplicity-controlled statistical analyses.

Radiographic Changes
Sharp/van der Heijde Score

Radiographic change, as measured by SHS, was only assessed in SELECT-PsA1 (Table 22). At week 24, the difference in mean change from baseline in SHS was statistically significant for the upadacitinib treatment group compared to placebo (−0.29; 95% CI, −0.44 to −0.14; P = 0.0004). An MID for SHS in patients with PsA is unknown; however, the clinical expert consulted for this review noted that the small changes seen are unlikely to be significantly clinically meaningful to patients, and that it is difficult to observe meaningful radiographic changes within 24 weeks in the study population.

Table 22: Change From Baseline in Psoriatic Arthritis Sharp/van der Heijde Score at Week 24

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)

P valuea

SHS at week 24 (ANCOVA,b FAS)

SELECT-PsA1

Placebo

372

13.05

13.31

0.25 (0.13 to 0.36)

−0.29 (−0.44 to −0.14) UPA vs. placebo

0.0004

ADA 40 mg

384

14.89

14.92

0.01 (−0.11 to 0.13)

UPA 15 mg

391

13.44

13.42

−0.04 (−0.16 to 0.07)

SELECT-PsA2

Placebo

NR

NR

NR

NR

NR

NR

UPA 15 mg

NR

NR

NR

NR

ADA = adalimumab; ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; LS = least squares; NR = not reported; SHS = Sharp/van der Heijde Score; UPA = upadacitinib; vs. = versus .

aStatistically significant at the 0.025 level.

bResults for SHS were based on an ANCOVA with linear extrapolation for missing data and rescue handling. Within-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and P value are based on an ANCOVA model including treatment and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and baseline value as covariate.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Harms

Only those harms identified in the review protocol are reported below. Table 23 provides detailed harms data.

Adverse Events

In SELECT-PsA1, the percentage of patients with TEAEs overall was numerically higher in the upadacitinib and adalimumab treatment groups compared to placebo. One or more AE was reported in 66.9% of patients treated with upadacitinib 15 mg once daily, 64.8% treated with adalimumab 40 mg every other week, and 59.6% of patients in the placebo group during the double-blind treatment period. In SELECT-PsA2, a similar proportion of patients experienced 1 or more AEs (64.0% of patients in the upadacitinib 15 mg once daily group and 65.6% in the placebo group) during the double-blind treatment period. Generally, the majority of AEs were mild or moderate in severity. The most frequently reported AE in both studies was upper respiratory tract infection. Across the 2 studies, a higher proportion of patients in PsA1 experienced upper respiratory tract infection, as well as elevated blood CPK, alanine aminotransferase, and aspartate aminotransferase levels; a higher proportion of patients in SELECT-PsA2 experienced psoriatic arthropathy, which referred to the worsening of the underlying PsA disease.

Serious Adverse Events

In SELECT-PsA1, the proportion of patients who experienced 1 or more SAEs was similar across all treatment groups (3.3% of upadacitinib 15 mg, 3.7% of adalimumab 40 mg, 3.1% in placebo). No more than 1 patient in any treatment group reported SAEs, with the exception of pneumonia (2 patients in the placebo group) and sepsis (2 patients in the upadacitinib 15 mg group).

In SELECT-PsA2, a greater proportion of patients in the upadacitinib 15 mg (5.7%) experienced an SAE compared to patients in the placebo group (1.9%). No more than 1 patient in any treatment group reported SAEs, with the exception of psoriatic arthropathy, and nephrolithiasis (each of which were reported in 2 patients in the upadacitinib 15 mg group). Psoriatic arthropathy referred to worsening of the underlying PsA disease. Details of the reported SAEs are presented in Table 23.

Withdrawals Due to Adverse Events

In SELECT-PsA1, the percentages of patients with AEs leading to discontinuation of study drug were numerically highest in the adalimumab group and similar between the upadacitinib and placebo groups. Up to week 24, 3.0% of patients treated with upadacitinib 15 mg, 5.1% of patients treated with adalimumab 40 mg, and 3.1% of patients in the placebo group discontinued study treatment due to an AE (Table 23). Most AEs leading to study drug discontinuation were mild to moderate in severity. Four patients in the placebo group, 6 patients in the adalimumab group, and 4 patients in the upadacitinib group experienced SAEs that led to study drug discontinuation. Of these, the SAEs that lead to treatment discontinuation and were thought to be reasonably related to the study drug were sepsis (2 patients) and pyrexia (1 patient) in the upadacitinib 15 mg group, and hepatic encephalopathy (1 patient) and portal vein thrombosis (1 patient) in the adalimumab 40 mg group.

In SELECT-PsA2, the percentage of patients who discontinued study treatment due to an AE was numerically higher in the upadacitinib group. Up to week 24, 7.1% of patients treated with upadacitinib 15 mg and 5.2% of patients in the placebo group discontinued study treatment due to an AE (Table 23). Most AEs leading to study drug discontinuation were mild to moderate in severity. Two patients in the placebo group and 6 patients in the upadacitinib 15 mg group experienced an SAE that led to study drug discontinuation. Of these, the SAEs that lead to treatment discontinuation and were reasonably assumed to be related to the study drug were rapidly progressive osteoarthritis, psoriatic arthropathy, blood loss anemia, acute respiratory failure, pulmonary embolism, cardiorespiratory arrest (1 patient each) in the upadacitinib 15 mg group.

Mortality

During the double-blind period (up to week 24), SELECT-PsA1 and SELECT-PsA2 each recorded a single treatment-emergent death. In both studies, the death occurred in a patient in the placebo group.

Notable Harms

Percentages of patients who experienced a notable harm identified for this review can be found in Table 23. Overall, the proportions of patients experiencing notable harms during the double-blind period were low, and no explicit imbalances between the 2 studies were seen, with the exception of a numerically higher proportion of patients who reported CPK elevation and hepatic disorder in SELECT-PsA1. In SELECT-PsA1, 8.9% of patients treated with upadacitinib 15 mg, 5.6% of patients treated with adalimumab 40 mg, and 1.4% of patients in the placebo group experienced elevated CPK levels. Comparatively, in SELECT-PsA2, 1.9% of patients in each treatment group (upadacitinib 15 mg and placebo) experienced elevated CPK levels. Hepatic disorder was reported in 9.1%, 15.6%, and 3.8% of SELECT-PsA1 patients treated with upadacitinib 15 mg, adalimumab 40 mg, and placebo, respectively. In SELECT-PsA2, 1.9% of patients treated with upadacitinib 15 mg and 1.4% of patients in the placebo group were reported as having hepatic disorder as an AE.

Table 23: Summary of Harms Up to Week 24 — Safety Population

Adverse events

SELECT-PsA1

SELECT-PsA2

PBO

n = 423

ADA 40 mg

n = 429

UPA 15 mg

n = 429

PBO

n = 212

UPA 15 mg

n = 211

Patients with ≥ 1 adverse event

n (%)

252 (59.6)

278 (64.8)

287 (66.9)

139 (65.6)

135 (64.0)

Most common events,a n (%)

  Upper respiratory tract infection

34 (8.0)

30 (7.0)

44 (10.3)

10 (4.7)

13 (6.2)

  Increase blood CPK

6 (1.4)

24 (5.6)

38 (8.9)

4 (1.9)

4 (1.9)

  Nasopharyngitis

21 (5.0)

29 (6.8)

21 (4.9)

17 (8.0)

10 (4.7)

  Increased ALT

12 (2.8)

32 (7.5)

19 (4.4)

1 (0.5)

2 (0.9)

  Urinary tract infection

10 (2.4)

14 (3.3)

18 (4.2)

12 (5.7)

9 (4.3)

  Diarrhea

10 (2.4)

9 (2.1)

18 (4.2)

12 (5.7)

5 (2.4)

  Increased AST

8 (1.9)

22 (5.1)

14 (3.3)

1 (0.5)

0

  Psoriatic arthropathyb

13 (3.1)

5 (1.2)

6 (1.4)

11 (5.2)

10 (4.7)

Patients with ≥ 1 serious adverse event

n (%)

13 (3.1)

16 (3.7)

14 (3.3)

4 (1.9)

12 (5.7)

Most common events,c n (%)

  Sepsis

0

0

2 (0.5)

NR

NR

  Pneumonia

2 (0.5)

1 (0.2)

1 (0.2)

0

1 (0.5)

  Nephrolithiasis

NR

NR

NR

0

2 (0.9)

  Psoriatic arthropathyb

NR

NR

NR

0

2 (0.9)

Patients who stopped treatment due to adverse events

n (%)

13 (3.1)

22 (5.1)

13 (3.0)

11 (5.2)

15 (7.1)

Most common events,c n (%)

  Sepsis

0

0

2 (0.5)

NR

NR

  Psoriatic arthropathyb

0

0

1 (0.2)

2 (0.9)

4 (1.9)

  Increased ALT

0

2 (0.5)

0

0

0

  Increased AST

0

2 (0.5)

0

0

0

  Alopecia

0

2 (0.5)

0

NR

NR

  Muscle spasms

2 (0.5)

0

0

NR

NR

  Decreased white blood cell count

0d

0d

0d

0

2 (0.9)

  Psoriasis

0

1 (0.2)

0

2 (0.9)

0

Treatment-emergent deaths

n (%)e

1 (0.2)

0

0

1 (0.5)

0

  Cardiac arrest (undetermined/unknown cause of death)

1 (0.2)

  Rib fracture, traumatic hemothorax

1 (0.5)

Notable harms, n (%)

  Serious infection

  4 (0.9)

  3 (0.7)

  5 (1.2)

  1 (0.5)

  1 (0.5)

  Serious pneumonia

  2 (0.5)

  1 (0.2)

  1 (0.2)

  0

  1 (0.5)

  Herpes zoster

  3 (0.7)

  0

  4 (0.9)

  2 (0.9)

  3 (1.4)

  Active tuberculosis

  0

  0

  0

  0

  0

  Anemia

  4 (0.9)

  1 (0.2)

  3 (0.7)

  2 (0.9)

  4 (1.9)

  Neutropenia

  1 (0.2)

  10 (2.3)

  4 (0.9)

  1 (0.5)

  2 (0.9)

  Lymphopenia

  5 (1.2)

  1 (0.2)

  6 (1.4)

  0

  2 (0.9)

  Malignancy (any)

  1 (0.2)

  3 (0.7)

  1 (0.2)

  0

  3 (1.4)

  VTEf (fatal and non-fatal)

  1 (0.2)

  2 (0.5)

  0

  0

  1 (0.5)

  Arterial thrombosisg

  0

  1 (0.2)

  0

  0

  0

  Gastrointestinal perforation

  0

  0

  0

  0

  0

  CPK elevation

  6 (1.4)

  24 (5.6)

  38 (8.9)

  4 (1.9)

  4 (1.9)

  Hepatic disorder

  16 (3.8)

  67 (15.6)

  39 (9.1)

  3 (1.4)

  4 (1.9)

  MACEh

  1 (0.2)

  2 (0.5)

  0

  0

  1 (0.5)

  Hyperlipidemia

  3 (0.7)

  1 (0.2)

  1 (0.2)

  1 (0.5)

  5 (2.4)

ADA = adalimumab; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; MACE = major adverse cardiovascular event; NR = not reported; PBO = placebo; UPA = upadacitinib, VTE = venous thromboembolic event.

aFrequency of 5% or greater in any treatment group.

bThe term psoriatic arthropathy refers to worsening of the underlying PsA disease.

cFrequency of at least 2 patients in any treatment group.

dClassified as leukopenia.

eTreatment-emergent deaths were captured for deaths occurring no more than 30 days after last dose (or no more than 70 days for patients in the adalimumab group). In SELECT-PsA1, from week 24 to the data cut-off, 1 additional death in the upadacitinib 15 mg treatment group was reported, occurring more than 30 days after the last dose of the study drug (participant had withdrawn consent).

fIncludes fatal and non-fatal deep-vein thrombosis and pulmonary embolism. None of the patients experience a fatal VTE.

gIncludes non-cardiac, non-neurologic, non-fatal events.

hDefined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Source: SELECT-PsA1 Clinical Study Report9 and SELECT-PsA2 Clinical Study Report.10

Critical Appraisal

Internal Validity

SELECT-PsA1 and SELECT-PsA2 were randomized trials with a double-blind period up to week 24. Appropriate methods of randomization, blinding, and allocation concealment were reported. Patients were stratified at randomization according to extent of psoriasis (≥ 3% BSA or < 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of enthesitis in SELECT-PsA1, and according to extent of psoriasis, current use of at least 1 DMARD, and number of prior failed bDMARDs (1 versus > 1) in SELECT-PsA2. Patients from China and Japan were stratified only by extent of psoriasis. All clinical laboratory tests (including clinical chemistry, hematology, and urinalysis) were analyzed by a central laboratory. Radiographs taken at screening were read by the investigator to determine if the patient fulfills the classification criteria for PsA; imaging of hands and feet taken during the study were reviewed and assessed centrally by qualified reader. In general, patients’ baseline demographic and disease characteristics were similar between treatment groups within each study. Only minor differences were seen between the upadacitinib and placebo group in SELECT-PsA2, which are unlikely to have a significant impact on the study results. For example, the placebo group enrolled patients with a slightly higher mean LDI, those with an sIGA score of 0, and those who had received no prior non-bDMARD. In both studies, the sponsor was unblinded at week 24 to conduct an analysis, but the investigators and patients remained blinded to their allocated treatment until the end of period 1 (week 56). In SELECT-PsA2, no more than approximately 30% of patients with prior failure of more than 1 bDMARD were enrolled. As a result, most patients had failed on only 1 previous treatment. Overall, the results were consistent with those seen in SELECT-PsA1, in which patients had not been exposed to a previous bDMARD.

Multiplicity-controlled analyses using a hierarchical test procedure for ranked primary and key secondary efficacy outcomes was used in both studies to control the overall type I error rate at 5%. Testing was performed sequentially, with alpha transferred down a specific path. Statistical testing for the hypotheses was performed only if the previous null hypothesis in the hierarchy could be rejected. A limitation with this approach is that only certain outcomes were selected and therefore it did not take into consideration all outcomes measured in the study, including HRQoL as measured by the EQ-5D-5L, patient symptom improvement (i.e., pain), or work productivity. These outcomes were identified as exploratory or additional outcomes in SELECT-PsA1 and SELECT-PsA2, even though HRQoL and work productivity were identified by patient groups as important outcomes. In addition, no rationales were provided for the choice of outcomes that were included in the hierarchy. Several outcomes that were identified in the CADTH review protocol and reported in the studies fell outside the statistical testing hierarchy and any interpretation should therefore consider the possibility of type I error. Given the large number of comparisons in the study, a statistically significant finding may be attributable to an inflated type I error.

Key end points comparing upadacitinib to adalimumab were measured at week 12. According to the clinical expert consulted for this review, this may not have provided adequate time for adalimumab to show maximal benefit. The benefits of JAK inhibitors are thought to be seen generally sooner than those of TNF inhibitors, and end points measured at week 12 may have favoured upadacitinib. While the results for both upadacitinib and adalimumab were consistent until 24 weeks, it is uncertain whether upadacitinib 15 mg is noninferior to adalimumab due to the lack of statistical testing at week 24. Also, the noninferiority and superiority comparison between upadacitinib and adalimumab was conducted only for the ACR20 efficacy outcome, making it unclear whether upadacitinib would be noninferior or superior to adalimumab for other outcome measures.

Despite showing statistically significant differences in the trials, some end points may not be clinically meaningful to patients. For example, subjective measures such as fatigue, or the small changes seen in SHS, may not translate to a true overall improvement in daily life, particularly when measured over such a short length of time relative to the long disease course of PsA. The clinical expert consulted for this review noted that it is difficult to extrapolate the significance of these changes over the lifetime of a patient with PsA. In particular, it is uncertain whether the radiographic changes seen in SELECT-PsA1 correlate with a direct and meaningful improvement in a patient’s physical function, quality of life, or permanent disability.

Rescue therapy was permitted starting at week 16. It is difficult to differentiate the effects of the drugs from changes in background therapy on the outcomes observed after week 16, making interpretation of results challenging. This may also confound the results of patient-reported outcomes, such as HRQoL, symptoms, and disability measures, as well as AEs in the long term. To adjust for patients who received rescue therapy, the end points of MDA, resolution of enthesitis, and resolution of dactylitis, all measured at week 24, considered patients who required rescue therapy to be nonresponders, which was appropriate for a more conservative assessment.

Several pre-specified subgroup analyses were performed for the primary end point. The CADTH systematic review protocol included subgroups by PsA disease severity at baseline, previous exposure to bDMARDs (treatment-naive versus -experienced), and concomitant treatment with a non-bDMARD. In both studies, the results of the subgroup analysis exploring concomitant treatment with a non-bDMARD was consistent with the primary analysis, regardless of whether patients received concurrent non-bDMARDs. Inclusion criteria for PsA1 and PsA2 allowed examination of treatment effects separately for biologic-naive (SELECT-PsA1) and biologic-experienced (SELECT-PsA2) patients. Neither study provided subgroup data based on disease severity at baseline. The results of the pre-specified subgroup analyses performed for the primary end point should be interpreted with caution due to the small sample sizes and lack of control for type I error, and also because the trial was not powered to test specific hypotheses in subgroups. As with the end points that were not part of the statistical testing hierarchy, the results of these subgroup analyses should be interpreted with caution. Although small differences in ACR20 were evident within some pre-specified subgroups, the results should be interpreted with caution due to the small sample sizes and lack of control for type I error, and also because the trial was not powered to test specific hypotheses in subgroups. As with the end points that were not part of the statistical testing hierarchy, the results of these subgroup analyses should be interpreted with caution.

A noninferiority analysis of upadacitinib compared to adalimumab was part of the key secondary end points in SELECT-PsA1. Initially, the noninferiority margin was set at 15% based on prior data but it was changed in Protocol Amendment 2. A rationale for the change and justification for the new analysis, which aimed to demonstrate preservation of at least 50% of the placebo-subtracted adalimumab effect by upadacitinib, were not provided. However, the clinical expert consulted for the review described this as a reasonable measure that reflected the noninferiority of upadacitinib versus the active control group. Similar numbers of patients were included in the PPS as the FAS, and consistent results were seen between the 2 analysis sets.

Missing data (i.e., randomized patients not included in the analysis) are a concern in the analyses of patient-reported outcomes and continuous end points, such as HAQ-DI, SF-36, patient’s assessment of pain NRS, FACIT-F, and EQ-5D-5L. Particularly in SELECT-PsA2, the placebo group was missing up to approximately 15% of patients at week 12, and approximately 20% at week 24 (EQ-5D). In the upadacitinib 15 mg group of SELECT-PsA2, generally less than 5% of data were missing at week 12, with 13% missing at week 24 for EQ-5D-5L. In SELECT-PsA1, generally less than 10% were missing up to week 24. Although a large proportion of missing data can make results more uncertain (particularly in the placebo group of PsA2 for EQ-5D-5L), the main secondary end points of this trial were likely less subject to this bias due to their evaluation at week 12, at which point there were fewer missing patients. Sensitivity analyses were conducted using different forms of imputation, including as-observed data handling and an analysis of covariance model for continuous efficacy outcomes, and tipping-point analysis of HAQ-DI at week 12 using multiple imputation. The results of these sensitivity analyses were consistent with the results from the primary analysis. The missing-imputation method for binary outcomes employed a nonresponder imputation; supplemental as-observed data-handing analysis showed consistent results, which suggests that missing data had a small impact on the results.

Some end points were only analyzed in a subset of randomized patients. For example, PASI was assessed only in patients in whom psoriasis affected at least 3% of their BSA at baseline, sIGA was assessed in patients with a score of at least 2 at baseline, and enthesitis and dactylitis were assessed in patients with an LEI or LDI greater than 0 at baseline. As such, there is a risk that randomization is broken in these subset of patients. However, with the exception of sIGA scores, most of these baseline characteristics were part of the randomization stratification in SELECT-PsA1, and the number of patients analyzed in each treatment group was generally balanced. In PsA2, only the baseline measure of BSA affected by psoriasis was included in the randomization stratification, but there was no major imbalance in the number of patients included in each treatment group for sIGA, and resolution of enthesitis and dactylitis were not included in the testing hierarchy.

Currently available outcome measures in PsA have been adopted in large part from other conditions, such as rheumatoid arthritis and psoriasis. Validity and reliability data specific to PsA are sparse, and some instruments, such as EQ-5D-5L, WPAI, sIGA, and SAPS, lack a known MID exclusively for patients with PsA.

External Validity

The included studies were multi-centre trials enrolling patients from different countries; however, only 2.3%, or 39 patients, in SELECT-PsA1, and 2.6%, or 17 patients, in SELECT-PsA2, were recruited from Canada.35 According to the clinical expert involved in the review, the patients’ baseline characteristics were consistent with what can be seen in Canadian clinical practice and in other PsA trials. The clinical expert indicated that the study results are likely generalizable to the Canadian patient population.

In SELECT-PsA2, as enrolment of patients with prior failure of multiple bDMARDs was limited to approximately 30%, a limited number of patients had failed several bDMARDs. This may limit the generalizability of the PsA2 study results in patients who had failed multiple bDMARD treatments.

Because adalimumab was an active comparator only in the SELECT-PsA1 study, the effects of upadacitinib were compared to those of adalimumab only in the bDMARD-naive patient population. Results from PsA1 cannot be generalized to the bDMARD-experienced patient population, and it is unknown whether patients previously exposed to bDMARDs would derive the same benefit from adalimumab. However, the responses to subsequent bDMARDs in patients who failed previous biologic treatment are generally suboptimal, and it would be reasonable to expect a similar direction of response (benefit) with upadacitinib, relative to adalimumab.

SELECT-PsA1 required patients to have the presence of either 1 or more examples of erosion on X-ray or an hs-CRP level greater than the ULN for inclusion into the study, which may affect the generalizability of this study’s results. According to the clinical expert consulted for this review, a substantial proportion of patients seen in clinical practice generally do not have evident erosions or inflammatory markers elevated to this degree and yet still require treatment with bDMARDs. Consistent with this, the main reason for screening failure (422 of 774 screened patients) was patient failure to meet the MDA criteria of at least 1 erosion on X-ray as determined by a central imaging review or an hs-CRP level exceeding a laboratory-defined ULN. At enrolment, most patients met the inclusion criteria for having elevated an hs-CRP level greater than ULN (approximately 75%) and approximately 40% of patients had at least 1 erosion. Despite this inclusion criteria being only part of 1 of the trials, the mean hs-CRP levels at baseline were similar between patients enrolled in SELECT-PsA-1 and SELECT-PsA-2.

The efficacy results as observed in the 2 trials were generally consistent. Overall, the magnitude of differences was comparable even though the characteristics of the population enrolled in SELECT-PsA2 were reflective of patients with long-standing disease that is more difficult to control. For example, the mean duration of PsA diagnosis in the treatment groups ranged from 5.9 to 6.2 years in SELECT-PsA1 and from 9.6 to 11.0 years in SELECT-PsA2. The mean TJC was higher in patients enrolled in PsA2, as was the baseline LDI score. Patients in PsA1 were bDMARD-naive but had been previously treated with at least 1 non-bDMARD whereas all patients in PsA2 were bDMARD-experienced. Most patients in SELECT-PsA2 (62%) had failed 1 prior biologic treatment; approximately 20% of patients had failed 2 biologics, and another 20% had failed 3 or more prior bDMARDs. During the study, a greater proportion of patients in SELECT-PsA1 (81% to 84%) received concomitant non-bDMARD compared to patients in SELECT-PsA2 (48% to 53%). The impact of these patient characteristics when generalizing results from the 2 trials to the Canadian patient population is uncertain.

Patients were permitted to continue stable background non-biologic treatment. Approximately 80% of patients in SELECT-PsA1 and 50% of patients in SELECT-PsA2 were treated with concomitant non-bDMARDs. Of these patients, most received concomitant methotrexate (approximately 70% and 40% of patients in SELECT-PsA1 and SELECT-PsA2, respectively). The number of patients who received other non-bDMARDs (varying in category and mechanism of action) were small for individual agents. Efficacy and safety data supporting the full effect of upadacitinib in combination with other non-bDMARDs (i.e., other than methotrexate) is limited, and cannot be generalized from the SELECT trials.

Several outcomes measured in the trials have limitations, including not being validated, or lacking a clearly defined MID in a change in score in the population of patients with PsA (see Appendix 4). However, for the purposes of this review, the clinical expert consulted for the review deemed the end points measured in both SELECT studies to be relevant to patients being treated for PsA.

The dosages of upadacitinib (15 mg orally once daily) and adalimumab (40 mg subcutaneous every 2 weeks) are consistent with Canadian practice, and a direct comparison between them can help inform the expected efficacy of upadacitinib in the Canadian practice setting. However, there is a lack of direct head-to-head comparisons of upadacitinib versus other active comparators, particularly non-TNF inhibitors, including JAK inhibitors such as tofacitinib, as well TNF inhibitors other than adalimumab. A critical appraisal of a sponsor-submitted ITC is included in this review to address some of these gaps.

Although long-term data were reported for up to week 56 for both studies, the only placebo-controlled data for upadacitinib are those up to week 24. Also, interpretation of results after week 24 is limited by the lack of a placebo group and the allowance for rescue treatment within the groups. However, continuation of active control beyond week 24 would have provided additional insight on the effect of upadacitinib compared to adalimumab in SELECT-PsA1. Also, both studies’ long-term extensions of up to 5 years in SELECT-PsA1 and 3 years in SELECT-PsA2 are ongoing and can be expected to provide further trends on efficacy and safety over time.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

Upadacitinib is a tsDMARDs indicated for the treatment of active PsA in adult patients who have responded inadequately or who are intolerant to methotrexate or other DMARDs. Due to the lack of direct evidence comparing the efficacy and safety of upadacitinib with that of other bDMARDs and tsDMARDs for the treatment of moderately to severely active PsA, a review of indirect evidence was undertaken. CADTH conducted a literature search to identify potentially relevant ITCs in patients with moderately to severely active PsA, in addition to reviewing the sponsor’s submission to CADTH. A focused literature search for NMAs dealing with PsA was run in MEDLINE All (1946–) on February 1, 2021. Titles, abstracts, and full-text articles were screened for inclusion by 1 reviewer based on the population, intervention, comparator, and outcome criteria outlined in Table 5.

The sponsor submitted an ITC that assessed the efficacy of upadacitinib compared to bDMARDs and tsDMARDs in adult patients with active PsA.47 No ITCs were identified in the literature search. This section summarizes and critically appraises the unpublished ITC submitted by the sponsor.

Description of Indirect Treatment Comparison

No systematic literature review or source of study selection was reported. The population, intervention, comparators, outcomes, and design of studies included in the sponsor’s ITC are provided in Table 24.

Table 24: Study Selection Criteria and Methods for the Sponsor-Submitted ITC

Criteria

Inclusion

Exclusion

Population

Adult patients with moderately to severely active PsA

  • Biologic-experienced population: patients who have previously undergone treatment with a biologic therapy

  • Biologic-naive population: patients who have not been previously treated with a biologic therapy

• Pediatric patients only or not report results for adult subgroup in an age-mixed patient population

• Only csDMARD-naive patients

• Only methotrexate-naive patients

• Moderate-to-severe psoriasis that reported subgroup results for patients with concomitant PsA

• Patients with primary failure to prior biologics

Interventions and comparators

  • JAK inhibitors (tofacitinib, upadacitinib)

  • CTLA4-Ig (abatacept)

  • Anti-TNF (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab)

  • IL-17 (secukinumab, ixekizumab)

  • IL-12/23 (ustekinumab)

  • IL-23 (guselkumab)

  • Anti-PDE4 (apremilast)

  • Placebo

NR

Outcomes

Efficacy

  • PsARC response rate

  • PASI 50, PASI 75, or PASI 90 response rate

  • HAQ-DI change conditional on PsARC response

  • ACR20, ARC50, and ARC70 response rate

Week 12 and week 24 data stratified by biologic-naive and biologic-experienced populations were used whenever available

Study design and factors

RCTs

Exclusion: single-arm trials or observational studies

Language

English abstracts of foreign publications were considered

Search period

NR

ACR = American College of Rheumatology; AE = adverse events; bDMARD = biologic DMARD; csDMARD = conventional synthetic DMARD; CLTA4-Ig = cytotoxic T lymphocyte–associated protein 4 immunoglobin; DMARD = disease-modifying antirheumatic drug; HAQ-DI = Health Assessment Questionnaire–Disability Index; IL = interleukin; JAK = Janus kinase; NR = not reported; PASI 50 = 50% reduction in Psoriasis Area Severity Index score; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PsA = psoriatic arthritis; PsARC = Psoriatic Arthritis Response Criteria; RCT = randomized controlled trial.

Source: Sponsor-submitted indirect treatment comparison.47

Methods of the Sponsor-Submitted Indirect Treatment Comparison

Objectives

The sponsor conducted an ITC that indirectly compared the efficacy of upadacitinib, bDMARDs, and tsDMARDs for the treatment of moderately to severely active PsA. The ITC reported overall results among biologic-naive and biologic-experienced patients separately.

Study Selection Methods
Eligibility Criteria

Any RCTs, irrespective of blinding status and enrolled adults (18 years and over) of biologic-naive or biologic-experienced with moderately or severely active PsA were eligible for inclusion (Table 24).

Study Selection and Data Extraction

Several electronic databases were searched via the Ovid platform on August 9, 2019. A first update of the search was conducted on May 21, 2020, and a second update was conducted on September 3, 2020, to identify relevant papers published post-August 2019.

Identified studies were independently assessed by 2 reviewers for inclusion at each stage of study selection. First, the title and abstracts of the references identified from the electronic bibliographic databases were screened by 2 independent reviewers. Any disputes between the inclusion and exclusion decisions were resolved by a third independent reviewer. The full texts of included titles and abstracts, where available, were then further assessed by independent reviewers. For both phases, the reviewers determined the eligibility according to pre-specified inclusion and exclusion criteria for the review based on Table 24.

Relevant information was extracted into the data extraction template by a reviewer. A second reviewer checked the data extraction, and any inconsistencies were resolved through discussion or by a third reviewer. Results from a clinical trial, if reported in multiple publications, were extracted as a single study.

Interventions and Comparators

Both bDMARDs and tsDMARDs were included in the ITC, with trials including at least 1 arm for upadacitinib or a treatment currently licensed by the FDA and/or the European Medicines Agency for biologic-naive and/or biologic-experienced patients with moderately to severely active PsA or anticipated to be licensed by the FDA and/or the EMA for moderately to severely active PsA by the time of upadacitinib approval.

Outcomes

The primary efficacy outcomes for the ITC were percentage of patients who achieved PsARC, 50% reduction in Psoriasis Area Severity Index score (PASI 50), PASI 75, PASI 90, ACR20, ACR50, ACR70, and change in HAQ-DI from baseline at week 12 and 24. The comparisons were stratified by patients with prior biologics use (biologic-experienced) and without prior biologics use (biologic-naive) to account for its potential modification of the treatment effects. The ITC included no safety outcomes.

Quality Assessment of Included Studies

Quality assessment of included RCTs was conducted using the 7-criteria checklist provided in section 2.5 of the National Institute for Health and Care Excellence single technology appraisal user guide.48

ITC Analysis Methods

The submitted ITC used Bayesian fixed- or random-effect NMAs. The methods used for conducting the ITC were reportedly consistent with the approach described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Documents 2 and 3.49,50 Outcomes were assumed to follow given distributions and associated link functions were used:

The following models were implemented for each outcome in each network:

Analyses were conducted using a Markov chain Monte Carlo method using JAGS and R software packages. Models used a typical “burn-in” method and estimates were based on additional iterations using 3 chains. Three Markov chains were run with different initial values. Each chain contains 5,000 adaptive iterations, 50,000 burn-in iterations, and 500,000 sampling iterations. The results are presented as odds ratios and 95% credible intervals (CrI) to compare PsARC, PASI 50, PASI 75, PASI 90, ACR20, ARC50, and ARC70 between each pair of treatments. Mean differences were used to compare HAQ-DI change between each pair of treatments among PsARC responders or nonresponders, respectively. The posterior distributions for the pairwise comparisons were summarized using posterior medians and their associated 95% CrIs. No sensitivity or subgroup analyses were reported to assess the heterogeneity and/or adjusted for potential effect modifiers across the comparisons. Model fit was assessed using the deviance information criterion. Model selection was not formally reported but was based on network sparsity. It was unclear how inconsistency was assessed was formally assessed.

Results of the Sponsor-Submitted ITC

Summary of Included Studies

A total of 34 RCTs (Table 25; as well as Table 58 and Table 59 of Appendix 3) were included in at least 1 of the pre-specified analyses.47 Both phase II and III trials were included. All were placebo-controlled, except 5 trials that included adalimumab as an active comparator arm. A total of 13,433 patients from all trials were included, with an average arm size of 152, and ranging from 30 to 429. The average age of the patients was 48.8 years, ranging from 43.5 to 54.1 years. The proportion of patients who were female was 50.8%, while 93.5% were White. At baseline the average duration of PsA was 7.3 years, ranging from 3.4 to 11.7 years. Prior DMARD use was 69.7%, ranging from 1% to 100% based on inclusion criteria. Importantly, different criteria for the inclusion of biologic-experienced patients were applied across trials, with 3 trials including only biologic-experienced patients. Important differences were noted in selection of concomitant therapy, background therapy, and rescue therapy. A summary of the study characteristics and patient’s baseline characteristics for each of the included studies is presented in Table 25, as well as Table 58 and Table 59 of Appendix 3.

Table 25: Summary of Studies Included and Baseline Characteristics

Characteristics

Value

Number of studies, n

34

Total number of patients, N

13,433

Patients per study arm, range

30 to 429

Age, range

43.5 to 54.1

Female (%), range

29 to 61

White (%), range

80.9 to 100

Duration of PsA (years), range

3.4 to 11.7

Prior DMARDs (%), range

1 to 100

Source: Sponsor-submitted indirect treatment comparison.47

Results
Biologic-Naive Patients

A total of 31 trials were included in the biologic-naive NMAs at week 12 (Table 58 and Table 59, Appendix 3). The majority of studies used the data from weeks 12 through 16 for the biologic-naive population. The ACR response at 12 weeks was reported from all 31 trials (Figure 4). Other outcomes had slightly reduced networks, with 16 trials for PsARC, 28 for PASI, and only 9 trials for HAQ-DI change from baseline conditional on PsARC response. A total of 25 trials were included in the analysis at week 24. The ACR responses at 24 weeks were reported from all 25 trials (Figure 5). Other outcomes had slightly reduced networks, with 14 trials for PsARC, 22 trials for PASI, and only 2 trials for HAQ-DI change from baseline conditional on PsARC response.

Figure 4: Network of Trials for NMA of Biologic-Naive Patients for ACR 50 at Week 12

Network diagram of the indirect treatment comparison for comparison of upadacitinib versus bDMARDs and tsDMARDs. The majority of the treatments were connected with placebo (or adalimumab) by only 1 trial; some connections were able to make use of data from multiple trials. These include the ADEPT, Genovese 2007, Mease 2018, SPIRIT-P1, OPAL-Broaden, and SELECT-PsA 1 trials all included both adalimumab and placebo. SPIRIT-H2H was a head-to-head trial for ixekizumab Q4W against adalimumab. EXCEED was a head-to-head trial for secukinumab 300 mg against adalimumab. Adalimumab can therefore be considered as another anchor comparator arm that connects upadacitinib, secukinumab 300 mg, ixekizumab, and tofacitinib. The Deodhar 2018, DISCOVER-1 and DISCOVER-2 trials studied guselkumab Q8W and placebo. The DISCOVER-1 and DISCOVER-2 trials studied guselkumab Q4W and placebo. The PALACE 1 to 3 and ACTIVE trials studied apremilast and placebo. The Mease 2000 and 2004 trials studied etanercept and placebo. The IMPACT and IMPACT 2 trials studied infliximab and placebo. The PSUMMIT 1 and PSUMMIT 2 trials studied ustekinumab and placebo. The FUTURE 2 to 5 and CHOICE trials studied secukinumab and placebo.

ABA = abatacept; ACR = American College of Rheumatology; ADA = adalimumab; APR = apremilast; bDMARD = biologic disease-modifying antirheumatic drug; BID = twice a day; BIW = twice a week; CZP = certolizumab; ETN = etanercept; GOL = golimumab; GUS = guselkumab; INF = infliximab; IXE = ixekizumab; mg = milligram; NMA = network meta-analysis; PBO = placebo; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W. = every 12 weeks; QD = every day; SC = subcutaneous; SEC = secukinumab; TOF = tofacitinib; tsDMARD = targeted synthetic disease-modifying antirheumatic drug; UPA = upadacitinib; UST = ustekinumab.

Source: Sponsor-submitted indirect treatment comparison.47

Figure 5: Network of Trials for NMA of Biologic-Naive Patients for ACR 50 at Week 24

Network diagram of the indirect treatment comparison for comparison of upadacitinib versus bDMARDs and tsDMARDs. The majority of the treatments were connected with placebo (or adalimumab) by only 1 trial; some connections were able to make use of data from multiple trials. These include the ADEPT, SPIRIT-P1, and SELECT-PsA 1 trials all included both adalimumab and placebo. SPIRIT-H2H was a head-to-head trial for ixekizumab Q4W against adalimumab. EXCEED was a head-to-head trial for secukinumab 300 mg against adalimumab. Adalimumab can therefore be considered as another anchor comparator arm that connects upadacitinib, secukinumab 300 mg, ixekizumab, and tofacitinib. The Deodhar 2018, DISCOVER-1 and DISCOVER-2 trials studied guselkumab Q8W and placebo. The DISCOVER-1 and DISCOVER-2 trials studied guselkumab Q4W and placebo. The Mease 2004 trial studied etanercept and placebo. The IMPACT 2 trial studied infliximab and placebo. The PSUMMIT 1 and PSUMMIT 2 trials studied ustekinumab and placebo. The FUTURE 2 to 5 trials studied secukinumab and placebo.

ABA = abatacept; ACR = American College of Rheumatology; ADA = adalimumab; APR = apremilast; bDMARD = biologic disease-modifying antirheumatic drug; BID = twice a day; BIW = twice a week; CZP = certolizumab; ETN = etanercept; GOL = golimumab; GUS = guselkumab; INF = infliximab; IV = IV infusion; IXE = Ixekizumab; mg = milligram; NMA = network meta-analysis; PBO = placebo; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; QD = every day; SC = subcutaneous injection; SEC = secukinumab; TOF = tofacitinib; tsDMARD = targeted synthetic disease-modifying antirheumatic drug; UPA = upadacitinib; UST = ustekinumab.

Source: Sponsor-submitted indirect treatment comparison.47

Summary of Results at 12 Weeks

Table 26 and Table 28 present the results among biologic-naive patients.

At week 12, all treatments had a higher response rate than did placebo for all ACR measures. Upadacitinib 15 mg showed a higher ACR response rate than did abatacept SC, apremilast, ustekinumab 45 mg, guselkumab, and secukinumab 150 mg. No difference was found when upadacitinib 15 mg was compared to abatacept IV, tofacitinib, certolizumab, golimumab, adalimumab, secukinumab, ixekizumab, etanercept, and infliximab (Table 26).

Other Outcomes: The results for the other outcomes of interest suggest that upadacitinib 15 mg at 12 weeks was superior to placebo for all outcomes measured, including PsARC, PASI, and HAQ-DI change from baseline.

For the PASI outcome measures, upadacitinib 15 mg at 12 weeks was favoured when compared to abatacept, apremilast, and etanercept; no difference was reported when upadacitinib 15 mg was compared to golimumab, certolizumab, ustekinumab, tofacitinib, adalimumab, secukinumab subcutaneous 150 mg, and infliximab. Guselkumab, ixekizumab, and secukinumab subcutaneous 300 mg were favoured when compared to upadacitinib 15 mg (Table 27).

For the PsARC outcome measures, upadacitinib 15 mg at 12 weeks was favoured when compared to tofacitinib and apremilast. No difference was reported when upadacitinib 15 mg was compared to ixekizumab, ustekinumab, adalimumab, secukinumab, certolizumab, etanercept, golimumab, and infliximab (Table 28).

Among PsARC responders, upadacitinib 15 mg had a larger reduction in HAQ-DI when compared with apremilast (between-group difference [95% CrI, ||||||||||||||||||||||) and etanercept was favoured when compared to upadacitinib 15 mg in HAQ-DI (between-group difference [95% CrI, ||||||||||||||||||). No difference was reported when upadacitinib 15 mg was compared to ustekinumab 45 mg, adalimumab, golimumab subcutaneous, and infliximab. Among PsARC nonresponders, no difference was reported when upadacitinib 15 mg was compared to apremilast, etanercept, ustekinumab 45 mg, adalimumab, golimumab subcutaneous, and infliximab.

Summary of Results at 24 Weeks

At week 24, all treatments had a higher response rate than did placebo for all ACR measures. For ACR 50, upadacitinib 15 mg was favoured when compared to abatacept subcutaneous, apremilast, and ustekinumab 45 mg. No difference was found when compared to abatacept IV, guselkumab, tofacitinib, certolizumab, golimumab, adalimumab, secukinumab, ixekizumab, etanercept, and infliximab (Table 26).

Other Outcomes: The results for the other outcomes of interest suggested that upadacitinib 15 mg at 24 weeks was favoured when compared to placebo for all PsARC, PASI, and HAQ-DI change from baseline.

For the PASI outcome measures, upadacitinib 15 mg at 24 weeks was favoured when compared to abatacept, apremilast, and etanercept, and no difference was reported when upadacitinib 15 mg was compared to golimumab, certolizumab, ustekinumab, tofacitinib, adalimumab, secukinumab, infliximab, ixekizumab, and secukinumab. Guselkumab was favoured when compared to upadacitinib 15 mg (Table 27).

For the PsARC outcome measures, upadacitinib 15 mg at 24 weeks was favoured when compared to apremilast, and no difference was reported when upadacitinib 15 mg was compared to tofacitinib, ixekizumab, ustekinumab, adalimumab, secukinumab, certolizumab, etanercept, golimumab, and infliximab (Table 28).

For HAQ-DI at 24 weeks, upadacitinib 15 mg was compared only with adalimumab and ustekinumab. Among PsARC responders, upadacitinib 15 mg had a larger reduction in HAQ-DI compared with adalimumab (between-group difference: ||||||||||||||||||||||||||||||||), and no difference was reported when upadacitinib 15 mg was compared to ustekinumab 45 mg (between-group difference: ||||||||||||||||||||||||||||||||||). Among PsARC nonresponders, no difference was reported when upadacitinib 15 mg was compared to adalimumab and ustekinumab 45 mg.

Table 26: Summary of ITC Results for ACR20, ACR50, and ACR70 for Biologic-Naive Patients at 12 and 24 Weeks for Upadacitinib 15 mg Versus Comparators

Comparator

Random-effects with placebo-response adjustment, odds ratio (95% CI)

12 weeks

24 weeks

ACR20

ACR50

ACR70

ACR20

ACR50

ACR70

Placebo

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Abatacept SC

||||||||||||||||||||||

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||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Apremilast

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ustekinumab SC 45 mg at weeks 0 and 4, then q.12.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

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||||||||||||||||||||||

Abatacept IV

||||||||||||||||||||||

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||||||||||||||||||||||

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Guselkumab SC 100 mg at weeks 0, and 4, then q.8.w

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Guselkumab SC 100 mg q.4.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

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Secukinumab SC 150 mg

||||||||||||||||||||||

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Tofacitinib

||||||||||||||||||||||

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Certolizumab

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

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Golimumab SC

||||||||||||||||||||||

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Adalimumab

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

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Secukinumab SC 300 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.2.w

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Etanercept

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Golimumab IV

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

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Infliximab IV

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; CrI = credible interval; q.2.w = every 2 weeks; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; SC = subcutaneous.

Source: Sponsor-submitted indirect treatment comparison.47

Table 27: Summary of ITC Results for PASI 50, PASI 75, and PASI 90 Among Biologic-Naive Patients at 12 and 24 Weeks for Upadacitinib 15 mg Versus Comparators

Comparator

Random-effects with placebo-response adjustment, odds ratio (95% CrI)

12 weeks

24 weeks

PASI 50

PASI 75

PASI 90

PASI 50

PASI 75

PASI 90

Placebo

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Abatacept IV

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Abatacept SC

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Apremilast

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Etanercept

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Golimumab SC

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Certolizumab

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ustekinumab SC 45 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Tofacitinib

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Adalimumab

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Secukinumab SC 150 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Golimumab IV

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Infliximab IV

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Secukinumab SC 300 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.4.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.2.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Guselkumab SC 100 mg at weeks 0, and 4, then q.8.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Guselkumab SC 100 mg q.4.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

CrI = credible interval; PASI 50 = 50% reduction in Psoriasis Area Severity Index score; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; q.2.w = every 2 weeks; q.4.w. = every 4 weeks SC = subcutaneous.

aUpadacitinib was more efficacious than the comparator.

bUpadacitinib was less efficacious than the comparator.

Source: Sponsor-submitted indirect treatment comparison.47

Table 28: Summary of ITC Results for PsARC Among Biologic-Naive Patients at 12 and 24 Weeks for Upadacitinib 15 mg Versus Comparators

Comparator

Random-effects with placebo-response adjustment, odds ratio (95% CrI)

12 weeks

24 weeks

Placebo

||||||||||||

||||||||||||

Tofacitinib

||||||||||||

||||||||||||

Apremilast

||||||||||||

||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.4.w.

||||||||||||

||||||||||||

Ustekinumab SC 45 mg

||||||||||||

||||||||||||

Ustekinumab SC 90 mg

||||||||||||

||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.2.w

||||||||||||

||||||||||||

Adalimumab

||||||||||||

||||||||||||

Secukinumab SC 300 mg

||||||||||||

||||||||||||

Certolizumab

||||||||||||

||||||||||||

Secukinumab SC 150 mg

||||||||||||

||||||||||||

Etanercept SC 25 mg b.i.w.

||||||||||||

||||||||||||

Golimumab SC

||||||||||||

||||||||||||

Infliximab IV

||||||||||||

||||||||||||

b.i.w. = twice weekly; PsARC = Psoriatic Arthritis Response Criteria; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneous.

aUpadacitinib was more efficacious than comparator.

Source: Sponsor-submitted indirect treatment comparison.47

Biologic-Experienced Patients

A total of 15 trials were included in the biologic-experienced NMAs at week 12 (Figure 6 and Figure 7). The majority used data from weeks 12 through 16 data for the biologic-naive population, with ACR responses reported from all 15 trials (Figure 6). Other outcomes had reduced networks with 4 trials for PsARC, 6 for PASI and only 2 for HAQ-DI change from baseline conditional on PsARC response. A total of 10 trials were included in the analysis at week 24. The ACR responses were reported from all 10 trials (Figure 7). Other outcomes had reduced networks, with 3 trials for PsARC, 5 trials for PASI, and only 2 trials for HAQ-DI change from baseline conditional on PsARC response.

Figure 6: Network of Trials for NMA of Biologic-Experienced Patients for ACR50 At Week 12

Network diagram of the indirect treatment comparison for comparison of upadacitinib versus bDMARDs and tsDMARDs. The majority of the treatments connecting the placebo with only 1 trial. In the biologic-experienced ACR network, there are 4 trials (FUTURE 2, 3, 4, and 5) connecting secukinumab 150 mg versus placebo, 3 trials (FUTURE 2, 3, and 5) connecting secukinumab 300 mg versus placebo, 3 trials (PALACE 1, 2, and 3) connecting apremilast 30 mg versus placebo, and 2 trials (Deodhar 2018 and DISCOVER 1) connecting guselkumab Q8W versus placebo.

ABA = abatacept; ACR = American College of Rheumatology; ADA = adalimumab; APR = apremilast; bDMARD = biologic disease-modifying antirheumatic drug; BID = twice a day; BIW = twice a week; CZP = certolizumab; ETN = etanercept; GOL = golimumab; GUS = guselkumab; INF = infliximab; IV = IV infusion; IXE = ixekizumab; NMA = network meta-analysis; PBO = placebo; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; QD = every day; SC = subcutaneous injection; SEC = secukinumab; TOF = tofacitinib; tsDMARD = targeted synthetic disease-modifying antirheumatic drug; UPA = upadacitinib; UST = ustekinumab.

Source: Sponsor-submitted indirect treatment comparison.47

Figure 7: Network of Trials for NMA of Biologic-Experienced Patients for ACR50 at Week 24

Network diagram of the indirect treatment comparison for comparison of upadacitinib versus bDMARDs and tsDMARDs. In the biologic-experienced ACR network, there are 3 trials (FUTURE 2, 3, and 5) connecting secukinumab 150 mg versus placebo, 3 trials (FUTURE 2, 3, and 5) connecting secukinumab 300 mg versus placebo, and 2 trials (Deodhar 2018 and DISCOVER 1) connecting guselkumab Q8W versus placebo.

ABA = abatacept; ACR = American College of Rheumatology; ADA = adalimumab; APR = apremilast; bDMARD = biologic disease-modifying antirheumatic drug; BID = twice a day; BIW = twice a week; CZP = certolizumab; ETN = etanercept; GOL = golimumab; GUS = guselkumab; INF = infliximab; IV = IV infusion; IXE = Ixekizumab; mg = milligram; NMA = network meta-analysis; PBO = placebo; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; QD = every day; SC = subcutaneous injection; SEC = secukinumab; TOF = tofacitinib; tsDMARD = targeted synthetic disease-modifying antirheumatic drug; UPA = upadacitinib; UST = ustekinumab.

Source: Sponsor-submitted indirect treatment comparison.47

Summary of Results at 12 Weeks

Table 29, Table 30, and Table 35 present the results among biologic-experienced patients.

At week 12, all treatments had a higher response rate than placebo for all ACR measures. Upadacitinib 15 mg showed a higher ACR response rate than did abatacept SC. No difference was found when compared to abatacept IV, secukinumab, tofacitinib, ustekinumab, apremilast, ixekizumab, and guselkumab (Table 29).

Other Outcomes: The results for the other outcomes of interest suggested that upadacitinib 15 mg at 12 weeks was superior to placebo for all outcomes measured including PsARC, PASI, and HAQ-DI change from baseline.

For the PASI outcome measures, upadacitinib 15 mg at 12 weeks was favoured when compared to abatacept and tofacitinib; and no difference was reported when upadacitinib 15 mg was compared to secukinumab, ixekizumab, and ustekinumab (Table 30).

For the PsARC outcome measures at 12 weeks, no difference was reported when upadacitinib 15 mg was compared to ixekizumab, ustekinumab, and tofacitinib (Table 31).

For HAQ-DI at 12 weeks, upadacitinib 15 mg was compared only with ustekinumab 45 mg. Among PsARC responders and PsARC nonresponders, no difference was reported when upadacitinib 15 mg was compared to ustekinumab 45 mg.

Summary of Results at 24 Weeks

Among biologic-experienced patients at week 24, all treatments had a higher response rate than did placebo for all ACR measures. Upadacitinib 15 mg showed a higher ACR response rate than abatacept. No difference was found when upadacitinib 15 mg was compared to abatacept IV, secukinumab, ustekinumab, ixekizumab, and guselkumab (Table 29).

Other Outcomes: The results for the other outcomes of interest suggest that upadacitinib 15 mg at 24 weeks was superior to placebo for all outcomes measured including PsARC, and PASI.

For the PASI outcome measures, upadacitinib 15 mg at 24 weeks was favoured when compared to abatacept. No difference was reported when upadacitinib 15 mg was compared to secukinumab, ixekizumab, and ustekinumab (Table 30).

For the PsARC outcome measures at 24 weeks, no difference was reported when upadacitinib 15 mg was compared to ixekizumab and ustekinumab (Table 31).

For HAQ-DI at 24 weeks, upadacitinib 15 mg was only compared with ustekinumab 45 mg. Among PsARC responders and PsARC nonresponders, no difference was reported when upadacitinib 15 mg was compared to ustekinumab 45 mg.

Table 29: Summary of ITC Results for ACR20, ACR50, and ACR70 Among Biologic-Experienced Patients at 12 and 24 Weeks for Upadacitinib Oral 15 mg Versus Comparators

Comparator

Fixed-effects model odds ratio (95% CrI)

12 weeks

24 weeks

ACR20

ACR50

ACR70

ACR20

ACR50

ACR70

Placebo

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Abatacept SC

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Abatacept IV

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Secukinumab SC 150 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Tofacitinib

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Secukinumab SC 300 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ustekinumab

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Apremilast

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.2.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.4.w

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Guselkumab SC

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; CrI = credible interval; ITC = indirect treatment comparison; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneous.

aUpadacitinib was more efficacious than the comparator.

Source: Sponsor-submitted indirect treatment comparison.47

Table 30: Summary of ITC Results for PASI 50, PASI 75, and PASI 90 Among Biologic-Experienced Patients at 12 and 24 Weeks for Upadacitinib 15 mg Versus Comparators

Comparator

Fixed-effects model odds ratio (95% CrI)

12 weeks

24 weeks

PASI 50

PASI 75

PASI 90

PASI 50

PASI 75

PASI 90

Placebo

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Abatacept SC

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Tofacitinib

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Secukinumab SC 150 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.4.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg then 80 mg q.2.w.

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Secukinumab SC 300 mg

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

Ustekinumab SC

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

||||||||||||||||||||||

CrI = credible interval; ITC = indirect treatment comparison; PASI 50 = 50% reduction in Psoriasis Area Severity Index score; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneous.

aUpadacitinib was more efficacious than comparator.

bUpadacitinib was less efficacious than comparator.

Source: Sponsor-submitted indirect treatment comparision.47

Table 31: Summary of Indirect Treatment Comparison of Results for PsARC Among Biologic-Experienced Patients at 12 and 24 Weeks for Upadacitinib 15 mg Versus Comparators

Comparator

Fixed-effects model odds ratio (95% CrI)

12 weeks

24 weeks

Placebo

||||||||||||||||||||||

||||||||||||||||||||||

Ustekinumab SC 90 mg

||||||||||||||||||||||

||||||||||||||||||||||

Ustekinumab SC 45 mg

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.4.w.

||||||||||||||||||||||

||||||||||||||||||||||

Ixekizumab SC 160 mg at week 0, then 80 mg q.2.w.

||||||||||||||||||||||

||||||||||||||||||||||

Tofacitinib

||||||||||||||||||||||

||||||||||||||||||||||

CrI = credible interval; PsARC = Psoriatic Arthritis Response Criteria; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneous.

aUpadacitinib was more efficacious than the comparator.

Source: Sponsor-submitted indirect treatment comparison.47

Critical Appraisal of the Sponsor-Submitted Indirect Treatment Comparison

The sponsor-submitted ITC included all clinically relevant efficacy outcomes for PsA. Due to limitations of the submitted ITC, the results should be interpreted with caution. The major concerns with the submitted ITCs are related to the analysis’ failure to fully account for effect modifiers. Specifically, although significant heterogeneity was noted across different trials, particularly regarding the clinical characteristics of the patient population (i.e., status of disease, type of prior therapies, and use of concomitant treatments), no sensitivity analysis or subgroup analysis was attempted to assess the impact of these potential effect modifiers on the comparison of upadacitinib and other biologics. Additionally, the submitted ITC did not include any safety outcome of interest.

Clinical heterogeneity across the trials was evident in terms of inclusion criteria and patient baseline characteristics. Significant differences were noted in potential effect modifiers, such as duration of disease, including years of active disease, use of prior DMARDs, and disease severity, including the status of disease (e.g., active, refractory, or intolerant to prior DMARDs). These factors are heightened due to the variation in inclusion and exclusion criteria across the included studies. Although the inclusion of a larger number of studies allows for a larger sample, which allows for more informative analysis, there is a greater chance that results may be swayed by differences in characteristics across studies. The study needs further analyses, such as a subgroup analysis or meta-regression, to assess the potential impact of these effect modifiers on the estimates of efficacy outcomes.

Importantly, the analysis did not include other clinically meaningful outcomes such as PsA symptoms (e.g., pain and fatigue) or HRQoL. Although some of these might be represented in the outcome scores analyzed, they have been highlighted as important outcomes to report separately by both clinicians and patients. Last, no assessment of safety or tolerability was conducted. An overall assessment of the efficacy and safety profile between upadacitinib versus other bDMARDs available in current practice is missing. At a minimum, a better understanding of potential differences in discontinuation due to AEs may have highlighted potential differences between treatments. Given the importance of treatment adherence that occurs with this class of biologic medications, information on comparative safety would help weigh against comparative efficacy in decision-making. This understanding can provide important context for any observed results and strong overlaps with the efficacy outcomes. Current concerns with potential safety signals with the drug class make this an important assessment.

Summary

Overall, in biologic-naive patients, the NMA suggests that upadacitinib 15 mg is more efficacious for ACR response at week 12 compared to some comparators, specifically an IL-17 inhibitor (secukinumab 15 mg), IL-12/23 inhibitor (ustekinumab 45 mg), and IL-23 inhibitor (guselkumab), but this advantage was only seen for the IL-12/23 inhibitor at 24 weeks. Upadacitinib was also more efficacious than etanercept at both weeks 12 and 24 for PASI response; however, this was not seen with other TNF inhibitors. The IL-17 inhibitors (secukinumab 300 mg and ixekizumab) and IL-23 inhibitor (guselkumab) appear to be more efficacious than upadacitinib for PASI at week 12, although only the IL-23 inhibitor was favoured over upadacitinib at week 24. For PsARC, upadacitinib was more efficacious than tofacitinib but only at week 12; this was not seen at week 24. For HAQ-DI measured in PsARC responders at week 12, etanercept was more efficacious than upadacitinib; this benefit was not seen with other TNF inhibitors. At week 24, adalimumab was more efficacious than upadacitinib. The number of comparators included in some analyses (i.e., HAQ-DI at 24 weeks) was limited. For other analyses, no difference was seen between upadacitinib and the relevant comparators, and no consistent benefit of upadacitinib over bDMARDs or tsDMARDs was demonstrated across the measured end points of weeks 12 and 24.

In biologic-experienced patients, upadacitinib 15 mg was favoured only when compared to tofacitinib (a JAK inhibitor) in PASI response at week 12; this comparison was not performed at week 24. No difference in treatment effect was demonstrated in any other comparisons between upadacitinib and the included IL inhibitors. Not all IL inhibitors were included in every analyses, and the IL-23 inhibitor in particular was absent from many comparisons. Furthermore, TNF inhibitors were not included in any of the NMA analyses as insufficient eligible data were available for the bDMARD-experienced patient population, and no conclusions can be drawn on the comparative efficacy of upadacitinib in these patients. Also, because JAK inhibitors were not included in any of the week 24 analyses, the long-term comparative efficacy of upadacitinib compared to tofacitinib is unknown.

Taken together, and based on the sponsor-submitted ITC, upadacitinib does not show a consistent or distinct difference in efficacy as measured by ACR response, PASI, PsARC, or HAQ-DI when compared to bDMARDs or tsDMARDs in either bDMARD-naive or experienced patients. Although the NMA suggests upadacitinib is more efficacious over certain comparators in some end points, a consistent effect across all comparators or with specific classes of DMARDs (e.g., TNF inhibitors) was not observed. In particular, upadacitinib was not consistently favoured over comparators that are clinically relevant to this review, namely TNF inhibitors, IL inhibitors, and JAK inhibitors across both time points. Furthermore, not all comparators were included in every analysis, and some results were specific to a particular dosing regimen. A comparison with the tsDMARD most relevant to this review (tofacitinib) was largely absent, particularly in the bDMARD-experienced population. It is therefore difficult to draw a universal conclusion regarding the relative efficacy of upadacitinib versus bDMARDs, tsDMARDs, or specific classes of DMARDs. Compared to the biologic-naive population, the relative efficacy of upadacitinib to active comparators in the biologic-experienced population is less certain due to the fact that fewer agents were included in the analyses. Most importantly, conclusions regarding the long-term efficacy of upadacitinib compared to the active comparators relevant to this review cannot be drawn as the NMA used study results collected over an inappropriately short period given the chronic nature of PsA. There is also uncertainty due to the inherent heterogeneity across trials in the networks. The robustness of the comparative efficacy was further compromised by the lack of precision in the findings, and results from the sponsor-submitted ITC must be interpreted with caution. Moreover, no information was obtained regarding safety compared to other biologic or tsDMARDs. In addition, no conclusion could be drawn on the HRQoL outcomes.

Other Relevant Evidence

This section includes submitted long-term extension studies and additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review.

Long-Term Extension Studies

Both SELECT-PsA1 and SELECT-PsA2 included 2 study periods. The study duration in SELECT-PsA1 included a 35-day screening period; a 56-week blinded period that included 24 weeks of randomized, double-blind, placebo-controlled, and active comparator–controlled treatment followed by an additional 32 weeks of active comparator–controlled treatment (period 1); and a long-term extension period of up to a total treatment duration of approximately 5 years (period 2).33 The study duration in SELECT-PsA2 included a 35-day screening period; a 56-week blinded period that included 24 weeks of randomized, double-blind, parallel-group, placebo-controlled treatment followed by an additional 32 weeks of blinded upadacitinib treatment (period 1); and a long-term extension period (period 2) of up to a total treatment duration of approximately 3 years.11 The 56-week data for both studies are summarized in the following section.

Methods

At week 24 in both SELECT-PsA1 and PsA2, patients who were randomized to placebo at the start of the study were switched to pre-assigned oral upadacitinib 15 mg or 30 mg once daily in a 1:1 ratio, regardless of response. Patients, study-site personnel, the investigator, and the sponsor study team were blinded to study drug assignment, until all patients completed the week 24 visit. Thereafter, an unblinded analysis was conducted by the sponsor but the study sites and patients remained blinded. When the last patient completed the last visit of period 1 (week 56), the drug assignments were unblinded and treatment was continued in an open-label manner until period 2 had completed.11,33

Populations and Patient Disposition

Because the data from week 24 to week 56 were collected during an extension of the initial 24 weeks of SELECT-PsA1 and SELECT-PsA2, the populations at baseline were the same as those reported earlier in this report. A summary of patient disposition through to week 56 is presented in Table 32. SELECT-PsA1 reported that 362 patients (84.2%) completed the study drug dosing in the upadacitinib arm, 353 patients (82.3%) completed the drug dosing in the adalimumab arm, and 172 patients (81.5%) completed in the placebo-to-upadacitinib arm for period 1.33 In SELECT-PsA2, 65 patients (61.3%), and 159 patients (75.4%) completed the drug dosing in the placebo-to-upadacitinib arm and the upadacitinib arm, respectively.11

Table 32: Patient Disposition up to Week 56

Disposition

SELECT-PsA1

SELECT-PsA2

PBO followed by UPA 15 mga

ADA

40 mg

UPA

15 mg

PBO followed by UPA 15 mga

UPA

15 mg

Randomized, N (%)

211

429

430

106

211

Completed period 1 (week 56) on study drug, N (%)

172 (81.5)

353 (82.3)

362 (84.2)

65 (61.3)

159 (75.4)

Discontinued study drug during period 1, N (%)

39 (18.5)

76 (17.7)

68 (15.8)

41 (38.7)

52 (24.6)

Primary reason for discontinuation, N (%)

  Adverse event

9 (4.3)

23 (5.4)

21 (4.9)

10 (9.4)

18 (8.5)

  Withdrawal by subject

12 (5.7)

20 (4.7)

24 (5.6)

10b (9.4)

3 (1.4)

  Lost to follow-up

3 (1.4)

4 (0.9)

7 (1.6)

3 (2.8)

6 (2.8)

  Lack of efficacy

12 (5.7)

24 (5.6)

11 (2.6)

17 (16.0)

20 (9.5)

  Met discontinuation criteria (from week 36)c

4 (1.9)

12 (2.8)

4 (0.9)

1 (0.9)

7 (3.3)

  Other

3 (1.4)

5 (1.2)

5 (1.2)

1 (0.9)

5 (2.4)

ADA = adalimumab; PBO = placebo; UPA = upadacitinib.

Note: UPA 30 mg oral once-daily (n = 423 in SELECT-PsA1; n = 219 in SELECT-PsA2) and PBO to UPA 30 mg oral once-daily treatment groups are not shown.

aPBO/UPA = PBO day 1 through week 24 and UPA thereafter. At week 24, patients randomized to placebo (N = 423 for SELECT-PsA1 and N = 212 for SELECT-PsA2) were switched to UPA. Patients who were randomized to placebo were pre-assigned to either UPA 15 mg or 30 mg, orally once daily, in a 1:1 ratio. During weeks 24 to 56, the following number of patients were switched to upadacitinib:

• SELECT-PsA1: n = 211 (PBO to UPA 15 mg), n = 212 (PBO to UPA 30 mg)

• SELECT-PsA2: n = 106 (PBO to UPA 15 mg), n = 106 (PBO to UPA 30 mg)

bOne participant met the criteria for discontinuation due to lack of efficacy but was reported as a withdrawal by subject.

cDiscontinuation criteria is failure to show at least 20% improvement in either or both tender joint count or swollen joint count compared to baseline at 2 consecutive visits.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Interventions

Patients who initially received placebo in SELECT-PsA1 and SELECT-PsA2 trials were switched to upadacitinib 15 mg or upadacitinib 30 mg at week 24. The long-term efficacy outcomes presented here include patients who received either upadacitinib, placebo followed by upadacitinib, or adalimumab (SELECT-PsA1 trial only) for all of period 1 (56 weeks).

All patients participating in SELECT-PsA1 who met eligibility criteria were randomized to receive upadacitinib 15 mg or 30 mg once daily (N = 430 and N = 423, respectively), adalimumab 40 mg every other week (N = 429), or placebo (N = 423) during the first 24 weeks, after which patients receiving placebo were switched to upadacitinib 15 mg (N = 211) or 30 mg (N = 212).33 All patients participating who met eligibility criteria for SELECT-PsA2 were randomized to receive upadacitinib 15 mg (N = 210) or 30 mg (N = 210), or placebo during the first 24 weeks, after which patients receiving placebo were switched to upadacitinib 15 mg (N = 105) or 30 mg (N = 105).11 Further description of the 30 mg upadacitinib group was not included in this review as the dose is higher than the dose approved by Health Canada.

After the last patient completed the week 24 study visit, the sponsor conducted an unblinded analysis for the purpose of initial regulatory submission. A second unblinded analysis was conducted for regulatory purposes after all patients completed period 1.11,33

Outcomes

The efficacy outcomes presented here correspond to the data available for the outcomes reported in the report above (week 24 data).

Statistical Analysis

Descriptive statistics and 95% CIs were provided for each randomized treatment group in the long term efficacy analysis. In SELECT-PsA1, treatment comparisons between each upadacitinib dose versus adalimumab were made for efficacy end points for the originally randomized upadacitinib groups and adalimumab group. No adjustment was made for multiple comparisons to evaluate long-term efficacy.

For non-radiographic binary end points, as-observed data analysis and as-observed data with imputation, missing measurements were imputed as nonresponders. As-observed data without imputation are presented in this section. Frequencies (point estimates) and 95% CIs using normal approximation were provided for the response rate for each randomized treatment group. Comparisons were made between each originally randomized upadacitinib dose group and the adalimumab group using the Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current DMARD use (yes/no).

For non-radiographic continuous end points, comparisons were made between each originally randomized upadacitinib dose group and the adalimumab group using the MMRM model based on as-observed data, with fixed effects of treatment, visit, treatment-by-visit interaction, and the stratification factor of current DMARD use (yes/no) and the continuous fixed covariate of baseline measurement. The LS mean and 95% CI for each randomized treatment group were provided.

For radiographic end points, analysis was based on linear extrapolation imputation and as-observed data.11,33

Long-term safety analyses that accounted for protocol-defined treatment switching for both SELECT-PsA1 and SELECT-PsA2 included reporting of AE rates adjusted by cumulative exposure. The TEAE rate per 100 PYs of exposure was presented by actual treatment received at the time of AE.11,33

Exposure to Study Treatments

Through the data cut-off, the mean durations of study drug exposure in SELECT-PsA1 were similar among the upadacitinib 15 mg and adalimumab group. The mean durations of exposure to adalimumab were 537.6 days (SD = 221.71), and 496.7 days (SD = 216.32) in the upadacitinib 15 mg group. For patients who switched from placebo to upadacitinib 15 mg or 30 mg at week 24, their exposure to upadacitinib is included in this data.33 The mean duration of exposure in SELECT-PsA2 to upadacitinib 15 mg was 528.3 days (SD = 273.17). Data for exposure in SELECT-PsA1 represents period 1 and period 2 combined exposure and is presented by treatment received.11

Efficacy

Only the efficacy outcomes identified in the review protocol and those indicated as important by patient groups are reported below. Data tables are only presented for end points that were included in the multiplicity-controlled analyses (primary and major secondary efficacy outcomes). These coincide with the end points for week 24 data. Data tables for end points that were not part of the statistical testing hierarchy are presented in Appendix 3. The results of as-observed analysis with imputation are consistent with the as-observed results.

ACR20, ARC50, and ARC70

The percentages of patients who achieved an ACR20, ARC50, or ARC70 at week 56 are summarized in Table 33. SELECT-PsA1 reported 85.9% (95% CI, 71.7 to 79.8), 68.2% (95% CI, 63.4 to 73.0) and 45.8% (95% CI, 40.8 to 50.9) of patients met criteria for ACR20, ARC50, and ARC70, respectively, at week 56 in the upadacitinib 15 mg group, and 81.2% (95% CI, 77.1 to 85.2), 60.1% (95% CI, 55.0 to 65.2) and 36.5% (95% CI, 31.5 to 41.5) in the adalimumab group. Among patients who started on placebo and switched to upadacitinib at week 24, the trajectory for achievement of ACR20, ARC50, or ARC70 after upadacitinib initiation was similar to that observed after upadacitinib initiation in patients who started upadacitinib on day 1, with respective response rates at week 56 of 87.6% (95% CI, 82.7 to 92.4), 64.4% (95% CI, 57.4 to 71.5), and 34.8% (95% CI, 27.8 to 41.8) in the placebo-to-upadacitinib 15 mg group. Compared with the adalimumab group, the proportion of patients who achieved an ACR20, ARC50, or ARC70 was greater in the upadacitinib 15 mg group at most visits beyond week 24 and through week 56, with response-rate differences of 6.3% (95% CI, 0.3 to 12.2) for ACR20, 8.1% (95% CI, 1.1 to 15.1) for ACR50, and 9.3% (95% CI, 2.2 to 16.4) for ACR70.33

Among patients randomized to initiate upadacitinib treatment on day 1 in SELECT-PsA2, the percentage of patients who achieved ACR20, ARC50, or ARC70 at week 24 continued to increase or was maintained throughout week 56 for the 15 mg dose. The percentages of patients who achieved ACR20, ARC50, or ARC70 at week 56 were 79.6% (95% CI, 73.4 to 85.8), 52.8% (95% CI, 45.1 to 60.4), and 31.1% (95% CI, 24.0 to 38.2), respectively, in the 15 mg dose group. For patients who started on placebo and switched to upadacitinib at week 24, the trajectory for achievement of ACR20, ARC50, or ARC70 after starting upadacitinib was similar to that observed after upadacitinib initiation in patients who started upadacitinib on day 1, with response rates at week 56 of 78.3% (95% CI, 68.5 to 88.0), 47.8% (95% CI, 36.0 to 59.6), and 24.6% (95% CI, 14.5 to 34.8), respectively, in the 15 mg dose group.11

Table 33: Clinical Response (ACR20, ARC50, and ARC70) at Week 56

Treatment group

Total N

Responders,

n (%)

Response rate

(95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

ACR20 response rate at week 56

SELECT-PsA1

PBO to UPA 15 mg q.d.

177

155 (87.6)

87.6 (82.7 to 92.4)

6.3 (0.3 to 12.2) UPA vs. ADA

0.0391

ADA 40 mg e.o.w.

356

289 (81.2)

81.2 (77.1 to 85.2)

UPA 15 mg q.d.

369

317 (85.9)

85.9 (71.7 to 79.8)

SELECT-PsA2

PBO to UPA 15 mg q.d.

69

54 (78.3)

78.3 (68.5 to 88.0)

NR

NR

UPA 15 mg q.d.

162

129 (79.6)

79.6 (73.4 to 85.8)

ACR50 response at week 56

SELECT-PsA1

PBO to UPA 15 mg q.d.

177

114 (64.4)

64.4 (57.4 to 71.5)

8.1 (1.1 to 15.1) UPA vs. ADA

0.0236

ADA 40 mg e.o.w

356

214 (60.1)

60.1 (55.0 to 65.2)

UPA 15 mg q.d.

368

251 (68.2)

68.2 (63.4 to 73.0)

SELECT-PsA2

PBO to UPA 15 mg q.d.

69

33 (47.8)

47.8 (36.0 to 59.6)

NR

NR

UPA 15 mg q.d.

163

86 (52.8)

52.8 (45.1 to 60.4)

ACR70 response at week 56

SELECT-PsA1

PBO to UPA 15 mg q.d.

178

62 (34.8)

34.8 (27.8 to 41.8)

9.3 (2.2 to 16.4) UPA vs. ADA

0.0105

ADA 40 mg e.o.w.

359

131 (36.5)

36.5 (31.5 to 41.5)

UPA 15 mg q.d.

371

170 (45.8)

45.8 (40.8 to 50.9)

SELECT-PsA2

PBO to UPA 15 mg q.d.

69

17 (24.6)

24.6 (14.5 to 34.8)

NR

NR

UPA 15 mg q.d.

164

51 (31.1)

31.1 (24.0 to 38.2)

ADA = adalimumab; CI = confidence interval; e.o.w = every other week; PBO = placebo; NR = not reported; q.d. = daily; UPA = upadacitinib; vs. = versus .

Note: Patients randomized to PBO to UPA 15 mg q.d. or PBO to UPA 30 mg q.d. switched to UPA 15 mg q.d. or UPA 30 mg q.d. at week 24 and their data up to week 24 are under PBO exposure.

a95% CIs for response rates are calculated based on normal approximation to the binomial distribution.

b95% CIs for response rates difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). However, no adjustment was made for multiple comparisons.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

HAQ-DI, Patient’s Assessment of Pain, FACIT-F, SF-36, SAPS, and PsA SHS

The change from baseline to week 56 for both SELECT-PsA1 and SELECT-PsA2 was reported for the HAQ-DI, patient’s assessment of pain scale, FACIT-F, SF-36, SAPS, and PsA SHS.

Among patients in both studies who were randomized to initiate upadacitinib 15 mg or adalimumab on day 1, the results for the ACR components (HAQ-DI and patient’s assessment of pain) at week 24 showed a reduction in disability or improvement in health status through to week 56 (Table 34 and Table 35). Improvement in patient-reported outcomes at week 24, as measured by mean changes from baseline in SF-36 PCS and MCS and FACIT-F were also improved over time or maintained through week 56. In SELECT-PsA1, a greater improvement in SF-36 PCS and FACIT-F was observed in the upadacitinib 15 mg group compared with the adalimumab group (Table 36 and Table 37). Additionally, the mean decreases from baseline in SAPS for those randomized to receive upadacitinib 15 mg or adalimumab continued to decrease or were maintained through week 56. In SELECT-PsA1, greater improvements in SAPS were observed in the upadacitinib 15 mg group compared with the adalimumab group at all visits beyond week 24 through week 56 (nominal P < 0.05) (Table 38). Among patients who started on placebo and switched to upadacitinib at week 24, the trajectory for improvements achieved after upadacitinib initiation was similar to that observed after upadacitinib initiation in patients who started upadacitinib on day 1, leading to comparable results at week 56.11,33

For SHS in SELECT-PsA1, results from as-observed analyses were consistent with the linear extrapolation analyses. At week 56, patients in the upadacitinib 15 mg group had a smaller mean increase in SHS from baseline compared with those initially randomized to placebo.33 In SELECT-PsA2, SHS was not measured in patients (Table 39).

Table 34: Change From Baseline in HAQ-DI at Week 56

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)b

LS mean difference

(95% CI)

P valuea

HAQ-DI at week 56 (as observed; FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

178

1.08

0.68

−0.40 (−0.48 to −0.32)

−0.11 (−0.18 to −0.03) UPA vs. ADA

0.0065

ADA 40 mg e.o.w.

361

1.09

0.65

−0.43 (−0.49 to −0.38)

UPA 15 mg q.d.

370

1.12

0.56

−0.54 (−0.59 to −0.48)

SELECT-PsA2

PBO to UPA 15 mg q.d.

69

1.21

0.81

−0.40 (−0.52 to −0.29)

NR

NR

UPA 15 mg q.d.

164

1.07

0.69

−0.35 (−0.43 to −0.27)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; HAQ-DI = Health Assessment Questionnaire–Disability Index; LS = least squares; NR = not reported; PBO = placebo; q.d. = daily; UPA = upadacitinib; vs. = versus .

Note: Patients randomized to placebo to upadacitinib 15 mg q.d. or placebo to upadacitinib 30 mg q.d. switched to the respective upadacitinib dosage at week 24 and their data up to week 24 are under placebo exposure.

aStatistically significant at the 0.05 level.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and nominal P value are based on a mixed model for repeated measures analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor current of disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 35: Change From Baseline in Patient’s Assessment of Pain at Week 56

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)

P valuea

Pain NRS at week 56 (as observed; FAS)

SELECT-PsA1b

PBO to UPA 15 mg q.d.

178

6.0

2.8

−3.1 (−3.5 to −2.8)

−0.4 (−0.8 to −0.1) UPA vs. ADA

0.0106

ADA 40 mg e.o.w.

362

5.9

2.9

−2.9 (−3.1 to −2.7)

UPA 15 mg q.d.

370

6.1

2.6

−3.3 (−3.6 to −3.1)

SELECT-PsA2c

PBO to UPA 15 mg q.d.

69

6.7

4.0

−2.4 (−3.0 to −1.9)

NR

NR

UPA 15 mg q.d.

164

6.3

3.5

−2.6 (−2.9 to −2.2)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; LS = least squares; NRS = numerical rating scale; NR = not reported; PBO = placebo; q.d. = daily; UPA = upadacitinib; vs. = versus .

Note: Patients randomized to PBO to UPA 15 mg q.d. or PBO to UPA 30 mg q.d. switched to UPA 15 mg q.d. or UPA 30 mg q.d. at week 24 and their data up to week 24 are under PBO exposure.

aP values are presented where available; however, analyses were not adjusted for multiple comparisons.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and nominal P values are based on a mixed model for repeated measures analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement.

c95% CIs were calculated based on mixed model for repeated measures analysis with an unstructured variance-covariance matrix.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 36: Change From Baseline in FACIT-F at Week 56

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)b

P valuea

FACIT-F at week 56 (as observed; FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

178

31.5

38.0

7.2 (5.9 to 8.6)

1.35 (−0.0 to 2.6) UPA vs. ADA

0.0510

ADA 40 mg e.o.w.

364

30.5

38.2

7.6 (6.7 to 8.6)

UPA 15 mg q.d.

370

29.3

38.7

8.9 (8.0 to 9.9)

SELECT-PsA2

PBO to UPA 15 mg q.d.

67

54.1

63.7

7.7 (2.6 to 12.7)

NA

NA

UPA 15 mg q.d.

163

54.4

66.2

10.6 (7.4 to 13.9)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; FAS = full analysis set; LS = least squares; NA = not applicable; PBO = placebo; q.d. = every day; UPA = upadacitinib; vs. = versus .

aP values are presented where available; however, analyses were not adjusted for multiple comparisons.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and nominal P values are based on a mixed model for repeated measurement analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 37: Change From Baseline in SF-36 at Week 56

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within-group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)

P valuea

PCS at week 56 (MMRM,b FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

178

35.78

44.82

9.27 (8.03 to 10.50)

1.93 (0.75 to 3.11) UPA vs. ADA

0.0014

ADA 40 mg e.o.w.

364

36.02

45.04

8.91 (8.04 to 9.78)

UPA 15 mg q.d.

371

34.96

46.34

10.84 (9.96 to 11.72)

SELECT-PsA2

PBO to UPA 15 mg q.d.

68

35.32

42.52

6.74 (4.88 to 8.60)

NA

NA

UPA 15 mg q.d.

163

35.07

42.91

7.21 (5.99 to 8.44)

MCS at week 56 (MMRM,b FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

178

45.60

49.25

3.63 (2.34 to 4.93)

0.86 (−0.38 to 2.10) UPA vs. ADA

0.1758

ADA 40 mg e.o.w

364

45.72

50.09

4.29 (3.37 to 5.21)

UPA 15 mg q.d.

371

45.18

50.57

5.15 (4.23 to 6.07)

SELECT-PsA2

PBO to UPA 15 mg q.d.

68

42.26

47.47

3.63 (1.67 to 5.60)

NR

NR

UPA 15 mg q.d.

163

45.05

48.56

3.33 (2.04 to 4.62)

ADA = adalimumab; CI = confidence interval; FAS = full analysis set; LS = least squares; MCS = mental component summary; MMRM = mixed model for repeated measures; PCS = physical component summary; NA = not applicable; NR = not reported; PBO = placebo; q.d. = daily; SF-36 = Short Form (36) Health Survey; UPA = upadacitinib; vs. = versus .

Note: Patients randomized to PBO to UPA 15 mg q.d. or PBO to UPA 30 mg q.d. switched to UPA 15 mg q.d. or UPA 30 mg q.d. at week 24 and their data up to week 24 are under PBO exposure.

aP values are presented where available; however, analyses were not adjusted for multiple comparisons.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and nominal P values are based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 12 before premature discontinuation of the study drug.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 38: Change From Baseline in SAPS at Week 56

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)

LS mean difference (95% CI)

P valuea

SAPS at week 56 (MMRM,b FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

178

44.2

15.1

−28.1 (−30.5 to −25.6)

−3.8 (−6.1 to −1.5) UPA vs. ADA

0.0014

ADA 40 mg e.o.w.

364

42.5

16.3

−25.8 (−27.6 to −24.1)

UPA 15 mg q.d.

370

44.3

13.2

−29.6 (−31.4 to −27.9)

SELECT-PsA2

PBO to UPA 15 mg q.d.

67

55.6

24.8

−26.6 (−30.9 to −22.3)

NR

NR

UPA 15 mg q.d.

163

48.0

19.9

−27.7 (−30.5 to −24.9)

ADA = adalimumab; CI = confidence interval; e.o.w = every other week; FAS = full analysis set; LS = least squares; MMRM = mixed model for repeated measures; NR = not reported; PBO = placebo; q.d. = daily; SAPS = Self-Assessment of Psoriasis Symptoms; UPA = upadacitinib; vs. = versus .

aP values are presented where available; however, analyses were not adjusted for multiple comparisons.

bWithin-group LS mean and 95% CI, and between-group LS mean difference and 95% CI and nominal P values are based on an MMRM analysis with unstructured variance-covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and the continuous fixed covariate of baseline measurement. The MMRM analysis used observed longitudinal data up to week 16 before premature discontinuation of the study drug.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 39: Change From Baseline in Psoriatic Arthritis SHS at Week 56

Treatment group

Total N

Baseline, mean

Visit, mean

Change from baseline

Within group

Between-group comparison

LS mean (95% CI)a

LS mean difference (95% CI)

P value

SHS at week 56 (as observed; FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

170

13.87

14.19

0.33 (0.15 to 0.51)

NR

NR

ADA 40 mg e.o.w.

337

14.35

14.29

−0.06 (−0.19 to 0.08)

NR

NR

UPA 15 mg q.d.

353

12.00

11.96

−0.03 (−0.11 to 0.16)

NR

NR

SELECT-PsA2

PBO to UPA 15 mg q.d.

NR

NR

NR

NR

NR

NR

UPA 15 mg q.d.

NR

NR

NR

NR

NR

NR

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; LS = least squares; NR = not reported; PBO = placebo; q.d. = daily; SHS = Sharp/van der Heijde Score; UPA = upadacitinib.

aWithin-group LS mean and 95% CI were based on an analysis of covariance model including treatment and the stratification factor of current disease-modifying antirheumatic drug use (yes/no) as fixed factors and baseline value as covariate.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Dactylitis, Enthesitis, MDA, PASI, and sIGA

Of the patients in both SELECT-PsA1 and SELECT-PsA2 who had dactylitis and enthesitis at baseline and were randomized to initiate upadacitinib or adalimumab on day 1, the proportion who achieved resolution of dactylitis and enthesitis continued to increase through week 56. The proportion of patients in SELECT-PsA1 who achieved resolution of dactylitis and enthesitis at week 56 were similar in the upadacitinib 15 mg group compared with the adalimumab group (Table 40 and Table 41).

Among patients in SELECT-PsA1 and SELECT-PsA2 randomized to upadacitinib 15 mg or adalimumab on day 1, the proportion of patients who achieved MDA at week 24 continued to increase or was maintained through week 56. In SELECT-PsA1, for all visits beyond week 24 and through week 56, a greater proportion of patients in the upadacitinib 15 mg group achieved MDA compared to the adalimumab group, producing a response-rate difference of 7.6% (95% CI, 0.4 to 14.8) (Table 42). Among those patients in SELECT-PsA1 and SELECT-PsA2 who had psoriasis on at least 3% of their BSA at baseline and were randomized to initiate upadacitinib 15 mg or adalimumab on day 1, the proportion of patients achieving PASI 75 at week 24 continued to increase or was maintained through week 56. In SELECT-PsA1, improvements in PASI 75 were similar among the upadacitinib 15 mg, and adalimumab groups at week 56 (Table 43).

Patients who started on placebo and switched to upadacitinib at week 24 had a similar trajectory for the resolution of dactylitis, resolution of enthesitis, achievement of MDA, and achievement of PASI 75 response after upadacitinib initiation to that of patients who started upadacitinib on day 1, leading to comparable results at week 56.

A similar trend was observed for the proportion of patients achieving sIGA score of 0 or 1 with an improvement of at least 2 points from baseline (Table 44).11,33

Table 40: Proportion of Patients Achieving Dactylitis Resolution at Week 56

Treatment group

Total N

Responders, n (%)

Response rate

(95% CI)a

Response-rate difference vs. control

Point estimate (95% CI)b

P valuec

LDI = 0 at week 56 (as observed, FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

56

50 (89.3)

89.3 (81.2 to 97.4)

0.7 (−5.9 to 7.2) UPA vs. ADA

0.8225

ADA 40 mg e.o.w

110

102 (92.7)

92.7 (87.9 to 97.6)

UPA 15 mg q.d.

121

113 (93.4)

93.4 (89.0 to 97.8)

SELECT-PsA2e

PBO to UPA 15 mg q.d.

20

20 (100)

100 (100.0 to 100.0)

NR

NR

UPA 15 mg q.d.

44

35 (79.5)

79.5 (67.6 to 91.5)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; LDI = Leeds Dactylitis Index; NR = not reported; PBO = placebo; q.d. = daily; UPA = upadacitinib; vs. = versus .

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). However, no adjustment was made for multiple comparisons.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 41: Proportion of Patients Achieving Enthesitis Resolution at Week 56

Treatment group

Total N

Responders, n (%)

Response rate

(95% CI)a

Response-rate difference

Point estimate (95% CI)b

P valuec

LEI = 0 at week 56 (as observed, FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

102

70 (68.6)

68.6 (59.6 to 77.6)

4.1 (−4.1 to 12.3) UPA vs. ADA

0.3111

ADA 40 mg e.o.w.

218

155 (71.1)

71.1 (65.1 to 77.1)

UPA 15 mg q.d.

234

176 (75.2)

75.2 (69.7 to 80.7)

SELECT-PsA2

PBO to UPA 15 mg q.d.

46

31 (67.4)

67.4 (53.8 to 80.9)

NR

NR

UPA 15 mg q.d.

101

62 (61.4)

61.4 (51.9 to 70.9)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; LEI = Leeds Enthesitis Index; NR = not reported; PBO = placebo; q.d. = daily; UPA = upadacitinib; vs. = versus .

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response-rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). However, no adjustment was made for multiple comparisons.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 42: Proportion of Patients Achieving Minimal Disease Activity at Week 56

Treatment group

Total N

Responders, n (%)

Response rate (95% CI)a

Response-rate difference

Point estimate (95% CI)b

P valuec

Minimal disease activity at week 56 (as observed; FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

178

79 (44.4)

44.4 (37.1 to 51.7)

7.6 (0.4 to 14.8) UPA vs. ADA

0.0414

ADA 40 mg e.o.w.

362

171 (47.2)

47.2 (42.1 to 52.4)

UPA 15 mg q.d.

374

205 (54.8)

54.8 (49.8 to 59.9)

SELECT-PsA2

PBO to UPA 15 mg q.d.

70

19 (27.1)

27.1 (16.7 to 37.6)

NR

NR

UPA 15 mg q.d.

166

64 (38.6)

38.6 (31.2 to 46.0)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; NR = not reported; PBO = placebo; q.d. = daily; UPA = upadacitinib; vs. = versus .

a95% CI for response rates is calculated based on normal approximation to the binomial distribution.

b95% CI for response-rate difference are calculated based on normal approximation.

cP value was constructed using Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). However, no adjustment was made for multiple comparisons.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 43: Proportion of Patients Achieving PASI 75 at Week 56

Treatment group

Total N

Responders,

n (%)

Response rate

(95% CI)a

Response-rate difference

Point estimate (95% CI)b

P valuec

PASI 75 at week 56 (as observed, FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

88

61 (69.3)

69.3 (59.7 to 79.0)

4.0 (−4.9 to 12.9) UPA vs. ADA

0.3806

ADA 40 mg e.o.w.

178

129 (72.5)

72.5 (65.9 to 79.0)

UPA 15 mg q.d.

187

143 (76.5)

76.5 (70.4 to 82.6)

SELECT-PsA2

PBO to UPA 15 mg q.d.

44

29 (65.9)

65.9 (51.9 to 79.9)

NR

NR

UPA 15 mg q.d.

104

70 (67.3)

67.3 (58.3 to 76.3)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; NR = not reported; PBO = placebo; q.d. = daily; UPA = upadacitinib; vs. = versus .

Note: Patients randomized to PBO to UPA 15 mg q.d. or PBO to UPA 30 mg q.d. switched to UPA 15 mg q.d. or UPA 30 mg q.d. at week 24 and their data up to week 24 are under PBO exposure. Analysis of PASI 75 was performed only in patients with psoriasis on at least 3% of their BSA at baseline.

a95% CI for response rates is calculated based on normal approximation to the binomial distribution.

b95% CI for response-rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). However, no adjustment was made for multiple comparisons.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Table 44: Proportion of Patients Achieving an sIGA of Psoriasis Score of 0 or 1 at Week 56

Treatment group

Total N

Responders, n (%)

Response rate

(95% CI)a

Response-rate difference

Point estimate (95% CI)b

P valuec

sIGA at week 56 (as observed; FAS)

SELECT-PsA1

PBO to UPA 15 mg q.d.

137

52 (38.0)

38.0 (29.8 to 46.1)

5.0 (−3.1 to 13.2) UPA vs. ADA

0.2429

ADA 40 mg e.o.w

283

156 (55.1)

55.1 (49.3 to 60.9)

UPA 15 mg q.d.

281

169 (60.1)

60.1 (54.4 to 65.9)

SELECT-PsA2

PBO to UPA 15 mg q.d.

56

24 (42.9)

42.9 (29.9 to 55.8)

NR

NR

UPA 15 mg q.d.

131

58 (44.3)

44.3 (35.8 to 52.8)

ADA = adalimumab; CI = confidence interval; e.o.w. = every other week; FAS = full analysis set; NR = not reported; PBO = placebo; q.d. = daily; sIGA = static Investigator Global Assessment; UPA = upadacitinib; vs. = versus .

Note: Analysis was performed for patients who achieved a score of 0 or 1 and an improvement of at least 2 points from baseline, and only in patients with a baseline sIGA at least 2%.

a95% CI for response rates are calculated based on normal approximation to the binomial distribution.

b95% CI for response-rate difference are calculated based on normal approximation.

cThe P value was constructed using a Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current disease-modifying antirheumatic drug use (yes/no). However, no adjustment was made for multiple comparisons.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Additional End Points

Data tables for the following additional end points from week 56 can be found in Appendix 3: Proportion of Patients Achieving Modified PsARC Response (Table 53), change from baseline in WPAI (Table 54), change from baseline in EQ-5D-5L (Table 55), change from baseline in BASDAI at week 56 (Table 56), and proportion of patients achieving PASI 90 or PASI 100 at week 56 (Table 57).These were not part of the original multiplicity-controlled testing hierarchy in the week 24 analyses.

Harms

The pooled harms data up to week 56 from SELECT-PsA1 and SELECT-PsA2 studies are summarized in Table 45. Safety data through the data cut-offs that include period 1 and period 2 are presented as exposure-adjusted event rates. Of those patients in SELECT-PsA1 receiving adalimumab, 265.9 events per 100 PY were reported for at least 1 AE, 9.3 events per 100 PY were reported for at least 1 SAE and 7.4 events per 100 PY were reported for patients who stopped treatment due to AEs, and death was reported as 0.2 per 100 PY. Of those patients in SELECT-PsA1 receiving upadacitinib (15 mg), 281.1 events per 100 PY were reported for at least 1 AE, 9.1 events per 100 PY were reported for at least 1 SAE and 4.6 events per 100 PY were reported for patients who stopped treatment due to AEs.33 Patients in SELECT-PsA2 receiving upadacitinib reported 260.6 events per 100 patient PY for at least 1 AE, 14.3 events per 100 PY were reported for at least 1 SAE and 10.0 events per 100 PY were reported for patients who stopped treatment due to AEs.11 In SELECT-PsA1, individual notable harms were higher in patients receiving upadacitinib (15 mg) for all individual harms except for neutropenia (4.2 events per 100 PY for adalimumab versus 2.4 events per 100 PY for upadacitinib) and hepatic disorder (24.9 events per 100 PY for adalimumab versus 19.1 events per 100 PY for upadacitinib).33

Table 45: Summary of Harms up to Week 56 — Safety Population

Adverse events

SELECT-PsA1

SELECT-PsA2

ADA 40 mg

N = 429

PY = 631.4

UPA 15 mga

N = 617

PY = 839.1

UPA 15 mga

N = 290

PY = 419.4

Patients with at least 1 adverse event

E (E/100 PY)

1,679 (265.9)

2,359 (281.1)

1,093 (260.6)

Most common events,b E (E/100 PY)

  Upper respiratory tract infection

73 (11.6)

124 (14.8)

46 (11.0)

  Increased blood CPK

46 (7.3)

100 (11.9)

22 (5.2)

  Nasopharyngitis

67 (10.6)

72 (8.6)

49 (11.7)

  Increased ALT

58 (9.2)

68 (8.1)

5 (1.2)

  Urinary tract infection

23 (3.6)

56 (6.7)

41 (9.8)

  Bronchitis

18 (2.9)

48 (5.7)

37 (8.8)

  Hypertension

17 (2.7)

47 (5.6)

24 (5.7)

  Increased AST

38 (6.0)

46 (5.5)

1 (0.2)

  Headache

29 (4.6)

43 (5.1)

6 (1.4)

  Psoriatic arthropathyc

32 (5.1)

25 (3.0)

28 (6.7)

  Influenza

5 (0.8)

27 (3.2)

22 (5.2)

  Sinusitis

15 (2.4)

21 (2.5)

23 (5.5)

Patients with ≥ 1 serious adverse event

E (E/100 PY)

59 (9.3)

76 (9.1)

60 (14.3)

Most common events,d E (E/100 PY)

  Pneumonia

1 (0.2)

6 (0.7)

3 (0.7)

  Herpes zoster

0

2 (0.2)

0

  Pulmonary embolism

0

2 (0.2)

1 (0.2)

  Corona virus infection

1 (0.2)

2 (0.2)

NR

  Angioedema

0

2 (0.2)

NR

  Depression

0

2 (0.2)

NR

  Diverticulitis

0

2 (0.2)

0

  Sepsis

0

2 (0.2)

0

  Uterine prolapse

0

2 (0.2)

NR

  Osteoarthritis

4 (0.6)

1 (0.1)

1 (0.2)

  Cellulitis

3 (0.5)

1 (0.1)

2 (0.5)

  Cholelithiasis

0

1 (0.1)

2 (0.5)

  Cerebrovascular accident

2 (0.3)

0

NR

  Psoriatic arthropathyc

0

0

4 (1.0)

  Acute kidney injury

0

0

2 (0.5)

  Dizziness

NR

NR

2 (0.5)

  Nephrolithiasis

1 (0.2)

0

2 (0.5)

Patients who stopped treatment due to adverse events

E (E/100 PY)

47 (7.4)

39 (4.6)

42 (10.0)

Most common events,d E (E/100 PY)

  Blood CPK increased

0

2 (0.2)

0

  Herpes zoster

0

2 (0.2)

0

  Sepsis

0

2 (0.2)

NR

  Psoriatic arthropathyc

3 (0.5)

1 (0.1)

5 (1.2)

  Increased ALT

3 (0.5)

0

0

  Alopecia

2 (0.3)

0

NR

  Increased AST

3 (0.5)

0

0

  Psoriasis

3 (0.5)

0

2 (0.5)

  Decreased white blood cell count

0e

0e

2 (0.5)

  Prostate cancer

NR

NR

2 (0.5)

Deaths

n/PY (n/100 PY)f

1/631.5 (0.2)

0

0

  Multiple injuries; road traffic accident

1/631.5 (0.2)

Notable harms, E (E/100 PY)

Serious infection

8 (1.3)

24 (2.9)

11 (2.6)

Serious pneumonia

1 (0.2)

6 (0.7)

3 (0.7)

Herpes zoster

3 (0.5)

33 (3.9)

16 (3.8)

Active TB

0

0

0

Anemia

10 (1.6)

25 (3.0)

9 (2.1)

Neutropenia

27 (4.3)

20 (2.4)

4 (1.0)

Lymphopenia

1 (0.2)

27 (3.2)

3 (0.7)

Malignancy (any)

6 (1.0)

11 (1.3)

10 (2.4)

VTEg (fatal and non-fatal)

2 (0.3)

3 (0.4)

1 (0.2)

Arterial thrombosish

1 (0.2)

0

0

Gastrointestinal perforation

  0

  2 (0.2)

0

CPK elevation

46 (7.3)

100 (11.9)

22 (5.2)

Hepatic disorder

157 (24.9)

160 (19.1)

20 (4.8)

MACEi

3 (0.5)

3 (0.4)

1 (0.2)

Hyperlipidemia

1 (0.2)

5 (0.6)

12 (2.9)

ADA = adalimumab; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; E = events; MACE = major adverse cardiovascular event; NR = not reported; PY = patient-year; UPA = upadacitinib; VTE = venous thromboembolic event.

Note: The event rate (E) counts the number of events, and the incidence rate (n/100) counts the number of patients.

aIncludes upadacitinib exposure in UPA 15 mg and placebo switched to UPA 15 mg dose groups.

bFrequency of at least 5 E/100 PY in any treatment group.

cThe term psoriatic arthropathy refers to worsening of the underlying PsA disease.

dFrequency of at least 2 events in any treatment group.

eClassified as leukopenia.

fTreatment-emergent deaths were captured for deaths occurring no more than 30 days after last dose (or ≤ 70 days for patients in the adalimumab group). Deaths are presented as number of patients that had died (incidence rate) rather than the event rate. Four additional deaths had been reported up to week 56. In SELECT-PsA1, a total of 2 non-treatment-emergent deaths in the upadacitinib 15 mg treatment group were reported, occurring more than 30 days after the last dose of the study drug; 1 had already been captured under week 24. Both non–treatment-emergent deaths were thought to have a reasonable possibility of being related to the study drug. In PsA1 and PsA2, just 1 death occurred in the placebo group of each study; both have been captured under week 24 data.

gIncludes fatal and non-fatal deep-vein thrombosis and pulmonary embolism. None of the patients experience a fatal VTE.

hIncludes non-cardiac, non-neurologic, and non-fatal events.

iDefined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Source: SELECT-PsA1 Week 56 Clinical Study Report33 and SELECT-PsA2 Week 56 Clinical Study Report.11

Critical Appraisal

The long-term data from week 24 to week 56 of both SELECT-PsA1 and SELECT-PsA2 provide an overview of the efficacy and safety of upadacitinib over a 56-week period. Overall, efficacy was maintained during this period, and there were no major safety signals to report; however, the data are subject to certain limitations. Both studies were initially double-blinded, but sponsors were unblinded after the last patient completed the week 24 study visit. An unblinded analysis was conducted for the purpose of initial regulatory submission. After week 24, patients in both studies were made aware that they were on some form of active treatment (either upadacitinib or adalimumab for PsA1 and upadacitinib for PsA2) as all patients in the placebo groups were switched to upadacitinib. Although the site investigators and patients remained blinded until the end of period 1, awareness that placebos were no longer being given may have affected patient performance and evaluation.

As mentioned in the critical appraisal of week 24 data, imbalance in missing data (i.e., randomized patients not included in the analysis) continues to be a potential concern in the analyses of patient-reported outcomes, particularly as more patients discontinued study treatment between week 24 and 56. Particularly in SELECT-PsA2, approximately 40% of patients had discontinued from the placebo-to-upadacitinib 15 mg group by week 56. The larger proportion of missing data in the placebo group makes results more uncertain.

Conclusions about the long-term efficacy and safety outcomes are also limited by a lack of control in both SELECT-PsA1 and SELECT-PsA2, as well as a lack of a comparator in SELECT-PsA2. This is particularly problematic for the interpretation of patient-reported outcomes. In addition, for both SELECT studies, harm data reported for the upadacitinib exposure in upadacitinib 15 mg and placebo groups that switched to upadacitinib 15 mg were combined. Type I error rate adjustments were not planned for any of the outcomes reported in the efficacy analyses, which can limit the interpretation of statistically significant findings.

In addition, although SELECT-PsA1 was designed as a 5-year trial, long-term efficacy or safety outcomes (from week 56 to week 260) were not reported by the sponsor. Similarly, while SELECT-PsA2 was designed as a 3-year trial, long-term efficacy or safety outcomes (from week 56 to week 156) were not reported.

The generalizability of the long-term safety and efficacy results is similar to what was described earlier in this report. The patients included in these studies represent a subset of the patients seen in Canadian clinical practice.

Discussion

Summary of Available Evidence

Two multi-centre, phase III, placebo-controlled RCTs — SELECT-PsA1 (N = 1,705) and SELECT-PsA2 (N = 642) — met the inclusion criteria for this systematic review. SELECT-PsA1 also included an active control group of patients receiving adalimumab. Both SELECT studies enrolled adults with an established diagnosis of moderate to severely active PsA who had been previously treated with a DMARD. SELECT-PsA1 studied patients who had an insufficient response or were intolerant to a non-bDMARD, whereas PsA2 included patients who had an insufficient response or were intolerance to a bDMARD. The trials investigated the efficacy and safety of 2 dosages of oral upadacitinib: 15 mg once daily and 30 mg once daily; however, to align with the Health Canada–approved dose of upadacitinib 15 mg once daily, data for the 30 mg dose were not presented in this review. Both studies consist of 2 periods. Period 1 was 56 weeks in duration and included a 24-week double-blind period. At week 24, all patients on placebo were switched to upadacitinib. Stable background non-bDMARD therapy was permitted to continue during the study, and rescue therapy was permitted starting at week 16. The primary end point for both SELECT-PsA1 and PsA2 was the proportion of patients who achieved an ACR20 at week 12. Both studies had an appropriate randomization strategy; treatment groups within each study were generally well balanced. Compared to SELECT-PsA1, patients enrolled in PsA2 had experienced PsA for longer, with disease that was more difficult to control (based on baseline characteristics and treatment history). Overall, study discontinuation at week 24 was low and similar across the treatment groups, except for the placebo group in SELECT-PsA2, in which approximately 20% of patients had discontinued treatment.

The primary and major secondary efficacy outcomes were assessed using a hierarchical testing procedure to control the overall type I error rate. Several additional end points that were not part of the multiplicity-adjusted analyses but were identified in the CADTH systematic review protocol are also discussed in this report. Results from both studies were presented from interim analyses, with data cut-offs of December 13, 2019, for PsA1 and October 9, 2019, for PsA2. At each data cut-off point, all patients had completed week 24 or had discontinued from the study. Additional data collected after all patients had completed week 56 (period 1) are also discussed. By week 56, discontinuation rates from the study continued to be similar across all treatment groups in PsA1. Discontinuation rates in PsA2 were generally higher than in PsA1, and the placebo-to-upadacitinib 15 mg group had the highest proportion of patients discontinuing study treatment (38.7%).

Interpretation of Results

Efficacy

The SELECT-PsA1 and SELECT-PsA2 trials demonstrated a largely consistent treatment effect of oral upadacitinib 15 mg once daily compared to placebo in both bDMARD-naive and -experienced patients in the following specific outcomes identified in the CADTH systematic review: clinical response in PsA symptoms, measure of function and disability, measure of PsA symptoms, HRQoL, measure of skin disease, and musculoskeletal disease. Both studies showed statistically significant improvement with upadacitinib 15 mg over placebo as the primary end point of ACR20 at week 12 in patients with PsA. This primary outcome is a clinically relevant end point in the treatment of PsA and is a composite measure that includes end points identified as an outcome of importance to patients. In SELECT-PsA1, results of the pre-specified subgroup analyses were consistent with results from the overall population for the primary end point. However, ACR20 is a general measure of clinical response of peripheral joint disease and does not include assessment of enthesitis, dactylitis, or effects on the spine or skin. The effect of upadacitinib on domains outside of this composite end point were explored using other scales and instruments as part of secondary outcomes. The clinician expert consulted on this review noted that, overall, results are generalizable to the relevant Canadian patient population.

Numerous end points were measured at various time points across the SELECT studies. In this review, a total of 20 end points were presented from SELECT-PsA1, and 15 end points were presented from SELECT-PsA2. Not all end points presented were part of the multiplicity-adjusted statistical testing hierarchy in each trial. End points that were not adjusted for multiple comparisons are at risk of type I error and should be interpreted with caution. This review made no definitive conclusions for end points that fell outside of the statistical testing hierarchy. In SELECT-PsA1, a statistically significant benefit of upadacitinib over placebo was evident for 9 end points: ACR20 at week 12, MDA at week 24, HAQ-DI at week 12, FACIT-F at week 12, SF-36 PCS at week 12, PASI 75 at week 16, sIGA at week 16, enthesitis resolution at week 24, and SHS at week 24. Noninferiority was also demonstrated for upadacitinib compared to adalimumab for ACR20 at week 12, although upadacitinib was not superior to adalimumab for ACR20 at week 12. In SELECT-PsA2, a statistically significant benefit of upadacitinib over placebo was evident for 8 end points: ACR20 at week 12, MDA at week 24, HAQ-DI at week 12, FACIT-F at week 12, SF-36 at week 12, PASI 75 at week 16, sIGA at week 16, and SAPS at week 16. Across both studies, upadacitinib demonstrated a largely consistent treatment effect in 7 common end points: ACR20 at week 12, MDA at week 24, HAQ-DI at week 12, FACIT-F at week 12, SF-36 PCS at week 12, PASI 75 at week 16, and sIGA at week 16.

Other key secondary end points that were included in the multiplicity-adjusted testing hierarchy in only 1 of the studies can be used to characterize the efficacy of upadacitinib in their respective populations (biologic-naive versus biologic-experienced). Statistically significant improvement with upadacitinib compared to placebo was demonstrated in radiographic changes (measured by SHS) and resolution of enthesitis in SELECT-PsA1, as well as SAPS in SELECT-PsA2. However, according to the clinical expert consulted for this review, the small changes seen in some end points (e.g., SHS) may not reflect clinically meaningful improvement, particularly when measured over such a short length of time relative to the long course of the disease.

In SELECT-PsA1, the statistical testing failed to show superiority of upadacitinib 15 mg versus adalimumab in ACR20 at week 12. Statistical testing for end points ranked below this point in the hierarchy therefore should not have been performed. This affected the interpretation of the results of 4 end points: resolution of dactylitis (versus placebo), patient’s assessment of pain NRS (versus adalimumab), HAQ-DI (versus adalimumab), and SAPS (versus placebo) in SELECT-PsA1, and it is uncertain whether the between-group difference reported is clinically meaningful.

Several end points presented in this report but not part of the multiplicity-adjusted statistical testing hierarchy should be interpreted with caution. Six end points common to both studies comparing upadacitinib to placebo were not part of the multiplicity-adjusted statistical testing hierarchies, and no definitive conclusions can be drawn for either patient population (bDMARD-naive or bDMARD-experienced): modified PsARC at week 24, WPAI at week 24, patient’s assessment of pain NRS at week 12, EQ-5D-5L at week 24, dactylitis resolution at week 24, and BASDAI at week 24. In these analyses, results were numerically favourable for the upadacitinib 15 mg treatment group compared to placebo. Additional exploratory end points were also included in this report to provide further details, including ACR50 and ARC70 or PASI 90 and PASI 100. Generally, results were numerically similar or in favour of upadacitinib, although the magnitude was less than results seen when compared to placebo.

The input from patients identified the importance of treatments that are effective for psoriasis as well as PsA symptoms; data from the SELECT-PsA1 and SELECT-PsA2 trials have shown benefit with upadacitinib compared to placebo in several parameters, including skin disease and other measures of PsA (as measured by ACR20, PASI 75, and sIGA) in both bDMARD-naive and bDMARD-experienced patients. Reduction in PsA symptoms, such as fatigue and pain, as well as improvements in quality of life, work productivity, mobility, and ability to carry out activities of daily living were also identified as important end points by patient groups. Upadacitinib 15 mg once daily showed consistent benefit over placebo in both bDMARD-naive and -experienced patients for improved quality of life as measured by SF-36, function according to HAQ-DI, and fatigue as assessed by FACIT-F in both SELECT studies. The end points of quality of life as measured by EQ-5D-5L, work productivity according to WPAI, and patient’s assessment of pain NRS were supplemental. These end points numerically favoured treatment with upadacitinib when compared to placebo. An estimated MID for the relevant patient population was not available for all continuous end points, and for end points with an identified estimated MID, the change in scores from baseline did not always achieve the threshold for within- and between-group differences.

With regards to comparisons with adalimumab, PsA1 demonstrated noninferiority of upadacitinib 15 mg in the clinical response of PsA symptoms (ACR20 at week 12). The hierarchical testing prevented a statistical comparison between the 2 active treatment groups after upadacitinib failed to show superiority over adalimumab in ACR20. Conclusions about the comparative efficacy between upadacitinib 15 mg and adalimumab therefore cannot be drawn aside from ACR20 at week 12.

The patient groups also mentioned preference for oral administration of medications. At this time, other publicly funded treatments for the same indication are administered by IV infusion or subcutaneous injection. The other oral products currently approved for PsA, tofacitinib and apremilast, are not funded by public jurisdictions.

Several sources of uncertainty in SELECT-PsA1 and PsA2 were identified. A key limitation was the timeline of assessment, as 12 weeks may not be an adequate length of time to fully appreciate the benefit of adalimumab. The clinical expert consulted for this review indicated that a noninferiority test at 16 or 24 weeks would have been more appropriate; however, no such statistical test was conducted. Also, because currently available outcome measures in PsA, such as rheumatoid arthritis and psoriasis, have largely been adopted from other conditions, validity and reliability data specific to PsA are sparse, and some instruments (e.g., EQ-5D, WPAI, sIGA, and SAPS) lack a known MID exclusively for patients with PsA. A comparison between upadacitinib and adalimumab was made only in the bDMARD-naive population (SELECT-PsA1), and it is not known whether patients previously exposed to bDMARDs would derive the same efficacy relative to adalimumab. Furthermore, there is a lack of direct head-to-head comparisons of upadacitinib versus other active controls, particularly versus non-TNF inhibitors or tofacitinib. It is therefore difficult to determine whether the analysis of the full benefit of upadacitinib versus other treatments used the same indication. Despite these uncertainties, the results that indicate an improved response and the conclusion of a consistent treatment effect of upadacitinib 15 mg over placebo in patients with PsA appear reasonable.

The approved indication states that upadacitinib may be used as monotherapy or in combination with methotrexate. This is reflective of the pivotal trials, in which approximately 80% of patients in SELECT-PsA1 and 50% of patients in PsA2 received concomitant non-bDMARDs, and most received concomitant methotrexate. The number of patients who received other non-bDMARDs (varying in category and mechanism of action) were small for individual drugs. The magnitude of benefit of upadacitinib as monotherapy, particularly in bDMARD-naive patients, or in combination with other non-bDMARDs (i.e., other than methotrexate) is therefore limited, and cannot be generalized from the SELECT trials. The approved indication includes patients who have responded inadequately or are intolerant to methotrexate or other DMARDs. The indication refers to DMARDs in general, which can include csDMARDs, tsDMARDs, or bDMARDs. In both trials, a significant proportion of patients received prior methotrexate (approximately 90% in PsA1 and 70% in PSA2), which is a csDMARD and reflective of current practice. SELECT-PsA2 provides additional information on the benefit of upadacitinib in patients who failed on previous bDMARDs. However, as the share of enrolled patients with prior failure on more than 1 bDMARD was limited to approximately 30%, there was a limited number of patients who had failed several bDMARDs. This may limit the generalizability of the PsA2 study results in patients who had failed multiple bDMARD treatments. Overall, data from the SELECT-PsA1 and PsA2 trials support the sponsor’s funding request.

Results from the end of period 1 (week 56 data) suggest that the improvements in clinical and patient-reported outcomes observed at week 24 were maintained throughout the 56-week treatment period. Patients who were switched from placebo to upadacitinib at week 24 also showed improvements in clinical and patient-reported outcomes at week 56; the trajectory for achievement of response or improvement in end points after switching to upadacitinib was similar to those observed in patients who started upadacitinib on day 1. Numerically similar or greater achievement of results was seen in patients treated with upadacitinib from day 1 compared with achievement results with adalimumab. The conclusions of the long-term efficacy and safety outcomes at week 56 are limited by the lack of a placebo control in both SELECT-PsA1 and SELECT-PsA2, as well as the lack of a comparator in SELECT-PsA2. In addition, rescue therapy, including change in background treatment, was permitted after week 16. Furthermore, given that all patients were aware they were receiving an active treatment (upadacitinib or adalimumab) after week 24, this may affect performance and evaluation of patient-reported outcomes. No adjustment was made for multiplicity to evaluate long-term data. Given the large number of analyses performed, there is a risk of inflated type I error with the week 56 data, and these results should be interpreted with caution.

The sponsor provided an ITC comparing the efficacy of upadacitinib with bDMARDs and tsDMARDs at 12 and 24 weeks, and results were reported separately for bDMARD-naive and bDMARD-experienced patients. Efficacy outcomes were limited to the PsARC response rate, PASI 50, PASI 70, and PASI 90 response rate, change in HAQ-DI, and ACR20, ARC50, and ACR70 response rates. Based on the sponsor-submitted ITC, upadacitinib did not show a consistent or distinct difference in efficacy in either bDMARD-naive or -experienced patients, as measured by ACR response, PASI, PsARC, or HAQ-DI when compared to bDMARDs or tsDMARDs. Although the NMA suggests upadacitinib is more efficacious over certain comparators in some end points, a consistent effect across all comparators or with specific classes of DMARDs (e.g., TNF inhibitors) was not observed. In particular, upadacitinib was not consistently favoured over comparators that are clinically relevant to this review, namely TNF inhibitors, IL inhibitors, and JAK inhibitors, across both time points. Furthermore, not all comparators were included in every analysis, and some results were specific to a particular dosing regimen. A comparison with the tsDMARD most relevant to this review (i.e., tofacitinib) was largely absent, particularly in the bDMARD-experienced population. It is therefore difficult to draw a universal conclusion regarding the relative efficacy of upadacitinib versus bDMARDs, tsDMARDs, or specific classes of DMARDs. Compared to the biologic-naive population, the relative efficacy of upadacitinib to active comparators in the biologic-experienced population is less certain due to the fact that fewer agents were included in the analyses. Most importantly, conclusions regarding the long-term efficacy of upadacitinib compared to the active comparators relevant to this review cannot be drawn as the NMA used study results collected over an inappropriately short period time for a chronic disease such as PsA. There is also uncertainty due to the inherent heterogeneity across trials in the networks. Because the robustness of the comparative efficacy was further compromised by the lack of precision in the findings, results from the sponsor-submitted ITC must be interpreted with caution. Moreover, no information was obtained regarding the comparative safety to other biologic or tsDMARDs. Finally, no conclusion could be drawn with respect to the HRQoL outcomes.

Harms

Overall, AEs reported in SELECT-PsA1 and PsA2 were consistent with the known AE profile of each drug included in the studies. During the double-blind period up to week 24, the frequencies of SAEs and WDAEs were low across all treatment groups and generally below 5%, with the exception of the upadacitinib 15 mg treatment group in SELECT-PsA2, which had the highest proportion of patients experiencing an SAE (5.7%) or WDAE (7.1%) across both studies. None of the specific SAEs were reported by more than 2 patients.

The proportion of patients in SELECT-PsA1 who experienced a TEAE with upadacitinib treatment (66.9%) was comparable to patients treated with adalimumab (64.8%), but higher than those who received placebo (59.6%). In SELECT-PsA2, the proportion of patients who experienced a TEAE was similar between the upadacitinib (64.0%) and placebo (65.6%) groups. The majority of AEs were mild or moderate in severity. In both studies, the most common infections reported as an AE were upper respiratory tract infections and nasopharyngitis. In SELECT-PsA1, the most common non-infectious AEs, particularly in the active treatment groups, were increases in blood CPK levels and elevated alanine aminotransferase. Across the 2 studies, a higher proportion of patients in PsA1 experienced upper respiratory tract infections, as well as elevated blood CPK counts and alanine aminotransferase and aspartate aminotransferase levels, and a higher proportion of patients in PsA2 experienced psoriatic arthropathy, which refers to the worsening of the underlying PsA disease. The patient group input identified a reduction in infection rates as an important consideration for treatment selection. Although patients treated with upadacitinib 15 mg still experienced various infections as AEs, the reported incidences were similar to those in the adalimumab and placebo groups.

Overall, the proportions of patients experiencing notable harms such as serious infections and malignancy during the double-blind period were low. No explicit imbalances between the 2 studies were seen, with the exception of a numerically higher proportion of elevated CPK levels and hepatic disorder reported in SELECT-PsA1. Both notable AEs were reported in a higher proportion of patients treated with upadacitinib and adalimumab compared to placebo; hepatic disorder was reported most frequently in the adalimumab group, in which an elevated CPK level was reported most often in the upadacitinib 15 mg group. Hepatic disorder may be confounded by the greater use of concomitant methotrexate treatment in PsA1 patients. During the double-blind period, 2 treatment-emergent deaths occurred in the relevant treatment groups (i.e., excluding upadacitinib 30 mg treatment). Both were reported in the placebo groups. One non-treatment-emergent death (i.e., occurring beyond 30 days after the last dose) was reported in the upadacitinib 15 mg treatment group of SELECT-PsA1.

The safety profile of oral upadacitinib 15 mg once daily for PsA over 56 weeks was consistent with that observed during the 24-week double-blind period in both SELECT-PsA1 and PsA2, with no unexpected safety signals reported. Similar types and patterns of AEs were observed, although, with longer exposure to treatment, some infections occurred more often in patients treated with upadacitinib compared to adalimumab. Of the notable AEs, herpes zoster was reported in a higher proportion of patients treated with upadacitinib across both studies compared to those treated with adalimumab. Across the 2 studies, an imbalance in elevated CPK levels and hepatic disorders were reported, and continued to occur more often, in SELECT-PsA1. Deaths in the active treatment groups were low; 5 deaths were reported in total (1 treated with adalimumab, 2 treated with upadacitinib, and 2 in the placebo group).

Although a MACE has been identified as an important AE of interest, particularly with recent findings of increased risk with tofacitinib, the incidence of such AEs was low in the SELECT-PsA1 and PsA2 studies, and they occurred at a rate similar to that of the adalimumab treatment group. Consistent results were seen between week 24 and 56, although, given the chronic nature of this disease, further data are required to confirm these results. Thus, it is unknown whether the recent identification of MACEs is a class effect of JAK inhibitors across different disease states at this time, and longer-term follow-up data are required to better characterize the overall safety profile of upadacitinib in patients with PsA.

A main limitation of the ITC submitted by the sponsor was the lack of comparisons regarding safety. As a result, conclusions regarding the relative safety of upadacitinib to comparators included in the sponsor’s ITC cannot be made.

Conclusions

Psoriatic arthritis is a complex disease due to the numerous domains of disease activity that need to be addressed with treatment. Based on the double-blind portion of both phase III randomized controlled trials (RCTs) (SELECT-PsA1 and SELECT-PsA2), treatment with oral upadacitinib 15 mg once daily is associated with statistically significant and clinically meaningful improvement compared to placebo in the clinical response of PsA symptoms, as measured by the primary efficacy outcome of an ACR20 response at week 12. In bDMARD-naive patients (SELECT-PsA1), upadacitinib 15 mg orally once daily was no worse than (i.e., noninferior to) adalimumab 40 mg administered subcutaneously every other week in achievement of an ACR20 at week 12. The efficacy of upadacitinib compared to adalimumab in bDMARD-experienced patients is unknown.

Additionally, an overall consistent effect of upadacitinib 15 mg compared to placebo was demonstrated for numerous clinically relevant manifestations of PsA, including function and disability, PsA symptoms (pain and fatigue), HRQoL or patient-reported health outcomes, skin disease or psoriasis, musculoskeletal symptoms (enthesitis, dactylitis, and spinal symptoms), and other measures of clinical response or disease control such as MDA. Improvement in these measures of treatment response with upadacitinib 15 mg compared to placebo was demonstrated across both studies in patients with inadequate response or intolerance to non-bDMARDs (SELECT-PsA1) and bDMARDs (SELECT-PsA2). Efficacy of upadacitinib in radiographic changes was only studied in bDMARD-naive patients, and the clinical meaningfulness of the small improvement seen versus placebo over this short duration is uncertain. Furthermore, an estimated MID for many of the measures used to assess continuous end points was not identified for patients with PsA, making the clinical significance of the numerical improvements seen in some end points, notably the patient’s assessment of pain NRS, uncertain.

Findings from the end of period 1 of SELECT-PsA1 and SELECT-PsA2 suggest that the improvements in outcomes observed at week 24 in the upadacitinib 15 mg treatment group were maintained throughout the 56-week extension.

By week 24, the proportion of patients who experienced a TEAE with upadacitinib in SELECT-PsA1 was comparable to the proportion treated with adalimumab but higher relative to the placebo group. In SELECT-PsA2, the proportion of patients who experienced a TEAE was similar between the upadacitinib and placebo groups. Upper respiratory tract infection was most commonly reported in both studies. The safety profile of upadacitinib 15 mg once daily over 56 weeks was consistent with that observed during the 24-week double-blind period, with no unexpected safety signals reported. However, long-term data from the ongoing extension phase of both SELECT-PsA1 (up to 5 years) and SELECT-PsA2 (up to 3 years) will help better characterize the efficacy and safety of upadacitinib in the treatment of this chronic condition.

No direct comparative evidence for upadacitinib 15 mg versus bDMARDs or tsDMARDs other than adalimumab was identified. A sponsor-submitted ITC comparing upadacitinib 15 mg to bDMARDs or tsDMARDs suggested that in both bDMARD-naive and DMARD-experienced patients, upadacitinib does not show either a consistent or distinct difference in efficacy as measured by ACR20, PASI, PsARC, or HAQ-DI when compared to bDMARDs or tsDMARDs. The value of the ITC results is uncertain due to the inherent heterogeneity across trials in the networks. Moreover, no information was obtained regarding safety compared to other bDMARDs or tsDMARDs. In addition, no conclusion could be drawn on the HRQoL outcomes.

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