CADTH Reimbursement Review

Guselkumab (Tremfya)

Sponsor: Janssen Inc.

Therapeutic Area: Psoriatic arthritis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

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 (tenderness and swelling at the insertion of tendons and ligaments into bone), dactylitis (swelling of whole digits), and axial disease (inflammation of the joints of the back)^.1,2 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, but it is estimated to be 1 to 2 cases per 1,000 in the general population^.1 A population-based Canadian study estimated the age- and sex-standardized cumulative prevalence of PsA in Ontario to range from 0.09% in 2008 to 0.15% in 2015.³

Several drug classes are used in the pharmacologic treatment of PsA, including nonsteroidal anti-inflammatory drugs (NSAIDs), conventional disease-modifying antirheumatic drugs (cDMARDs) (i.e., methotrexate, sulfasalazine, leflunomide), biologic disease-modifying antirheumatic drugs (bDMARDs) (i.e., tumour necrosis factor [TNF] inhibitors, interleukin [IL]-23 inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors), and targeted synthetic DMARDs (e.g., apremilast, upadacitinib, or tofacitinib).⁴

Guselkumab is a human immunoglobulin G1 lambda monoclonal antibody that binds to the IL-23 protein and inhibits its binding with the cell surface IL-23 receptor.⁵ Guselkumab is approved for the treatment of adult patients with active PsA.⁵ It may be used alone or in combination with a cDMARD (e.g., methotrexate) and is available as a 100 mg/mL solution for subcutaneous (SC) injection in either 1 mL pre-filled syringes or patient-controlled injector devices. The recommended dose for PsA is 100 mg SC at week 0, week 4, and every 8 weeks thereafter.⁵

The objective of this report was to perform a systematic review of the beneficial and harmful effects of guselkumab SC injection for the treatment of active PsA in adults.

Stakeholder Perspectives

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

Patient Input

Three patient group inputs were submitted for this review by 6 different patient groups: Arthritis Consumer Experts, 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 and CreakyJoints. Five patient organizations (CAPP, CPN, CAPA, the Arthritis Society, and CreakyJoints Canada) collaborated by collectively developing survey questions using SurveyMonkey for the inputs submitted. Each of the 3 patient group inputs used the same survey data. There were 71 respondents to the joint survey. In addition, Arthritis Consumer Experts gathered information from 1 respondent through email on May 4, 2022 and from 5 respondents through an online survey from December 18, 2020 to January 26, 2021.

Respondents reported a range of symptoms that are difficult to manage, including joint stiffness (79%), fatigue (75%), changes in fingernails and toes (63%), hip pain (61%), back pain (51%), anxiety (47%), and stress (33%). With regards to the most significant impacts of PsA on their daily quality of life, respondents expressed that PsA interfered with work (54%), social connections (52%), self-esteem (50%), mental health (50%), intimacy (50%), family life (38%), and friendships (24%). Other impacts included embarrassment and self-consciousness from the symptoms caused by PsA. Given that the disease would reduce their mobility and ability to participate in activities and affect their mental and social health, respondents indicated that there were additional tasks or chores for caregivers, such as cooking, cleaning, shopping, and helping patients get to and from medical appointments.

Survey respondents indicated that they had experience with several treatment approaches, including NSAIDs, corticosteroids, cDMARDs (such as methotrexate), and bDMARDs. Among respondents, 32% considered biologics as very effective, followed by oral steroids (23%) and other DMARDs (21%). Respondents expressed their ongoing unmet needs for symptom management and more tolerable side effects with current treatments.

Two respondents who had experience with guselkumab indicated that the drug was effective in terms of improving psoriasis and arthritis and slowing disease progression. Both respondents stated that they did not experience side effects.

Respondents expected new treatments to improve the following key outcomes: management of symptoms (e.g., reducing pain and fatigue, increasing mobility); tolerability of side effects; ease of drug administration; improved ability to work and carry out tasks and daily activities; and quality of life.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

A substantial proportion of patients lose their response to therapy over time or do not achieve a minimal response with their first therapy. In addition, some treatments have more adverse effects than others. There is a need for medications with new mechanisms of action or a different safety profile to offer alternate treatment options for these patients who have an inadequate response or intolerance to therapy. According to the clinical expert, guselkumab may be used as first- or second-line biologic therapy. It may be a preferred first-line treatment for patients with moderate psoriasis in addition to musculoskeletal disease. Guselkumab may be used in combination with methotrexate or leflunomide; however, there is no evidence to support its use in combination with other biologics.

Response to therapy is based on a reduction in the number of inflamed joints, improvement in the skin, and improvements in patient-reported outcomes (i.e., based on assessments of pain, function, and fatigue). According to the clinical expert, a major improvement would constitute at least a 50% improvement, but may also include achievement of minimal disease activity (MDA) and remission as measured by specific instruments. An initial response may be expected within 3 months, with more significant improvement by 6 months after initiating therapy. The expert indicated that if a patient shows no change within 3 to 6 months, they would be considered a nonresponder and may be switched to another medication. The expert stated that ideally, guselkumab would be prescribed by specialists who are familiar with the drug and its uses, or at least in consultation with a dermatologist or rheumatologist.

Clinician Group Input

CADTH received 1 clinician group input submission from the Canadian Rheumatologist Psoriatic Arthritis Interest Group, based on responses from 6 clinicians who practise in academic and community settings. This clinician input largely agreed with the input received from the clinician consulted by CADTH. No major contrary views among the views provided by the clinical experts consulted by CADTH for this review were presented.

Drug Program Input

The drug programs identified the following issues that may affect these programs’ ability to implement a recommendation: relevant comparators, consideration for initiation of therapy, consideration for continuation or renewal of therapy, consideration for discontinuation of therapy, consideration for prescribing of therapy, and system and economic issues. Refer to Table 5.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

Three double-blind, placebo-controlled, randomized controlled trials (RCTs) met the inclusion criteria for the systematic review. The pivotal trials (DISCOVER-1 and DISCOVER-2) included patients with active PsA who had experienced an inadequate response to cDMARDs, apremilast, and/or NSAIDs. The DISCOVER-1 study (N = 381) enrolled a mixed population that included patients with no prior biologic treatment experience; however, up to 30% of patients had previously received 1 or 2 TNF alpha inhibitors. In the DISCOVER-2 study, all enrolled patients were biologic-naive (N = 741). The COSMOS study enrolled patients with active PsA who were intolerant to or had experienced an inadequate response to 1 or 2 TNF alpha inhibitors (N = 285). The trials were conducted mainly in Europe, with some sites in Asia, the US, Australia, Israel, and Canada (DISCOVER-1 only).

Patients were randomized to receive placebo or guselkumab 100 mg SC at week 0, week 4, and every 8 weeks thereafter for 24 weeks. The DISCOVER trials included a third treatment group (guselkumab 100 mg every 4 weeks). However, the latter dosage is not consistent with the Health Canada–recommended dose; therefore, results for this treatment group are not included in this report. The total trial durations were 52 weeks (DISCOVER-1), 100 weeks (DISCOVER-2), and 48 weeks (COSMOS), with placebo patients switching to guselkumab starting at week 24. During the trials, patients could continue receiving methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, oral corticosteroids, or NSAIDs if the doses were stable and did not exceed the protocol-specified maximum doses. Early escape therapy consisting of cDMARDs, corticosteroids, or NSAIDs — or a switch to guselkumab (COSMOS) — was available at week 16 for patients who had an improvement of less than 5% in tender and swollen joint counts.

The primary outcome in all trials was the proportion of patients who achieved an American College of Rheumatology (ACR) 20% improvement (ACR 20) at week 24. The ACR 20 was defined as a greater than or equal to 20% improvement from baseline in both swollen joint count (66 joints) and tender joint count (68 joints), and a greater than or equal to 20% improvement from baseline in 3 of the 5 assessments: patient’s assessment of pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, the Health Assessment Questionnaire Disability Index (HAQ-DI), and C-reactive protein (CRP). Other outcomes of interest included the change from baseline in the HAQ-DI and Short Form (36) Health Survey (SF-36) Physical Component Summary (PCS) and the impact on plaque psoriasis (as measured by the Investigator’s Global Assessment of Psoriasis [IGA] or Psoriasis Area and Severity Index [PASI] response).

The mean age of patients enrolled ranged from 44.9 years (standard deviation [SD] = 11.9 years) to 49.1 years (SD = 12.3 years) across treatment groups in the 3 trials. The proportion of female patients ranged from 46% to 55%, and most patients were White (89% to 98%; not reported for the COSMOS study). The mean number of swollen joints ranged from 9.0 (SD = 5.7) to 12.3 (SD = 6.9), and the mean number of tender joints ranged from 18.2 (SD = 10.7) to 21.6 (SD = 13.1). Approximately 2-thirds of patients had psoriatic involvement affecting at least 3% of their body surface area (BSA). Two-thirds of patients reported enthesitis, while approximately 40% had dactylitis at baseline. The majority of patients (54% to 63%) were receiving methotrexate at baseline, with a lower percentage (0% to 7%) receiving other permitted cDMARDs. In the DISCOVER trials, 14% to 20% of patients were receiving oral corticosteroids at baseline versus 4% to 5% of patients in the COSMOS study.

Efficacy Results

In the DISCOVER-1 study, 52.0% of patients in the group receiving guselkumab every 8 weeks achieved ACR 20 at 24 weeks, compared with 22.2% of patients in the placebo group. The absolute difference was 29.8% (95% confidence interval [CI], 18.6% to 41.1%; P < 0.001), favouring guselkumab versus placebo (Table 2). The proportion of patients who achieved at least an American College of Rheumatology 50% improvement (ACR 50) was 29.9% versus 8.7% (absolute difference = 21.4%; 95% CI, 12.1% to 30.7%) for guselkumab every 8 weeks versus placebo; the proportion of patients who achieved an American College of Rheumatology 70% improvement (ACR 70) was 11.8% versus 5.6% (absolute difference = 6.4%; 95% CI, −0.3% to 13.1%) for guselkumab every 8 weeks versus placebo. However, ACR 50 and ACR 70 were not controlled for multiple testing and should be interpreted considering the inflated risk of type I error rate.

Among patients who were biologic-naive (DISCOVER-2), 64.1% and 32.9% achieved ACR 20 at 24 weeks in the group receiving guselkumab every 8 weeks and the placebo group, respectively, with an absolute difference of 31.2% (95% CI, 22.9% to 39.5%; P < 0.001) (Table 2). The proportion of patients who achieved ACR 50 was 31.5% versus 14.2% (absolute difference = 17.2%; 95% CI, 10.0% to 24.4%), and the proportion of patients who achieved ACR 70 was 18.5% versus 4.1% (absolute difference = 14.5%; 95% CI, 9.1% to 19.9%). ACR 50 and ACR 70 were not controlled for multiple testing (i.e., the type I error rate has not been controlled).

For biologic-experienced patients who were enrolled in the COSMOS study, 44.4% and 19.8% achieved ACR 20 at week 24 in the group receiving guselkumab every 8 weeks and the placebo group, respectively. The absolute difference between groups favoured guselkumab: 24.6% (95% CI, 14.1% to 35.2%; P < 0.001) (Table 2). The difference also favoured guselkumab every 8 weeks versus placebo for the proportion who achieved ACR 50 (19.6% versus 5.2%; absolute difference = 14.3%; 95% CI, 7.2% to 21.4%; P < 0.001). ACR 70 was achieved by 7.9% versus 1.0% of patients in the group receiving guselkumab every 8 weeks versus the placebo group, with an absolute difference of 6.8% (95% CI, 2.6% to 11.1%). ACR 70 was not controlled for multiple testing.

In the DISCOVER trials, the odds ratios of ACR 20 response were generally consistent across subgroups based on prior TNF alpha inhibitor use, use of non-biologic DMARDs, oral corticosteroids, or NSAIDs at baseline; however, the trials may not have been powered to detect subgroup differences. The COSMOS study did not report data for any subgroups of interest to this review.

Disability was assessed using the HAQ-DI, a patient-reported, 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). The overall score is the average of 8 domains ranging from 0 (no disability) to 3 (completely disabled). The change from baseline to week 24 in the HAQ-DI favoured guselkumab every 8 weeks versus placebo in all trials (Table 2). The least squares (LS) mean differences versus placebo reported were −0.25 (95% CI, −0.36 to −0.13; P < 0.001) in the DISCOVER-1 study; −0.24 (95% CI, −0.32 to −0.15; P < 0.001) in the DISCOVER-2 study; and −0.17 (95% CI, −0.28 to −0.06; P = 0.003) in the COSMOS study. Across the trials, the between-group and within-group differences did not exceed the 0.35 minimal important difference (MID) cited by the sponsor,⁶ with the exception of the change from baseline within the group receiving guselkumab every 8 weeks in the DISCOVER-2 study.

The change from baseline to week 24 in the SF-36 PCS favoured guselkumab every 8 weeks versus placebo in all 3 studies (Table 2). The LS mean differences were 4.1 (95% CI, 2.4 to 5.9; P < 0.001) in DISCOVER-1, 4.0 (95% CI, 2.7 to 5.2; P = 0.011) in DISCOVER-2, and 3.9 (95% CI, 2.5 to 5.4; P < 0.001) in the COSMOS study. The Clinical Study Report defined at least a 5-point increase as clinically meaningful, but a MID of 3.74 points has also been reported in the literature.⁷ No statistically significant differences were detected between guselkumab every 8 weeks and placebo in the change from baseline to week 24 in the SF-36 Mental Component Summary (MCS).

In all trials, psoriasis skin disease outcome measures were analyzed in the subgroup of patients who had psoriasis affecting greater than or equal to 3% BSA and an IGA score of greater than or equal to 2 at baseline (55% to 74% of patients per treatment group). Psoriasis severity was assessed using composite physician-reported assessments: IGA and PASI response. For the IGA, the severity of a patient’s psoriasis is scored as cleared (0), minimal (1), mild (2), moderate (3), or severe (4). IGA response was defined as a score of 0 or 1, and at least a 2-point decrease from baseline. The PASI evaluates the extent and severity of psoriasis and is scored from 0 to 72 points, with a PASI score greater than 10 considered to represent severe disease. Patients with 90% improvement in their PASI score (PASI 90) or 100% improvement in their PASI score (PASI 100) would meet PASI 90 or PASI 100 response criteria, respectively.

The proportion of patients who achieved an IGA response at week 24 was higher in the groups receiving guselkumab every 8 weeks than in the placebo groups in the DISCOVER-1 study (57.3% versus 15.4%; absolute difference = 42.0% [95% CI, 28.9% to 55.1%; P < 0.001]) and DISCOVER-2 study (70.5% versus 19.1%; absolute difference = 50.9% [95% CI, 42.2% to 59.7%; P < 0.001]) (Table 2). In the COSMOS study, 48.1% versus 9.4% of patients in the guselkumab-every-8-weeks versus placebo group achieved in IGA response, with an absolute difference of 38.8% (95% CI, 27.3% to 50.4%); however, the P value has not been adjusted to control for multiple testing and should be interpreted with caution because of the potential for inflated type I error rate. PASI 100 response at week 24 was a secondary outcome in the COSMOS study. In the guselkumab group, 30.8% of patients achieved a PASI 100 response compared with 3.8% of patients in the placebo group (absolute difference = 27.4% [95% CI, 17.9% to 36.8%; P < 0.001). In the DISCOVER trials, the proportion of patients who achieved a PASI 100 response was nominally higher for the guselkumab versus placebo groups; however, these outcomes were not controlled for multiple testing and should be interpreted considering the inflated risk of type I error rate.

For patients with enthesitis or dactylitis at baseline, the results of the DISCOVER-2 and COSMOS studies suggest an improvement in enthesitis or dactylitis end points, with guselkumab every 8 weeks relative to placebo, but no statistically significant difference was detected between groups in DISCOVER-1. Based on the preplanned pooled analysis of data from DISCOVER-1 and DISCOVER-2, 49.6% and 29.4% of patients in the guselkumab-every-8-weeks and placebo groups had resolution of enthesitis at week 24, with a between-group difference of 20.1% (95% CI, 11.8% to 28.5%; P = 0.03). The proportion of patients whose dactylitis resolved at week 24 was 59.4% versus 42.2% in the guselkumab-every-8-weeks versus placebo groups (between-group difference = 18.0%; (95% CI, 7.4% to 28.6%; P = 0.03). None of the trials detected a statistically significant difference between guselkumab every 8 weeks and placebo in the proportion of patients who reported a clinically important improvement in axial disease based on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). It is noteworthy that these outcomes were tested in subgroups of patients that may not have been balanced with respect to baseline demographic and disease characteristics between treatment groups, due to the lack of stratification at randomization.

Symptoms of fatigue were assessed using the Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue). The scores ranged from 0 to 52, with lower scores reflecting more severe fatigue. Estimates of the MID ranged from 3.1 points to 4 points.^8,9 The DISCOVER-1 study reported an LS mean difference of 3.4 points (95% CI, 1.4 to 5.4); DISCOVER-2 reported an LS mean difference of 4.0 (95% CI, 2.5 to 5.5); and COSMOS reported an LS mean difference of 3.6 (95% CI, 1.7 to 5.4) for guselkumab every 8 weeks versus placebo. This outcome was not controlled for multiple testing (i.e., the type I error rate has not been controlled).

Radiographic progression was a major secondary outcome in the DISCOVER-2 study. Progression was assessed using the modified van der Heijde-Sharp (vdH-S) score, which ranges from 0 (best) to 528 (worst) and is the sum of the joint erosion score and the joint space narrowing score.¹⁰ At 24 weeks, the study failed to detect a statistically significant difference between guselkumab every 8 weeks and placebo in the change from baseline in vdH-S score. However, the duration of the trial may have been insufficient to detect a difference.

Harms Results

The frequency of adverse events was generally similar between groups in all trials, with 42% to 54% of patients in the groups receiving guselkumab every 8 weeks and 41% to 60% of patients in the placebo groups reporting 1 or more adverse events during the 24-week treatment period (Table 3). Nasopharyngitis (4% to 13%), upper respiratory tract infection (2% to 5%), and increased alanine aminotransferase (2% to 6%) were the most common adverse events in the guselkumab groups, with a comparable frequency of these events reported in the placebo groups. Generally, the frequency of infections was similar in the guselkumab groups (16% to 26%) and placebo groups (18% to 25%) across trials. Few serious infections were reported (0% to 0.5% in the guselkumab groups).

The frequency of serious adverse events ranged from 1% to 4% in the groups receiving guselkumab every 8 weeks and 3% to 4% in the placebo groups. No specific serious adverse events were reported in more than 1 patient per treatment group. Adverse events that resulted in treatment discontinuation were generally low and similar between groups (1% to 3%). In the DISCOVER-1 study, 1 patient in the placebo group died due to cardiac failure. No other deaths were reported in the first 24 weeks of the trials.

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

ACR 20 = American College of Rheumatology 20% improvement; ANCOVA = analysis of covariance; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; CRP = C-reactive protein; DMARD = disease-modifying antirheumatic drug; FAS = full analysis set; GUSE = guselkumab; HAQ-DI = Health Assessment Questionnaire Disability Index; IGA = Investigator’s Global Assessment of Psoriasis; LS = least squares; MMRM = mixed-effects model for repeated measures; PBO = placebo; q8w = every 8 weeks; SD = standard deviation; SF-36 PCS = Short Form (36) Health Survey Physical Component Summary; TNF = tumour necrosis factor.

^aBased on composite estimand (either observed response data or nonresponse for patients who met the treatment failure criteria). Patients with missing data were imputed as nonresponders. P values were based on stratified CMH tests and 95% CIs were based on the Wald statistic. The DISCOVER-1 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and prior exposure to TNF alpha inhibitors (yes, no). The DISCOVER-2 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and CRP before randomization (< 2 mg/dL vs. ≥ 2 mg/dL). The COSMOS study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and number of prior TNF alpha inhibitors (1 or 2).

^bChange from baseline was based on observed data or 0 (no improvement) if a patient met the treatment failure criteria before week 24 (composite estimand). The DISCOVER-1 and DISCOVER-2 studies used an ANCOVA model, with missing data imputed using multiple imputation, assuming data were missing at random. The COSMOS study used MMRM under the missing-at-random assumption.

^cThere were 2 statistical testing procedures used to control the type I error rate. According to the US-based statistical testing procedure, this outcome was statistically significant, with a P value of 0.011. According to the global testing procedure, this outcome was not formally tested for statistical significance due to the failure of a prior outcome. The US-specific procedure was preferred by Health Canada.

^dThe P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks);¹³ Coates et al. (2022).¹⁴

Table 3: Summary of Key Safety Results From Pivotal and Protocol Selected Studies

GUSE = guselkumab; PBO = placebo; q8w = every 8 weeks; SAE = serious adverse event.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Critical Appraisal

The risk of bias related to randomization and treatment allocation concealment was rated as low for all studies. In general, patient characteristics and co-interventions appeared to be balanced between groups at baseline. The trials were double blind and took steps to maintain blinding of patients and investigators. Joint assessments were conducted by an independent rater who was not otherwise involved in the trial. Therefore, the risk of bias in the measurement of the outcomes was low for all trials. The frequency of withdrawal in all trials was low and similar between groups; therefore, there is a low risk of bias due to missing outcome data. The full analysis set (FAS), which excluded only 1 randomized patient in DISCOVER-2, was used for all efficacy outcomes; therefore, the analyses were appropriate for estimating the effect of assignment to the intervention.

In all trials, the primary and other dichotomous end points were analyzed using a Cochran-Mantel-Haenszel (CMH) test that was stratified by randomization stratification factors, with missing data imputed as nonresponders. The DISCOVER trials used an adjusted analysis of covariance (ANCOVA) model, and the COSMOS study used an unadjusted mixed-effects model for repeated measures (MMRM) to analyze continuous outcomes. Missing data were imputed under the missing-at-random assumption. This assumption may not hold true, but was not thought to be a major source of bias. Efficacy analyses were based on the composite estimand, with any patients meeting treatment failure criteria considered nonresponders for binary end points, or as no change from baseline for continuous measures. Treatment failure criteria included early study withdrawal or discontinuation of the study drug, or initiation of new treatments for PsA. This estimand, which considers any treatment failure end point to be an unfavourable outcome, may be considered a more conservative estimate of treatment effects. Of note, the COSMOS study incorrectly assigned 20 patients to early escape despite these patients not having met the escape criteria. Although the sponsor conducted sensitivity analyses to explore the impact of this error, these analyses cannot fully address the potential bias. The type I error rate was controlled for the primary and selected secondary outcomes in all studies. However, several outcomes of interest to this review were not controlled for multiplicity; these data should be interpreted with caution, given the potential for inflated type I error rate. Randomization was not stratified by the presence of psoriasis, enthesitis, dactylitis, or axial disease; thus, interpretation of the results for these outcomes should consider the possibility of imbalances in baseline demographic and disease characteristics between treatment groups in these subpopulations. The primary outcome was ACR 20 response; however, according to the clinical expert, this represents the minimum level of improvement that may be relevant to patients. In practice, the goal of therapy is to achieve higher levels of response.

Although the trials were 48 weeks to 100 weeks in duration, the comparative period was limited to 24 weeks for this chronic condition. For outcomes such as radiologic changes, the duration of treatment may have been insufficient to detect the impact of guselkumab. Moreover, none of the trials included an active control group; thus, direct evidence comparing guselkumab to other DMARDs available in Canada is not available.

With regards to external validity, the clinical expert did not identify any substantial limits to generalizability based on the patient population enrolled. The guselkumab dosing regime used in the trials (i.e., once every 8 weeks) was consistent with the Health Canada–recommended dose, and the expert stated that concomitant utilization of cDMARDs was similar to what may be expected in clinical practice. However, the expert also noted that the use of oral corticosteroids in the DISCOVER trials was higher than would be expected in Canada (14% to 20%). The use of a placebo comparator as an add-on to cDMARDs and NSAIDs is not consistent with Canadian practice for patients who have demonstrated an inadequate response to cDMARDs or bDMARDs. The trials excluded patients who had previously been treated with biologics other than TNF inhibitors; thus, the efficacy in patients with intolerance or inadequate response to other biologics, such as Janus kinase (JAK) or other IL inhibitors, is not known.

Indirect Treatment Comparisons

Description of Studies

The sponsor conducted a network meta-analysis (NMA) of RCTs that assessed the comparative efficacy and safety of guselkumab and 13 other bDMARDs for the short-term treatment of acute PsA. The indirect treatment comparison (ITC) was based on a systematic literature review, and 34 RCTs provided data to inform the Bayesian NMA. Analyses were conducted for the overall PsA population, with subgroup analyses restricted to patients who were biologic-naive or biologic-experienced. Treatment durations were 12 weeks to 24 weeks.

One other NMA was identified by CADTH through a literature search. The NMA by McInnes et al. (2022)¹⁵ evaluated the efficacy and safety of licensed and unlicensed bDMARDs for patients with active PsA. A total of 46 RCTs, which were identified through a systematic review, were included in the Bayesian analyses. The MNA included 19 biologics with outcomes assessed at 12 weeks to 26 weeks.

Efficacy Results

For the overall PsA population in the sponsor-submitted NMA, the results suggest that patients who received guselkumab every 8 weeks ||| || |||| |||||| || ||||||| || ||| || |||||||| than those who received apremilast or abatacept, but were |||| |||||| || respond than infliximab, golimumab, and secukinumab 300 mg (34 RCTs; ordinal baseline risk-adjusted random-effects model). Comparisons between guselkumab and other biologics had 95% credible intervals (CrIs) that |||||||||| ||| |||| |||||. The NMA results for PASI 90 response |||||||| |||||||||| |||||| ||||||||||| ||| ||| ||| ||||| |||||||||| ||||||| |||||||||||| ||| ||||||||||| ||||||||| ||| ||||||||||. Other comparisons with biologics reported 95% CrIs that |||||||| ||| ||||. For the change in HAQ-DI, SF-36 PCS or MCS, or vdH-S scores, |||| || ||| ||||||||||| |||||||| guselkumab over other biologics, with analyses reporting 95% CrIs that |||||||||| ||| ||||. Across all networks, many comparisons showed imprecise 95% CrIs that included the possibility of appreciable benefit and/or worse outcomes, and || |||||||||| ||||||| |||||||||| ||| ||||| |||||||||, which limits the ability to draw conclusions from these data.

The results in the biologic-naive population were generally |||||||||| |||| ||| |||||||| || ||| ||||||| ||||||||||, although the networks were smaller (17 studies to 30 studies), not all comparators were available for all outcomes, and with |||| || ||| |||||||| ||||||| ||||||| |||||||||. The NMAs in biologic-experienced patients included fewer trials (8 studies to 16 studies) and the reported results were imprecise, limiting the ability to draw conclusions.

The results for ACR 20 and PASI 90 in the NMA by McInnes et al. (2022)¹⁵ were largely consistent with the findings of the sponsor-submitted NMA.

Harms Results

In the overall population, the analysis of serious adverse events in the sponsor-submitted NMA |||||| ||| ||| |||| |||||||||| ||| |||| ||| |||| |||||||||||| |||| |||||||| ||||| |||| ||| |||||||||| |||||| |||||||||| || |||||||||||| ||| || |||| ||| |||||||| |||||||| ||||||||||||| |||||| ||||||| ||||||. For all other comparisons, the 95% CrI was |||||||||| limiting the ability to draw a conclusion. In most cases, ||| ||||||| || ||| ||| || ||||||| |||||| |||||| ||||||| ||||||||.

||| ||| ||| ||||||| |||||| || ||||||| ||||||| |||||| || |||||||||||||| ||| ||||||| ||| |||||||||||||||||||| |||||||| || ||||||| |||||| ||| ||| |||| |||||||||| ||| ||||| |||| |||| ||||||||||| ||||||| |||| |||| |||||||| ||| ||||||| || |||| | ||||||||||. No comparative safety data for guselkumab were reported in the NMA by McInnes et al. (2022).¹⁵

Critical Appraisal

Although the sponsor-submitted ITC was based on a systematic review, 46 RCTs were excluded from the NMA, and the criteria for selecting trials or outcomes for analysis were not stated. Heterogeneity in patient and study characteristics was identified, and it is unclear if the transitivity assumption has been met. The authors of the NMA attempted to address potential variability in effect modifiers by using a baseline risk-adjusted model, but it is unclear if these effect modifiers have the same level of effect on the active arms. Given that it is unclear to what extent placebo response is an adequate proxy for specific characteristics or effect modifiers, uncertainty remains in these analyses. Subgroup analyses based on prior treatment exposure were conducted to create more homogenous patient populations, but some of these analyses included data from a limited number of trials, and often showed substantial uncertainty, with wide CrIs. There were no subgroup or sensitivity analyses conducted to explore the potential impact of differences in the timing of outcome assessment, duration of disease, background therapies, or year of study.

ACR and PASI percentage improvements were analyzed using an ordinal model, which assumed that the relative treatment effects were the same for each response level. Thus, although data were reported separately for each response level, the inferences for each comparison are the same across the ACR 20, ACR 50, and ACR 70 levels or PASI levels. It is not clear if this assumption of the model holds true (i.e., if relative treatment effects are consistent across response levels), given that data were pooled for different time points. No sensitivity analyses were run to examine the impacts of this assumption.

In the sponsor-submitted NMA, there was limited ability to assess the consistency between direct and indirect evidence because there were few closed loops (i.e., there were only 4 head-to-head studies), and the statistical tests for inconsistency are generally underpowered. Further, most of the contributing trials were judged to be at high or unclear risk of bias in at least 1 domain.

Issues with heterogeneity in patient and study characteristics, lack of ability to assess consistency, and potential bias in the included RCTs were also identified as limitations for the NMA by McInnes et al. (2022).¹⁵

The indirect evidence was limited to short-term efficacy and safety; thus, longer-term comparative effects are uncertain.

Other Relevant Evidence

Description of Studies

Efficacy and safety data were available for the uncontrolled extension phase of DISCOVER-1 (52 weeks), DISCOVER-2 (100 weeks), and COSMOS (48 weeks) trials. Descriptive results for patients who received guselkumab 100 mg every 8 weeks are summarized in this section, including results for patients from the placebo group in the COSMOS study who crossed over to guselkumab.

Efficacy Results

The extension phase data suggest that treatment effects may be maintained in patients who remain on guselkumab therapy every 8 weeks for 48 weeks to 100 weeks. In DISCOVER-1, 76 patients out of 112 patients (68%), and in COSMOS, 120 patients out of 172 patients (70%), achieved ACR 20 at week 48 or week 52. In the DISCOVER-2 study, 85 patients out of 234 patients (79%) achieved ACR 20 at week 52, and 183 patients out of 223 patients (82%) achieved ACR 20 at week 100. PASI 100 response was reported by 36 patients out of 75 patients (48%) in DISCOVER-1 (week 52), by 94 patients out of 169 patients (57%) in DISCOVER-2 (100 weeks), and by 80 patients out of 121 patients (66%) in COSMOS (48 weeks).

Harms Results

During the extension period, 31% to 72% of patients reported 1 or more adverse event; 3% to 9% reported a serious adverse event; and 1% to 3% stopped treatment due to adverse events. No deaths were reported. Infections were reported in 43% of patients in DISCOVER-1 and in 29% and 38% of patients at week 52 and week 100 of the DISCOVER-2 study. Over the 48-week treatment period of the COSMOS study, 22% of patients who received guselkumab every 8 weeks experienced an infection.

Critical Appraisal

Limitations of the extension study include selection bias and lack of a control group. Data were available only as descriptive statistics; and because there were no comparator groups, the interpretation of the results is limited. The outcomes were based on observed case data, with no imputation for missing data, and reflect treatment effects in patients who continue on therapy. As such, the results may overestimate the response in the broader population, given that patients who drop out are more likely to have unfavourable outcomes or poor tolerance to therapy.

Conclusions

Based on data from 3 double-blind RCTs, adults with active PsA who received guselkumab 100 mg every 8 weeks were more likely to show clinically relevant improvements in PsA disease activity and tender and swollen joint counts than patients who received placebo, based on the proportion who achieved an ACR 20 response at week 24. Favourable clinical responses in PsA activity and symptoms were observed among patients who were biologic-naive or had prior intolerance or inadequate response to TNF alpha inhibitors. This was also the case for a mixed population that included patients with and without prior TNF inhibitor exposure.

Patients on guselkumab also showed statistically significant improvements in disability as measured using the HAQ-DI, although the clinical relevance of the difference versus placebo is uncertain. Improvements in the physical component (but not the mental component) of the SF-36 were observed favouring guselkumab versus placebo. Outcomes related to psoriatic skin lesions demonstrated superiority of guselkumab every 8 weeks versus placebo at 24 weeks. Among patients with enthesitis or dactylitis at baseline, pooled data from the pivotal trials suggest that patients who receive guselkumab every 8 weeks may be more likely to have enthesitis or dactylitis resolved at 24 weeks than those receiving placebo. The impact of guselkumab on radiographic progression is unclear, given that no statistically significant differences were detected between guselkumab every 8 weeks and placebo for the change in the modified vdH-S score at 24 weeks among patients with active PsA who were biologic-naive.

No new safety signals were identified in the controlled or extension phases of the PsA trials. The frequency of infection was similar in the guselkumab and placebo groups up to 24 weeks.

There is no direct evidence comparing guselkumab to other bDMARDs available in Canada. The indirect evidence for ACR response rates, change in HAQ-DI scores, change in SF-36 PCS and MCS, and risk of adverse events or serious adverse events for guselkumab versus most biologic comparators showed imprecise results; this imprecision limits the ability to draw conclusions from these data. Based on the indirect evidence, short-term PASI response rates may favour guselkumab versus some other biologics. However, there is uncertainty in these findings, given that several sources of heterogeneity were identified across the trials included in the NMAs and that it is unclear whether the methods used to control for potential bias were adequate. In addition, many of the studies included in the NMAs were at an unclear or a high risk of bias in 1 or more study domains.

The direct comparative evidence versus placebo and indirect evidence versus other biologics was limited to short-term outcomes (i.e., up to 24 weeks). Although results from the extension phase of the trial suggest that treatment effects may be maintained up to 100 weeks, these data are difficult to interpret because of the lack of comparator group and bias due to attrition. Thus, the longer-term comparative efficacy and safety of guselkumab in patients with PsA is unclear.

Introduction

Disease Background

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 (tenderness and swelling at the insertion of tendons and ligaments into bone), dactylitis (swelling of the whole digit), and axial disease (inflammation of the joints of the back).^1,2 Extra-articular manifestations include inflammation of the eye and inflammatory bowel disease. Diagnosis of PsA can be a challenge, given that there is no gold standard diagnostic test; it is typically diagnosed 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 are usually seronegative for rheumatoid factor (95%).^2,16 Pain and stiffness of the affected joints are the most predominant presenting symptoms, with fatigue also occurring in many patients.¹ Patients with psoriasis and PsA are at risk for the development of comorbidities, including cardiovascular disease, diabetes, gout, metabolic syndrome, and depression.¹

The prevalence of PsA varies, depending on the case definition and geography, and is estimated to be 1 to 2 cases per 1,000 in the general population.¹ A population-based Canadian study estimated the age- and sex-standardized cumulative prevalence of PsA in Ontario to range 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 100,000.³

About 30% of patients with psoriasis develop PsA; skin disease usually precedes manifestations of PsA by several years (10 years on average); however, in some individuals, both can occur simultaneously, or PsA may occur before the onset of psoriasis.² A Canadian prospective cohort study estimated the annual incidence of PsA to be 2.7 cases per 100 psoriasis patients.¹⁷ 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).^2,16

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. This disease affects more than just patients’ joints; therefore, treatment is individualized based on various factors, including disease activity, structural damage, comorbid conditions, and previous therapies.¹⁸ Recent recommendations by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) have suggested the use of a domain-based approach (peripheral arthritic, axial disease, enthesitis, dactylitis, psoriasis, nail disease, inflammatory bowel disease, and uveitis) that considers patient preference and previous and/or concomitant therapies; the choice of therapy should address as many domains as possible (Figure 1).

Several drug classes are employed in the pharmacologic treatment of PsA, including NSAIDs, cDMARDs (i.e., methotrexate, sulfasalazine, or leflunomide), bDMARDs (i.e., TNF inhibitors, IL-23 inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors), and targeted synthetic DMARDs (e.g., apremilast, upadacitinib, or tofacitinib). Key characteristics of select drugs used in the treatment of PsA that are relevant to this review are summarized in Table 4.

Figure 1: GRAPPA Treatment Schema — Redacted

This figure was removed by CADTH because permission to reproduce could not be obtained from the publisher. Please refer to Figure 2 in the source publication.

Source: Reproduced from Coates et al. (2022).¹⁹

Drug

Guselkumab is human immunoglobulin G1 lambda monoclonal antibody that binds to the IL-23 protein and inhibits its binding with cell surface IL-23 receptor.⁵ IL-23 is a cytokine that is involved in normal inflammatory and immune response. Guselkumab is approved for the treatment of adult patients with active PsA.⁵ It may be used alone or in combination with a cDMARD (e.g., methotrexate). Guselkumab is available as a 100 mg/mL solution for SC injection in either 1 mL pre-filled syringes or patient-controlled injector devices. The recommended dose is 100 mg SC at week 0, week 4, and every 8 weeks thereafter.⁵

Guselkumab underwent a standard Health Canada review and was approved by for PsA in September 2020. The sponsor has requested reimbursement as per the Health Canada indication.²⁰

Guselkumab is also approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.⁵ In 2018, the CADTH Canadian Drug Expert Committee (CDEC) recommended that guselkumab be reimbursed for adults with plaque psoriasis if the following clinical criteria and conditions were met:

• Reimburse in a manner similar to other biologics for the treatment of moderate to severe plaque psoriasis.

• Treatment should be discontinued if a response has not been demonstrated after 16 weeks.

• The drug plan cost for guselkumab should not exceed the drug plan cost of treatment with the least costly biologic reimbursed for moderate to severe plaque psoriasis.²¹

Table 4: Key Characteristics of Select Drugs Used in the Treatment of PsA

cDMARD = conventional disease-modifying antirheumatic drug; COPD = chronic obstructive pulmonary disease; DMARD = disease-modifying antirheumatic drug; Fab’ = fragment, antigen binding; IgG1κ = immunoglobin G1 kappa; IL = interleukin; JAK = Janus kinase; MTX = methotrexate; PP = plaque psoriasis; PsA = psoriatic arthritis; q2w = every 2 weeks; q4w = every 4 weeks; q8w = every 8 weeks; RPLS = reversible posterior leukoencephalopathy syndrome; SAE = serious adverse event; SC = subcutaneous; TB = tuberculosis; TNF = tumour necrosis factor.

Note: only bDMARDs and targeted synthetic DMARDs identified as relevant comparators in the CADTH systematic review are included in this table. Comparators are drugs used in the treatment of PsA that are publicly funded. Although tofacitinib, upadacitinib, abatacept, and apremilast are not currently reimbursed by public drug programs in Canada, these were deemed to be relevant comparators to guselkumab by the clinical expert consulted for this review.

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

Source: Product monographs.^5,22-34

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient inputs received by CADTH are included in the stakeholder section at the end of this report.

Three inputs were submitted for this review from 6 different patient groups: Arthritis Consumer Experts, CAPP in partnership with CPN, and CAPA in partnership with the Arthritis Society and CreakyJoints.

Arthritis Consumer Experts is Canada’s largest, longest-running national arthritis patient organization. It is headquartered in Vancouver, British Columbia, with 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.

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.

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. It 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.

CAPA is a grassroots, patient-driven and managed, independent, national education and advocacy organization with members and supporters across Canada. It creates links between people in Canada with arthritis, assists them to 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 a world where people are free from the devastating effects of arthritis. It is Canada’s principal health charity, providing education, programs, and support to the more than 6 million people in Canada living with arthritis.

CreakyJoints Canada has served for more than 2 decades as a digital community for millions of arthritis patients and caregivers worldwide who seek education, support, advocacy, and patient-centred research. All of its programming and services are provided free of charge. CreakyJoints is part of the non-profit Global Healthy Living Foundation, whose mission is to improve the quality of life for people living with chronic illnesses.

Five patient organizations (CAPP, CPN, CAPA, the Arthritis Society, and CreakyJoints Canada) collaborated by collectively developing survey questions using SurveyMonkey for the inputs submitted. Each organization shared the surveys with its respective memberships or patient communities through email, social media, and organization websites. CAPA, CreakyJoints Canada, and the Arthritis Society submitted 1 collaborative patients’ input; the CAPP and CPN analyzed data and prepared 1 submission collectively, while the Arthritis Consumer Experts made its own submission based on survey response data and its unique community perspectives. Survey data were collected from April 20, 2022 to May 16, 2022. In addition, Arthritis Consumer Experts gathered information from 1 respondent through email on May 4, 2022 and from 5 respondents through an online survey from December 18, 2020 to January 26, 2021.

There were 71 respondents to the joint survey: 12 respondents were from British Columbia (17%), 7 were from Alberta (10%), 3 were from Manitoba (4%), 34 were from Ontario (49%), 4 were from Quebec (6%), 4 were from New Brunswick (6%), 4 were from Nova Scotia (6%), and 3 were from Newfoundland and Labrador (4%). Two survey participants had experience taking guselkumab.

Respondents reported a range of symptoms that were difficult to manage, including joint stiffness (79%), fatigue (75%), changes in fingernails and toes (63%), hip pain (61%), back pain (51%), anxiety (47%), and stress (33%). With regards to the most significant impacts of PsA on their daily quality of life, respondents reported that PsA interfered with their work (54%), social connections (52%), self-esteem (50%), mental health (50%), intimacy (50%), family life (38%), and friendships (24%). Other impacts included embarrassment and self-consciousness from symptoms caused by PsA. Because the disease would reduce their mobility and ability to participate in activities and affect their mental and social health, respondents indicated that caregivers had to take on additional tasks or chores, such as cooking, cleaning, shopping, and helping patients get to and from medical appointments.

Survey respondents indicated that they had experience with several treatment approaches, including NSAIDs, corticosteroids, cDMARDs (such as methotrexate), and bDMARDs. Among responders, 32% considered biologics to be highly effective, followed by oral steroids (23%) and other DMARDs (21%). Respondents expressed their ongoing unmet need to manage symptoms and side effects with current treatments.

Two respondents who had experience with guselkumab indicated that the drug was effective in terms of improving psoriasis and arthritis and slowing disease progression. Both stated that they did not experience side effects.

Respondents expected new treatments to improve the following key outcomes: management of symptoms (i.e., reducing pain and fatigue, increasing mobility); tolerability of side effects; ease of drug administration; improved ability to work and carry out tasks and daily activities; and quality of life.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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

The goals of therapy are to control the symptoms of PsA (i.e., pain stiffness, swelling, fatigue), reduce impacts on patients’ quality of life and function, and prevent the progression of joint damage. A substantial proportion of patients do not achieve a minimal response with their first therapy or lose their response over time. In addition, some treatments have more adverse effects than others. Thus, there is a need for medications with new mechanisms of action or a different safety profile to offer alternate treatment options. There also needs to be a choice for patients in terms of preference with regards to the frequency of injections, injection versus infusion, and oral administration versus injection.

Place in Therapy

According to the clinical expert, guselkumab may be used as first- or second-line biologic therapy. It may be a preferred first-line treatment for patients with moderate psoriasis in addition to musculoskeletal disease. Guselkumab may be used in combination with methotrexate or leflunomide. There is no evidence to support its use in combination with other biologics. The expert stated that it would not be appropriate to recommend that patients try other biologics before receiving guselkumab.

Patient Population

There are currently no biomarkers that may be used to identify the patients who will be most suited for a particular drug. Clinicians make these decisions based on patient history, physical examination, imaging, and discussion.

There is currently no diagnostic test for PsA. Rheumatologists can usually diagnose PsA after evaluating the patient and may seek confirmation of the psoriasis diagnosis from a dermatologist. The expert stated that 30% to 80% of psoriasis patients had a missed PsA diagnosis.

Assessing Response to Treatment

Response to therapy is based on a reduction in the number of inflamed joints, improvement in the skin, and patient-reported outcomes. According to the clinical expert, a major improvement would be considered an improvement of at least 50%, but may also include achievement of MDA and remission as measured by specific instruments. Assessment of response requires the physician to perform a physical examination, including a joint count and skin evaluation, and also includes patient-reported outcomes (i.e., assessment of pain, function, fatigue). Less frequently, structural damage may be assessed using X-rays.

An initial response may be expected within 3 months, with more significant improvement by 6 months after initiating therapy. The expert indicated that if a patient shows no change within 3 months to 6 months, they would be considered a nonresponder and may be switched to another medication.

Discontinuing Treatment

Patients may be switched to another medication if no improvement is observed within 3 months to 6 months or if the patient experiences intolerable or serious adverse effects. If a patient has responded in some but not all manifestations, another medication may be added to address the area that has not responded.

Prescribing Conditions

Ideally, guselkumab would be prescribed by specialists who are familiar with the drug and its uses, or at least in consultation with a dermatologist or rheumatologist. The administration of guselkumab may take place in any setting, including self-administration by the patient in their home.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group input(s) received by CADTH have been included in the stakeholder section at the end of this report.

CADTH received 1 submission from Canadian Rheumatologist Psoriatic Arthritis Interest Group, based on responses from 6 clinicians practising in academic and community settings. The Canadian Rheumatologist Psoriatic Arthritis Interest Group consists of a group of clinical rheumatologists across Canada who have extensive experience managing inflammatory arthritis, including PsA. No major views contrary to those provided by the clinical experts consulted by CADTH for this review were presented.

The clinician group stated that PsA is a complex disease with varied manifestations. The current treatment options include nonpharmacological treatments and pharmaceutical interventions, such as cDMARDs and biologic therapies (i.e., TNF alpha inhibitors and IL-17A inhibitors) as first-line therapies and IL-12/23 inhibitors and JAK inhibitors as second-line therapies. The clinician group highlighted that not all patients achieve a good response (defined as ACR 20 or MDA) to current treatments. In addition, the adverse effects of TNF inhibitors (lupus-like syndromes or multiple sclerosis) and IL-17A (inflammatory bowel disease) limit the use of the 2 most common classes of biologics used to manage PsA. Moreover, biologic therapies are associated with increased risk of serious infections. Thus, the clinician group identified significant unmet need in the management of PsA.

According to the clinician group, the goals of treatment are to improve quality of life and physical function by controlling symptoms (i.e., joint pain and stiffness, concomitant psoriasis, and extra-articular manifestations) and to limit structural damage and minimize long-term complications arising from inadequately controlled inflammation related to PsA. The clinician group expressed that guselkumab may be used alone or in combination with cDMARDs as a first-line biologic therapy or as a second-line treatment after failure to respond to a TNF inhibitor. The clinician group stated that rheumatologists can identify patients who are suitable for treatment with guselkumab based on inflammatory arthritis in the presence of psoriasis; the clinicians did not identify any potential challenges associated with the diagnosis.

According to the clinician group, patients with early disease and moderate to severe skin and joint involvement are most likely to respond to guselkumab. Those who are refractory to current therapeutic drugs or unable to take current classes of biologic drugs have the greatest need for an intervention such as guselkumab. The clinicians noted that improvement in tender and swollen joint counts, psoriasis, enthesitis, patient global impression, and ACR 20 are commonly used to determine whether a patient is responding to guselkumab. They also noted that composite measures — including MDA, Disease Activity Index for PsA, and PsA Disease Activity Score — would be considered as well. With regards to discontinuation, the clinician group noted several factors that would be considered when deciding to stop guselkumab treatment, such as inflammatory pain and stiffness, swollen or tender joint count, worsening psoriasis, poor function, intolerability due to adverse effects, or the development of severe extra-articular manifestations. The clinician group indicated that rheumatologists or experienced nurse practitioners with extensive rheumatology experience are required to diagnose and manage PsA. In addition, the clinician group mentioned that guselkumab has shown effectiveness in the treatment of joints in both biologic naive patients and patients with an inadequate response to TNF, and has been shown to improve pain and fatigue in clinical trials.

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 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

CDEC = CADTH Canadian Drug Expert Committee; cDMARD = conventional disease-modifying antirheumatic drug; DMARD = disease-modifying antirheumatic drug; IL = interleukin; JAK = Janus kinase; NSAID = nonsteroidal anti-inflammatory drug; pCPA = pan-Canadian Pharmaceutical Alliance; PsA = psoriatic arthritis; RCT = randomized controlled trial; TNF = tumour necrosis factor.

^aApremilast is not covered for PsA in any Canadian jurisdiction.

Clinical Evidence

The clinical evidence included in the review of guselkumab 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 that were 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 guselkumab 100 mg/mL administered through a 1 mL pre-filled syringe or patient-controlled injector for SC injection for the treatment of active PsA in adults.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.³⁵

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) through Ovid and Embase (1974—) through Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. 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 Tremfya (guselkumab). Clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

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

The initial search was completed on May 31, 2022. Regular alerts updated the search until the meeting of the CADTH CDEC on September 28, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the CADTH Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.³⁶ Included in this search were the websites of regulatory agencies (FDA and the European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

In addition to the literature search, 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.

Findings From the Literature

A total of 3 studies were identified from the literature for inclusion in the systematic review (Figure 2). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 2: Flow Diagram for Inclusion and Exclusion of Studies

Table 7: Details of Included Studies

ACR 20 = American College of Rheumatology 20% improvement; ACR 50 = American College of Rheumatology 50% improvement; ACR 70 = American College of Rheumatology 70% improvement; ACR 90 = American College of Rheumatology 90% improvement; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; CASPAR = Classification Criteria for Psoriatic Arthritis; CRP = C-reactive protein; DAPSA = Disease Activity Index for Psoriatic Arthritis; DAS 28 = Disease Activity Score 28; DB = double blind; DLQI = Dermatology Life Quality Index; DMARD = disease-modifying antirheumatic drug; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy – Fatigue Scale; GRACE = GRAPPA composite score; HAQ-DI = Health Assessment Questionnaire Disability Index; IGA = Investigator’s Global Assessment of Psoriasis; IL = interleukin; JAK = Janus kinase; MCS = Mental Component Summary; MDA = minimal disease activity; NSAID = nonsteroidal anti-inflammatory drug; PASDAS = Psoriatic Arthritis Disease Activity Score; PASI 75 = Psoriasis Area and Severity Index 75% improvement; PASI 90 = Psoriasis Area and Severity Index 90% improvement; PASI 100 = Psoriasis Area and Severity Index 100% improvement; PCS = Physical Component Summary; PsA = psoriatic arthritis; PsARC = Psoriatic Arthritis Response Criteria; RA = rheumatoid arthritis; RCT = randomized controlled trial; SC = subcutaneous; SF-36 = Short Form (36) Health Survey; TB = tuberculosis; TNF = tumour necrosis factor; VLDA = very low disease activity; vdH-S = van der Heijde-Sharp; WPAI = Work Productivity and Activity Impairment.

Note: Six additional reports were included (Health Canada reviewer’s report;⁴⁰ EPAR;⁴¹ Deodhar et al. [2020];³⁷ Mease et al. [2020];³⁹ Rahman et al. [2021];³⁸ and Coates et al. [2021]¹⁴).

^aNon-biologic DMARD (≥ 3 months), apremilast (≥ 4 months), and/or NSAID therapy (≥ 4 weeks).

^bPatients had shown either a lack of benefit after at least 12 weeks of etanercept, adalimumab, golimumab or certolizumab pegol (or biosimilars) and/or at least 14 weeks of infliximab (or biosimilar), or intolerance to 1 of the TNF alpha inhibitors. A washout period for TNF inhibitors was required before study entry (8 weeks for infliximab, 6 weeks for golimumab, adalimumab or certolizumab pegol, and 4 weeks for etanercept).

^cStable doses of NSAIDs or other analgesics, oral corticosteroids (≤ 10 mg of prednisone per day or equivalent), and select cDMARDs (i.e., 1 of the following: methotrexate [≤ 25 mg/week], sulfasalazine [≤ 3 g/day], hydroxychloroquine [≤ 400 mg/day], or leflunomide [≤ 20 mg/day]) were allowed during the study.

^dAt week 16, patients with less than 5% improvement from baseline in both tender and swollen joint counts were considered to have met the early escape criteria and were allowed to start therapy or increase the dose of 1 of the permitted concomitant psoriatic medications (methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, oral corticosteroids, or NSAIDs) up to the maximum dose specified in the protocol.

^eNot a Health Canada–recommended dosage regimen.

^fAt week 16, patients with less than 5% improvement from baseline in both tender and swollen joint counts were considered to have met the early escape criteria and were allowed to start therapy or increase the dose of 1 of the permitted concomitant psoriatic medications (up to the maximum dose specified in the protocol). Patients in the placebo group who qualified for early escape received guselkumab at week 16, week 20, and every 8 weeks thereafter.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Description of Studies

Three double-blind, randomized, placebo-controlled trials met the inclusion criteria for the systematic review.

The objective of the DISCOVER-1 study was to evaluate the efficacy of guselkumab in patients with active PsA who had inadequate response to standard therapies (e.g., non-biologic DMARDs, apremilast, and/or NSAIDs). Up to 30% of patients enrolled had received prior treatment with 1 or 2 TNF alpha inhibitors. Patients were randomized (1:1:1) to guselkumab 100 mg SC every 4 weeks for 48 weeks; guselkumab 100 mg SC at week 0, week 4, and every 8 weeks thereafter (with placebo injections at other time points); or placebo every 4 weeks until week 20, crossing over to guselkumab 100 mg SC at week 24 and then every 4 weeks thereafter until week 48 (Figure 3). Patients were randomized centrally through an interactive web response system using permuted block randomization, stratified by non-biologic DMARD use at baseline (yes, no) and by prior exposure to TNF alpha inhibitors (yes, no) (N = 381). The trial was conducted at a total of 6 sites in Asia, Europe, the US, and Canada.

The objective of the DISCOVER-2 study was to evaluate the efficacy of guselkumab in patients with active PsA who were biologic-naive and had an inadequate response to standard therapies (e.g., non-biologic DMARDs, apremilast, and/or NSAIDs). Patients were randomized (1:1:1) to guselkumab 100 mg SC every 4 weeks for 100 weeks; guselkumab 100 mg SC at week 0, week 4, and every 8 weeks thereafter (with placebo injections at other time points); or placebo every 4 weeks until week 20, crossing over at week 24 to guselkumab 100 mg SC every 4 weeks to week 100 (similar to the design shown in Figure 3). Permuted block randomization was used in the trial, with randomization stratified by non-biologic DMARD use at baseline (yes, no) and most recent CRP value (< 2.0 mg/dL versus ≥ 2.0 mg/dL) (N = 741). The trial was conducted in Europe, Asia, and the US.

The objective of the COSMOS study was to evaluate the efficacy of guselkumab in patients with active PsA who had an inadequate response or intolerance to 1 or 2 prior TNF alpha inhibitors. Patients were randomized (1:1) to guselkumab 100 mg SC at week 0, week 4, and every 8 weeks thereafter (with placebo injections at other time points) or to placebo until week 20 before crossing over to guselkumab 100 mg SC at weeks 24, 28, 36, and 44 (Figure 4). Patients were randomized through an interactive web response system (N = 285). Central permuted block randomization was used, with randomization stratified by non-biologic DMARD use at baseline (yes, no) and number of prior TNF alpha inhibitors (1 or 2). The trial was conducted in Europe and Israel.

Data for the placebo-controlled portion of the 3 studies (i.e., first 24 weeks) have been summarized as part of the systematic review, including data from the interim database lock on March 2019 for the DISCOVER-1 and DISCOVER-2 studies and August 2020 for the COSMOS study. The study results after placebo patients crossed over to guselkumab have been summarized in the Other Relevant Evidence section, given that these uncontrolled follow-up periods did not meet the study design criteria for the systematic review.

Data from the groups receiving guselkumab every 4 weeks in the DISCOVER-1 and DISCOVER-2 studies have not been summarized in this report because this dose is not consistent with the Health Canada–recommended dose and dose adjustment.⁵

Figure 3: DISCOVER-1 Study Schematic

CO = placebo crossover; DBL = database lock; EE = early escape; GUS = guselkumab; PE = primary end point; q4w = every 4 weeks; q8w = every 8 weeks; SC = subcutaneous; W0 = week 0; W8 = week 8; W20 = week 20; W24 = week 24; W48 = week 48.

Source: Clinical Study Report for DISCOVER-1.¹¹

Figure 4: COSMOS Study Schematic — Redacted

Figure redacted at the request of the sponsor.

Source: Clinical Study Report for COSMOS study (24 weeks).¹³

Populations

Inclusion and Exclusion Criteria

All 3 included studies enrolled adults greater than or equal to 18 years of age with active PsA diagnosed at least 6 months prior who met the Classification Criteria for Psoriatic Arthritis (Table 7). In the DISCOVER-1 and COSMOS studies, patients were required to have least 3 tender and swollen joints — and in DISCOVER-2, at least 5 tender and swollen joints — to qualify. Key inclusion criteria differences were as follows:

• In the DISCOVER studies, patients had to have documented evidence of inadequate response or intolerance to standard PsA therapies, including non-biologic DMARDs (≥ 3 months), apremilast (≥ 4 months), and/or NSAID therapy (≥ 4 weeks). In DISCOVER-1, up to 30% of patients enrolled in had previously received 1 or 2 TNF alpha inhibitors. DISCOVER-2 enrolled patients with no prior exposure to bDMARDs.

• COSMOS enrolled patients with an inadequate response or intolerance to 1 or 2 TNF alpha inhibitors.

In all trials, the patients enrolled were required to have at least 1 PsA subset: distal interphalangeal joint involvement, polyarticular arthritis with absence of rheumatoid nodules, arthritis mutilans, asymmetric peripheral arthritis, or spondylitis with peripheral arthritis. Patients were also required to have active plaque psoriasis with 1 or more lesions at least 2 cm in diameter, nail changes of psoriasis, or documented history of plaque psoriasis.

Key exclusion criteria were the presence of other inflammatory diseases, a nonplaque form of psoriasis or drug-induced psoriasis, significant risk of suicide, recent serious infection, or herpes zoster, tuberculosis, HIV, hepatitis B, or hepatitis C. Those with prior treatment with JAK inhibitors or recent exposure to a prohibited medication without an adequate washout period were also excluded.

Baseline Characteristics

The demographics of patients were generally similar within and across trials (Table 8). The mean age of patients enrolled ranged from 44.9 years (SD = 11.9 years) to 49.1 years (SD = 12.3 years) across treatment groups. The proportion of female patients ranged from 46% to 55%, and most patients were White (89% to 98% in the DISCOVER studies; not reported for the COSMOS study). The mean number of swollen joints ranged from 9.0 (SD = 5.7) to 12.3 (SD = 6.9), and the mean number of tender joints ranged from 18.2 (SD = 10.7) to 21.6 (SD = 13.1). Approximately 2-thirds of patients had psoriatic involvement affecting at least 3% of their BSA. Two-thirds of patients reported enthesitis, while approximately 40% had dactylitis at baseline. Some potential imbalances were noted in the COSMOS study in the proportion of female patients (55% versus 46%) and psoriasis at baseline (70% versus 55%), and in the DISCOVER-2 study in the proportion with enthesitis at baseline (64% versus 73%) in the groups receiving guselkumab every 8 weeks versus placebo, respectively.

Across the studies, 89% to 95% of patients per treatment group had received a prior non-biologic DMARD, of which methotrexate was the most commonly received drug (80% to 92%). Prior use of any immunosuppressive or apremilast was less common, and was reported by 2% to 6% of patients. In the DISCOVER-1 and DISCOVER-2 studies, 39% to 48% of patients had previously received systemic corticosteroids, while 87% to 92% had received NSAIDs (data not reported for COSMOS).

In the DISCOVER-1 study, 41 patients (32%) and 39 patients (31%) in the guselkumab and placebo groups, respectively, had received prior TNF alpha inhibitors, including 7 and 4 patients, respectively, who had received 2 prior drugs from this class. The reasons for stopping TNF alpha inhibitor therapy in the guselkumab and placebo groups, respectively, were financial (42% and 41%), inadequate response (37% and 31%), adverse events (2% and 8%), contraindications (5% and 3%), or unspecified (22% and 23%). In the COSMOS studies, all patients had received TNF alpha inhibitors. Among them, 88% had received 1 prior drug and 12% had received 2 prior TNF inhibitors. As per the inclusion criteria, no patients in DISCOVER-2 had prior exposure to TNF inhibitors.

Table 8: Summary of Baseline Characteristics

BMI = body mass index; BSA = body surface area; CRP = C-reactive protein; DMARD = disease-modifying antirheumatic drug; FAS = full analysis set; GUSE = guselkumab; IGA = Investigator’s Global Assessment of Psoriasis; NA = not applicable; NR = not reported; NSAID = nonsteroidal anti-inflammatory drug; PASI = Psoriasis Area and Severity Index; PBO = placebo; PsA = psoriatic arthritis; q8w = every 8 weeks; SD = standard deviation; TNF = tumour necrosis factor; VAS = visual analogue scale.

^aImmunosuppressives included cyclosporine, azathioprine, tacrolimus, mycophenolate mofetil, and others.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks);¹³ Coates et al. (2022).¹⁴ Additional data provided by the sponsor.⁴²

Interventions

In all trials, the study drug was supplied as 1 mL pre-filled syringes that contained either placebo solution or guselkumab 100 mg. In the DISCOVER-1 and DISCOVER-2 trials, the study drugs were described as identical in appearance and packaging. Patients and site investigators remained blinded to treatment allocation until the ends of the studies (i.e., 60 weeks for DISCOVER-1, 112 weeks for DISCOVER-2, and 56 weeks for COSMOS). An interim database lock was planned for 24 weeks in all studies, and the sponsor’s personnel were unblinded to patient-level data at that time to conduct the primary data analysis. In the trials, the study drug was administered by health care workers at week 0 and week 4, but patients had the option to self-administer at later visits under the supervision of a health care professional at the study site.

In DISCOVER-1 and DISCOVER-2, patients were randomized (1:1:1) to guselkumab 100 mg SC every 4 weeks; guselkumab 100 mg SC at week 0, week 4, and every 8 weeks thereafter (with placebo injections at other time points); or placebo every 4 weeks until week 20, crossing over at week 24 to guselkumab 100 mg SC and continuing every 4 weeks until the end of the study. The double-blind treatment durations were 48 weeks for DISCOVER-1 and 100 weeks for DISCOVER-2. At week 16, patients were assessed to determine if they met the early escape criteria. Patients with less than 5% improvement from baseline in tender and swollen joint counts were considered to have met the early escape criteria and were allowed to start therapy or increase the dose of 1 of the permitted concomitant psoriatic medications (up to the daily maximum dose outlined in the study’s protocol). Titration to a stable dose was to be completed by week 24.

In the DISCOVER-1 and DISCOVER-2 studies, stable use of NSAIDs or other analgesics, oral corticosteroids (≤ 10 mg of prednisone per day or equivalent), and 1 of either methotrexate [≤ 25 mg/week], sulfasalazine [≤ 3 g/day], hydroxychloroquine [≤ 400 mg/day], or leflunomide [≤ 20 mg/day]) was allowed during the trial. A washout period was required for patients who had recently stopped treatment with 1 of these medications (2 weeks for NSAIDs or corticosteroids, 12 weeks for leflunomide, and 4 weeks for the other 3 DMARDs). Other psoriasis or PsA treatments had to be stopped 2 weeks to 4 weeks before the start of the study drug. Medications prohibited during the trial included other biologic or non-biologic DMARDs, systemic immunosuppressants, apremilast, JAK inhibitors, and cytotoxic drugs. Injectable systemic corticosteroids or topical psoriasis treatments (except salicylic acid or coal tar shampoo) were prohibited until after week 24. Low- and mid-potency topical or intralesional corticosteroids were allowed after week 24. In DISCOVER-2, high-potency topical corticosteroids, phototherapy, and systemic treatments for psoriasis were prohibited until week 24, whereas DISCOVER-1 prohibited these therapies for the entire study duration. In both trials, patients were allowed to have up to 2 intra-articular, tendon sheath, or bursal corticosteroid injections in no more than 2 sites within any 24-week period of the study.

In the COSMOS study, patients were randomized 2:1 to guselkumab 100 mg SC at week 0, week 4, and every 8 weeks thereafter (with placebo injections at other time points), or to placebo at week 0, week 4, week 12, and week 20 before crossing over to guselkumab 100 mg SC at week 24 and continuing with it at week 28, week 36, and week 44. The double-blind treatment duration was 48 weeks.

The same early escape criteria used in the DISCOVER trials were applied in the COSMOS study. Patients who met the early escape criteria could initiate or increase the dose of permitted concomitant medications, as described previously. In addition, patients randomized to placebo who met the escape criteria received guselkumab 100 mg SC at week 16, week 20, and every 8 weeks thereafter.

Stable doses of NSAIDs, oral corticosteroids, and select cDMARDs (i.e., 1 of methotrexate [≤ 25 mg/week], sulfasalazine [≤ 3 g/day], hydroxychloroquine [≤ 400 mg/day], or leflunomide [≤ 20 mg/day]) were allowed during the study. A washout period was required for patients who had recently stopped treatment with 1 of these medications (2 weeks for NSAIDs or corticosteroids, 12 weeks for leflunomide, and 4 weeks for the other 3 DMARDs).

Medications prohibited during the COSMOS study included other biologic or non-biologic DMARDs, systemic immunosuppressants, apremilast, JAK inhibitors, and lithium. Phototherapy, injectable systemic corticosteroids, and topical psoriasis treatments that could affect psoriasis assessments were also prohibited.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are further summarized here. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

After reviewing the outcomes reported, some exploratory or other end points were not summarized in this report if there were data for a similar end point that was listed as a secondary outcome or was part of the statistical testing hierarchy. Examples include the EQ-5D and some composite measures related to PsA symptoms (i.e., the Psoriatic Arthritis Disease Activity Score, GRAPPA Composite Score, and Disease Activity Index for Psoriatic Arthritis [DAPSA]).

Clinical Response in PsA Symptoms

In all studies, a trained, independent joint assessor who was not otherwise involved in the conduct of the trial evaluated each of 68 joints for tenderness and each of 66 joints for swelling (hips were excluded for swelling). This assessor also conducted enthesitis and dactylitis assessments.

ACR 20, ACR 50, and ACR 70 are measurements of improvement in multiple disease assessment criteria. The ACR 20 is defined as a greater than or equal to 20% improvement from baseline in both swollen joint count (66 joints) and tender joint count (68 joints), and a greater than or equal to 20% improvement from baseline in 3 of the following 5 assessments: the patient’s assessment of pain (visual analogue scale [VAS]), the patient’s global assessment of disease activity (arthritis, VAS), the physician’s global assessment of disease activity (VAS), the HAQ-DI, and CRP. ACR 50 and ACR 70 response criteria require changes from baseline of 50% and 70%, respectively. The ACR 20 is generally accepted as the MID, indicating a response to treatment, while the ACR 50 and ACR 70 more likely reflect truly important change for the long-term management of arthropathy.^43,44

The MDA is a composite measure that encompasses different aspects of PsA disease.⁴⁵ To meet the MDA criteria, patients had to achieve at least 5 out of the following 7 items: tender joint count less than or equal to 1, swollen joint count less than or equal to 1, PASI score less than or equal to 1, patient’s assessment of pain less than or equal to 15 (VAS), patient’s global assessment of disease activity less than or equal to 20 (arthritis and psoriasis, VAS), HAQ-DI score less than or equal to 0.5, and tender entheseal points less than or equal to 1.⁴⁵

The Disease Activity Score 28 (DAS 28) using CRP (DAS 28 CRP) is composite measure of disease activity developed for patients with rheumatoid arthritis. It combines tender joints (28 joints) and swollen joints (28 joints) of the arms, shoulders, and knees with the CRP and the patient’s global assessment of disease activity.⁴⁶ The range of the DAS 28 is 0 to 9.4, with higher scores indicating more active disease.⁴⁷ No evidence was found to support the validity, reliability, or responsiveness in patients with PsA. According to the clinical expert consulted by CADTH, the relevance of this outcome measure in patients with PsA has been questioned because the DAS 28 does not include an assessment of inflammation in the feet, which is more common in patients with PsA than in those with rheumatoid arthritis. Assessment of 66 and 68 swollen and tender joints over the 28-joint count in patients with PsA has been endorsed by GRAPPA and the Outcome Measures in Rheumatology working group.⁴⁸

Functioning or Disability

The HAQ-DI is a patient-reported, 20-question instrument that assesses the degree of difficulty a patient has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Each functional area is scored from 0 (indicating no difficulty) to 3 (indicating inability to perform a task in that area). The overall score is the average of 8 domains, ranging from 0 (no disability) to 3 (completely disabled). The Clinical Study Report (CSR) states that in PsA, a decrease in score of 0.35 has been determined to indicate a clinically meaningful improvement.⁶ Other sources have reported MIDs of 0.131 and 0.16 in patients with PsA.^49,50

Health-Related Quality of Life

The SF-36 is a 36-item general health status instrument that consists of 8 health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The SF-36 also provides 2 component summaries, the PCS and the MCS, which are derived by aggregating the 8 domains according to a scoring algorithm. All domain and component scores are based on a scale of 0 to 100, with higher scores indicating higher health status. Scores were standardized with a mean of 50 points and an SD of 10 points in the general US population. The CSR defined a change of greater than or equal to 5 points in the PCS and MCS as a clinically meaningful improvement; however, this threshold was not specific to patients with PsA.^11,51 MIDs of 3.74 points for the PCS and 1.77 points for the MCS have been reported for patients with PsA.^7,52

Psoriasis-Specific Measures

Psoriasis-specific end points were evaluated in the subgroup of patients with psoriatic involvement affecting at least 3% of their BSA and an IGA score of 2 (mild) or higher at baseline.

The IGA is a composite score of physician assessment of the overall severity of the patient’s psoriatic lesions. The static version of the IGA was used in all included studies, and is a measurement of disease severity at a given time point. The investigator assessed the overall severity of induration, erythema, and scaling of lesions based on a 5-point scale scored as 0 (no evidence), 1 (minimal), 2 (mild), 3 (moderate), and 4 (severe). The IGA score was the average of the induration, erythema, and scaling scores. The patient’s psoriasis was assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4).⁵³ IGA response was defined as a score of 0 or 1 and at least a 2-point decrease from baseline.

The PASI is a widely used instrument in psoriasis trials that grades the extent and severity of psoriatic lesions. It combines an assessment of the BSA affected in 4 anatomic regions (head, trunk, arms, and legs) and the severity of desquamation, erythema, and plaque induration or infiltration (thickness) in each region. Scores range from 0 points to 72 points, with a PASI score greater than 10 representing more severe disease.⁵⁴ A PASI 75, PASI 90, or PASI 100 response is defined, respectively, as a greater than or equal to 75%, greater than or equal to 90%, or greater than or equal to 100% improvement in PASI score from baseline. No MID for the PASI has been estimated among patients with PsA.

Other Musculoskeletal Outcomes

Dactylitis was assessed in both hands and feet using a scoring system from 0 to 3 for each digit (where 0 = no dactylitis, 1 = mild dactylitis, 2 = moderate dactylitis, and 3 = severe dactylitis). The results were summed to produce a final score ranging from 0 to 60. Enthesitis was assessed using the Leeds Enthesitis Index (LEI), which counts the number of painful entheses among the left and right lateral epicondyle humerus, left and right medial femoral condyle, and left and right Achilles tendon insertion. The LEI index ranges from 0 to 6.⁵⁵ No MID was identified for the LEI and dactylitis score. In all trials, only patients with dactylitis or enthesitis at baseline were included in the analysis of these end points.

The BASDAI is a patient-reported assessment for ankylosing spondylitis. It consists of 6 questions relating to the 5 major symptoms of ankylosing spondylitis (fatigue, spinal pain, peripheral joint pain, localized tenderness, and morning stiffness). Each question is scored using a 10-unit VAS to indicate the degree of symptoms over the past week. The total score ranges from 0 to 10, with higher scores indicate greater disease severity.^56,57 According to the CSR, a 50% decrease in the score is clinically meaningful.^11,58 The MID in patients with PsA is unclear. In the clinical trials, only patients with spondylitis with peripheral arthritis as the primary arthritic presentation of PsA completed the BASDAI.

Symptoms

FACIT-Fatigue consists of 13 questions that assess a patient’s level of fatigue and tiredness over the last 7 days. Each question was graded on a 5-point scale (where 0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = very much). The score ranges from 0 to 52, with lower scores reflecting more severe fatigue.⁸ The CSR states that in rheumatology, a change of 4 points is considered meaningful and has been used in the PsA population.⁸ An MID of 3.1 points has also been reported for patients with PsA.⁹

Radiologic End Points

For the assessment of radiographic changes, single radiographs of the hands and feet were evaluated by central independent readers and scored using the modified vdH-S score. The modified vdH-S score, which ranges from 0 (best) to 528 (worst), is the sum of the joint erosion score and the joint space narrowing score.¹⁰ In addition to reporting the change from baseline in the modified vdH-S score, the DISCOVER-2 study also reported the number of patients with radiographic progression based on the smallest detectable change. The smallest detectable change is defined as the amount of change from baseline for which any smaller change cannot be reliably distinguished from random error in the measurement. The MID in patients with PsA is not known.

Safety

Treatment-emergent adverse events included any adverse events that occurred after the start of study drug administration and any adverse events that were present at baseline but worsened in severity after the start of study drug administration. Serious adverse events included any event that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability, was a congenital anomaly, was the suspected transmission of an infectious drug through a medicinal product, or was medically important (e.g., required intervention to prevent 1 of the other outcomes listed).

Statistical Analysis

Primary Analysis Methods

In all of the trials, the primary analysis of efficacy outcomes was based on the composite estimand, which assessed the treatment effects based on the outcome variable as well as events that met the treatment failure criteria. Patients who met any of the treatment failure criteria up to week 24 were considered nonresponders for the binary (responder) outcomes, or were considered as no change from baseline for the continuous outcomes. Treatment failure was defined as 1 of the following: discontinued study drug injections due to any reason; terminated study participation due to any reason; initiated or increased the dose of non-biologic DMARDs (methotrexate, sulfasalazine, hydroxychloroquine, leflunomide) or oral corticosteroids over baseline for PsA; initiated protocol-prohibited medications or therapies for PsA; or met early escape criteria (COSMOS only). An alternate estimand, the treatment policy strategy, was the primary estimand for radiologic outcomes in DISCOVER-2 (refer to the Sensitivity and Subgroup Analyses section for details).

The statistical methods used in the included studies have been summarized in Table 10. The primary outcome (i.e., ACR 20 at week 24) and other binary outcomes were tested using a CMH test (or Fisher’s exact test, if CMH was not appropriate) stratified by baseline factors specific to each trial. In DISCOVER-1, the stratification factors were the use of a non-biologic DMARD at baseline (yes, no) and prior exposure to TNF alpha inhibitors (yes, no). DISCOVER-2 patients were stratified by baseline use of non-biologic DMARDs (yes, no) and most recent CRP value (< 2.0 mg/dL versus ≥ 2.0 mg/dL). In the COSMOS study, the stratification factors were non-biologic DMARD use at baseline (yes, no) and number of prior TNF alpha inhibitors (1 or 2). The differences in response rates and 95% CI between the guselkumab and placebo groups were calculated based on the Wald statistic. Patients who met any of the treatment failure criteria were considered nonresponders at week 24, regardless of their ACR 20 response status. In addition, any patients with missing data were imputed as not achieving the response.

In the DISCOVER trials, major secondary continuous outcomes were analyzed using an ANCOVA model based on multiple imputation data, with missing data imputed under the missing-at-random assumption (Table 10). The model included covariates for baseline score and each studies’ stratification factors. Other continuous outcomes (e.g., FACIT-Fatigue, BASDAI) were analyzed using an MMRM with no imputation for missing data in the DISCOVER trials. In the COSMOS study, continuous outcomes were analyzed using an MMRM with no imputation for missing data. Any patients who met the treatment failure criteria were imputed as no change (i.e., no improvement) from baseline in the model.

Sensitivity and Subgroup Analyses

Several sensitivity analyses were planned for the primary outcome in the DISCOVER-1 and DISCOVER-2 studies. These included the following: a tipping point analysis where all combinations of missing data, imputed as responders and nonresponders, were analyzed; a treatment policy analysis, which was based on observed ACR 20 response data for all patients regardless of whether treatment failure criteria were met before week 24 and using multiple imputation methods for missing data (missing-at-random assumption); a tipping point analysis based on multiple imputation methods for missing data for the treatment policy estimand; an alternate composite analysis where patients who stopped treatment for reasons other than lack of efficacy were not considered as nonresponders; and a per-protocol analysis that was based on the last non-missing data before stopping therapy or meeting treatment failure criteria in patients who did not have any major protocol violations.

In the DISCOVER trials, subgroup analyses based on treatment history and concomitant DMARD use were of interest to this review. These preplanned analyses for the ACR 20 end point were based on a logistic regression model and reported as odds ratios and 95% CIs. P values for the treatment by subgroup interaction terms were reported.

In the COSMOS study, a supplementary analysis was conducted based on the treatment policy estimand, which evaluated treatment effects using all observed data, regardless of the intercurrent events that met the treatment failure criteria, with imputation for missing data. In this trial, this estimand ignored the week 16 crossover of placebo patients who met the early escape criteria and received guselkumab. The sponsor stated that this analysis biases the results against guselkumab because it does not consider any benefit that patients in the placebo group may have received from switching to active treatment. A second supplementary analysis was conducted where discontinuation of the study drug due to reasons other than lack of efficacy was not considered as treatment failure.

A total of 20 patients in the COSMOS study (8 patients [8%] in the placebo group and 12 patients [6%] in the guselkumab group) were incorrectly assigned to early escape. Patients in the placebo group were incorrectly switched to guselkumab, and there was no change to the study drug received by the patients who had been incorrectly assigned to early escape in the guselkumab group. Two sensitivity analyses were conducted for these patients. The first ignored the early escape criterion, which meant that the 12 patients on guselkumab were not considered to have experienced treatment failure (i.e., no change in therapy); however, the 8 placebo patients were analyzed as a treatment failure because they had received a prohibited medication. The second analysis set the week 16 to week 24 end point values as missing. These were imputed using multiple imputation methods for binary outcomes or MMRM for continuous end points.

The preplanned subgroup analyses based on patient demographics were not of interest to this review and have not been summarized in this report.

Statistical Power

The DISCOVER-1 study was estimated to have greater than 90% power at a 2-sided alpha level of 0.05 for the primary outcome of ACR 20 response. This estimate was based on enrolling a total of 360 patients and assuming a 40% ACR 20 response rate in the guselkumab group and a 20% ACR 20 response in the placebo group at week 24.

For the DISCOVER-2 study, assuming ACR 20 response rates of 45% and 20% in the guselkumab and placebo groups, respectively, a sample size of 228 patients per group would have 99% power to detect a significant treatment effect at a 2-sided significance level of 0.05. With a sample size of 228 patients per group, the trial would have 90% power to detect a difference in the mean change from baseline in the vdH-S score, assuming a mean change of 0.9 in the placebo group and 0.3 in the guselkumab group, with an SD of 2.5. No references were listed to support the assumptions used in the calculations.

The COSMOS study was planned to have 90% power to detect a difference in the primary outcome (i.e., ACR 20) at a 2-sided significance level of 0.05 based on a sample size of 163 patients in the guselkumab group and 82 patients in the placebo group, assuming a response rate of 41% versus 20% for guselkumab and placebo, respectively. The estimated ACR 20 response rates were based on data from an ustekinumab trial in patients previously treated with TNF alpha inhibitors.⁵⁹

Table 10: Statistical Analysis of Efficacy End Points

ACR 20 = American College of Rheumatology 20% improvement; ANCOVA = analysis of covariance; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; CI = confidence interval; CRP = C-reactive protein; DAS 28 = Disease Activity Score 28; DAS 28 CRP = Disease Activity Score 28 using C-reactive protein; DMARD = disease-modifying antirheumatic drug; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy – Fatigue Scale; HAQ-DI = Health Assessment Questionnaire Disability Index; MAR = missing at random; MCS = Mental Component Summary; MMRM = mixed-effects model for repeated measures; NR = not reported; PCS = Physical Component Summary; SF-36 = Short Form (36) Health Survey; TNF = tumour necrosis factor; vdH-S = van der Heijde-Sharp.

^aThe sensitivity analyses for major secondary outcomes included a tipping point analysis based on the treatment policy estimand and multiple imputation for missing data.

^bThe sensitivity analyses for major secondary outcomes included analyses based on treatment policy estimand and 2 analyses that corrected for early escape errors for 20 patients.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Control of Type I Error Rate

In the DISCOVER trials, the overall type I error was controlled at a significance level of less than or equal to 0.05 for the primary outcome (i.e., ACR 20) and select major secondary outcomes. Due to regulatory requirements, there were 2 pre-specified multiplicity adjustment procedures used: 1 for the US and 1 for countries except the US (global). In both procedures, the primary outcome was tested first for the group receiving guselkumab every 4 weeks versus the placebo group, and then for the group receiving guselkumab every 8 weeks versus the placebo group. Testing of select major secondary outcomes proceeded if the primary outcome was statistically significant. In the DISCOVER-1 study, the global testing procedure included 8 major secondary outcomes that were tested for each guselkumab dose group independently in the order specified in Table 11. In the US testing procedure, the 2 dosage groups were tested in parallel, as shown in Figure 5. The overall significance level of less than or equal to 0.05 was controlled for the 24-week IGA response and the HAQ-DI and SF-36 PCS outcomes. Other secondary outcomes were not controlled for type I error rate. The testing procedures stated that ACR 20 at week 16, ACR 50 at week 16, ACR 50 at week 24, ACR 70 at week 24, and change from baseline DAS 28 at week 24 were tested (with a nominal P value) only if the primary outcome for the corresponding guselkumab dosage group was statistically significant.

In the DISCOVER-2 study, the US-based testing procedure controlled the type I error at an overall significance level of less than or equal to 0.05 for the primary outcome (i.e., ACR 20) and for 3 major secondary end points that were not highly correlated with each other (IGA response, HAQ-DI, and SF-36 PCS at week 24). Figure 6 shows the testing procedure for these 4 outcomes in the 2 dosage groups. The global testing procedure controlled the type I error rate for 12 outcomes, as shown in Figure 7, and included a pooled analysis of the resolution of enthesitis or dactylitis based on data from DISCOVER-1 and DISCOVER-2. Five other outcomes highly correlated with ACR 20 were tested (with nominal P values) only if statistical significance was achieved for ACR 20 response at week 24 for the corresponding guselkumab dose group. These outcomes included ACR 20 and ACR 50 response at week 16, ACR 50 and ACR 70 response at week 24, and change from baseline in DAS 28 at week 24. Other secondary outcomes were not formally tested, and nominal P values were reported. Of note: the Health Canada reviewer’s report stated that the US analyses were deemed the preferred method.⁴⁰

For the COSMOS study, the type I error rate was controlled for the primary outcome and 4 major secondary outcomes. These were tested in a fixed sequence (week 24 HAQ-DI, ACR 50, SF-36 PCS, PASI 100 response). Statistical testing was performed sequentially only if the previous outcome reported a P value of less than 0.05. The P values for the other outcomes reported were not controlled for multiple testing, and the sponsor stated that these were descriptive and not to be used to determine statistical significance.

Figure 5: US-Specific Multiplicity Testing Procedure — DISCOVER-1 — Redacted

ACR 20 = American College of Rheumatology 20% improvement; HAQ-DI = Health Assessment Questionnaire Disability Index; IGA = Investigator’s Global Assessment of Psoriasis; PCS = Physical Component Summary; q4w = every 4 weeks; q8w = every 8 weeks.

Figure redacted at the request of the sponsor.

Source: Clinical Study Report for DISCOVER-1.¹¹

Figure 6: US-Specific Multiplicity Testing Procedure — DISCOVER-2 — Redacted

ACR 20 = American College of Rheumatology 20% improvement; ACR 50 = American College of Rheumatology 50% improvement; ACR 70 = American College of Rheumatology 70% improvement; DAS 28 = Disease Activity Score 28; HAQ-DI = Health Assessment Questionnaire Disability Index; IGA = Investigator’s Global Assessment of Psoriasis; MCS = Mental Component Summary; PCS = Physical Component Summary; q4w = every 4 weeks; q8w = every 8 weeks; vdH-S = van der Heijde-Sharp.

Figure redacted at the request of the sponsor.

Source: Clinical Study Report for DISCOVER-2 (24 weeks).¹²

Figure 7: Global Multiplicity Testing Procedure — DISCOVER-2 — Redacted

ACR 20 = American College of Rheumatology 20% improvement; ACR 50 = American College of Rheumatology 50% improvement; ACR 70 = American College of Rheumatology 70% improvement; DAS 28 = Disease Activity Score 28; HAQ-DI = Health Assessment Questionnaire Disability Index; IGA = Investigator’s Global Assessment of Psoriasis; PCS = Physical Component Summary; vdH-S = van der Heijde-Sharp.

Figure redacted at the request of the sponsor

Source: Clinical Study Report for DISCOVER-2 (24 weeks).¹²

Analysis Populations

In all studies, most efficacy outcomes were analyzed based on the FAS, which included all randomized patients who received at least 1 dose of the study drug according to their randomized group. Psoriasis-specific outcomes (i.e., IGA or PASI response) were analyzed in specific FAS subpopulations that had greater than or equal to 3% BSA psoriatic involvement and an IGA score of greater than or equal to 2 at baseline. Patients included in the enthesitis analyses had to have at least 1 tender enthesis among the 6 sites included in the LEI at baseline. The dactylitis outcomes were analyzed in patients with dactylitis at baseline, and the BASDAI was analyzed in the subset of patients with spondylitis and peripheral joint PsA as their primary presentation. DISCOVER-2 also included a preplanned, pooled analysis of enthesitis and dactylitis outcomes that were based on relevant subgroup data from the DISCOVER-1 and DISCOVER-2 trials.

The safety population included all randomized patients who received at least 1 dose of the study drug and were analyzed according to the actual treatment received.

Results

Patient Disposition

In the DISCOVER-1 study, 624 patients were screened, and 381 patients (61%) were randomized to 1 of 3 treatment groups. By week 24, 7% versus 2% of patients in the placebo group and the group receiving guselkumab every 8 weeks, respectively, had discontinued from the study, and 10% versus 3% stopped treatment early. Table 12 describes the reasons for discontinuation. More patients met the treatment failure criteria (17% versus 6%) and qualified for early escape (19% and 3%) in the placebo group than in the guselkumab group.

Of the 1,153 patients screened in the DISCOVER-2 study, 741 patients were randomized, and 739 patients were treated (64%). The proportion of patients who discontinued the study was low (1% and 2%), as were the proportions who discontinued the study drug (2% and 3% in both the placebo and guselkumab groups, respectively). The treatment failure criteria were met by 7% and 5% of patients — and the early escape criteria were met by 15% and 5% of patients — in the placebo group and the group receiving guselkumab every 8 weeks, respectively.

In the COSMOS study, 328 patients were screened, of whom 285 patients (87%) were randomized. By week 24, 2% of patients in each group had discontinued the study, and 10% and 8% in the placebo and guselkumab groups, respectively, had discontinued the study drug. Approximately half of the patients in the placebo group met the treatment failure criteria or early escape criteria (54% and 47%, respectively), compared with 27% and 21% of patients in the guselkumab group. The CSR reported that a total of 20 patients were incorrectly assigned to early escape without having met the escape criteria. This affected 8 patients in the placebo group (8%) and 12 patients (6%) in the guselkumab group (Table 12).

Table 12: Patient Disposition

FAS = full analysis set; GUSE = guselkumab; NR = not reported; PBO = placebo; q8w = every 8 weeks.

^aIn the DISCOVER-1 study, 624 patients were screened and 381 were randomized (including 128 patients who were assigned to the guselkumab-every-4-weeks group whose data have not been summarized in this table).

^bIn the DISCOVER-2 study, out of the 1,153 patients screened, 741 patients were randomized and 739 patients were treated (including 245 patients who were randomized to the guselkumab-every-4-weeks group whose data have not been summarized in this table).

^cIn the COSMOS study, 43 patients failed screening due to exclusionary lab criteria (9 patients), TB criteria (7 patients), underlying conditions (7 patients), unwillingness to adhere to protocols (6 patients), or other reasons (16 patients).

^dOne additional patient was randomized to placebo, but was not treated.

^eIncludes 12 patients (6.3%) in the guselkumab group and 8 patients (8.3%) in the placebo group who were incorrectly assigned to early escape therapy (without having met the early escape criteria).

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks);¹³ Coates et al. (2022).¹⁴

Exposure to Study Treatments

The durations of study follow-up were similar across the studies (mean = 23.7 weeks [SD = 2.4 weeks] to 24.0 weeks [SD = 0.5 weeks]). In the DISCOVER studies, the mean number of study drug administrations ranged from 5.8 weeks (SD = 0.8 weeks) to 5.9 weeks (SD = 0.5 weeks). In the COSMOS study, these numbers were 4.1 weeks (SD = 0.6 weeks) in the group receiving guselkumab every 8 weeks and 4.3 weeks (SD = 0.9 weeks) in the placebo group (Table 13).

In general, the proportions of patients receiving permitted concomitant therapies for PsA were similar between groups in the trials. In the DISCOVER trials, at baseline, 54% to 63% of patients per group were receiving methotrexate, || || || were receiving sulfasalazine, || || || were receiving leflunomide, and 14% to 20% were receiving oral corticosteroids. Mean daily or weekly doses of permitted concomitant therapies are listed in Table 13. In the COSMOS study, 58% and 61% of patients were receiving methotrexate at baseline.

In the DISCOVER-1 study, 3% of patients in the group receiving guselkumab every 8 weeks met the early escape criteria compared with 19% of patients in the placebo group. Similarly, 5% and 15% in the guselkumab and placebo groups of the DISCOVER-2 study met the early escape criteria. In the COSMOS study, 39 patients (21%) in the group receiving guselkumab every 8 weeks versus 45 patients (47%) in the placebo group were assigned to early escape. However, 20 patients were erroneously assigned to receive early escape therapy without having met the criteria. This error affected 12 patients (6.3%) in the guselkumab and 8 patients (8.3%) in the placebo group.

Table 13: Exposure to Study Treatments and Permitted Concomitant Therapies

DMARD = disease-modifying antirheumatic drug; FAS = full analysis set; GUSE = guselkumab; NR = not reported; NSAID = nonsteroidal anti-inflammatory drug; PBO = placebo; PsA = psoriatic arthritis; q8w = every 8 weeks; SD = standard deviation.

^aIncludes 12 patients (6.3%) in the guselkumab group and 8 patients (8.3%) in the placebo group who were incorrectly assigned to early escape therapy without having met the early escape criteria.

^bPermitted concomitant medications for PsA included oral corticosteroids (≤ 10 mg of prednisone per day or equivalent) and 1 of either methotrexate (≤ 25 mg/week), sulfasalazine (≤ 3 g/day), hydroxychloroquine (≤ 400 mg/day), or leflunomide (≤ 20 mg/day), or NSAIDs.

^cIncluded joint replacement, arthroscopy (surgical or diagnostic), amputation, arthrocentesis, synovectomy, excision or resection, and radio synovectomy.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported. Refer to Appendix 3 for detailed efficacy data.

The systematic review protocol identified pain as an outcome of interest. None of the trials included pain as a secondary or exploratory outcome; however, patient-reported pain severity was included as part of the ACR and MDA response criteria and the SF-36.

Clinical Response in PsA Symptoms

In the DISCOVER-1 study, which enrolled both biologic-naive and biologic-experienced patients, 52.0% of patients in the group receiving guselkumab every 8 weeks achieved ACR 20 at 24 weeks compared with 22.2% of patients in the placebo group. The absolute difference was 29.8% (95% CI, 18.6% to 41.1%; P < 0.001) (Table 14) favouring guselkumab versus placebo. At week 24, 29.9% of patients versus 8.7% of patients in the guselkumab versus placebo groups, respectively, achieved ACR 50 (absolute difference = 21.4%; 95% CI, 12.1% to 30.7%; P < 0.001), and 11.8% versus 5.6% achieved ACR 70 (6.4%; 95% CI, −0.3% to 13.1%; P = 0.086). ACR 50 and ACR 70 outcomes were controlled for multiple testing based on the global testing procedure rather than the US-specific testing procedure. The US-specific procedure was preferred by Health Canada.

Among patients who were biologic-naive (in DISCOVER-2), 64.1% and 32.9% of patients achieved ACR 20 in the group receiving guselkumab every 8 weeks and the placebo group, respectively, with an absolute difference of 31.2% (95% CI, 22.9% to 39.5%; P < 0.001) (Table 14). The difference between guselkumab and placebo in the proportion of patients who achieved ACR 50 was 17.2% (95% CI, 10.0% to 24.4%), and the proportion of patients who achieved ACR 70 was 14.5% (95% CI, 9.1% to 19.9%). However, neither outcome was statistically tested according to the global testing procedure due to failure of a prior outcome in the hierarchy. ACR 50 and ACR 70 were not controlled for multiple testing in the US-specific procedure.

Among biologic-experienced patients in the COSMOS study, 44.4% and 19.8% achieved ACR 20 at week 24 in the guselkumab and placebo groups, respectively. The absolute difference between groups (24.6%) favoured guselkumab (95% CI, 14.1% to 35.2%; P < 0.001) (Table 14). The difference for guselkumab versus placebo for the proportion who achieved ACR 50 was 19.6% versus 5.2%; the absolute difference was 14.3% (95% CI, 7.2% to 21.4%; P < 0.001). ACR 70 response was achieved by 7.9% versus 1.0% of patients in the guselkumab versus placebo groups, with an absolute difference of 6.8% (95% CI, 2.6% to 11.1%). ACR 70 was not controlled for multiple testing and should be interpreted considering the inflated risk of type I error rate.

In the DISCOVER-1 and 2 studies, the results of the sensitivity analyses for ACR 20 were generally consistent with the results of the primary analysis. In the COSMOS study, the analysis that was based on observed case data regardless of meeting treatment failure criteria reported an absolute difference of 10.9% (95% CI, −1.3% to 23.2%), which the investigators stated was due to the doubled ACR 20 response rate in the placebo group, noting that almost half of patients in the placebo group received early escape therapies starting at week 16. Other sensitivity analyses (per-protocol population and analyses adjusting for errors in early escape assignment) showed results that were consistent with the primary analysis.

The proportion of patients who achieved MDA at week 24 was higher in the group receiving guselkumab every 8 weeks versus the placebo group in all 3 studies. However, this outcome was not controlled for multiple testing and should be interpreted with caution because of the potential for inflated type I error rate. The absolute differences between guselkumab and placebo were 11.9% (95% CI, 2.9% to 20.9%) for DISCOVER-1, 18.9% (95% CI, 12.8% to 25.0%) for DISCOVER-2, and 11.7% (95% CI, 5.6% to 17.7%) for the COSMOS study (Table 14).

Subgroup analyses of interest to this review for the DISCOVER studies are shown in figures 11 to 14 in Appendix 3. The odds ratios for ACR 20 response were generally consistent across subgroups based on prior use of TNF alpha inhibitors, non-biologic DMARDs, oral corticosteroids, or NSAIDs at baseline. The COSMOS study did not report data for any subgroups of interest.

Table 14: ACR and MDA Response at Week 24

ACR = American College of Rheumatology; ACR 20 = American College of Rheumatology 20% improvement; ACR 50 = American College of Rheumatology 50% improvement; ACR 70 = American College of Rheumatology 70% improvement; CI = confidence interval; FAS = full analysis set; GUSE = guselkumab; HAQ-DI = Health Assessment Questionnaire Disability Index; MDA = minimal disease activity; PBO = placebo; q8w = every 8 weeks; VAS = visual analogue scale.

^aBased on composite estimand (either observed response data or nonresponse for patients who met the treatment failure criteria). Patients with missing data were imputed as nonresponders. P values were based on stratified CMH tests and 95% CIs were based on Wald statistic. The DISCOVER-1 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and prior exposure to TNF alpha inhibitors (yes, no). The DISCOVER-2 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and CRP before randomization (< 2 mg/dL vs. ≥ 2 mg/dL). The COSMOS study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and number of prior TNF alpha inhibitors (1 or 2).

^bControlled for multiple testing based on the global testing procedure, but not the US-specific testing procedure. The US-specific procedure was preferred by Health Canada.

^cOutcome was not formally tested for statistical significance due to failure of a prior outcome, according to the global testing procedure. This outcome was not controlled for multiple testing, according to the US-based testing procedure.

^dThe P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^eMDA is achieved if at least 5 of 7 criteria are met (tender joint count ≤ 1, swollen joint count ≤ 1, Psoriasis Activity and Severity Index ≤ 1, patient’s assessment of pain VAS ≤ 15, patient’s global assessment of disease activity VAS ≤ 20 [arthritis and psoriasis], HAQ-DI score ≤ 0.5, and tender entheseal points ≤ 1).

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Additional data on the ACR 20 and ACR 50 response rates at week 16 are summarized in Appendix 3, Table 42. These findings were generally consistent with the ACR 20 results at week 24; however, the ability to draw statistical inferences from the data may be limited, whether because no statistical testing was performed (DISCOVER-2), there was no control for multiple testing (COSMOS), or control of the type I error rate was based on global rather than US-specific testing procedures (DISCOVER-1). For ACR 50, the DISCOVER-1 study failed to detect a statistically significant difference between guselkumab every 8 weeks and placebo at week 16 (based on global testing procedure). No statistical testing was performed in DISCOVER-2 (due to failure of a prior outcome). The response rates were nominally higher for the guselkumab versus placebo groups in the COSMOS study, but there was no control of the type I error rate.

Data on the changes from baseline in DAS 28 CRP scores are summarized in Appendix 3, Table 43. The point estimates for the LS mean differences ranged from −0.61 to −0.73, suggesting an improvement with guselkumab every 8 weeks versus placebo in all trials; however, in the COSMOS study, this outcome was not controlled for multiple testing, and in the DISCOVER studies, it was controlled for multiple testing based on the global testing procedure rather than the US-specific procedure.

Function or Disability

Changes from baseline to week 24 in the HAQ-DI favoured guselkumab every 8 weeks versus placebo in all trials. The LS mean differences reported were −0.25 (95% CI, −0.36 to −0.13; P < 0.001) in the DISCOVER-1 study, −0.24 (95% CI, −0.32 to −0.15; P < 0.001) in the DISCOVER-2 study, and −0.17 (95% CI, −0.28 to −0.06; P = 0.003) in the COSMOS study. Across the trials, only the group receiving guselkumab every 8 weeks in the DISCOVER-2 study achieved a change from baseline that exceeded the 0.35 MID cited in the study’s protocol.^6,7,51

The proportion of HAQ-DI responders was reported as another secondary outcome in the DISCOVER trials (i.e., no control for type I error rate). Response was defined achieving a point improvement of greater than or equal to a 0.35 in the HAQ-DI score from baseline (among the subset of patients who had a HAQ-DI score ≥ 0.35 points at baseline). At 24 weeks in the DISCOVER-1 study, 50.9% of patients (57 of 112) in the guselkumab group and 29.1% of patients (32 of 110) in the placebo group achieved HAQ-DI responses (absolute difference = 21.8%; 95% CI, 9.3% to 34.2%). In DISCOVER-2, 50.0% of patients (114 of 228) and 31.4% of patients (74 of 236) in the guselkumab versus placebo groups, respectively, achieved HAQ-DI responses (absolute difference = 18.7%; 95% CI, 10.0% to 27.3%).

Table 15: Change From Baseline in HAQ-DI to Week 24

ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; GUSE = guselkumab; HAQ-DI = Health Assessment Questionnaire Disability Index; LS = least squares; MMRM = mixed-effects model for repeated measures; PBO = placebo; q8w = every 8 weeks; SD = standard deviation.

^aChange from baseline was based on observed data or 0 (no improvement) if a patient met the treatment failure criteria before week 24 (composite estimand). The DISCOVER-1 and DISCOVER-2 analyses used an ANCOVA model with missing data imputed using multiple imputation, assuming data were missing at random. The COSMOS analysis used an MMRM under the missing-at-random assumption.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (2 weeks).¹³

Health-Related Quality of Life

The change from baseline in the SF-36 PCS was a secondary outcome in all studies. Most treatment groups reported an improvement at week 24, with a difference that favoured guselkumab every 8 weeks versus placebo in all studies (Table 16). The LS mean difference was 4.1 (95% CI, 2.4 to 5.9; P < 0.001) in the DISCOVER-1 study, 4.0 (95% CI, 2.7 to 5.2; P = 0.011) in the DISCOVER-2 study, and 3.9 (95% CI, 2.5 to 5.4; P < 0.001) in the COSMOS study. The CSR defined an increase of at least 5 points as clinically meaningful, but a MID of 3.74 has also been reported in the literature.^7,51

All trials failed to detect a statistically significant difference between guselkumab every 8 weeks and placebo in the change from baseline to week 24 in the SF-36 MCS (Table 16).

Table 16: Change From Baseline in the SF-36 PCS and MCS to Week 24

ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; GUSE = guselkumab; LS = least squares; MCS = Mental Component Summary; MMRM = mixed-effects model for repeated measures; PBO = placebo; PCS = Physical Component Summary; q8w = every 8 weeks; SD = standard deviation; SF-36 = Short Form (36) Health Survey.

^aChange from baseline was based on observed data or 0 (no improvement) if a patient met the treatment failure criteria before week 24 (composite estimand). The DISCOVER-1 and DISCOVER-2 analyses used an ANCOVA model with missing data imputed using multiple imputation, assuming data were missing at random. The COSMOS analysis used an MMRM under the missing-at-random assumption.

^bAccording to the US-based testing procedure, this outcome was statistically significant, with a P value of 0.011. According to the global testing procedure, this outcome was not formally tested for statistical significance due to failure of a prior outcome.

^cP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^dThis outcome was not formally tested for statistical significance due to failure of a prior outcome, according to the global testing procedure. According to the US-based testing procedure, this outcome was not statistically significant (P = 0.072).

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks);¹³ Coates et al. (2022).¹⁴

Psoriasis Skin Disease

In all trials, psoriasis skin disease outcome measures were analyzed in the subgroup of patients who had psoriasis affecting greater than or equal to 3% of their BSA and an IGA score of greater than or equal to 2 at baseline (55% to 74% of patients per treatment group). Randomization was not stratified by the presence of skin disease at baseline.

The proportion of patients who achieved an IGA response at week 24 was higher in the group receiving guselkumab every 8 weeks than in the placebo group in the DISCOVER-1 study (57.3% versus 15.4%; absolute difference = 42.0% [95% CI, 28.9% to 55.1%; P < 0.001]) and the DISCOVER-2 study (70.5% versus 19.1%; absolute difference = 50.9% [95% CI, 42.2% to 59.7%; P < 0.001]). In the COSMOS study, 48.1% versus 9.4% of patients achieved an IGA response in the guselkumab and placebo groups; the absolute difference was 38.8% (95% CI, 27.3% to 50.4%). However, the P value was not adjusted to control for multiple testing; it should be interpreted with caution because of the potential for inflated type I error rate.

PASI 100 response at week 24 was a secondary outcome in the COSMOS study. In the group receiving guselkumab every 8 weeks, 30.8% of patients achieved a PASI 100 response compared with 3.8% of patients in the placebo group (absolute difference = 27.4%; 95% CI, 17.9% to 36.8%; P < 0.001]). The PASI 90 and PASI 75 results in the COSMOS study were nominally higher in the guselkumab versus placebo groups, but the type I error rate was not controlled for these outcomes. The PASI 100, PASI 90, and PASI 75 response rates in the DISCOVER trials were nominally higher for guselkumab versus placebo, but these outcomes were not part of the statistical testing procedure and should be interpreted with caution, considering the potential for inflated type I error rate (Table 17).

Table 17: IGA and PASI Response at Week 24

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DMARD = disease-modifying antirheumatic drug; FAS = full analysis set; GUSE = guselkumab; IGA = Investigator’s Global Assessment of Psoriasis; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% improvement from baseline in Psoriasis Area and Severity Index score; PASI 90 = 90% improvement from baseline in Psoriasis Area and Severity Index score; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index score; PBO = placebo; q8w = every 8 weeks; TNF = tumour necrosis factor.

^aBased on composite estimand (either observed response data or nonresponse for patients who met the treatment failure criteria). Patients with missing data were imputed as nonresponders. P values were based on stratified CMH tests and 95% CIs were based on the Wald statistic. The DISCOVER-1 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and prior exposure to TNF alpha inhibitors (yes, no). The DISCOVER-2 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and CRP before randomization (< 2 mg/dL vs. ≥ 2 mg/dL). The COSMOS study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and number of prior TNF alpha inhibitors (1 or 2).

^bThe P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Other Musculoskeletal Disease

Outcomes related to enthesitis and dactylitis were analyzed for patients reporting these symptoms at baseline. Approximately 2-thirds of patients reported enthesitis at baseline (57% to 72%), whereas 35% to 45% of patients reported dactylitis across treatment groups in the 3 trials. Randomization was not stratified by the presence of enthesitis or dactylitis at baseline. These outcomes were not controlled for multiple testing; thus, P values of less than 0.05 should be interpreted with caution, considering the potential for inflated type I error rate. The results for these outcomes in each trial are shown in Table 18.

The DISCOVER-2 study planned a prior pooled analysis of the resolution of enthesitis and dactylitis end points using combined data from the DISCOVER-1 and DISCOVER-2 trials. Based on the pooled analysis, 49.6% and 29.4% of patients in the group receiving guselkumab every 8 weeks and the placebo group had resolution of enthesitis at week 24, with a between-group difference of 20.1% (95% CI, 11.8% to 28.5%; P = 0.03 [based on the US-specific testing procedure]). The proportion of patients whose dactylitis resolved at week 24 was 59.4% versus 42.2% in the guselkumab versus placebo group; the between-group difference was 18.0% (95% CI, 7.4% to 28.6%; P = 0.03 [based on the US-specific testing procedure]). In accordance with the global testing procedure, these outcomes were not formally tested due to the failure of a prior outcome in the testing hierarchy.

Table 18: Enthesitis and Dactylitis Outcomes at 24 Weeks

ANCOVA = analysis of covariance; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; CRP = C-reactive protein; DMARD = disease-modifying antirheumatic drug; FAS = full analysis set; GUSE = guselkumab; LEI = Leeds Enthesitis Index; LS = least squares; MMRM = mixed-effects model for repeated measures; PBO = placebo; q8w = every 8 weeks; SD = standard deviation; TNF = tumour necrosis factor.

Note: LEI is the total score based on 6 enthesitis sites with 1 point per digit (range = 0 to 6). Dactylitis was scored on a scale of 0 to 60, with a maximum of 3 points per digit. For both scales, a negative change indicates improvement. Resolution of enthesitis or dactylitis was defined as an LEI score or dactylitis score of 0 at 24 weeks among patients with scores greater than or equal to 0 at baseline.

^aBased on composite estimand (either observed response data or nonresponse for patients who met the treatment failure criteria). Patients with missing data were imputed as nonresponders. P values were based on stratified CMH tests and 95% CIs were based on the Wald statistic. The DISCOVER-1 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and prior exposure to TNF alpha inhibitors (yes, no). The DISCOVER-2 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and CRP before randomization (< 2 mg/dL vs. ≥ 2 mg/dL). The COSMOS study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and number of prior TNF alpha inhibitors (1 or 2).

^bThe P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^cChange from baseline was based on observed data or 0 (no improvement) if a patient met the treatment failure criteria before week 24 (composite estimand). The DISCOVER-1 and DISCOVER-2 analyses used an ANCOVA model with missing data imputed using multiple imputation, assuming data were missing at random. The COSMOS study used an MMRM with a missing-at-random assumption.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

The change in the BASDAI score was analyzed for the subgroup of patients with spondylitis and peripheral joint PsA as their primary presentation at baseline (18% to 37% of patients per treatment group across the studies). Randomization was not stratified by the presence of axial disease at baseline. The sponsor stated that a 50% improvement in the BASDAI represents a clinically important change.⁵⁸

Among biologic-naive patients (DISCOVER-2), 39% and 22% in the guselkumab and placebo groups, respectively, achieved at least a 50% improvement in the BASDAI score at week 24 (absolute difference = 15%) (95% CI, 0.4% to 30%; not controlled for type I error rate) (Table 19). The proportion of patients with an improvement of greater than or equal to 50% was the same in both treatment groups (19%) among patients who were biologic-experienced in the COSMOS study. In the mixed population enrolled in the DISCOVER-1 study, 42% and 13% of patients in the guselkumab and placebo groups achieved at least a 50% improvement, respectively, with an absolute difference of 24% (95% CI, −1% to 49%).

Table 19: Improvement in BASDAI Score at Week 24

BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DMARD = disease-modifying antirheumatic drug; FAS = full analysis set; GUSE = guselkumab; NE = not estimable; PBO = placebo; q8w = every 8 weeks; TNF = tumour necrosis factor.

^aBased on composite estimand (either observed response data or nonresponse for patients who met the treatment failure criteria). Patients with missing data were imputed as nonresponders. P values were based on stratified CMH tests and 95% CIs were based on Wald statistic. The DISCOVER-1 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and prior exposure to TNF alpha inhibitors (yes, no). The DISCOVER-2 study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and CRP before randomization (< 2 mg/dL vs. ≥ 2 mg/dL). The COSMOS study CMH test stratified patients by baseline use of non-biologic DMARDs (yes, no) and number of prior TNF alpha inhibitors (1 or 2).

^bThe P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

PsA Symptoms

FACIT-Fatigue scores range from 0 to 52, with higher scores indicating less fatigue. This outcome was not controlled for multiple testing; thus, P values of less than 0.05 should be interpreted with caution, considering the potential for inflated type I error rate. MIDs of 3.1 to 4 points have been reported in the literature.^8,9

The FACIT-Fatigue scores suggest improvement in fatigue, with point estimates for the within-group change from baseline to week 24 that exceeded the MID for all groups receiving guselkumab every 8 weeks and for the placebo group in the DISCOVER-2 study (Table 20). The DISCOVER-1 study reported an LS mean difference of 3.4 points (95% CI, 1.4 to 5.4); the DISCOVER-2 study reported an LS mean difference of 4.0 (95% CI, 2.5 to 5.5); and the COSMOS study reported an LS mean difference of 3.6 (95% CI, 1.7 to 5.4) for guselkumab every 8 weeks versus placebo. In all studies, the between-group difference exceeded the MID of 3.1, while only the DISCOVER-2 study met the 4-point threshold.

Radiologic Outcomes

The change from baseline to week 24 in the modified vdH-S score was a major secondary outcome in the DISCOVER-2 study. At 24 weeks, the LS mean difference observed for guselkumab versus placebo was −0.43 (95% CI, −0.90 to 0.03) (P = 0.068) (Table 21).

The proportions of patients with no progression (defined as a change from baseline that was less than or equal to the smallest detectable change for the modified vdH-S total score) were 89.0% in the group receiving guselkumab every 8 weeks and 84.0% in the placebo group (absolute difference = 5.0%; 95% CI, –1.0% to 10.9%).

Table 20: Change From Baseline in FACIT-Fatigue Score to Week 24

CI = confidence interval; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy – Fatigue Scale; FAS = full analysis set; GUSE = guselkumab; LS = least squares; MMRM = mixed-effects model for repeated measures; PBO = placebo; q8w = every 8 weeks; SD = standard deviation.

^aChange from baseline based on observed data or 0 (no improvement) if a patient met the treatment failure criteria before week 24 (composite estimand). Analyzed using an MMRM under a missing-at-random assumption.

^bThe P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks);¹³ Coates et al. (2022).¹⁴

Table 21: Change From Baseline in Modified vdH-S of PsA to 24 Weeks

ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; GUSE = guselkumab; LS = least squares; PBO = placebo; q8w = every 8 weeks SD = standard deviation; vdH-S = van der Heijde-Sharp.

^aChange from baseline is based on observed data regardless of meeting the treatment failure criteria before week 24 (treatment policy estimand). Analyzed using ANCOVA model with missing data imputed using multiple imputation and assuming data were missing at random.

Source: Clinical Study Report for DISCOVER-2 (24 weeks).¹²

Harms

Only those harms identified in the review protocol are reported in this section. Refer to Table 22 for detailed harms data.

Adverse Events

The frequency of adverse events was generally similar between groups, with 42% to 54% of patients in the groups receiving guselkumab every 8 weeks and 41% to 60% of patients in the placebo groups reporting 1 or more adverse events during the 24-week treatment period (Table 22). Nasopharyngitis (4% to 13%), upper respiratory tract infection (2% to 5%), and increased alanine aminotransferase (2% to 6%) were the most commonly reported adverse events in the guselkumab groups. The corresponding proportions of patients experiencing these adverse events in the placebo groups were 4% to 6% for nasopharyngitis, 3% to 7% for upper respiratory tract infections, and 3% to 6% for increased alanine aminotransferase.

In the COSMOS study, adverse event data were reported separately for 45 patients who switched from placebo to guselkumab every 8 weeks before week 24. Six patients (13%) experienced an adverse event, including 1 patient with a serious adverse event (a buttock injury) and 2 patients with infections (4%).

Serious Adverse Events

The frequency of serious adverse events ranged from 1% to 4% in the groups receiving guselkumab every 8 weeks and from 3% to 4% in the placebo groups (Table 22). No specific serious adverse events were reported in more than 1 patient per treatment group (Table 23). In the DISCOVER-1 study, only 1 of the serious adverse events (plasma cell myeloma in the guselkumab group) resulted in treatment discontinuation. One patient in the guselkumab group of the COSMOS study experienced increased alanine aminotransferase that was categorized as a serious adverse event. This patient was subsequently diagnosed with autoimmune hepatitis and the study drug was stopped.

Treatment Discontinuation Due to Adverse Events

Adverse events that resulted in treatment discontinuation were generally low (1% to 3%) and similar between groups (Table 22). Other than 2 patients in the placebo group of the DISCOVER-1 study, who stopped treatment due to psoriasis, all other events were reported in 1 patient (Table 23).

Mortality

In the DISCOVER-1 study, 1 patient in the placebo group died due to cardiac failure. No other deaths were reported in the guselkumab groups or placebo groups during the first 24 weeks of the 3 studies.

Notable Harms

Generally, the frequency of infections was similar in the groups receiving guselkumab every 8 weeks (16% to 26%) and the placebo groups (18% to 25%) across trials (Table 22). In the DISCOVER-1 study, no patients in the guselkumab group reported a serious infection. Two patients in the placebo group experienced a serious infection, which included a serious upper respiratory tract infection and an abscessed limb. In the DISCOVER-2 study, 1 patient in each group reported a serious infection, including pyrexia in the guselkumab group and post-procedural fistula in the placebo group. In the COSMOS study, 1 patient in the guselkumab group reported a serious community-acquired pneumonia that required hospitalization. No serious infections were reported among patients who received placebo. No cases of tuberculosis or opportunistic infections were reported in the first 24 weeks of all 3 trials.

The other notable harms identified in the systematic review protocol were infrequently reported (i.e., injection-site reactions, anaphylactic adverse events, and liver-related adverse events).

Table 22: Summary of Harms Up to 24 Weeks (Safety Set)

ALT = alanine aminotransferase; AST = aspartate aminotransferase; GUSE = guselkumab; NR = not reported; PBO = placebo; q8w = every 8 weeks; SAE = serious adverse event; SOC = system organ class; URTI = upper respiratory tract infection.

Note: The data reported for the placebo group include patients who received only placebo. For any patients on placebo who received guselkumab by mistake (DISCOVER-1) or who received escape therapy with guselkumab (COSMOS), the data excluded any events that occurred after the patients received the active drug.

^aFrequency greater than 5%.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Table 23: Description of SAEs or Adverse Events Leading to Treatment Discontinuation Up to 24 Weeks (Safety Set)

ALT = alanine aminotransferase; COPD = chronic obstructive pulmonary disease; GUSE = guselkumab; IBD = inflammatory bowel disease; PBO = placebo; q8w = every 8 weeks; SAE = serious adverse event; UA = unstable angina; URTI = upper respiratory tract infection.

^aUnless otherwise stated, each event described was reported by a single patient.

Source: Clinical Study Report for DISCOVER-1 (24 weeks);¹¹ Clinical Study Report for DISCOVER-2 (24 weeks);¹² Clinical Study Report for COSMOS (24 weeks).¹³

Critical Appraisal

Internal Validity

The risk of bias related to randomization and treatment allocation concealment was rated as low for all studies, and, in general, the patient characteristics and co-interventions appeared to be balanced between groups at baseline. However, some differences were noted in the proportion of female patients and patients with psoriasis at baseline in the COSMOS study and in the proportion of patients with enthesitis at baseline in the DISCOVER-2 study. No issues were identified in the methods used to randomize patients and conceal allocation. The trials were double blind and took steps to maintain blinding of patients and investigators. In the DISCOVER studies, where the frequency of dosing varied across treatment groups (i.e., every 4 weeks or every 8 weeks), patients in the group receiving the study drug every 8 weeks also received placebo injections at alternate visits to match the every-4-weeks dosing schedule of the other guselkumab group. In all studies, an independent joint assessor not otherwise involved in the conduct of the trial evaluated patients’ joints for tenderness and swelling and the presence of enthesitis and dactylitis. Central raters assessed radiographs in DISCOVER-2. Therefore, the risk of bias in the measurement of the outcomes was low for all trials. In general, the type and frequency of adverse events were similar across groups, so there was low risk that adverse events led to substantial unblinding.

In all trials, the primary and other dichotomous end points were analyzed using a CMH test that was stratified by randomization stratification factors, with missing data imputed as nonresponders. The DISCOVER trials used an adjusted ANCOVA model, while the COSMOS study used an unadjusted MMRM model to analyze continuous outcomes. Missing data were imputed under the missing-at-random assumption, which may not hold true; however, this was not thought to be a major source of bias, given the low frequency of withdrawals and the use of the composite estimand to conduct the analyses. The efficacy analyses were based on the FAS (randomized and treated), which is not a true intention-to-treat population; however, only 1 patient in the DISCOVER-2 study was excluded. As a result, the analyses were appropriate for estimating the effect of assignment to the intervention.

All efficacy analyses were based on the composite estimand, where any patients who met the treatment failure criteria were considered nonresponders for binary end points, or to have experienced no change from baseline for continuous measures (e.g., HAQ-DI). Based on the composite estimand, patients who discontinued the study or study drug, initiated or increased the dose of cDMARDs or corticosteroids, initiated prohibited medication, or, in the COSMOS study, met early escape criteria, were considered treatment failures. This estimand, which considers any treatment failure end points to be unfavourable outcomes, may be considered a more conservative estimate of treatment effects, and was the estimand preferred by Health Canada. Of note, the COSMOS study incorrectly assigned 20 patients to early escape even though they had not met the escape criteria. As a result, 8 patients in the placebo group (8.3%) were switched to guselkumab treatment at week 16, and 12 patients (6.3%) in the guselkumab group were analyzed as nonresponders in the primary analysis. Although the sponsor conducted sensitivity analyses to explore the impact of this error, these analyses cannot fully address the potential bias.

The type I error rate was controlled for the primary and selected secondary outcomes in all studies. Two different testing strategies were used in the DISCOVER trials to meet US and other regulators’ requirements. The Health Canada reviewer’s report indicated that the US-based strategy was preferred.⁴⁰ Several outcomes of interest to this review were tested, and nominal P values reported (e.g., MDA, ACR 70, PASI response, resolution of enthesitis and dactylitis, FACIT-Fatigue); however, any results with a P of less than 0.05 should be interpreted with caution, considering the potentially inflated type I error rate. Although the subgroup analyses were pre-specified, there is no evidence that the studies were powered to detect subgroup differences, and the 95% CIs for some subgroups were imprecise.

Of note, skin-related end points — as well as enthesitis, dactylitis, and axial disease outcome measures — were tested in subgroups of patients affected with these conditions at baseline. Randomization was not stratified for the presence of these conditions; thus, the interpretation of the results for these outcomes should consider the possibility of imbalances in baseline demographic and disease characteristics between treatment groups in these subpopulations. According to the expert consulted by CADTH, the DAS 28 is not relevant for PsA because it assesses only 28 joints and excludes the lower extremities (which may be important in PsA).⁴⁸ Moreover, CADTH found limited data on the validity — and no data on the reliability and responsiveness — of the DAS 28 in patients with PsA. Thus, although this end point was a major secondary outcome in the DISCOVER trials, it should be interpreted with caution. Based on CADTH’s review, there was also limited evidence to support the validity or reliability of the BASDAI and the enthesitis and dactylitis scales used in the clinical trials. In addition, the MID for the change in vdH-S scores was unknown.

Although the trials were 48 weeks to 100 weeks in duration, the comparative period was limited to 24 weeks for this chronic condition. For outcomes such as radiologic changes, this duration of treatment may have been insufficient to detect the impact of guselkumab every 8 weeks. Moreover, none of the trials included an active control group (other than the group receiving guselkumab every 4 weeks, which is not a Health Canada–approved dosage); thus, direct evidence comparing guselkumab every 8 weeks to other biologics available in Canada is not available.

The primary outcome was ACR 20 response, but according to the clinical expert, this represents the minimum level of improvement that may be relevant to patients. In practice, the goal of therapy is to achieve higher levels of response, such as MDA or low disease activity as measured by the DAPSA. The COSMOS study included ACR 50 in its statistical testing procedures to control the type I error rate, but according to the US-based procedure in the DISCOVER trials, ACR 50 and ACR 70 were not controlled for multiple testing. The MDA end point was not controlled for multiple testing in any of the trials, which limits the ability to draw statistical inference from these data.

External Validity

The trials enrolled adults who, on average, were in their mid to late forties and predominantly White. There were a roughly equal number of male and female patients enrolled. Although patients with only 3 or 5 tender or swollen joints could enrol, the mean number of tender joints was about 20 and the mean number of swollen joints was about 11. The mean PASI score was generally less than 10, which the expert stated was consistent with scores seen in rheumatology clinics, given that most patients had received DMARDs (which may help to control psoriasis). Approximately 8% of patients in the trials had not previously received a cDMARD before being enrolled. Of the patients screened, 13%, 36%, and 39% were excluded. However, based on reporting in the CSRs, there was limited information about the characteristics of these patients and the reasons for their screening failures. Most of the trials were conducted in Europe, with some sites in Asia, the US, Australia, and Israel. Only the DISCOVER-1 study included sites in Canada, which enrolled 15 patients (4%). Based on the inclusion and exclusion criteria and the characteristics of patients, the clinical expert did not identify any substantial limits to the generalizability of the results of the trials.

The guselkumab-every-8-weeks dosing regime used in the trials was consistent with the Health Canada–recommended dose, and the clinical expert stated that concomitant utilization of cDMARDs was similar to what may be expected in practice. However, the clinical expert also noted that the use of oral corticosteroids in the DISCOVER trials (14% to 20%) was higher than would be expected in Canada, where chronic corticosteroid use is generally avoided. The trials excluded patients who had previously been treated with biologics other than TNF inhibitors; thus, the efficacy in patients with intolerance or inadequate response to other biologics is not known.

The trials assessed several of the outcomes that patients report as important. However, not all were part of the statistical testing strategy; as a result, the ability to draw conclusions from these data may be limited. The 24-week duration of the comparative part of the trials may be considered short, given that PsA is a chronic condition. Moreover, the comparator used in the trials (i.e., placebo plus cDMARD) may not reflect current practice, given that most patients who show an inadequate response cDMARDs or bDMARDs DMARDs would be offered biologic therapy.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

A review of indirect evidence was required because none of the clinical trials included in the systematic review included an active control group (other than guselkumab every 4 weeks, which is not a Health Canada–approved dosage). In addition, an appraisal of the ITC submitted by the sponsor was necessary, given that these data were used to inform the pharmacoeconomic model.

A focused literature search for ITCs dealing with PsA was run in MEDLINE All (1946–) on May 30, 2022. No limits were applied to the search. The results were reviewed by 1 researcher to select any ITCs that met the patient, intervention, comparator, and outcome criteria listed in the review protocol (Table 6).

Nine potentially relevant ITCs^15,60-67 were identified in the literature search. However, 4 of these trials did not include guselkumab, and were excluded.^60,63,64,67

Another 4 ITCs were not summarized in this report. In 1 ITC, the only guselkumab data available was from a phase II trial; thus, it was missing key evidence to inform the indirect comparison.⁶¹ Another ITC was an earlier version of the sponsor’s ITC and was considered out of date,⁶² and a third ITC had a limited scope (comparing guselkumab to secukinumab only) and was missing many comparators that were relevant to the Canadian context.⁶⁵ The ITC by Torres et al. (2020)⁶⁶ included guselkumab PsA trials in the systematic review, but these studies were excluded from the NMA. Thus, Torres et al. (2020) was excluded because it did not provide any additional data to support the reimbursement decision.

This section provides a critical appraisal of the sponsor’s ITC^20,68 as well as a brief summary of the published ITC by McInnes et al. (2022)¹⁵ that was identified in the literature search conducted by CADTH.

Description of ITC

The sponsor conducted an NMA of RCTs that assessed the comparative efficacy and safety of guselkumab and other bDMARDs for the short-term treatment of acute PsA. The NMA by McInnes et al. (2022)¹⁵ evaluated the efficacy and safety of licensed and unlicensed bDMARDs for patients with active PsA.

Methods of the Sponsor-Submitted ITC

Objectives

The objective of the sponsor-submitted ITC was to assess the relative efficacy and safety of guselkumab compared with other biologics after 12 weeks to 24 weeks of therapy in patients with active PsA.

Study Selection Methods

The ITC was based on a systematic literature review of RCTs that evaluated biologic and non-biologic DMARDs in adults with active PsA. The review was based on a protocol that was drafted a priori and published to PROSPERO in April 2020. The systematic review was first conducted in 2018, was updated in 2020 and 2021, and was published in 2021.^62,68 Table 24 outlines the patients, interventions, comparators, outcomes, and study designs included in the current version of the sponsor’s systematic review. The review included phase II and III RCTs in adults with active PsA who were treated with 1 or more DMARD or placebo for at least 12 weeks. The review included a broad scope of treatments for PsA; however, the authors made no statement with regards to doses of treatments that would be accepted in the systematic review. No limits were placed on the outcomes of interest to the review.

The systematic review was based on a peer-reviewed literature search of the Embase, MEDLINE, and Cochrane Central databases and a search of ClinicalTrials.gov. Studies were selected based on the criteria listed in Table 24, with screening conducted by 2 reviewers independently. Data were extracted by 1 reviewer and verified by a second. Trials were assessed for study quality by a single reviewer using the National Institute for Health and Care Excellence clinical effectiveness quality assessment checklist. Although not explicitly stated, it appears that no trials were excluded based on study quality.

Additional criteria were applied to determine which studies were included in the quantitative analysis; however, no rationale was provided for these criteria, and it is unclear if these were determined a priori. Based on the description of the excluded studies, the ITC was limited to phase III RCTs of a biologic (including small-molecule inhibitors apremilast, tofacitinib, and upadacitinib) at dosages approved by the FDA or European Medicines Agency. It is not clear how outcomes were selected for analysis in the ITC.

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

CSR = Clinical Study Report; CTLA-4 = cytotoxic T‐lymphocyte‐associated protein-4; DMARD = disease-modifying antirheumatic drug; EMA = European Medicines Agency; IL = interleukin; ITC = indirect treatment comparison; JAK = Janus kinase; NICE = National Institute for Health and Care Excellence; PDE-4 = phosphodiesterase type 4; RCT = randomized controlled trial; TNF = tumour necrosis factor.

Source: Sponsor’s submission for Tremfya.²⁰

ITC Analysis Methods

The authors conducted an NMA using Bayesian methods (Table 25). The authors stated that a random-effects model was selected a priori as the primary analysis method due to the known clinical heterogeneity in PsA trials. Unadjusted fixed-effects models would also be run, but would be accepted only if there were compelling reasons, such as the between-trial heterogeneity prior not being updated by the data, leading to conclusions (based on overlap of the 95% CrIs) that are contrary to primary trial results. Further, a baseline risk-adjusted model (adjusting for placebo response, described by the authors as a proxy for measured and unmeasured patient characteristics) was planned to adjust for known heterogeneity in patient and study characteristics, as has been done in other NMAs for PsA.⁶⁹ Model fit was assessed based on 4 factors: estimated regression coefficient (beta) and a 95% CrI that excludes the null for a meta-regression covariate; lower between-study SD compared with the unadjusted model; lower deviance information criterion (by ≥ 5 points) compared with the unadjusted model; and posterior mean of the residual deviance approximately equal to the number of treatment arms. The first 2 factors were given more weight when determining if the baseline risk-adjusted model fit best.

An inconsistency model was used to identify loops with inconsistency, although the authors stated that this method had low power to detect a difference. Of note, the network had few closed loops; only 5 studies had an active comparator. The authors stated that their interpretation of the reliability of estimates was based on their quality assessment of the transitivity assumption and evaluation of the estimated between-trial heterogeneity.

The NMA included trials with outcomes assessed at 12 weeks to 24 weeks. Although not explicitly stated, it appears that each dosage regimen was a separate node. Outcomes assessed include ACR response, PASI response, change from baseline in HAQ-DI, Psoriatic Arthritis Response Criteria response, SF-36 PCS and MCS, change from baseline in vdH-S, adverse events, and serious adverse events. No rationale was provided for the selection of these outcome measures.

The primary analysis included a mixed population of biologic-naive and biologic-experienced patients. Subgroup analyses were run, restricted to patients who were biologic-naive and biologic-experienced. For the overall and biologic-experienced populations, sensitivity analyses were run to test the impact of the early escape errors in the COSMOS study. The primary analysis used the main findings from COSMOS, with a secondary analysis that accounted for errors in early escape.

Table 25: ITC Analysis Methods

ACR = American College of Rheumatology; ACR 0 = American College of Rheumatology 0% improvement; ACR 20 = American College of Rheumatology 20% improvement; ACR 50 = American College of Rheumatology 50% improvement; ACR 70 = American College of Rheumatology 70% improvement; DIC = deviance information criterion; HAQ-DI = Health Assessment Questionnaire Disability Index; ITC = indirect treatment comparison; MCS = Mental Component Summary; NICE = National Institute for Health and Care Excellence; OR = odds ratio; PASI = Psoriasis Area and Severity Index; PASI 0 = % improvement from baseline in Psoriasis Area and Severity Index score;;PASI 50 = 50% improvement from baseline in Psoriasis Area and Severity Index score;;PASI 75 = 75% improvement from baseline in Psoriasis Area and Severity Index score; PASI 90 = 90% improvement from baseline in Psoriasis Area and Severity Index score; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index score; PCS = Physical Component Summary; PsARC = Psoriatic Arthritis Response Criteria; RR = relative risk; SAE = serious adverse events; SD = standard deviation; SF-36 = Short Form (36) Health Survey; vdH-S = van der Heijde-Sharp.

^aUsed to inform the pharmacoeconomic model.

Source: Sponsor’s submission for Tremfya.²⁰

Results of Sponsor-Submitted ITC

Summary of Included Studies

The systematic review included 169 citations of 80 RCTs. Of these, 46 RCTs were excluded from the ITC because the trials included a treatment or dose that was not approved by the European Medicines Agency or FDA (17 studies), included only 1 relevant treatment (1 study), did not include a biologic (21 studies), or were a phase II study (8 studies). A total of 34 RCTs published between 2004 and 2021 were included in the ITCs.

Fourteen bDMARDs were included in the NMA: abatacept, adalimumab, apremilast; certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tofacitinib, upadacitinib, and ustekinumab. Most studies included a placebo group (32 trials). Of the 16 studies that compared active treatments, most included 2 dosing regimens of the same drug. Four trials compared 2 different active treatments. The sample size of the studies ranged from 100 patients to 1,281 patients.

The authors of the ITC acknowledged that there was heterogeneity across studies and provided data tables describing the patient and study characteristics of the included trials. The enrolment criteria of all studies specified adults (≥ 18 years) with active PsA; however, the definition of active PsA varied across trials. Most trials required patients to have at least 3 tender or swollen joints and a history or presence of plaque psoriasis at enrolment. The mean age of patients enrolled ranged from 45.7 years to 53.6 years. In terms of gender and race, 41.9% to 61% of patients enrolled were male, and 76.5% to 99.7% were White (not reported in 2 studies). The mean duration of PsA ranged from 3.1 years to 13.4 years across the studies. At baseline, the mean number of swollen and tender joints ranged from 6.1 to 18.3 and 14 to 27.3, respectively. The proportion of patients with psoriasis affecting more than 3% of their BSA ranged from 42% to 100% (not available in 6 studies). At baseline, the mean PASI score ranged from 5.9 to 12.2 (not reported in 9 studies).

Eighteen trials involved patients who were biologic-naive, 4 trials involved patients who were biologic-experienced, and 12 trials involved a mixed population. In the mixed-population studies, 14% to 61% of patients had prior experience with a biologic treatment. Where reported, 21% to 100% of patients had previously received cDMARDs (not reported in 16 studies). In most studies, patients were receiving methotrexate at baseline (38% to 83% of those enrolled). No information was provided about other co-interventions received during the trials.

The primary time point in 9 trials was 12 weeks. Ten trials had time points of 14 weeks to 16 weeks, and 15 trials lasted 24 weeks. In general, the trials of TNF inhibitors, JAK inhibitors, and apremilast were 16 weeks or shorter, whereas the studies of abatacept and the IL-17, IL-12 to 23, and IL-23 inhibitors were 24 weeks in duration. The exceptions were adalimumab and secukinumab — for which there were data from both shorter- and longer-duration trials — and etanercept, for which there were data from only a 24-week trial. Twelve of the 16 24-week studies (75%) had an early escape route available before the primary efficacy end point, which is a potential source of confounding. There were no details provided on how patients who received escape therapy were handled in each study.

To explore clinical heterogeneity within and across the studies, bar plots of the distribution of placebo responses and scatterplots of the relationships between placebo response and the treatment effect from each study were examined by the authors of the ITC (data not available). The authors stated that the placebo response varied across trials and tended to be lower for stricter ACR categories. Across the trials, the ACR 20 response rate in the placebo groups ranged from 9% to 33% (median = 20%; N = 32). The authors also noted that the trials evaluating guselkumab tended to have a higher-than-average placebo response (i.e., ACR 20 = 20% to 33%). The authors stated that a strong, negative association between treatment effect and placebo response was evident for all ACR response levels, with studies with larger placebo responses appearing to have smaller treatment effects. The authors of the ITC stated that failure to adjust for baseline risk could result in biased estimates of comparative efficacy. A summary of the CADTH assessment of clinical heterogeneity is provided in Table 26.

The authors of the ITC rated most of the included studies as having a low overall risk of bias; however, 53% were rated as having an unclear risk of bias, and 18% were rated as having a high risk of bias in at least 1 domain. Eight of 34 studies (24%) had unclear risk of bias related to randomization and/or allocation concealment. Blinding of patients, care providers, and/or outcome assessors was unclear in 6 studies (18%); and study participants were unblinded in 1 study (3%). The authors of the ITC assessed that the groups were balanced at the start of all studies, and that only 1 study had an unclear risk of bias related to imbalances in dropouts. Seventeen studies (50%) had an unclear risk of bias and 1 study (3%) had a high risk of bias related to the methods used to account for missing data. Three studies (9%) had a high risk of reporting bias.

Table 26: Assessment of Homogeneity for Sponsor-Submitted ITC

ACR = American College of Rheumatology; ACR 20 = American College of Rheumatology 20% improvement; DMARD = disease-modifying antirheumatic drug; HAQ-DI = Health Assessment Questionnaire Disability Index; ITC = indirect treatment comparison; PASI = Psoriasis Area and Severity Index; PsA = psoriatic arthritis; RCT = randomized controlled trial; TNF = tumour necrosis factor.

Source: Sponsor’s submission for Tremfya.²⁰

Results

ACR Response

The evidence network for ACR response in the overall PsA population (biologic-naive or experienced) is shown in Figure 8. All 34 studies reported data for ACR 20; 33 studies reported data for ACR 50; and 31 studies reported data for ACR 70 (number of patients not reported). Based on the multinomial model used in this analysis, the conclusions for ACR 50 and ACR 70 are the same as for ACR 20.

For the overall PsA population, the results of the baseline risk-adjusted random-effects model suggest that patients who received guselkumab every 8 weeks may || |||| |||||| || ||||||| || ||| || |||||||| |||| ||||| ||| |||||||| apremilast, abatacept, or placebo, given that the 95% CrI for the pairwise comparisons excluded the null (Table 27). The ACR 20 results |||||||| ||||||||||| ||||||||| ||| ||||||||||| ||| || |||||| |||||||||| |||. Comparisons between |||||||||| ||| ||| ||||| ||||||||| ||| ||| ||| |||| |||||||||| ||| |||| |||||| || |||| |||||| ||| ||| ||| ||| ||||||||||| |||||| |||||||| ||| ||||||||||| || ||||||||||| ||||||| |||||| ||||| ||||||||| ||| || |||||||||||| |||||||| ||| ||||||| || |||| | ||||||||||.

In the analysis of biologic-naive patients (30 studies, Figure 9), the baseline risk-adjusted random-effects model suggested patients who received guselkumab were |||| |||||| || ||||||| ||| || |||||||| |||| |||||||||| || ||||||| (Table 28). For other comparisons, the 95% CrI |||||||| ||| |||| |||||. In some cases, the 95% CrI was |||||||||| |||||||| ||| ||||||| || |||| | ||||||||||. The results in biologic-experienced patients (16 studies, Figure 10) |||||||| |||||||||| |||||| ||||||| ||||| || || |||||||||| |||||| ||||||| |||||| ||| ||| ||| ||| ||||| ||||||||||| |||||||||| ||| |||| ||||| ||| || ||| ||||| ||| ||| ||| ||| |||||||||| |||||||| ||| ||||||| || |||| | |||||||||| (Table 29).

Change in HAQ-DI

The NMA of the change in HAQ-DI in the overall, biologic-naive, and biologic-experienced populations were informed by data from 32 RCTs (unadjusted random-effects model), 21 RCTs (unadjusted random-effects model), and 8 RCTs (unadjusted fixed-effects model), respectively. In all 3 populations, ||| |||||| || |||||| |||||||| |||||||||| |||||| |||||||| ||| ||||||| |||||||| ||| ||||| |||| ||||| ||||||||||| |||||||| ||| ||||| ||||||||| |||| | |||| ||| |||| |||||||| ||| ||||||| || |||| | |||||||||| (Table 27, Table 28, Table 29). ||| ||||||| |||||||| ||||||||| || |||||| |||||||||| || ||| ||||||| ||| |||||||||||||| |||||||||||| ||| |||||||| |||||||||| || || ||||| |||||| |||||| |||||||||| || ||| ||||||| ||||||||||.

PASI Response

Thirty RCTs provided PASI response data to inform the ordinal baseline-adjusted random-effects Bayesian NMA. Based on this model, the results of the PASI 90 response are the same for other PASI thresholds. ||| ||||||| |||||||| |||||||||| |||||| ||||||||||| ||| ||| ||| ||||| |||||||||| ||||||| |||||||||||| ||| ||||||||||| |||||||||| |||||||||| ||| ||||||| (Table 27). ||| ||||||| |||||||| ||| ||||| ||||||||||| |||||||| ||| ||||| ||| ||| ||| ||| ||| ||||||||| |||||||||| |||||||| ||| ||||||| || |||| | ||||||||||| ||| ||| |||||||| |||| ||||||| ||| ||| |||||||||||||| |||||||| || | || |||||||| (Table 28).

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

Changes in SF-36 PCS and MCS

For the overall PsA population, ||| ||||||| |||||||| |||||||||| ||| ||||||||| || |||||| |||||||||| ||| ||| |||||| || ||||| ||| ||| |||||||| ||| |||||||| |||||||||| ||| |||||||||| |||||| |||||||||| ||| ||| |||||| || ||||| ||| ||| ||||||||| |||| ||| ||||| |||||||| ||||||||||| ||||||||| ||| |||| |||| |||||||| ||| |||| |||||| || |||||||||| |||||| ||||||| |||||||. The findings were similar for the biologic-naive subgroup (MCS = 13 studies and PCS = 18 studies; unadjusted random-effects models). The NMAs in the biologic-experienced population were conducted using unadjusted fixed-effects models that included 6 trials for the MCS and 7 trials for the PCS. ||| |||| ||||||||| ||| ||||||||||| ||||||| |||||||||| ||| ||||| ||||||||| |||||||| ||| |||| |||| |||||||| ||| ||||| |||| || ||||| |||| |||||||||.

Change in VdH-S Score

|| ||| ||||||| ||||||||||| ||| |||||||||| ||||| |||||| ||| ||| |||||||| |||||||| |||||||||| ||| ||||||||| || |||||| |||||||||| ||| ||| |||||| |||| |||||||| || ||| ||||| |||||| ||| ||||| ||||||||||| |||||||| ||| ||| |||| |||||||| ||| ||||| ||| |||||||| |||| ||||||| ||| ||| |||||||||||||| ||||||||| |||| ||||||| ||| ||| |||||||| || ||| |||||||||||||||||||| |||||||||||||.

Serious Adverse Events

The NMA of serious adverse events in the overall population included data from 32 RCTs and was analyzed using a baseline risk-adjusted, random-effects model. ||| ||||||| ||||||| |||||||||| ||| |||| | ||||| |||| || ||||||| ||||||| |||||| |||| |||||||||| ||| |||||||||||| ||||| |||| ||| ||||| ||||||||||| ||||||| |||||||||| ||| ||||||| || ||||||||| |||||||| ||||||||| ||| |||| |||| |||||||||| ||| ||||| |||||||| ||| ||||||| || |||| ||||||||||| |||||| |||| ||| ||||||||||| ||||||| |||||||||| ||| ||||||| || ||||||||| || ||| ||| || |||||||| ||| |||| |||||||||||||| || | || |||||||| ||||| ||| || |||||||||||||||||||| || | | |||||||| ||||| ||| |||||| ||| |||| |||| |||| |||||||||| ||||| |||||| ||| ||||||| || |||| | |||||||||| |||| ||||| ||||.

Adverse Events

The NMA of adverse events was conducted using a baseline risk-adjusted, random-effects model for the overall population (32 studies) and biologic-naive populations (17 studies). ||| ||||||| ||||||| |||| |||||||||| ||| |||| | ||||| |||| || |||||||||| ||||||| |||||| |||| ||||||||||| |||||||||| || ||||||||||| ||| ||||| ||||||||||| |||||| ||| |||| |||| |||||||| ||| ||||| ||| || |||| ||||| |||| |||||||||| || ||| |||||||||||||| ||||||||||| ||| ||||||||||| ||||||| |||||||||| ||| ||||||||| |||||||| ||| ||| |||| |||||||| ||| |||| ||| |||| |||||||||| ||| ||| || ||| |||||||||||||||||||| |||||||||| || |||||||| |||||||||| ||||| |||||| |||||| ||||||||| |||| ||||||||||| ||| |||| | ||||| |||| || ||||||| |||||| |||| |||||||||| ||| ||| |||||||||||| ||||| ||||||||||| |||||||| ||| |||| |||| |||||||| ||| ||||| |||| |||| ||||||| ||||||||| |||||||.

Figure 8: Evidence Network for ACR Response in the Overall PsA Population

ABA = abatacept; ADA = adalimumab; APR = apremilast; CERT = certolizumab; ETA = etanercept; GOL = golimumab; GUS = guselkumab; IFX = infliximab; IXE = ixekizumab; LD = loading dose; PBO = placebo; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; RIS = risankizumab; SEC = secukinumab; TOF = tofacitinib; UPA = upadacitinib; UST = ustekinumab; WT = weight based.

Source: Sponsor’s submission for Tremfya.²⁰

Table 27: Key NMA Results for the Overall PsA Population — Guselkumab Every 8 Weeks Versus Biologics

ABA = abatacept; ADA = adalimumab; ACR 20 = American College of Rheumatology 20% improvement; APR = apremilast; BIW = twice weekly; CERT = certolizumab; Crl = credible interval; ETA = etanercept; GOL = golimumab; HAQ-DI = Health Assessment Questionnaire Disability Index; IFX = infliximab; IL = interleukin; IXE = ixekizumab; JAK = Janus kinase; LD = loading dose; MD = mean difference; NA = not applicable; NMA = network meta-analysis; PASI 75 = 75% improvement from baseline in Psoriasis Area and Severity Index score; PASI 90 = 90% improvement from baseline in Psoriasis Area and Severity Index score; PsA = psoriatic arthritis; q2w = every 2 weeks; q4w = every 4 weeks; RIS = risankizumab; RR = relative risk; SAE = serious adverse event; SEC = secukinumab; TNF = tumour necrosis factor; TOF = tofacitinib; UPA = upadacitinib; UST = ustekinumab.

Note: Data reported for guselkumab every 8 weeks vs. comparator. An RR is greater than 1 favours guselkumab for ACR 20 and PASI 75. For the change in HAQ-DI, negative MD values favour guselkumab. For SAE, an RR less than 1 favours guselkumab. Results shown in bold had 95% CrIs that excluded the null value.

Source: Sponsor’s submission for Tremfya.²⁰

Figure 9: Evidence Network for ACR Response in Biologic-Naive PsA Population

ABA = abatacept; ACR = American College of Rheumatology; ADA = adalimumab; APR = apremilast; CERT = certolizumab; ETA = etanercept; GOL = golimumab; GUS = guselkumab; IFX = infliximab; IXE = ixekizumab; LD = loading dose; PBO = placebo; PsA = psoriatic arthritis; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; RIS = risankizumab; SEC = secukinumab; TOF = tofacitinib; UPA = upadacitinib; UST = ustekinumab; WT = weight based.

Source: Sponsor’s submission for Tremfya.²⁰

Table 28: Key NMA Results for the Biologic-Naive Population — Guselkumab Every 8 Weeks Versus Biologics

ABA = abatacept; ACR 20 = American College of Rheumatology 20% improvement; ADA = adalimumab; APR = apremilast; BIW = twice weekly; CERT = certolizumab; Crl = credible interval; ETA = etanercept; GOL = golimumab; HAQ-DI = Health Assessment Questionnaire Disability Index; IFX = infliximab; IL = interleukin; IXE = ixekizumab; JAK = Janus kinase; LD = loading dose; MD = mean difference; NA = not applicable; NMA = network meta-analysis; PASI 75 = 75% improvement from baseline in Psoriasis Area and Severity Index score; PASI 90 = 90% improvement from baseline in Psoriasis Area and Severity Index score; PsA = psoriatic arthritis; q2w = every 2 weeks; q4w = every 4 weeks; RIS = risankizumab; RR = relative risk; SAE = serious adverse event; SEC = secukinumab; TNF = tumour necrosis factor; TOF = tofacitinib; UPA = upadacitinib; UST = ustekinumab.

Note: Data reported guselkumab every 8 weeks vs. comparator. RR greater than 1 favours guselkumab for ACR 20 and PASI 75. For the change in HAQ-DI, negative MD values favour guselkumab. For SAE, RR less than 1 favours guselkumab. Results shown in bold had 95% CrIs that excluded the null value.

Source: Sponsor’s submission for Tremfya.²⁰

Figure 10: Evidence Network for ACR Response in Biologic-Experienced PsA Population

ABA = abatacept; American College of Rheumatology; APR = apremilast; CERT = certolizumab; GUS = guselkumab; IXE = ixekizumab; LD = loading dose; PBO = placebo; PsA = psoriatic arthritis; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; RIS = risankizumab; SEC = secukinumab; TOF = tofacitinib; UPA = upadacitinib; UST = ustekinumab.

Source: Sponsor’s submission for Tremfya.²⁰

Table 29: Key NMA Results for the Biologic-Experienced Population — Guselkumab Every 8 Weeks Versus Biologics