CADTH Reimbursement Review

Bimekizumab (Bimzelx)

Sponsor: UCB Canada Inc.

Therapeutic area: Psoriatic arthritis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

cDMARD = conventional nonbiologic disease-modifying antirheumatic drug; NOC = Notice of Compliance; PsA = psoriatic arthritis; q.4.w. = every 4 weeks; SC = subcutaneous.

Sources: Sponsor’s submission package for review of bimekizumab and bimekizumab product monograph.^1,2

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory, immune-mediated disease with heterogenous presentation and disease course. Patients present with a variety of disease manifestations,^3-6 with peripheral arthritis and psoriasis as the most common disease manifestations of PsA.⁷ The joint inflammation associated with PsA is known to worsen over time and, if left untreated, can lead to permanent joint damage and long-term disability.^4,8-10 The prevalence estimate for PsA is variable depending on the case definition and geography,¹¹ and is estimated to be approximately 1 to 2 per 1,000 people in the general population, globally.¹² A population-based Canadian study, conducted in Ontario, estimated the age- and sex-standardized cumulative prevalence of PsA in Ontario to range from 0.9 per 1,000 people in 2008 to 1.5 per 1,000 people in 2015.¹³

The goals of treatment for managing PsA include achieving the lowest level of disease activity (with a target of disease remission), maximizing functional status and health-related quality of life (HRQoL), preventing further disease progression, controlling symptoms, and avoiding complications (from untreated disease or adverse effects from treatment).^14-16 First-line, pharmacological treatment of PsA typically includes disease-modifying antirheumatic drugs (DMARDs) such as conventional nonbiologic disease-modifying antirheumatic drugs (cDMARDs) (e.g., methotrexate, sulfasalazine, leflunomide, cyclosporine). Later-line, targeted treatments are usually reserved for patients who have an inadequate response to cDMARDs and include biologic disease-modifying antirheumatic drugs (bDMARDs) (e.g., tumour necrosis factor inhibitor [TNFi], interleukin-17 inhibitor [IL-17i], interleukin-12 and interleukin-23 inhibitor [IL-12/23i], interleukin-23 inhibitor [IL-23i]), and targeted synthetic disease-modifying antirheumatic drugs [tsDMARDs]) (e.g., Janus kinase inhibitor [JAKi] and phosphodiesterase type 4 inhibitor [PDE4i]).^15,16 The clinical expert noted that the continuation of cDMARDs may be necessary until effectiveness of the targeted therapies is confirmed.

Bimekizumab is a humanized immunoglobulin G1 kappa monoclonal antibody with 2 identical, high-affinity antigen-binding regions that neutralize interleukin-17A (IL-17A), interleukin-17F (IL-17F), and interleukin-17AF (IL-17AF) cytokines, blocking their interaction with the interleukin-17RA and interleukin-17RC (IL-17RA/IL-17RC) receptor complex, which plays a role in PsA-related inflammation.² The recommended dose of bimekizumab for adult patients with active PsA is 160 mg (given as 1 subcutaneous [SC] injection of 160 mg) every 4 weeks.² The sponsor has requested reimbursement as per the approved Health Canada indication. Bimekizumab was previously reviewed by CADTH in April 2022 for the indication of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and a final recommendation for reimbursement with conditions was issued.^17,18 In addition to the current CADTH review for the indication of adults with active PsA (with or without cDMARDs), bimekizumab is also under CADTH review for the indication of adults with active ankylosing spondylitis.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of bimekizumab 160 mg every 4 weeks for SC injection in the treatment of adult patients with active PsA, alone or in combination with a cDMARD.

Stakeholder Perspectives

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

Patient Input

Input was submitted for this CADTH review by 7 different patient groups. Input was received from Arthritis Consumer Experts and, in a joint submission, from the Canadian Psoriasis Network, Arthritis Society Canada, the Canadian Arthritis Patient Alliance, the Canadian Association of Psoriasis Patients, the Canadian Spondyloarthritis Association, and CreakyJoints. Arthritis Consumer Experts gathered information from patients via email on October 16, 2023 (n = 2), and through an online survey available from December 18, 2020, to January 26, 2021 (n = 5). The joint input obtained responses (n = 214) through an online survey that was available through the 6 collaborating organizations from September 27 to October 11, 2023. The latter survey was also sent to clinics in Canada that conducted bimekizumab trials for PsA to capture the experience of patients living with PsA or ankylosing spondylitis and the experiences of their caregivers.

The symptoms described as being the most challenging to manage included joint stiffness, fatigue, and pain, among others. According to the respondents, PsA interfered with their physical activity, sleep, work, social life, mental health, intimacy, and self-esteem. It was also noted that caregivers had to take on additional tasks or daily chores due to patients’ reduced mobility and the impact the disease has on patients’ mental and social health.

Survey results showed that 32% of respondents found nonsteroidal anti-inflammatory drugs (NSAIDs) effective, 39% found DMARDs effective, 40% found biologic therapies effective (with 24% rating them as very effective), and 44% found steroids effective. Respondents indicated that efficacious treatments are costly and accessing them was challenging, and adverse effects can be very difficult to manage. Among the 3 respondents who had experience with bimekizumab for PsA, 1 respondent noted that treatment was easy to use and effective in improving HRQoL without adverse effects.

Patients seek treatments that improve disease symptoms and HRQoL, have fewer adverse effects, are easier to administer, and are accessible and affordable.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

Despite there being various treatment options for managing PsA, the clinical expert stated that not all patients respond to available therapies and that treatments tend to improve disease in some domains but have variable or suboptimal efficacy in others. There is also concern over safety with all DMARDs, including the increased risk of infection and new onset or worsening of existing comorbidities. According to the expert, few patients attain a state of low disease activity, and it is important to have safe, well-tolerated treatments that are effective in all domains.

The clinical expert indicated that bimekizumab would be used after the failure of cDMARDs and, in accordance with its Health Canada indication, with or without a cDMARD. Additionally, it was noted that without good quality evidence to support combination therapy, bimekizumab would not likely be used concomitantly with other bDMARDs or tsDMARDs at this time.

The clinical expert was of the opinion that any patient with active PsA could receive bimekizumab, and that those with coexisting severe psoriasis may also benefit. They added that the drug would be avoided in those with inflammatory bowel disease (IBD), severe uveitis, or active infection. The expert also noted that patients with an inadequate response to targeted DMARDs are most in need of new treatments.

According to the clinical expert, treatment response is typically assessed at 3 months based on improvements in the number of tender and swollen joints, enthesitis, dactylitis, and skin psoriasis, and sometimes using composite indices (e.g., minimal disease activity [MDA], Disease Activity index in PSoriatic Arthritis [DAPSA]). Improvements in physical function, pain, fatigue, and lack of radiographic progression (the last of which is not typically used in clinical practice) may take longer than 3 months in patients with longstanding PsA. Moreover, due to the heterogeneity of the disease, response can differ across patients, though the clinical expert suggested that assessments are not likely to vary among rheumatologists.

The clinical expert stated that lack of response in musculoskeletal or skin domains, disease relapse, intolerance, and patient choice are the most important factors when considering the discontinuation of bimekizumab. Moreover, it was explained that some amount of disease activity can be considered acceptable, but that recurrent infections and IBD would require discontinuation.

The expert noted that diagnosis by primary care physicians and dermatologists can be challenging, and misdiagnosis is a possibility; therefore, a PsA diagnosis should be made by a rheumatologist trained in identifying inflammatory arthritis. Patients are typically treated in an outpatient setting in community clinics and clinics attached to community and academic hospitals, though severe skin and joint disease may require hospital admission. The expert noted that the treatment and management of PsA involves a rheumatologist and can include a dermatologist to manage the associated psoriasis.

Clinician Group Input

One clinician group, the Canadian Rheumatology Association (whose input was authored by the therapeutics committee), responded to CADTH’s call for clinician group input. The treatment goals, unmet needs, patient population, and reasons for discontinuation described by the clinician group largely aligned with that of the clinical expert consulted by CADTH. The group suggested that measures of treatment response also include improvement in axial disease, Psoriasis Area Severity Index (PASI), and body surface area (BSA) affected by psoriasis. They also noted that composite measures, such as the Composite Psoriatic Disease Activity Index, DAPSA, and Psoriatic Arthritis Disease Activity Score, can be used but are not practical for everyday use in clinics. For axial disease, the most frequently used measure for disease activity in Canada is the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The group indicated that a specialist would be required to prescribe bimekizumab and monitor for adverse events (AEs), but because the drug is administered as an SC injection, a patient could self-administer it.

Drug Program Input

The drug programs asked if the initiation, continuation, discontinuation, prescribing, and combination criteria from the most recent Canadian Drug Expert Committee recommendation for guselkumab for the treatment of PsA should be applied to bimekizumab. The programs also asked for clarification if ever there is a potential indication for bimekizumab to treat juvenile PsA, what an adequate trial of DMARDs would be, what type of specialist should treat adults with PsA, if bimekizumab should be used in combination with other DMARDs, and if a patient could be re-treated with bimekizumab.

The clinical expert consulted by CADTH agreed that the same initiation, continuation, discontinuation, and prescribing criteria from the Canadian Drug Expert Committee recommendation for guselkumab for the treatment of PsA can be applied to bimekizumab. They also noted that, with evidence from good quality trials in a younger population, bimekizumab could be used to treat juvenile PsA. According to the expert, an adequate trial of 3 months at the recommended therapeutic dose is necessary to determine if a patient is responding to a cDMARD, bDMARD, or tsDMARD before switching to or adding another therapy. The expert indicated that patients with PsA should be diagnosed, treated, and managed by a rheumatologist, and when 1 cannot be accessed, internists or dermatologists may be acceptable specialists. Regarding combination therapy, the Health Canada indication states that bimekizumab can be used alone or in combination with a cDMARD (e.g., methotrexate),² and there is currently limited evidence for concomitant use with bDMARDs or tsDMARDs for the treatment of PsA. The expert was of the opinion that after switching from bimekizumab to another therapy, a patient could be re-treated with bimekizumab in the future.

Clinical Evidence

Systematic Review

Description of Studies

Two double-blind (DB), randomized controlled trials (RCTs) of adults with active PsA who had no prior exposure to biologic therapies (the BE OPTIMAL trial, N = 852) or who had a history of inadequate response or intolerance to 1 TNFi or 2 TNFis (the BE COMPLETE trial, N = 400) assessed whether bimekizumab 160 mg for SC injection every 4 weeks increased the proportion of patients attaining at least an American College of Rheumatology 50% improvement in rheumatoid arthritis (ACR50) response compared to placebo at 16 weeks.^19,20 ACR50 response is defined as an improvement of at least 50% in both swollen joint counts (SJCs) and tender joint counts (TJCs) and at least 3 of 5 additional disease criteria. Other clinically relevant outcomes included the measurement of MDA, musculoskeletal response, skin response, and changes in function and symptom scores. Patients received either bimekizumab or placebo during the 16-week DB phase of each trial. After 16 weeks in the BE OPTIMAL trial, patients randomized to placebo were reallocated to bimekizumab for the 36-week active treatment–blind phase.

In the BE OPTIMAL trial, the mean age of patients ranged from 48.5 (standard deviation [SD] = 12.6) years to 48.7 (SD = 11.7) years and demographic characteristics were generally similar between the bimekizumab and placebo groups. The mean time since diagnosis of PsA was approximately 6 years and the mean time since diagnosis of psoriasis was approximately 15 years. Baseline clinical characteristics were generally balanced between the 2 treatment groups, except for the presence of enthesitis being higher in the bimekizumab group (33.2%) compared to the placebo group (24.9%). In the BE COMPLETE trial, the mean age of patients ranged from 50.1 (SD = 12.4) years to 51.3 (SD = 12.9) years and demographic characteristics were generally similar between the bimekizumab and placebo groups. The mean time since diagnosis of PsA was more than 9 years and the mean time since diagnosis of psoriasis was more than 17 years across the treatment groups. More than 76% of patients had an inadequate response to at least 1 TNFi and more than 11% of patients to at least 2 TNFis, and approximately 12% of patients had an intolerance to TNFis. Baseline clinical characteristics were imbalanced between the 2 treatment groups for the presence of enthesitis (higher in the bimekizumab group), NSAID therapy (lower in the bimekizumab group), and methotrexate use (higher in the bimekizumab group).

Efficacy Results

Signs and symptoms of disease activity were measured by American College of Rheumatology (ACR) response, MDA, Patient’s Assessment of Arthritis Pain (PtAAP), and SJC.

ACR Response

In the BE OPTIMAL trial, a greater proportion of patients in the bimekizumab treatment group reached the primary end point of ACR50 at week 16 than did those in the placebo group; the difference between treatment groups was 31.2% (95% confidence interval [CI], 25.2% to 37.3%; P < 0.001) for ACR50. Similarly, a greater proportion of patients in the bimekizumab treatment group reached an American College of Rheumatology 20% improvement in rheumatoid arthritis (ACR20) and an American College of Rheumatology 70% improvement in rheumatoid arthritis (ACR70) response (which are improvements of at least 20% and 70%, respectively, in both SJC and TJC and at least 3 of 5 additional disease criteria) at week 16 than did those in the placebo group. The difference between treatment groups was 37.2% (95% CI, 30.5% to 44.0%) for ACR20, and 19.3% (95% CI, 14.1% to 24.5%) for ACR70. Week 52 ACR results during the active treatment–blind period at all 3 ACR thresholds indicated that response rates increased in both groups and that there was a similar response between patients who crossed over from placebo to bimekizumab and those originally randomized to bimekizumab.

In the BE COMPLETE trial, a greater proportion of patients in the bimekizumab treatment group reached the primary end point of ACR50 at week 16 than did those in the placebo group; the difference between treatment groups was 29.0% (95% CI, 21.9% to 36.2%; P < 0.001) for ACR50. Similarly, a greater proportion of patients in the bimekizumab treatment group reached the ACR20 and ACR70 responses at week 16 than did those in the placebo group; the difference between treatment groups was 52.8% (95% CI, 43.6% to 61.9%) for ACR20 and 17.2% (95% CI, 12.2% to 22.2%) for ACR70. A larger proportion of patients in the bimekizumab group compared to those in the placebo group attained an ACR50 response for each of the subgroup categories of inadequate response to 1 TNFi (47.8% versus 6.8%, respectively), inadequate response to 2 TNFis (20.0% versus 0%, respectively), and intolerance to TNFis (38.2% versus 13.3%, respectively).

Minimal Disease Activity

Signs and symptoms of disease activity were also measured by MDA, where MDA is a composite end point and is considered to be attained if at least 5 of 7 criteria are reached: TJC of 0 or 1, SJC of 0 or 1, PASI of 1 or lower or affected BSA of 3% or less, a pain visual analogue scale score of 15 or lower, a Patient’s Global Assessment of PsA visual analogue scale score of 20 or lower, a Health Assessment Questionnaire–Disability Index (HAQ-DI) score of 0.5 or lower, and tender entheseal points of 0 or 1.

In the BE OPTIMAL trial, for clinical responses measured with the MDA criteria, patients treated with bimekizumab had higher response rates compared with placebo at week 16. The difference between treatment groups was 31.0% (95% CI, 24.5% to 37.5%; P < 0.001). MDA results at week 52 of the active treatment–blind period indicated that response rates increased in both groups and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab.

In the BE COMPLETE trial, patients treated with bimekizumab had higher response rates compared with placebo at week 16. The difference between treatment groups was 34.2% (95% CI, 26.1% to 42.2%; P < 0.001).

Patient’s Assessment of Arthritis Pain

PtAAP is a 100-point visual analogue scale for patients to record their arthritis pain from 0 (no pain) to 100 (most severe pain). The minimal important difference (MID) from the literature is estimated to be a 10-point decrease from baseline.²¹

In the BE OPTIMAL trial, the bimekizumab group had a greater mean decrease from baseline (i.e., improvement) in PtAAP compared with the placebo group at week 16. The mean difference between treatment groups was –19.1 (95% CI, –22.7 to –15.5). PtAAP results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the mean difference between treatment groups was –25.0 (95% CI, –30.0 to –20.0).

Swollen Joint Count

SJC evaluation includes 6 joints of the upper body, 34 joints of the upper extremities, and 26 joints of the lower extremities for a total of 66 joints. Each joint is assessed using a 2-point scale: 0 for no swelling and 1 for swollen joints.

In the BE OPTIMAL trial, the mean reduction at week 16 was greater in the bimekizumab group compared to the placebo group, with the mean difference between treatment groups being –4.0 joints (95% CI, –4.8 joints to –3.1 joints). SJC results at week 52 indicated that response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the mean reduction at week 16 was greater in the bimekizumab group compared to the placebo group, with the mean difference between treatment groups being –5.3 joints (95% CI, –6.5 joints to –4.2 joints).

Measurement of Other Musculoskeletal Disease

The impact of treatment on musculoskeletal disease was assessed by measuring the resolution of enthesitis (with the Leeds Enthesitis Index [LEI]), and the resolution of dactylitis (with the Leeds Dactylitis Index [LDI]).

Enthesitis-Free State Based on LEI: For the pooled population of patients with enthesitis at baseline in the BE OPTIMAL and BE COMPLETE trials, a greater proportion of patients in the bimekizumab treatment group had resolution of enthesitis (LEI = 0) at week 16 than did those in the placebo group; the difference between treatment groups was 14.9% (95% CI, 4.0% to 25.9%; P = 0.008).

Dactylitis-Free State Based on LDI: For the pooled population of patients with dactylitis at baseline in the BE OPTIMAL and BE COMPLETE trials, a greater proportion of patients in the bimekizumab treatment group had resolution of dactylitis (LDI = 0) at week 16 than did those in the placebo group; the difference between treatment groups was 29.4% (95% CI, 11.7% to 47.1%; P = 0.002).

Measurement of Skin Disease

The extent and severity of skin disease was measured in both studies using PASI and Investigator’s Global Assessment (IGA).

PASI grades the extent and severity of psoriatic lesions and combines an assessment of the BSA affected with the severity of desquamation, erythema, and plaque induration or infiltration. It is scored from 0 to 72, with higher scores representing more severe disease. A 90% reduction in Psoriasis Area Severity Index score (PASI 90) is a dichotomous (yes or no) scale indicating whether a patient attained at least 90% improvement from baseline PASI score. In both trials, only patients who had psoriasis involving at least 3% BSA at baseline were assessed for PASI 90 at week 16.

The IGA is a 5-point composite physician assessment of the overall severity of the patient’s psoriatic lesions, where 0 is clear, 1 is almost clear, 2 is mild, 3 is moderate, and 4 is severe. In both trials, only patients who had an IGA score of at least 2 and psoriasis involving at least 3% BSA at baseline were evaluated for the outcome of at least a 2-grade reduction in IGA score at week 16.

90% Reduction in PASI Score: In the BE OPTIMAL trial, for PASI 90, patients treated with bimekizumab had higher response rates compared with placebo at week 16. The difference between treatment groups was 56.5% (95% CI, 48.6% to 64.3%; P < 0.001). PASI 90 results at week 52 indicated that response rates increased in both groups and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, for PASI 90, patients treated with bimekizumab had higher response rates compared with placebo at week 16. The difference between treatment groups was 57.6% (95% CI, 47.6% to 67.6%; P < 0.001). A larger proportion of patients in the bimekizumab group compared to the placebo group attained a PASI 90 response for each of the subgroup categories of inadequate response to 1 TNFi (difference versus placebo = 64.4% [95% CI, 53.6% to 75.3%]), inadequate response to 2 TNFis (difference versus placebo = 25.0% [95% CI, –16.2% to 66.1%]), and intolerance to TNFis (difference versus placebo = 49.7% [95% CI, 18.5% to 80.9%]).

IGA Score of 0 or 1 and At Least 2-Grade Reduction From Baseline: In the BE OPTIMAL trial, a larger proportion of patients in the bimekizumab group compared to the placebo group attained at least a 2-grade reduction from baseline in the IGA score at week 16. The difference between treatment groups was 46.0% (95% CI, 37.1% to 55.0%). IGA results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, a larger proportion of patients in the bimekizumab group compared to the placebo group attained at least a 2-grade reduction from baseline in the IGA score at week 16. The difference between treatment groups was 58.2% (95% CI, 46.7% to 69.8%).

Physical Function

The improvement in physical function at week 16 was assessed using the HAQ-DI and Short Form (36) Health Survey (SF-36) physical component summary (PCS). HAQ-DI is a self-assessment questionnaire of 8 domains (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities); patients’ difficulty in performing these activities is scored from 0 (without any difficulty) to 3 (unable to do). SF-36 is a 36-item, general health status instrument consisting of 8 health domains: physical functioning, pain, vitality, social functioning, psychological functioning, general health perceptions, role limitations due to physical challenges, and role limitations due to emotional challenges. The PCS ranges from 0 to 100, with higher scores indicating better health status.

Health Assessment Questionnaire–Disability Index: In the BE OPTIMAL trial, the bimekizumab group had a greater mean decrease from baseline (i.e., improvement) in HAQ-DI compared with the placebo group at week 16; the least squares mean (LSM) difference between treatment groups was –0.19 (95% CI, –0.25 to –0.13; P < 0.001). HAQ-DI results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the bimekizumab group had a greater mean decrease from baseline (i.e., improvement) in HAQ-DI compared with the placebo group at week 16; the LSM difference between treatment groups was –0.33 (95% CI, –0.42 to –0.23; P < 0.001). A larger proportion of patients in the bimekizumab group compared to the placebo group attained a HAQ-DI score decrease of at least 0.35 for each of the subgroup categories of inadequate response to 1 TNFi (difference versus placebo = 40.8% [95% CI, 28.6% to 53.1%]), inadequate response to 2 TNFis (difference versus placebo = 11.5% [95% CI, –19.9% to 42.9%]), and intolerance to TNFis (difference versus placebo = 24.7% [95% CI, –6.0% to 55.5%]).

SF-36 PCS: In the BE OPTIMAL trial, the bimekizumab group had a greater mean increase from baseline (i.e., improvement) in the SF-36 PCS compared with the placebo group at week 16; the LSM difference between treatment groups was 4.3 (95% CI, 3.2 to 5.4; P < 0.001). SF-36 PCS results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the bimekizumab group had a greater mean increase from baseline (i.e., improvement) in the SF-36 PCS compared with the placebo group at week 16; the LSM difference between treatment groups was 6.0 (95% CI, 4.4 to 7.7; P < 0.001).

Harms Results

Patients reporting at least 1 AE during the DB treatment periods of the BE OPTIMAL and BE COMPLETE trials ranged from 40.4% to 59.6% of patients in the bimekizumab groups and from 33.3% to 49.5% of patients in the placebo groups. Nasopharyngitis was the most common AE (3.7% to 9.3% in the bimekizumab groups versus 0.8% to 4.6% in the placebo groups), followed by upper respiratory tract infection (2.2% to 5.1% in the bimekizumab groups versus 1.5% to 6.4% in the placebo groups). During the BE OPTIMAL trial’s active treatment–blind period, 72.0% of patients in the bimekizumab group and 70.5% of patients in the placebo-bimekizumab crossover group reported at least 1 AE, with the most common being nasopharyngitis (7.0% and 8.5% in the bimekizumab and crossover groups, respectively).

The frequency of serious adverse events (SAEs) was 1.9% in the bimekizumab groups and ranged from 0 to 1.1% in the placebo groups during the DB period of both trials. During the BE OPTIMAL trial’s active treatment–blind period, 5.6% of patients in the bimekizumab group and 5.9% of patients in the placebo-bimekizumab crossover group reported at least 1 SAE.

Withdrawals from treatment due to AEs ranged from 0.7% to 1.9% of patients in the bimekizumab groups and from 0 to 1.1% of patients in the placebo groups during the DB period of both trials. During the BE OPTIMAL trial’s active treatment–blind period, 2.7% of patients in the bimekizumab group and 1.8% of patients in the placebo-bimekizumab crossover group reported an AE leading to drug discontinuation.

There were no deaths during the DB periods of the trials and 1 death in the placebo-bimekizumab crossover group (due to traumatic shock from a motorcycle accident) during the BE OPTIMAL trial’s active treatment–blind period.

During the DB period of both trials, few notable harms were reported among either the bimekizumab or placebo group (i.e., 0 or 1 patient per treatment group) for liver dysfunction based on Hy’s law, opportunistic infection, a major cardiovascular event, malignancy, anaphylaxis, or IBD. In the trials, approximately 4.5% of patients in the bimekizumab groups and 1% of patients in the placebo groups reported any fungal infection. Of these, 2.6% of patients in the bimekizumab groups and less than 1% of patients in the placebo groups reported a candida infection, approximately 2% of patients in the bimekizumab groups and less than 1% of patients in the placebo groups reported a fungal infection not elsewhere classified (NEC), and less than 1% of patients in the bimekizumab groups and no patients in the placebo groups reported a tinea infection.

During the BE OPTIMAL trial’s active treatment–blind period, there were few reports (< 5 patients in the treatment groups) of liver dysfunction based on Hy’s law, opportunistic infection, a major cardiovascular event, malignancy, anaphylaxis, or IBD. Of the 11.4% of patients who reported any fungal infection in the bimekizumab group, 6.8% reported a candida infection, 4.6% reported a fungal infection NEC, and 1.2% reported a tinea infection. Of the 9.2% of patients who reported any fungal infection in the placebo-bimekizumab crossover group, 7.0% reported a candida infection, 2.6% reported a fungal infection NEC, and 0.7% reported a tinea infection.

Liver toxicity, reactivation of tuberculosis infection, and serious injection-related AEs were not reported in either of the trials.

Critical Appraisal

There were some imbalances in baseline characteristics between the bimekizumab and placebo groups for the presence of enthesitis (both trials), the proportion of patients with 10% or greater BSA affected by psoriasis, PASI, and methotrexate use (the BE COMPLETE trial), which may have biased the results in favour of patients who start out with low disease activity at baseline, though the direction of bias for the overall treatment groups is less certain. Results during the active treatment–blind period of the BE OPTIMAL trial may have been confounded by the lack of a placebo comparison group (patients randomized to placebo were reallocated to bimekizumab) and any rescue therapies used (these were permitted after the 16-week DB period and use ranged from 4.8% to 7.0% of patients). Moreover, it is possible that permitted concomitant therapies (particularly cDMARDs) may not have reached full effect during the minimum 8 weeks that defined a stable dose, making it difficult to attribute treatment effects and harms to either bimekizumab or a concomitant drug. Four outcomes relevant to the CADTH review (PASI 90, IGA, LEI, and LDI) used subsets of the randomized set and it is uncertain if the known and unknown treatment effect modifiers were still balanced between the groups.

In general, both trials had limited racial diversity, which is not necessarily reflective of patients with PsA across Canada. Patients with other bDMARD or tsDMARD experience (other than TNFis) were not included and it is uncertain if the trial results are generalizable to these patients. However, based on the reported baseline characteristics, the clinical expert consulted by CADTH indicated that the patients in the trials were generally similar to those who are treated in clinical practice and could receive bimekizumab in Canada. Also, of the permitted concomitant medications, it was noted that hydroxychloroquine is rarely used in Canadian practice and apremilast is a targeted therapy accessed after cDMARDs. It was noted that ACR and some patient-reported outcomes are not typically used in clinical practice, though they may still provide important information to patients and clinicians.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^22,23

Following the GRADE approach, evidence from RCTs started as high certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance was unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of an important effect based on thresholds identified in the literature for HAQ-DI, SF-36 PCS, and PtAAP. The target of the certainty of evidence assessment was the presence or absence of an important effect based on thresholds informed by the clinical expert consulted for this review for ACR, MDA, LEI, LDI, SJC, PASI 90, and IGA.

For the GRADE assessments, findings from the BE OPTIMAL and BE COMPLETE trials were assessed together per outcome because these studies were similar in population, intervention, design, and outcome measures.

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence,²⁴ consultation with the clinical expert, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: composite measures of disease activity (ACR50, ACR20, ACR70, and MDA), musculoskeletal-related outcomes (LEI, LDI, and SJC), skin-related outcomes (PASI 90 and IGA), and patient-reported outcomes for physical functioning and symptoms (HAQ-DI, SF-36 PCS, and PtAAP).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for bimekizumab versus placebo for patients with PsA.

Table 2: Summary of Findings for Bimekizumab Versus Placebo for Patients With PsA

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; BSA = body surface area; CI = confidence interval; HAQ-DI = Health Assessment Questionnaire–Disability Index; IGA = Investigator’s Global Assessment; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; LSM = least squares mean; MDA = minimal disease activity; MID = minimal important difference; NA = not available; OR = odds ratio; PASI = Psoriasis Area Severity Index; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PCS = physical component summary; PsA = psoriatic arthritis; PtAAP = Patient’s Assessment of Arthritis Pain; RCT = randomized controlled trial; SE = standard error; SF-36 = Short Form (36) Health Survey; SJC = swollen joint count; TNFi = tumour necrosis factor inhibitor.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aA difference of 20% between groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^bAnalysis of this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.

^cA difference of 30% to 40% between groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^dA difference of 10% to 15% between groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^eA difference of 15% to 20% between groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^fRated down 1 level for study limitations due to the loss of randomization in the population used for outcome analysis and the results being at a higher risk of bias.

^gRated down 1 level for serious imprecision. The 95% CI for difference between groups includes the possibility of no benefit compared to the threshold of clinical importance that the clinical expert suggested for achieving an enthesitis-free state (150 more per 1,000 patients).

^hRated down 1 level for serious imprecision. The 95% CI for difference between groups includes the possibility of no benefit compared to the lower threshold of clinical importance that the clinical expert suggested for achieving a dactylitis-free state (150 to 200 more per 1,000 patients).

ⁱRated down 2 levels for very serious imprecision. Both boundaries of the 95% CI for difference between groups exclude the threshold of clinical importance that the clinical expert suggested for improvement in SJC (5 fewer swollen joints).

^jRated down 1 level for serious imprecision. The 95% CI for difference between groups includes the possibility of no benefit compared to the threshold of clinical importance that the clinical expert suggested for improvement in SJC (5 fewer swollen joints).

^kDid not rate down for serious imprecision. The 95% CI for difference between groups includes the possibility of no benefit compared to the threshold of clinical importance that the clinical expert suggested for PASI 90 (500 more per 1,000 patients); however, the lower bound of the 95% CI was close to the threshold and bimekizumab has previously been reviewed and approved for the treatment of patients with moderate-to-severe plaque psoriasis.

^lRated down 1 level for study limitations. The increased risk of bias is due to an imbalance in baseline characteristics between treatment groups (a higher proportion of patients with a larger percentage of BSA affected by psoriasis and higher PASI scores in the bimekizumab group).

^mRated down 1 level for serious imprecision. The 95% CI for difference between groups includes the possibility of no benefit compared to the threshold of clinical importance that the clinical expert suggested for IGA (500 more per 1,000 patients).

ⁿA difference of −0.35 to −0.13 points between groups was identified from the literature as an MID for this outcome.

^oA difference of 3.74 points between groups was identified from the literature as an MID for this outcome.

^pA difference of –10 points between groups was identified from the literature as an MID for this outcome.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24

Long-Term Extension Studies

Description of Studies

Two long-term extension studies were submitted by the sponsor that evaluated bimekizumab for the treatment of adult patients with PsA. The completed BE ACTIVE 2 study²⁵ was a 104-week, phase II, open-label extension (OLE) study that aimed to assess the long-term safety, tolerability, and efficacy of bimekizumab in 184 adult patients with PsA who completed the preceding phase IIb BE ACTIVE study.²⁶ The BE ACTIVE study, not included in the systematic review, was a 48-week, randomized, DB, placebo-controlled, parallel-group, dose-ranging study that included adults with PsA who had previously been exposed to 1 TNFi. Patients were randomized to receive placebo or 1 of several bimekizumab dosing regimens for the initial 12-week placebo-controlled period, and then rerandomized to receive bimekizumab 160 mg every 4 weeks or 320 mg every 4 weeks up to week 48.

The BE VITAL study^27,28 is an ongoing (estimated completion date: May 25, 2026), phase III, OLE study of the BE COMPLETE and BE OPTIMAL trials that is evaluating the long-term efficacy (up to week 140) and long-term safety (up to week 212) of bimekizumab in 1,131 patients with PsA who received bimekizumab 160 mg every 4 weeks.

The inclusion and exclusion criteria for the BE ACTIVE 2²⁵ and BE VITAL^27,28 studies were consistent with those of the preceding trials (the BE ACTIVE,²⁶ BE OPTIMAL,²⁰ and BE COMPLETE¹⁹ trials). In both the BE ACTIVE 2 and BE VITAL studies, bimekizumab 160 mg every 4 weeks SC was administered. All data from the extension studies were analyzed descriptively using summary statistics.

Efficacy Results

In the BE ACTIVE 2 study, rates of ACR20, ACR50, and ACR70 response were similar at baseline and at week 104 with continued bimekizumab treatment. The proportion of patients who had attained MDA response was 58.6% at week 104 of the BE ACTIVE 2 study. For a 75% reduction in Psoriasis Area Severity Index score (PASI 75), PASI 90, and a 100% reduction in Psoriasis Area Severity Index score (PASI 100), data were limited at several visits due to an error in the original study protocol, which was later amended. For visits with what the sponsor considered to be a meaningful sample size of data collected, the proportion of patients who attained PASI 75, PASI 90, and PASI 100 at week 104 were 79.2%, 73.3%, and 65.8%, respectively. The SF-36 PCS score in the BE ACTIVE 2 study was sustained with continued bimekizumab treatment up to week 104 with a mean PCS change of 9.5 (standard error [SE] = 0.8).

In the BE VITAL study, sustained efficacy was observed with bimekizumab from week 16 to week 52 across clinical and patient-reported outcomes. At week 52, 51.7% of patients originally randomized to bimekizumab and 40.6% of patients randomized to placebo who crossed over to bimekizumab at week 16 had an ACR50 response. ACR20 and ACR70 responses similarly improved over time for these groups.

MDA was attained by 47.2% of bimekizumab patients and 33.1% of placebo-bimekizumab crossover patients at week 52. The proportions of patients attaining PASI 75, PASI 90, and PASI 100 increased out to week 52 in both those who were initially placebo-randomized patients and those who were bimekizumab-randomized patients with psoriasis affecting at least 3% BSA at baseline. Data for the SF-36 PCS were only reported up to week 40. The mean SF-36 PCS change from baseline was 7.3 (SE = 0.9) at week 40 for patients who switched from placebo to bimekizumab. For those who were originally randomized to bimekizumab, the mean SF-36 PCS change from baseline was 8.4 (SE = 0.6) at week 40.

Harms Results

The total time at risk was 392.3 patient-years during the BE ACTIVE 2 study. Most patients (80.9%) reported treatment-emergent adverse events (TEAEs), which were most commonly infections and infestations (55.2%). Overall, 7.7% of patients reported an SAE, 4.9% of patients discontinued bimekizumab due to TEAEs, and there were no deaths reported.

In the BE VITAL study, at least 1 TEAE was reported by 243 of 388 (62.6%) patients while receiving bimekizumab up to week 52. The most frequently reported TEAEs were hypersensitivity (4.9%), SARS-CoV-2 (COVID-19) infections (7.2%), fungal infections (9.5%), nasopharyngitis (5.9%), and urinary tract infection (5.9%). Serious infections occurred among 1.8% of patients, and 1.3% of patients had neutropenia. The proportion of patients who reported SAEs was 5.9%. The discontinuation of bimekizumab treatment due to TEAEs was among 4.1% of patients. One death was reported, which the sponsor deemed was unrelated to study treatment.

Critical Appraisal

The open-label design of the BE ACTIVE 2 and BE VITAL studies could bias the magnitude of the treatment effect due to unblinded exposure to the study medication during the treatment period, though the direction of bias is uncertain. In addition to that, the absence of control groups in both studies and the lack of data beyond week 52 in the BE VITAL study make interpretation of the findings challenging. Only those who completed the BE ACTIVE, BE OPTIMAL, and BE COMPLETE studies moved on to the BE ACTIVE 2 and BE VITAL studies, and there may have been selection bias involved.

As the BE ACTIVE 2 and BE VITAL studies consisted of patients who took part in the pivotal studies (the BE ACTIVE, BE OPTIMAL, and BE COMPLETE studies), it is reasonable to expect that the same strengths and limitations related to generalizability apply to the extension studies. The patient population of those studies may not be reflective of the wider, more heterogeneous clinical population in terms of demographic and clinical characteristics; therefore, the results presented may differ from those observed in a real-world clinical setting.

Indirect Comparisons

Description of Studies

The sponsor submitted a network meta-analysis (NMA) and a matching-adjusted indirect comparison (MAIC) for the indirect treatment comparison (ITC).^29,30 The NMA assessed ACR20, ACR50, ACR70, MDA, PASI 90, and safety outcomes at week 12 to week 24, while the MAIC assessed ACR20, ACR50, ACR70, and MDA at week 52. Included trials were phase II to phase IV RCTs conducted in patients with adult-onset PsA treated with 1 drug from a set of specified interventions and dosing regimens that included IL-17is, IL-23is, and IL-12/23is (NMA and MAIC), as well as specific TNFis, CTLA immunoglobulin, JAKis, and PDE4is (NMA only).

Efficacy Results

The NMA for the biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)–naive population indicated that bimekizumab was more efficacious than most IL-12/23is and IL-23is, and abatacept for ACR outcomes, but may be similar to IL-17is, TNFis, or JAKis, with a few exceptions. The results for the TNFi-experienced population indicated that bimekizumab was favoured over interleukin-17 comparators for ACR20 response, but favourability varied relative to comparators for both ACR50 and ACR70 outcomes, and wide credible intervals (CrIs) suggest high imprecision in this subpopulation. The results for PASI 90 indicated that bimekizumab was favoured over most TNFi comparators and may be similar to other classes, but fewer comparisons were made in TNFi-experienced patients. Results for MDA indicated that bimekizumab was favoured for the comparisons of the combined interleukin-12 and interleukin-23, as well as interleukin-23, made in b/tsDMARD-naive patients, but favourability varied in TNFi-experienced patients and overall, there were fewer comparisons made for this outcome. Golimumab was favoured over bimekizumab for ACR20 and ACR50. The MAIC was subject to important limitations that preclude drawing firm conclusions about efficacy.

Harms Results

Comparison of specific harms was not possible due to a lack of specific information from the trials. Overall, bimekizumab was neither favoured, nor was it less favoured than most comparators for AEs, SAEs, or discontinuations due to AEs. One exception was that bimekizumab was favoured over ustekinumab for discontinuations due to AEs.

Critical Appraisal

While methods to mitigate sources of uncertainty were implemented, the results of the NMA are subject to some uncertainty due to the unmeasurable limitations of baseline risk adjustment and uncertainty over the extent to which it accounts for patient heterogeneity, as well as differences in study design and model selection that impact the comparability of the studies across the network. The results from the MAIC are highly uncertain, at risk of unmeasured bias, and also of limited applicability to the clinical context due to the inclusion of only some treatment options being available in the Canadian context.

Studies Addressing Gaps in the Evidence From the Systematic Review

No additional relevant studies addressing gaps in the evidence of the systematic review were submitted by the sponsor.

Conclusions

Based on the evidence from 2 DB RCTs, adults with PsA who received bimekizumab 160 mg every 4 weeks were more likely to demonstrate clinically meaningful improvements in composite measures of disease activity, dermatological manifestations (i.e., psoriasis), physical function, HRQoL, and pain at week 16. Results were generally consistent whether patients were biologic-naive or TNFi-experienced. Evidence that bimekizumab reduces the number of musculoskeletal manifestations (e.g., enthesitis, dactylitis, swollen joints) was less certain, but demonstrated a consistent direction of effect. The trial outcomes address some of the needs patients have for new PsA treatments as well as treatment goals that patients and clinicians have when managing PsA. Longer-term results indicated that treatment effects were maintained with the continued use of bimekizumab for up to 2 years for patients who had had prior TNFis; data for biologic-naive patients are forthcoming. There was no direct evidence comparing bimekizumab and other targeted DMARDs for PsA available for review. The indirect evidence suggests that bimekizumab is superior or similar to other bDMARDs for composite measures of disease activity (e.g., ACR and MDA) and plaque psoriasis outcomes; however, inconsistency in results across comparators, imprecision in results, study and patient characteristic heterogeneity, and methodological flaws reduce the certainty in these results. No new safety signals were identified with extended bimekizumab use in the trials and reports of patients experiencing notable harms were low. Given the available direct and indirect comparative evidence and its approval as a treatment for psoriasis, bimekizumab is an option for adults with PsA, including those with concurrent psoriasis.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of bimekizumab 160 mg every 4 weeks for SC injection in the treatment of adult patients with active PsA, alone or in combination with a cDMARD.

Disease Background

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

PsA is a heterogeneous, chronic inflammatory, immune-mediated disease characterized by musculoskeletal inflammation, in which patients present with a variety of different disease manifestations across multiple tissues and clinical domains, including psoriasis (and nail psoriasis), peripheral arthritis, axial disease, enthesitis, and dactylitis.^3-6 The variable involvement of a number of disease domains among patients makes it hard to establish clear-cut stages and to assess disease severity.³¹ Therefore, composite outcome measures like MDA and ACR response are often used to measure low disease activity state and treatment response, respectively, in PsA.³¹

Peripheral arthritis (the involvement of peripheral joints, assessed by SJC and TJC) and psoriasis (skin disease) are the most common disease manifestations of PsA, occurring in 86% to 90.8% of patients and 82% of patients with PsA, respectively.^7,32 Joint inflammation is known to worsen over time and, if left untreated, can lead to permanent joint damage, deformities, and long-term disability.^4,8-10 Up to 80% of patients with PsA present with psoriasis for several years before developing joint problems⁴ or being diagnosed with PsA; however, for some, arthritis symptoms may occur simultaneously or before the onset of psoriasis. PsA is typically associated with psoriasis and has been reported in up to 30% of patients with psoriasis but can also occur in individuals who do not have skin disease.^4,6 The most prevalent type of psoriasis in patients with PsA is plaque psoriasis; however, other types (e.g., pustular psoriasis, guttate psoriasis, nail psoriasis, erythrodermic psoriasis, inverse psoriasis) have also been reported.⁴

In addition to peripheral arthritis and psoriasis, PsA manifestations include axial involvement (inflammation in the spine and sacroiliac joints),^4,5 occurring in 25% to 70% of patients with PsA,⁴ as well as dactylitis (swelling of the whole digit) and enthesitis (tenderness and swelling at the insertion of tendons and ligaments into bone), which occur in 40% to 50% of patients and 30% to 40% of patients with PsA, respectively.^4,33 In addition to musculoskeletal manifestations, patients with PsA can often experience immune-mediated extra-articular manifestations such as uveitis and IBD (including ulcerative colitis and Crohn disease).^4,34 Other comorbidities commonly observed in PsA include depression, cardiovascular disease, fibromyalgia, diabetes, metabolic syndrome, osteoporosis, and obesity, which further increase the burden of disease.^4,35

Patients with PsA can experience debilitating pain and fatigue that result in decreased physical function and social participation and contribute to overall poor emotional and mental well-being.^8,36-38 Moreover, longer disease duration, worse physical, emotional, and social aspects associated with PsA, work absenteeism due to sickness, and decreased household productivity are all associated with a profound negative impact on HRQoL.^39-41

PsA symptoms usually start between the ages of 30 years and 50 years, and PsA affects both men and women equally.^4,42 Prevalence and incidence estimates for PsA are variable depending on the case definition and geography,¹¹ with an estimated incidence of 6 per 100,000 people and a prevalence of approximately 1 to 2 per 1,000 people in the general global population.¹² A population-based Canadian study estimated the age- and sex-standardized cumulative prevalence of PsA in Ontario to range from 0.9 per 1,000 people in 2008 to 1.5 per 1,000 people in 2015.¹³ The same study estimated the age- and sex-standardized incidence in 2015 to be 14 per 100,000 people.¹³

With the lack of definitive diagnostic tests for PsA and the heterogeneous presentation and course of the disease, diagnosis can be complex.^3,43,44 In Canada, PsA is typically diagnosed by a rheumatologist.⁴⁵ The tools used in the diagnosis of PsA (i.e., blood testing for CRP levels and erythrocyte sedimentation rate, X-ray, ultrasound, and MRI scans) are widely available across Canada, as they are common diagnostic tools used in the Canadian health care setting.^44,46,47

Standards of Therapy

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

According to clinical practice guidelines available for the management of PsA and input from the clinical expert consulted by CADTH, treatment goals include achieving the lowest level of disease activity (with a target of disease remission), maximizing functional status and HRQoL, preventing further disease progression, controlling symptoms, and avoiding complications (from untreated disease or adverse effects from treatment).^14-16 The guidelines recommend that the choice of treatment should be a shared discussion and decision made between a patient and clinician and should consider the following factors: disease domain(s) affected, disease activity, existing comorbidities, prior treatments, and patient preferences.^14,16 The 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines recommend that treatment be guided by the domain(s) that are most impacted by the disease as well as relevant comorbidities, which include peripheral arthritis, axial disease, enthesitis, dactylitis, skin psoriasis, psoriatic nail disease, uveitis, and IBD.¹⁶ Other health considerations include obesity, metabolic syndrome, cardiovascular disease, liver disease, mood disorders, chronic infections, malignancies, bone health, central sensitization, and reproductive health.¹⁶ The clinical expert also noted that the impact of disease on pain, function, HRQoL, and structural damage should be assessed and considered when managing PsA. In discussion with the patient, treatment decisions may be further impacted by personal goals, preferences, adverse effects, route of administration, convenience, and cost.^16,48

The management of PsA can be nonpharmacological (e.g., physical therapy, exercise) or pharmacological, where first-line treatment typically includes cDMARDs, such as methotrexate, sulfasalazine, leflunomide, or cyclosporine.^15,16 According to the guidelines and clinical expert consulted by CADTH, additional treatment can be included to address joint symptoms (e.g., NSAIDs, intra-articular glucocorticoid injections) or psoriasis and nail disease (e.g., topical therapies) as required.^15,16 Later-line, targeted treatments are usually reserved for patients who have an inadequate response to cDMARDs and include bDMARDs (e.g., TNFi, IL-17i, IL-12/23i, IL-23i) and tsDMARDs (e.g., JAKi, PDE4i).¹⁶ The clinical expert noted that continuation of cDMARDs may be necessary until effectiveness of the targeted therapies is confirmed. The guidelines also indicate that the failure or intolerance of a treatment can lead to switching drugs within a class or to another class of medication.^14-16 The clinician group that provided input also considered adverse effects and patient preference as reasons to discontinue a treatment. As per the clinical expert and the literature, surgical intervention (to correct joint deformities or severe joint destruction and to improve pain and function) may be an option later in the disease course.⁴⁸ The 2019 European Alliance of Associations for Rheumatology guidelines suggest that cautious tapering of treatments can be considered when a patient attains complete and sustained remission for at least 6 months.¹⁴ Regular monitoring is necessary for treatment response, comorbidities, and AEs, and may take place at 3-month intervals during periods of active disease or changes in treatment.⁴⁸ Patients with stable disease may be monitored at 6-month intervals, though some treatments may require more frequent lab monitoring.⁴⁸

Drug Under Review

Key characteristics of bimekizumab and other treatments available for PsA are summarized in Table 3.

Bimekizumab is a humanized immunoglobulin G1 kappa monoclonal antibody with 2 identical, high-affinity, antigen-binding regions that bind and neutralize IL-17A, IL-17F, and IL-17AF cytokines, blocking their interaction with the IL-17RA/IL-17RC receptor complex, which plays a role in PsA-related inflammation.² IL-17F is produced by innate immune cells and can be independent of IL-23. In vitro, dual neutralization of both IL-17A and IL-17F with bimekizumab suppresses the expression of inflammation-related genes and proteins and inhibits the migration of inflammatory cells and pathological osteogenesis to a greater extent than inhibition of IL-17A alone.^2,49

Bimekizumab is currently being reviewed by Health Canada for the treatment of adult patients with active PsA. Bimekizumab can be used alone or in combination with a cDMARD (e.g., methotrexate). The recommended dose of bimekizumab for adult patients with active PsA is 160 mg (given as 1 SC injection of 160 mg) every 4 weeks.² For patients with PsA with coexistent moderate-to-severe plaque psoriasis, the recommended dose is the same as for plaque psoriasis (i.e., 320 mg given as 2 SC injections of 160 mg each every 4 weeks for the first 16 weeks, and then every 8 weeks thereafter); regular assessment of efficacy is recommended after 16 weeks and if a sufficient clinical response in joints cannot be maintained, a switch to the recommended dose for PsA can be considered.² After proper training in SC injection technique, patients may be able to self-administer bimekizumab at home.² The sponsor has requested reimbursement as per the approved Health Canada indication.

Bimekizumab was previously reviewed by CADTH in April 2022 for the indication of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy and a final recommendation for reimbursement with conditions was issued.^17,18 In addition to the current CADTH review for the indication of adults with active PsA (with or without cDMARDs), bimekizumab is also being reviewed for the indication of adults with active ankylosing spondylitis.

Table 3: Key Characteristics of Bimekizumab and Drug Comparators for the Treatment of PsA

bDMARD = biologic disease-modifying antirheumatic drug; cDMARD = conventional nonbiologic disease-modifying antirheumatic drug; COPD = chronic obstructive pulmonary disease; DMARD = disease-modifying antirheumatic drug; IBD = inflammatory bowel disease; IL-12/23 = interleukin-12 and interleukin-23; IL-17 = interleukin-17; IL-17A = interleukin-17A; IL-17A/F = interleukin-17A and interleukin-17F; IL-23 = interleukin-23; JAK = Janus kinase; PDE4 = phosphodiesterase type 4; PsA = psoriatic arthritis; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; RPLS = reversible posterior leukoencephalopathy syndrome; SC = subcutaneous; TB = tuberculosis; TNF = tumour necrosis factor.

^aHealth Canada–approved indication.

Sources: Product monographs for bimekizumab, ixekizumab, secukinumab, ustekinumab, guselkumab, risankizumab, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, apremilast, tofacitinib, upadacitinib, and abatacept.^2,50-63

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the 2 submissions provided by 7 patient groups. The full original patient input received by CADTH has been included in the Stakeholder section of this report.

Patient group input was submitted for this CADTH review by 7 different patient groups: 1 submission from Arthritis Consumer Experts and 1 joint input from the Canadian Psoriasis Network, Arthritis Society Canada, Canadian Arthritis Patient Alliance, Canadian Association of Psoriasis Patients, Canadian Spondyloarthritis Association, and CreakyJoints.

Arthritis Consumer Experts gathered information from patients via email on October 16, 2023 (n = 2), and through an online survey available from December 18, 2020, to January 26, 2021 (n = 5). The joint input obtained responses (n = 214) through an online survey that was available through the 6 collaborating organizations’ communication channels from September 27 to October 11, 2023. The latter survey was also sent to clinics in Canada that conducted bimekizumab trials for PsA to capture the experience of patients living with PsA or ankylosing spondylitis and the experiences of their caregivers.

Of the 214 respondents to the joint survey, 100 (47%) participants identified as living with PsA and 3 participants had experience taking bimekizumab. A total of 92 respondents described the many disease symptoms that are challenging to manage, including joint stiffness (95%), fatigue (87%), hip pain (64%), changes in fingernails and toes (61%), difficulties concentrating (58%), sore heels (50%), stress (44%), and anxiety (38%). Regarding the most significant impacts on their everyday HRQoL, respondents reported that PsA interfered with their physical activity (80%), sleep (75%), work (59%), social life (51%), mental health (50%), and intimacy and self-esteem (48%). Because the disease reduces their ability to participate in activities and affects their mental and social health, respondents indicated that caregivers have to take on additional tasks or daily chores and help patients get to and from medical appointments. Patients from the Arthritis Consumer Experts input indicated that pain and lack of mobility affect their daily activities and HRQoL.

Among the 85 joint survey respondents who shared their experience with currently available treatments, 32% found NSAIDs effective, 39% found DMARDs effective, 40% found biologic therapies effective (with 24% rating them as very effective), and 44% found steroids effective. According to both patient inputs, respondents indicated that efficacious treatments are costly, accessing them can be challenging, and adverse effects are very difficult to manage.

Among the 3 survey respondents in the joint input who had experience with bimekizumab for PsA, 1 respondent answered questions about the drug, indicating the treatment was easy to use and effective in improving HRQoL without experiencing adverse effects.

Patients seek treatments that improve disease symptoms, improve HRQoL, have fewer adverse effects, are easier to administer, are accessible, and are affordable.

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, providing guidance on the potential place in therapy). The following input was provided by a clinical specialist with expertise in the diagnosis and management of PsA.

Unmet Needs

Despite there being various treatment options for managing PsA, the clinical expert stated that not all patients respond to available therapies or that treatments may be effective initially but can fail over time. The expert also noted that currently available treatments tend to be effective for treating skin disease but have variable or suboptimal efficacy with other domains, including musculoskeletal symptoms. Because it is rare to reverse existing joint damage, the expert highlighted the importance of early diagnosis and treatment before damage occurs. There is also concern over safety with all DMARDs, including an increased risk of infection and new onset or worsening of existing comorbidities. According to the clinical expert, few patients attain a state of low disease activity; therefore, it is important to have safe, well-tolerated treatments that are effective with all domains.

Place in Therapy

The clinical expert indicated that bimekizumab would be used after the failure of cDMARDs and, in accordance with its Health Canada indication, with or without a cDMARD. It was also noted that, without good quality evidence to support combination therapy, bimekizumab would not likely be used concomitantly with other bDMARDs or tsDMARDs at this time.

Patient Population

Although there are currently no biomarkers to indicate which patients would respond better to a particular drug, the expert was of the opinion that any patient with active PsA could receive bimekizumab and that those with coexisting severe psoriasis may also benefit. They added that the drug would be avoided in those who have IBD or severe uveitis, as this class of medications has not been very effective in these disease areas, and patients with active infection (especially fungal infection) would be cautioned against using bimekizumab. As per the expert, patients with an inadequate response to targeted DMARDs are most in need of new treatments.

Assessing the Response Treatment

According to the clinical expert, treatment response is typically assessed at 3 months based on improvements in TJC and SJC, enthesitis, dactylitis, and skin psoriasis, and sometimes using composite indices (e.g., MDA or DAPSA, which are used in clinical trials). The clinical expert added that improvements in physical function, pain, fatigue, and lack of radiographic progression (not typically used in clinical practice) may take longer than 3 months in patients with longstanding PsA. Moreover, due to the heterogeneity of the disease, response can differ across patients, though the clinical expert suggested that assessments are not likely to vary among rheumatologists.

Discontinuing Treatment

The clinical expert stated that lack of response in musculoskeletal or skin domains, disease relapse, intolerance, and patient choice are the most important factors when considering the discontinuation of bimekizumab. Moreover, it was explained that some amount of disease activity can be considered acceptable, but that recurrent infections and IBD would require discontinuation.

Prescribing Considerations

The expert explained that due to the heterogeneous nature of the disease, the lack of biomarkers, and the similarity of symptoms with other musculoskeletal conditions, diagnosis by primary care physicians and dermatologists can be challenging, and misdiagnosis is a possibility. Therefore, diagnosis, management, and treatment should be led by a rheumatologist trained in identifying inflammatory arthritis and can include a dermatologist to manage the associated psoriasis. Patients are typically treated in an outpatient setting in community clinics and clinics attached to community and academic hospitals, though severe skin and joint disease may require hospital admission.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by 1 clinician group. The full original clinician group input received by CADTH has been included in the Stakeholder section of this report.

One clinician group, the Canadian Rheumatology Association, provided input for this CADTH review (3 clinicians from the association contributed to the input).

According to the clinician group, PsA is a complex disease with varied manifestations. Current treatment regimens include nonpharmacologic therapies (such as graded exercise programs, occupational therapy, diet, weight loss, and smoking cessation) and pharmaceutical treatments (such as topical emollients, corticosteroids, vitamin D analogues, coal tar, phototherapy, nonbiologic DMARDs, PDE4i, and biologic therapies).

As per the clinician group, the goals of treatment are to maximize HRQoL by controlling disease symptoms and inflammation, improving function, and preventing structural damage. The clinician group highlighted unmet patient needs similar to those described by the clinical expert consulted by CADTH: some patients do not respond to treatment and treatments have variable effect on the PsA disease domains. The clinician group also noted that current biologic treatments are associated with a secondary loss of effect that can lead to dose creep, adverse effects, and the persistence of active extra-articular manifestations despite improvement in musculoskeletal symptoms.

The clinician group expressed that bimekizumab may be used for patients who have not experienced improvement as a result of treatment with cDMARDs and continue to have high measures of disease activity. Measures of treatment response were consistent with what the clinical expert consulted by CADTH outlined and included improvement in axial disease, and MDA. The clinician group also noted that composite measures, such as Composite Psoriatic Disease Activity Index, DAPSA, and Psoriatic Arthritis Disease Activity Score, can be used as well, though they are not practical for everyday use in clinics. For skin disease, PASI and percentage of BSA affected by psoriasis are also used. For axial disease activity, the most frequently used measure in Canada is the BASDAI.

The clinician group highlighted the same reasons for the discontinuation of therapy that were noted by the clinical expert. The group indicated that a specialist would be required to prescribe bimekizumab and monitor for AEs, but because the drug is administered as an SC injection, a patient could self-administer it.

Drug Program Input

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

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

bDMARD = biologic disease-modifying antirheumatic drug; cDMARD = conventional nonbiologic disease-modifying antirheumatic drug; DMARD = disease-modifying antirheumatic drug; JAKi = Janus kinase inhibitor; PsA = psoriatic arthritis; tsDMARD = targeted synthetic disease-modifying antirheumatic drug.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of bimekizumab on adult patients with active PsA, alone or in combination with a cDMARD. The focus will be placed on comparing bimekizumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor for the review of bimekizumab is presented in 4 sections with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence; however, no relevant studies were submitted.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• Two pivotal RCTs identified in the systematic review

• Two long-term OLE studies

• Two ITCs (1 NMA and 1 MAIC).

Systematic Review

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5. Figure 1 and Figure 2 show the study designs for the BE OPTIMAL and BE COMPLETE trials, respectively.

Two phase III, DB, placebo-controlled RCTs were included in the systematic review: the BE OPTIMAL trial (N = 852) and the BE COMPLETE trial (N = 400).^19,20 The 2 trials were conducted to evaluate the efficacy and safety of bimekizumab in adults with active PsA. The BE OPTIMAL trial consisted of a 2-week to 5-week screening phase, a 16-week DB treatment period, a 36-week active treatment–blind period, and a 20-week safety follow-up phase. During the 36-week period, all patients who received placebo during the DB phase were reallocated to receive bimekizumab and patients in the active treatment groups continued their respective treatments. The BE COMPLETE trial was similarly designed, but without the 36-week active treatment–blind period. Following treatment completion, eligible patients from both trials could enrol in the BE VITAL OLE study.

Table 5: Details of Studies Included in Systematic Review

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; BSA = body surface area; CASPAR = ClASsification criteria for Psoriatic ARthritis; CCP = cyclic citrullinated peptide; COX-2 = cyclooxygenase-2; DAS28(CRP) = Disease Activity Score 28 based on CRP; DB = double-blind; HAQ-DI = Health Assessment Questionnaire–Disability Index; HCQ = hydroxychloroquine; hs-CRP = high-sensitivity CRP; IBD = inflammatory bowel disease; IGA = Investigator’s Global Assessment; IMP = investigational medicinal product; LDI = Leeds Dactylitis Index; LEF = leflunomide; LEI = Leeds Enthesitis Index; MCS = mental component summary; MDA = minimal disease activity; MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug; OLE = open-label extension; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PCS = physical component summary; PsA = psoriatic arthritis; PsAID-12 = Psoriatic Arthritis Impact of Disease-12; PsAQoL = Psoriatic Arthritis Quality of Life instrument; PSO = psoriasis; PtAAP = Patient’s Assessment of Arthritis Pain; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; RA = rheumatoid arthritis; SC = subcutaneous; SF-36 = Short Form (36) Health Survey; SJC = swollen joint count; SSZ = sulfasalazine; TJC = tender joint count; TNFi = tumour necrosis factor inhibitor; vdHmTSS = van der Heijde modified total Sharp score.

^aAdalimumab was included as an active reference treatment but was not included in any statistical testing in the trial.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Figure 1: Study Design for the BE OPTIMAL Trial

ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; BKZ = bimekizumab; DB = double-blind; OLE = open-label extension; Q2W = every 2 weeks; Q4W = every 4 weeks; sc = subcutaneous; SFU = safety follow-up; W = week.

^a Adalimumab 40 mg sc Q2W.

^b After 16 weeks of DB treatment, patients entered the active treatment–blind period. All patients randomized to placebo were reallocated to receive BKZ 160 mg Q4W. Patients randomized to BKZ or adalimumab continued to receive their respective treatments.

^c Permitted rescue therapy as defined in the study.

Source: BE OPTIMAL Clinical Study Report.²⁰

Populations

Inclusion and Exclusion Criteria

To be eligible for the trials, patients must have been 18 years or older with a documented diagnosis of adult-onset PsA and must have had at least 1 active plaque psoriatic lesion or a history of plaque psoriasis. Patients in the BE COMPLETE trial must have had a history of inadequate response (lack of efficacy after at least 3 months of treatment at an approved dose) or intolerance to 1 TNFi or 2 TNFis for PsA or psoriasis. Individuals were not eligible for either study if they had current or prior exposure to any biologic therapies (except TNFis in the BE COMPLETE trial) for the treatment of PsA or psoriasis, or for another inflammatory condition other than PsA or psoriasis, or had a form of psoriasis other than chronic plaque type.

Figure 2: Study Design for BE COMPLETE Trial

ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; DB = double-blind; OLE = open-label extension; Q4W = every 4 weeks; sc = subcutaneous; SFU = safety follow-up; W = week.

Source: BE COMPLETE Clinical Study Report.¹⁹

Interventions

Patients in the BE OPTIMAL trial were randomized 3:2:1 (stratified by region and bone erosion status) to receive bimekizumab 160 mg every 4 weeks SC via 1 mL injection (n = 431), matching 1 mL SC placebo (n = 281), or adalimumab 40 mg every 2 weeks SC via 0.8 mL or 0.4 mL injection (n = 140). Due to adalimumab being administered every 2 weeks, placebo every 4 weeks was also administered to the bimekizumab group on a staggered schedule to maintain the blinded treatment assignment. Adalimumab was included as an active reference treatment, but the trial was not powered for statistical comparisons between adalimumab and either bimekizumab or placebo and will not be further discussed in the direct evidence section of the CADTH review.

Patients in the BE COMPLETE trial were randomized 2:1 (stratified by region and TNFi exposure) to receive bimekizumab 160 mg every 4 weeks (n = 267) or matching placebo (n = 133). All administrations of the study drug were performed in the clinic by site staff.

Patients in both trials were permitted to continue NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, oral corticosteroids, methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, or apremilast for PsA if they were on a stable dose before baseline and during the study. Stable doses were required for at least 2 weeks for NSAIDs, COX-2 inhibitors, and oral corticosteroids (up to 10 mg per day prednisone or equivalent); for at least 8 weeks for methotrexate (up to 25 mg per week) and leflunomide (up to 20 mg per day); and for at least 4 weeks for sulfasalazine (up to 4 g per day), hydroxychloroquine (up to 400 mg per day), and apremilast (up to 60 mg per day). Changes in concomitant medications were not permitted — except for decreases in drug dose or frequency due to intolerance or AEs — during the first 16 weeks of the trials. Patients also could not use phototherapy, topical corticosteroids, vitamin D analogues, topical retinoids, keratolytics, coal tar, fumaric acid esters, or systemic retinoids for treatment of psoriasis during the first 16 weeks of the trials.

Rescue treatment was permitted after completion of the 16-week DB period in the BE OPTIMAL trial for patients who did not respond to treatment and patients continued to receive bimekizumab (either randomized to the treatment or crossed over from placebo after week 16) for the remainder of the trial. Rescue treatment included changes in a patient’s background therapy and consisted of NSAIDs, COX-2 inhibitors, methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, apremilast, and up to 2 joint injections (for a total dose of 80 mg prednisone or equivalent, but not in the same joint). Doses were allowed up to the respective maximum permitted doses that were considered for stable treatment during the trial.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures in Table 7. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence²⁴ as well as any outcomes identified as important to this review according to the clinical expert consulted by CADTH and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points that were considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE.

The following were considerations that went into the selection of outcomes summarized in the report and assessed using GRADE:

• the assessment of disease activity was an important clinical outcome according to the clinician group and clinical expert

• response in the joints and evaluation of concurrent skin disease was important to patients and clinicians

• improving HRQoL and symptoms were identified as being high priorities according to input provided by the patient group, clinician group, and clinical expert.

The primary end point for both trials was an ACR50 response at week 16. Relevant secondary end points for both trials included in the statistical testing hierarchy consisted of HAQ-DI, a PASI 90 response in patients with psoriasis involving at least 3% BSA at baseline, SF-36 PCS, and an MDA response. The BE OPTIMAL trial’s statistical testing hierarchy also included an enthesitis-free state based on LEI and a dactylitis-free state based on LDI in patients who had enthesitis or dactylitis at baseline, respectively, whose data were pooled from the BE OPTIMAL and BE COMPLETE trials. Other relevant secondary and exploratory outcomes in both trials included ACR20, ACR70, IGA, PtAAP, and SJC.

ACR Response

The ACR response rate is the percentage improvement relative to baseline (e.g., ACR50 is a 50% improvement in the ACR response) for a set of outcome measures.^19,20 These include the TJC (based on 68 joints), the SJC (based on 66 joints), and at least 3 of the 5 remaining core measures: Patient’s Global Assessment of PsA, Physician’s Global Assessment of PsA, PtAAP, HAQ-DI, and high-sensitivity CRP.

Patient’s Global Assessment of Psoriatic Arthritis and Physician’s Global Assessment of Psoriatic Arthritis are evaluated using a 100-point visual analogue scale ranging from 0 (no symptoms) to 100 (severe symptoms).^19,20 SJC, HAQ-DI, and PtAAP are described as follows.

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; BSA = body surface area; HAQ-DI = Health Assessment Questionnaire–Disability Index; IGA = Investigator’s Global Assessment; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MDA = minimal disease activity; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PCS = physical component summary; PtAAP = Patient’s Assessment of Arthritis Pain; SF-36 = Short Form (36) Health Survey; SJC = swollen joint count.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchical testing).

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Minimal Disease Activity

MDA is a composite end point and is considered to be attained if at least 5 of the 7 criteria are reached: TJC of 0 or 1, SJC of 0 or 1, PASI of 1 or lower or affected BSA of 3% or less, a pain visual analogue scale score of 15 or lower, a Patient’s Global Assessment of Psoriatic Arthritis visual analogue scale score of 20 or lower, a HAQ-DI score of 0.5 or lower, and tender entheseal points of 0 or 1.^19,20

Enthesitis-Free State Based on LEI

Enthesitis (inflammation where the tendon, ligament, or joint capsule meets bone) was measured using LEI.²⁰ Assessments for enthesitis are performed by bilateral palpation on the lateral epicondyles of the humerus (elbows), medial femoral epicondyles (knees), and Achilles tendons (heels). Each location is scored as 0 (no pain) or 1 (pain) and ranges from 0 (no enthesitis) to 6 (severe enthesitis).

Dactylitis-Free State Based on LDI

Dactylitis (swelling of the entire digit related to articular and periarticular inflammation) was measured using LDI.²⁰ The ratio of the circumference of the affected digit to the circumference of the digit on the contralateral hand or foot is measured and a minimum difference of 10% is used to define a dactylitic digit.^68,69 If the contralateral digit is also affected, normative values based on population averages are used for comparison. The ratio is multiplied by the tenderness score (0 for absent and 1 for present), and the results from each digit with dactylitis are summed for a final score.

Swollen Joint Counts

SJC evaluation includes 6 joints of the upper body, 34 joints of the upper extremities, and 26 joints of the lower extremities for a total of 66 joints.^19,20 Each joint is assessed using a 2-point scale: 0 for no swelling and 1 for swollen joints.

Psoriasis Area Severity Index

PASI assesses the severity and extent of psoriasis along with the percentage of BSA involved across 4 body areas (head [10%], upper limbs [20%], trunk [30%], and lower limbs [40%]).^19,20 The redness, thickness, and scaliness of lesions for each area are evaluated using a 5-point scale from 0 (none) to 4 (very marked) for a total score ranging from 0 to 72 points, where higher scores indicate greater disease severity.

Investigator’s Global Assessment

IGA measures severity of psoriasis using a 5-point scale, where 0 is clear (no psoriasis, postinflammatory hyperpigmentation present), 1 is almost clear (no thickening, normal to pink colouration, no to minimal focal scaling), 2 is mild (detectable to mild thickening, pink to light red colouration, fine scaling), 3 is moderate (distinguishable to moderate thickening, dull to bright red colouration, moderate scaling), and 4 is severe (severe thickening with hard edges, bright to dark red colouration, severe and/or coarse scaling).⁷⁰ In the pivotal trials, only patients with at least 3% BSA affected by psoriasis with an IGA score of at least 2 at baseline (i.e., at least mild psoriasis) were evaluated for this outcome.^19,20 Treatment response was defined as a score of 0 or 1 (clear or almost clear) and at least a 2-category improvement from baseline.

Health Assessment Questionnaire–Disability Index

HAQ-DI consists of 20 items from 8 domains: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities.^19,20 Each domain is rated on a 4-point scale from 0 (able to do without difficulty) to 3 (unable to do) and patients indicate if they typically use a mobility aid for the activity. The sum of the highest score in each domain (0 to 24) is divided by the number of domains in which at least 1 question is answered. The score is considered missing if fewer than 6 domains are completed. The overall score ranges from 0 to 3, with lower scores indicating better function. The MID from the literature is estimated to range from 0.13 to 0.35.^71,72

SF-36 PCS

SF-36 is a generic HRQoL instrument consisting of 8 domains: physical functioning (10 items), role physical (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social functioning (2 items), role emotional (3 items), mental health (5 items), and 1 item for perceived stability or change in health (health transition) during the last year.^19,20 Two summary scores (PCS and mental component summary) are calculated from the domains. Norm-based t scores for the summary and domain scores are standardized to a population (e.g., general US population) and higher scores indicate better health. The MID from the literature is estimated to be 3.74 for the PCS.⁷³

Patient’s Assessment of Arthritis Pain

PtAAP is a 100-point visual analogue scale for patients to record their arthritis pain from 0 (no pain) to 100 (most severe pain).^19,20 The MID from the literature is estimated to be a 10-point decrease from baseline.²¹

Safety

Safety was assessed by the proportion of patients who reported AEs (coded using Medical Dictionary for Regulatory Activities, version 19.0), SAEs, withdrawals from treatment due to AEs, and deaths during the DB treatment period and active treatment–blind period.^19,20 Liver dysfunction based on Hy’s law, liver toxicity, opportunistic infection, fungal infection, candida infection, reactivation of tuberculosis infection, a major cardiovascular event, malignancy, a serious injection-related AE, anaphylaxis, and IBD were notable harms included in the CADTH review.

Statistical Analysis

The statistical analysis methods are summarized in Table 8.

Table 8: Statistical Analysis of Efficacy End Points for the BE OPTIMAL and BE COMPLETE Trials

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; ANCOVA = analysis of covariance; BSA = body surface area; FAS = full analysis set; HAQ-DI = Health Assessment Questionnaire–Disability Index; IGA = Investigator’s Global Assessment; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MCMC = Markov chain Monte Carlo; MDA = minimal disease activity; MI = multiple imputation; NRI = nonresponder imputation; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PCS = physical component summary; PP = per-protocol; PtAAP = Patient’s Assessment of Arthritis Pain; RS = randomized set; SF-36 = Short Form (36) Health Survey; SJC = swollen joint count; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aSequentially tested in the BE OPTIMAL and BE COMPLETE trials.

^bSequentially tested in the BE OPTIMAL trial only.

^cDescriptive analyses in the BE OPTIMAL and BE COMPLETE trials.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Sample Size and Power Calculation

The sample size to demonstrate statistical superiority of bimekizumab over placebo used a 2-sided 2-sample chi-square test with continuity correction.¹⁰² In the BE OPTIMAL trial, a sample of 420 patients in the bimekizumab group and 280 patients in the placebo group provided more than 99% power to demonstrate superiority of bimekizumab in the primary end point (ACR50 response at week 16) based on a true treatment difference of 27.8% (odds ratio [OR] = 4.09). The placebo response rate in the primary end point was assumed to be 16%, based on data from the BE ACTIVE study (6.1% at week 12, biologic therapy–naive population),²⁶ the FUTURE 2 study (15.9%, biologic therapy–naive population),¹⁰³ the FUTURE 3 study (11.8%, biologic therapy–naive population),¹⁰⁴ and the FUTURE 5 study (8.1% at week 16, mixed tumour necrosis factor exposure population).¹⁰⁵ In the BE COMPLETE trial, a sample of 260 patients in the bimekizumab group and 130 patients in the placebo group provided 96% power to demonstrate the superiority of bimekizumab in the primary end point (ACR50 response at week 16) based on a true treatment difference of 16% (OR = 3.16). The placebo response rate in the primary end point was assumed to be 10%, based on data from the BE ACTIVE study (11.1% at week 12, population whose disease responded inadequately to TNFi)²⁶ and the SPIRIT-P2 study (< 10% at week 16, population whose disease responded inadequately to TNFi).¹⁰⁶

Statistical Testing

Statistical tests of efficacy results were calculated using 2-sided P values (alpha of 0.05). The primary end point in the BE OPTIMAL trial was adjusted for, using 2 stratification variables: region (North America, Western Europe, Eastern Europe, and Asia or North America, Eastern Europe, and Western Europe with Asia if less than 10% of patients was randomized in either the Asia or Western Europe regions) and bone erosion (0 or at least 1) at baseline. The primary end point in the BE COMPLETE trial was similarly adjusted for, using 2 stratification variables: region (the same as previously listed) and prior TNFi exposure (inadequate response to 1 or 2 prior TNFis, or intolerance to TNFis). Stratification variable suitability was assessed using the Pearson and Deviance and Hosmer-Lemeshow goodness-of-fit tests,¹⁰⁷ where if the logistic regression model was unable to converse, the stratification variables were dropped from both the primary analyses and all supportive analysis and imputed models.

A sequential testing procedure was used to control the familywise type I error rate at an alpha of 0.05 (2-sided) for the primary end point and some secondary end points in both trials. End points were tested as outlined in Table 9. Statistical testing of an end point occurred only if the null hypothesis for the previous end point was rejected (i.e., bimekizumab was superior to placebo, P < 0.05).

Table 9: Sequential Testing Procedure for the BE OPTIMAL and BE COMPLETE Trials

ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; BSA = body surface area; HAQ-DI = Health Assessment Questionnaire–Disability Index; hs-CRP = high-sensitivity CRP; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MDA = minimal disease activity; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PCS = physical component summary; SF-36 = Short Form (36) Health Survey; vdHmTSS = van der Heijde modified total Sharp score.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Data Imputation Methods

Both trials used nonresponder imputation (NRI) for missing primary end point data at week 16. Patients were considered nonresponders if they had missing data at week 16, had discontinued treatment before week 16 but remained in the trial, or were missing the relevant baseline value. For ACR50, nonresponse was imputed based on available ACR components when the value could not be derived (i.e., was missing).

Where multiple imputation methods were used, a missing value was replaced with a set of plausible values. Each value was a Bayesian draw from the conditional distribution of the missing data given the observed data. The Markov chain Monte Carlo method was used to impute intermittent missing data, then regression for monotone missing data. It was assumed that data were missing at random.

Reference-based multiple imputation methods were used for outcomes in the testing hierarchy and the ACR response components. Missing data were imputed based on data from only the placebo group.¹⁰⁸ It was assumed that the statistical behaviour of patients who discontinued treatment (from either group) was the same as those in the placebo group. Data for all time points after treatment discontinuation were considered missing. Multiple imputation methods involved multiple draws from the posterior predictive distribution estimated from the placebo group.

Subgroup Analyses

Prespecified subgroup analyses were performed on the ACR50, HAQ-DI, and PASI 90 end points at week 16, and were not adjusted for multiplicity in the trials. Most subgroups were assessed at baseline, except concomitant cDMARDs, concomitant methotrexate, and antibimekizumab antibody status, which were assessed during the 16-week DB treatment period. A logistic regression was fitted using the same terms that were retained when running the primary analysis model, plus a term for the subgroup and the subgroup by treatment interaction for each analysis, except for analyses by region, by bone erosion at baseline, by high-sensitivity CRP value combined with bone erosion at baseline, and by antidrug antibody status. Of the subgroups assessed in the trials, prior treatment TNFi exposure (TNFi intolerance, inadequate response to at least 1 TNFi, or inadequate response to at least 2 TNFis), which was conducted in the BE COMPLETE trial only, was identified as relevant to the CADTH review.

Sensitivity Analyses

In the trials, sensitivity analyses included using the per-protocol set (to evaluate the impact of important protocol deviations), using the full analysis set (to evaluate the consistency between the randomized set and full analysis set if the populations differed), and assessing the individual ACR components.

Secondary Outcomes of the Studies

Efficacy results for the BE OPTIMAL trial were collected at baseline and week 2, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 44, and week 52, while safety was assessed at every study visit (i.e., every 2 weeks). Study visits for the BE COMPLETE trial took place every 4 weeks.

Power calculation assumptions for secondary end points in the statistical testing hierarchy were based on results from the BE ACTIVE,²⁶ FUTURE 1,¹⁰⁹ FUTURE 2,¹⁰³ FUTURE 5,¹⁰⁵ and SPIRIT-P1¹¹⁰ studies. Power calculations were based on the 2-sided 2-sample chi-square test with continuity correction (binary end points)¹⁰² or a 2-sided 2-group Satterthwaite t test (continuous end points).¹¹¹

The BE OPTIMAL trial had more than 99% power to detect a difference of –0.24 for the mean change from baseline in HAQ-DI at week 16, more than 99% power to detect a difference for PASI 90 response at week 16 in patients with at least 3% BSA affected by psoriasis, more than 99% power to detect a difference in means of 5.83 for the change from baseline in SF-36 PCS at week 16, more than 99% power to detect an absolute difference of 32% (OR = 5.17) for MDA response at week 16, 69% power to detect a true treatment difference of 16% (OR = 1.91) for an enthesitis-free state at week 16, and 66% power to detect a true treatment difference of 24% (OR = 2.71) for a dactylitis-free state at week 16.

The BE COMPLETE trial had 85% power to detect a difference of 0.23 in the mean change from baseline in HAQ-DI at week 16, 99% power to detect a treatment difference of 28% (OR = 5.52) for PASI 90 response at week 16 in patients with at least 3% BSA affected by psoriasis, 89% power to detect a difference in means of 4.4 in the change from baseline in SF-36 PCS at week 16, and 92% power to detect an absolute difference of 12% (OR = 3.892) for MDA response at week 16.

As with the primary efficacy end point, secondary binary end points used the same estimand structure, with a nonresponder approach to handling missing data and the same analysis model. Secondary continuous end points used an analysis of covariance model with treatment, region, and bone erosion at baseline as fixed effects and the baseline value as covariate, and missing data were imputed using the Markov chain Monte Carlo (monotone regression) technique.

Analysis Populations

The analysis populations of the included studies are summarized in Table 10.

Results

Patient Disposition

The patient disposition of the included studies is summarized in Table 11.

For the BE OPTIMAL trial, 1,158 individuals were screened, of whom 306 were screened out mostly due to eligibility criteria. Subsequently, 431 patients were randomized to receive bimekizumab and 281 patients were randomized to receive placebo. More than 96% of patients in either group completed the 16-week DB treatment period; the most common reasons for discontinuing were due to AEs (1.9%) in the bimekizumab group and patient choice (1.4%) in the placebo group. Following the DB period, 414 patients continued to receive bimekizumab in the 36-week active treatment–blind period and 271 patients were reallocated from placebo to bimekizumab. More than 92% of patients in the treatment groups completed the active treatment–blind period, where the most common reason for discontinuing was due to AEs (2.2%). Finally, 379 patients and 254 patients originally randomized to bimekizumab and placebo, respectively, entered the BE VITAL OLE study.

For the BE COMPLETE trial, 556 individuals were screened, of whom 156 were screened out mostly due to ineligibility. Afterward, 267 patients were randomized to receive bimekizumab and 133 patients were randomized to receive placebo. Of these patients, 98.5% of those in the bimekizumab group and 94.0% of those in the placebo group completed the DB treatment period. The most common reason for discontinuing was due to AEs (0.7%) in the bimekizumab group and patient choice (3.0%) in the placebo group. Finally, 256 patients and 122 patients from the bimekizumab and placebo groups, respectively, entered the BE VITAL OLE study.

Table 10: Analysis Populations of the BE OPTIMAL and BE COMPLETE Trials

FAS = full analysis set; IMP = investigational medicinal product; PP = per-protocol; RS = randomized set; SS = safety set.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 11: Summary of Patient Disposition From the BE OPTIMAL and BE COMPLETE Trials

AMS = active medication set; ATS = active treatment–blind set; DB = double-blind; FAS = full analysis set; OLE = open-label extension; PP = per-protocol; q.4.w. = every 4 weeks; RS = randomized set; SS = safety set.

^aPatients were summarized according to randomized treatment at baseline in the DB treatment period. Patients who were randomized to placebo switched to bimekizumab 160 mg q.4.w. after week 16.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics summarized in Table 12 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

In the BE OPTIMAL trial, the mean age of patients ranged from 48.5 (SD = 12.6) years to 48.7 (SD = 11.7) years and demographic characteristics were generally similar between the bimekizumab and placebo groups. There were 5 patients and 4 patients in the bimekizumab and placebo groups, respectively, from Canada. The mean time since diagnosis of PsA was approximately 6 years and the mean time since diagnosis of psoriasis was approximately 15 years. Half of patients had at least 3% BSA affected by psoriasis and nearly 80% of patients reported prior use of cDMARDs. Baseline clinical characteristics were generally balanced between the 2 treatment groups, except for enthesitis being higher in the bimekizumab group (33.2%) than in the placebo group (24.9%).

In the BE COMPLETE trial, the mean age of patients ranged from 50.1 (SD = 12.4) years to 51.3 (SD = 12.9) years and demographic characteristics were generally similar between the bimekizumab and placebo groups. There were 6 patients and 3 patients in the bimekizumab and placebo groups, respectively, from Canada. The mean time since diagnosis of PsA was more than 9 years and the mean time since diagnosis of psoriasis was more than 17 years across the treatment groups. More than 76% of patients had an inadequate response to at least 1 TNFi, more than 11% of patients had an inadequate response to at least 2 TNFis, and approximately 12% of patients had an intolerance to TNFis. More than 65% of patients had at least 3% of their BSA affected by psoriasis and more patients had a higher PASI in the bimekizumab group. Baseline clinical characteristics were imbalanced between the groups for enthesitis (higher in the bimekizumab group, 39.7%, versus the placebo group, 27.1%), NSAID therapy (lower in the bimekizumab group, 53.6%, versus the placebo group, 60.2%), and methotrexate use (higher in the bimekizumab group, 44.6%, versus the placebo group, 38.3%).

Table 12: Summary of Baseline Characteristics From the BE OPTIMAL and BE COMPLETE Trials (Randomized Set)

BSA = body surface area; cDMARD = conventional nonbiologic disease-modifying antirheumatic drug; DIP = distal interphalangeal; HAQ-DI = Health Assessment Questionnaire–Disability Index; hs-CRP = high-sensitivity CRP; LEI = Leeds Enthesitis Index; NA = not available; NSAID = nonsteroidal anti-inflammatory drug; PASI = Psoriasis Area Severity Index; PsA = psoriatic arthritis; SD = standard deviation; SJC = swollen joint count; TJC = tender joint count; TNFi = tumour necrosis factor inhibitor.

^aFor patients with psoriasis involving at least 3% of BSA at baseline.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The main differences between the trials were that in the BE COMPLETE trial, patients with an inadequate response or intolerance to TNFis were included and patients had a longer time since PsA and psoriasis diagnoses, a higher percentage of BSA affected by psoriasis and PASI, and a lower number of prior cDMARDs and methotrexate use at baseline.

Exposure to Study Treatments

Exposure to study treatments is summarized in Table 13.

During the DB treatment period of the BE OPTIMAL trial, patients had a mean exposure to study drug of 110.2 (SD = 10.3) days in the bimekizumab group and 108.9 (SD = 14.2) days in the placebo group. Mean adherence was 97.0% in the 2 groups. During the active treatment–blind period, patients had a mean exposure of 239.4 (SD = 44.0) days in the bimekizumab group and 243.5 (SD = 32.0) days in the placebo group. Mean adherence was 95.0% in the 2 groups.

In the BE COMPLETE trial, patients had a mean exposure of 110.7 (SD = 8.7) days in the bimekizumab group and 109.2 (SD = 14.6) days in the placebo group. Mean adherence was more than 98.1% in the 2 groups.

In the BE OPTIMAL trial, 4.8% of patients and 7.0% of patients in the bimekizumab and placebo groups, respectively, used rescue therapy during the active treatment–blind period. The most commonly used medications were systemic hormonal preparations (1.4% to 2.6%), musculoskeletal system drugs (1.2% to 1.8%), and antineoplastic and immunomodulating drugs (1.2% to 1.5%).

Table 13: Summary of Patient Exposure From the BE OPTIMAL and BE COMPLETE Trials

ATS = active treatment–blind set; DB = double-blind; IMP = investigational medicinal product; SD = standard deviation; SS = safety set.

^aTotal IMP duration was a subset of total time at risk excluding nontreated periods.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Protocol Deviations

In the BE OPTIMAL trial, approximately 23% of patients in both the bimekizumab and placebo groups had an important protocol deviation during the DB treatment period, where procedural noncompliance was the most common deviation for both groups (16.7% to 18.6%). Approximately 5% of patients in the treatment groups were excluded from the per-protocol set, mostly due to prohibited concomitant medication use.

In the BE COMPLETE trial, approximately 9% of patients in both treatment groups had an important protocol deviation, where inclusion criteria deviation (4.5% to 4.9%) and procedural noncompliance (3.4% to 3.8%) were the main reasons. Overall, 4.5% of patients in the treatment groups were excluded from the per-protocol set, mostly due to inclusion criteria deviation.

Efficacy

ACR Response

ACR50, ACR20, and ACR70 response results are summarized in Table 14.

In the BE OPTIMAL trial, a greater proportion of patients in the bimekizumab treatment group reached the primary end point of ACR50 at week 16 than did those in the placebo group; the difference between treatment groups for ACR50 was 31.2% (95% CI, 25.2% to 37.3%; P < 0.001). ACR50 results at week 52 indicated that response rates increased in both groups and that there was a similar response between patients who crossed over from placebo to bimekizumab and patients originally randomized to bimekizumab during the active treatment–blind period. Results for the sensitivity analyses using the per-protocol set supported those of the primary analysis.

In the BE OPTIMAL trial, a greater proportion of patients in the bimekizumab treatment group reached the secondary end points of ACR20 and ACR70 at week 16 than did those in the placebo group; the difference between treatment groups was 37.2% (95% CI, 30.5% to 44.0%) for ACR20 and 19.3% (95% CI, 14.1% to 24.5%) for ACR70. ACR20 and ACR70 results at week 52 indicated that response rates increased in both groups and that there was a similar response between placebo-bimekizumab crossover patients and bimekizumab patients during the active treatment–blind period.

In the BE COMPLETE trial, a greater proportion of patients in the bimekizumab treatment group reached the primary end point of ACR50 at week 16 than did those in the placebo group; the difference between treatment groups for ACR50 was 29.0% (95% CI, 21.9% to 36.2%; P < 0.001). Subgroup analyses for ACR50 at week 16 for prior TNFi exposure are summarized in Table 49 in Appendix 1. A larger proportion of patients in the bimekizumab group compared to those in the placebo group attained ACR50 response for each of the subgroup categories of inadequate response to 1 TNFi (47.8% versus 6.8%), inadequate response to 2 TNFis (20.0% versus 0%), and intolerance to TNFis (38.2% versus 13.3%) in the bimekizumab and placebo groups, respectively.

Table 14: ACR Response at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set)

ACR = American College of Rheumatology; ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; CI = confidence interval; IMP = investigational medicinal product; OR = odds ratio; TNFi = tumour necrosis factor inhibitor; vs. = versus.

Note: Patients who had missing ACR50 data at week 16 or who discontinued the IMP before week 16, regardless of whether they had data or not, were considered nonresponders.

^aCalculated using a logistic regression model with factors for treatment, bone erosion at baseline, and region in the BE OPTIMAL trial. Calculated using a logistic regression model with factors for treatment, prior TNFi exposure at baseline, and region in the BE COMPLETE trial.

^bP value adjusted for multiple testing. Outcomes in both trials were sequentially tested to control the familywise type I error rate at alpha of 0.05 (2-sided).

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

In the BE COMPLETE trial, a greater proportion of patients in the bimekizumab treatment group reached the secondary end points of ACR20 and ACR70 at week 16 than did those in the placebo group, the difference between treatment groups was 52.8% (95% CI, 43.6% to 61.9%) for ACR20 and 17.2% (95% CI,12.2% to 22.2%) for ACR70.

Minimal Disease Activity

MDA results are summarized in Table 15.

In the BE OPTIMAL trial, for clinical responses measured with the MDA criteria, patients treated with bimekizumab had higher response rates compared with placebo at week 16. The difference between treatment groups was 31.0% (95% CI, 24.5% to 37.5%; P < 0.001). MDA results at week 52 indicated that response rates increased in both groups and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, patients treated with bimekizumab had higher response rates compared with placebo at week 16; the difference between treatment groups was 34.2% (95% CI, 26.1% to 42.2%; P < 0.001).

Enthesitis-Free State Based on LEI

LEI results for the pooled population of patients with enthesitis at baseline in the BE OPTIMAL and BE COMPLETE trials are summarized in Table 16.

A greater proportion of patients in the bimekizumab treatment group had resolution of enthesitis at week 16 (LEI = 0) than did those in the placebo group; the difference between treatment groups was 14.9% (95% CI, 4.0% to 25.9%; P = 0.008).

Table 15: MDA Response at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set)

CI = confidence interval; MDA = minimal disease activity; OR = odds ratio; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aCalculated using a logistic regression model with factors for treatment, bone erosion at baseline, and region in the BE OPTIMAL trial. Calculated using a logistic regression model with factors for treatment, prior TNFi exposure at baseline, and region in the BE COMPLETE trial.

^bP value adjusted for multiple testing. Outcomes in both trials were sequentially tested to control the familywise type I error rate at alpha of 0.05 (2-sided).

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 16: Enthesitis-Free State at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Pooled Randomized Set With Enthesitis at Baseline)

CI = confidence interval; ID = identification; OR = odds ratio; vs. = versus.

^aCalculated using a logistic regression model with factors for treatment, study ID, and region.

^bP value adjusted for multiple testing. Outcomes in both trials were sequentially tested to control the familywise type I error rate at alpha of 0.05 (2-sided).

Sources: BE OPTIMAL Clinical Study Report and sponsor’s summary of clinical evidence.^20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Dactylitis-Free State Based on LDI

LDI results for the pooled population of patients with dactylitis at baseline from the BE OPTIMAL and BE COMPLETE trials are summarized in Table 17.

A greater proportion of patients in the bimekizumab treatment group had resolution of dactylitis at week 16 (LDI = 0) than did those in the placebo group. The difference between treatment groups was 29.4% (95% CI, 11.7% to 47.1%; P = 0.002).

Table 17: Dactylitis-Free State at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Pooled Randomized Set With Dactylitis at Baseline)

CI = confidence interval; ID = identification; OR = odds ratio; vs. = versus.

^aCalculated using a logistic regression model with factors for treatment, study ID, and region.

^bP value adjusted for multiple testing. Outcomes in both trials were sequentially tested to control the familywise type I error rate at alpha of 0.05 (2-sided).

Sources: BE OPTIMAL Clinical Study Report and the sponsor’s summary of clinical evidence.^20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Swollen Joint Count

SJC results are summarized in Table 18.

Table 18: Swollen Joint Count at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set)

ANCOVA = analysis of covariance; CI = confidence interval; LSM = least squares mean; SE = standard error; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aCalculated using ANCOVA with treatment, bone erosion at baseline, and region as fixed effects, and baseline value as a covariate in the BE OPTIMAL trial. Calculated using ANCOVA with treatment, prior TNFi exposure at baseline, and region as fixed effects, and baseline value as a covariate in the BE COMPLETE trial.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

In the BE OPTIMAL trial, at week 16, the mean reduction at week 16 was greater in the bimekizumab group compared to the placebo group, with the mean difference between treatment groups being –4.0 joints (95% CI, –4.8 joints to –3.1 joints). SJC results at week 52 indicated that response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the mean reduction at week 16 was greater in the bimekizumab group compared to the placebo group, with the mean difference between treatment groups being –5.3 joints (95% CI, –6.5 joints to –4.2 joints).

90% Reduction in PASI Score

PASI 90 results for patients who had psoriasis involving at least 3% BSA at baseline in the trials are summarized in Table 19.

In the BE OPTIMAL trial, for PASI 90, patients treated with bimekizumab had higher response rates compared with those treated with placebo at week 16. The difference between treatment groups was 56.5% (95% CI, 48.6% to 64.3%; P < 0.001). PASI 90 results at week 52 indicated that response rates increased in both groups and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, for PASI 90, patients treated with bimekizumab had higher response rates compared with those treated with placebo at week 16. The difference between treatment groups was 57.6% (95% CI, 47.6% to 67.6%; P < 0.001). Subgroup analyses for PASI 90 (patients with at least 3% BSA affected by psoriasis at baseline) at week 16 for prior TNFi exposure is summarized in Table 49 in Appendix 1. A larger proportion of patients in the bimekizumab group compared to those in the placebo group attained a PASI 90 response for each of the subgroup categories of inadequate response to 1 TNFi (difference versus placebo = 64.4% [95% CI, 53.6% to 75.3%]), inadequate response to 2 TNFis (difference versus placebo = 25.0% [95% CI, –16.2% to 66.1%]), and intolerance to TNFis (difference versus placebo = 49.7% [95% CI, 18.5% to 80.9%]).

Table 19: PASI 90 Response at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set With Psoriasis Involving At Least 3% BSA at Baseline)

BSA = body surface area; CI = confidence interval; OR = odds ratio; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aCalculated using a logistic regression model with factors for treatment, bone erosion at baseline, and region in the BE OPTIMAL trial. Calculated using a logistic regression model with factors for treatment, prior TNFi exposure at baseline, and region in the BE COMPLETE trial.

^bP value adjusted for multiple testing. Outcomes in both trials were sequentially tested to control the familywise type I error rate at alpha of 0.05 (2-sided).

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

IGA Score of 0 or 1 and At Least 2-Grade Reduction From Baseline

IGA results for the patients who had an IGA score of at least 2 and psoriasis involving at least 3% BSA at baseline are summarized in Table 20.

In the BE OPTIMAL trial, a larger proportion of patients in the bimekizumab group compared to those in the placebo group attained at least a 2-grade reduction from baseline in the IGA score at week 16. The difference between treatment groups was 46.0% (95% CI, 37.1% to 55.0%). IGA results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, a larger proportion of patients in the bimekizumab group compared to those in the placebo group attained at least a 2-grade reduction from baseline in the IGA score at week 16. The difference between treatment groups was 58.2% (95% CI, 46.7% to 69.8%).

Table 20: IGA Response at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set With IGA Score of At Least 2 and Psoriasis Involving At Least 3% BSA at Baseline)

BSA = body surface area; CI = confidence interval; IGA = Investigator’s Global Assessment; OR = odds ratio; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aResponders were patients with a score of 0 or 1 and at least a 2-grade reduction from baseline.

^bCalculated using a logistic regression model with factors for treatment, bone erosion at baseline, and region in the BE OPTIMAL trial. Calculated using logistic regression with factors for treatment, prior TNFi exposure at baseline, and region in the BE COMPLETE trial.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Health Assessment Questionnaire–Disability Index

HAQ-DI results are summarized in Table 21.

In the BE OPTIMAL trial, the bimekizumab group had a greater mean decrease from baseline (i.e., improvement) in HAQ-DI compared with the placebo group at week 16; the LSM difference between treatment groups was –0.19 (95% CI, –0.25 to –0.13; P < 0.001). HAQ-DI results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the bimekizumab group had a greater mean decrease from baseline (i.e., improvement) in HAQ-DI compared with the placebo group at week 16; the LSM difference between treatment groups was –0.33 (95% CI, –0.42 to –0.23; P < 0.001). Subgroup analyses for HAQ-DI (patients who had a score decrease from baseline of at least 0.35) at week 16 for prior TNFi exposure are summarized in Table 49 in Appendix 1. A larger proportion of patients in the bimekizumab group compared to those in the placebo group attained a HAQ-DI score decrease of at least 0.35 for each of the subgroup categories of inadequate response to 1 TNFi (difference versus placebo = 40.8% [95% CI, 28.6% to 53.1%]), inadequate response to 2 TNFis (difference versus placebo = 11.5% [95% CI, –19.9% to 42.9%]), and intolerance to TNFis (difference versus placebo = 24.7% [95% CI, –6.0% to 55.5%]).

Table 21: HAQ-DI at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set)

ANCOVA = analysis of covariance; CI = confidence interval; HAQ-DI = Health Assessment Questionnaire–Disability Index; LSM = least squares mean; SD = standard deviation; SE = standard error; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aCalculated using ANCOVA with treatment, bone erosion at baseline, and region as fixed effects, and baseline value as a covariate in the BE OPTIMAL trial. Calculated using ANCOVA with treatment, prior TNFi exposure at baseline, and region as fixed effects, and baseline value as a covariate in the BE COMPLETE trial.

^bP value adjusted for multiple testing. Outcomes in both trials were sequentially tested to control the familywise type I error rate at alpha of 0.05 (2-sided).

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

SF-36 PCS

SF-36 PCS results are summarized in Table 22.

In the BE OPTIMAL trial, the bimekizumab group had a greater mean increase from baseline (i.e., improvement) in the SF-36 PCS compared with the placebo group at week 16; the LSM difference between treatment groups was 4.3 (95% CI, 3.2 to 5.4; P < 0.001). SF-36 PCS results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the bimekizumab group had a greater mean increase from baseline (i.e., improvement) in the SF-36 PCS compared with the placebo group at week 16; the LSM difference between treatment groups was 6.0 (95% CI, 4.4 to 7.7; P < 0.001).

Patient’s Assessment of Arthritis Pain

PtAAP results are summarized in Table 23.

In the BE OPTIMAL trial, the bimekizumab group had a greater mean decrease from baseline (i.e., improvement) in PtAAP compared with the placebo group at week 16. The mean difference between treatment groups was –19.1 (95% CI, –22.7 to –15.5). PtAAP results at week 52 indicated that the response was maintained in the bimekizumab group and that there was a similar response between placebo-bimekizumab crossover patients and patients originally randomized to bimekizumab during the active treatment–blind period.

In the BE COMPLETE trial, the bimekizumab group had a greater mean decrease from baseline (i.e., improvement) in PtAAP compared with the placebo group at week 16. The mean difference between treatment groups was –25.0 (95% CI, –30.0 to –20.0).

Table 22: SF-36 PCS at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set)

ANCOVA = analysis of covariance; CI = confidence interval; LSM = least squares mean; PCS = physical component summary; SE = standard error; SF-36 = Short Form (36) Health Survey; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aCalculated using ANCOVA with treatment, bone erosion at baseline, and region as fixed effects, and baseline value as a covariate in the BE OPTIMAL trial. Calculated using ANCOVA with treatment, prior TNFi exposure at baseline, and region as fixed effects, and baseline value as a covariate in the BE COMPLETE trial.

^bP value adjusted for multiple testing. Outcomes in both trials were sequentially tested to control the familywise type I error rate at alpha of 0.05 (2-sided).

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

Harms results during the 16-week DB treatment period are summarized in Table 24 while harms results during the 36-week active treatment–blind period are summarized in Table 50 in Appendix 1.

Adverse Events

During the DB treatment period of the BE OPTIMAL trial, 59.6% of patients in the bimekizumab group and 49.5% of patients in the placebo group reported at least 1 AE. The most common AEs were nasopharyngitis (9.3% and 4.6% in the bimekizumab and placebo groups, respectively) and upper respiratory tract infection (5.1% and 6.4% in the bimekizumab and placebo groups, respectively). During the active treatment–blind period, 72.0% of patients in the bimekizumab group and 70.5% of patients in the placebo-bimekizumab crossover group reported at least 1 AE. The most common AE was nasopharyngitis (7.0% and 8.5% in the bimekizumab and crossover groups, respectively).

During the DB treatment period of the BE COMPLETE trial, 40.4% of patients in the bimekizumab group and 33.3% of patients in the placebo group reported at least 1 AE. The most common AE was nasopharyngitis (3.7% and 0.8% in the bimekizumab and placebo groups, respectively).

Table 23: Patient’s Assessment of Arthritis Pain at Week 16 in the BE OPTIMAL and BE COMPLETE Trials (Randomized Set)

ANCOVA = analysis of covariance; CI = confidence interval; LSM = least squares mean; SD = standard deviation; SE = standard error; TNFi = tumour necrosis factor inhibitor; vs. = versus.

^aCalculated using ANCOVA with treatment, bone erosion at baseline, and region as fixed effects, and baseline value as a covariate in the BE OPTIMAL trial. Calculated using ANCOVA with treatment, prior TNFi exposure at baseline, and region as fixed effects, and baseline value as a covariate in the BE COMPLETE trial.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Serious Adverse Events

During the DB treatment period of the BE OPTIMAL trial, 1.9% of patients in the bimekizumab group and 1.1% of patients in the placebo group reported at least 1 SAE. No SAEs occurred in more than 2 patients per treatment group. During the active treatment–blind period, 5.6% of patients in the bimekizumab group and 5.9% of patients in the placebo-bimekizumab crossover group reported at least 1 SAE. The only SAE to occur in at least 2 patients per treatment group was osteoarthritis (0.3% in the bimekizumab group and no patients in the crossover group).

During the DB treatment period of the BE COMPLETE trial, 1.9% of patients in the bimekizumab group and no patients in the placebo group reported an SAE. No SAEs occurred in more than 2 patients per treatment group.

Withdrawals Due to Adverse Events

During the DB treatment period of the BE OPTIMAL trial, 1.9% of patients in the bimekizumab group and 1.1% of patients in the placebo group reported an AE leading to drug discontinuation. During the active treatment–blind period, 2.7% of patients in the bimekizumab group and 1.8% of patients in the placebo-bimekizumab crossover group reported an AE leading to drug discontinuation. No AEs leading to drug discontinuation occurred in more than 2 patients per treatment group throughout the trial.

During the DB treatment period of the BE COMPLETE trial, 0.7% of patients in the bimekizumab group and no patients in the placebo group reported an AE leading to drug discontinuation. No AEs leading to drug discontinuation occurred in more than 2 patients per treatment group.

Mortality

There were no deaths reported during the DB treatment period of the BE OPTIMAL trial. During the active treatment–blind period, 1 death in the placebo-bimekizumab crossover group occurred due to traumatic shock from a motorcycle accident.

There were no deaths reported during the DB treatment period of the BE COMPLETE trial.

Notable Harms

Liver toxicity, reactivation of tuberculosis infection, and serious injection-related AEs were not reported on in either of the trials.

During the 16-week treatment period of the BE OPTIMAL trial, there was 1 patient in the bimekizumab group and no patients in the placebo group who reported liver dysfunction based on Hy’s law. Of the 20 (4.6%) patients who reported any fungal infection in the bimekizumab group, 11 patients reported a candida infection and 9 patients reported a fungal infection NEC. Of the 4 (1.4%) patients who reported any fungal infection in the placebo group, 2 patients reported a candida infection and 2 patients reported a fungal infection NEC. There was 1 patient in each treatment group who reported a malignancy event. There were no reports of opportunistic infection, a major cardiovascular event, anaphylaxis, or IBD during the 16-week DB treatment period.

During the active treatment–blind period of the BE OPTIMAL trial, there was 1 patient in the bimekizumab group and no patients in the placebo-bimekizumab crossover group who reported liver dysfunction based on Hy’s law. There were 5 patients in the bimekizumab group and 4 patients in the crossover group who reported opportunistic infection. Of the 47 (11.4%) patients who reported any fungal infection in the bimekizumab group, 28 patients reported a candida infection, 19 patients reported a fungal infection NEC, and 5 patients reported a tinea infection. Of the 25 (9.2%) patients who reported any fungal infection in the crossover group, 19 patients reported a candida infection, 7 patients reported a fungal infection NEC, and 2 patients reported a tinea infection. There were 3 patients in the bimekizumab group and 1 patient in the crossover group who reported major cardiovascular events. There were 3 patients in the bimekizumab group and 4 patients in the crossover group who reported a malignancy event. There were 2 patients in the bimekizumab group and no patients in the crossover group who reported experiencing IBD. There were no reports of anaphylaxis during the active treatment–blind period.

Table 24: Summary of Harms Results During the Double-Blind Treatment Period From the BE OPTIMAL and BE COMPLETE Trials (Safety Set)

AE = adverse event; NEC = not elsewhere classified; NR = not reported; SAE = serious adverse event.

^aOccurring in at least 5% of patients.

^bOccurring in at least 2 patients in any treatment group.

^cHy’s law is defined as an alanine transaminase or aspartate transaminase level at least 3 times the upper limit of normal with coexisting total bilirubin at least 2 times the upper limit of normal in the absence of alkaline phosphatase at least 2 times the upper limit of normal.

Sources: BE OPTIMAL Clinical Study Report, BE COMPLETE Clinical Study Report, and the sponsor’s summary of clinical evidence.^19,20,24 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

In the BE COMPLETE trial, there were 12 (4.5%) patients in the bimekizumab group who reported any fungal infection, of whom 7 patients reported a candida infection, 4 patients reported a fungal infection NEC, and 1 patient reported a tinea infection. There were no reports of any fungal infection in the placebo group. There were no patients in the bimekizumab group and 1 patient in the placebo group who reported a malignancy. There were no reports of liver dysfunction based on Hy’s law, opportunistic infection, a major cardiovascular event, anaphylaxis, or IBD in the trial.

Critical Appraisal

Internal Validity

For both trials, there appeared to be a low risk of bias arising from the randomization process. Randomization was conducted using an interactive voice or web response system and the treatment groups of interest (bimekizumab and placebo) were generally balanced for most baseline characteristics. In the BE OPTIMAL trial, the proportion of patients with enthesitis at baseline was higher in the bimekizumab group than in the placebo group. In the BE COMPLETE trial, the proportion of patients with 10% or greater BSA affected by psoriasis, PASI, enthesitis, and methotrexate use at baseline was higher in the bimekizumab group than the placebo group. These imbalances could bias the results for musculoskeletal-related and skin-related outcomes as well as composite outcomes such as ACR and MDA, which include musculoskeletal and skin assessments. The bias is likely in favour of patients who start out with low disease activity at baseline, though the direction of bias for the overall treatment groups is less certain.

The risk of bias due to deviations from intended interventions was likely low. A bimekizumab-matching placebo was used in both trials for the first 16 weeks of treatment. The number of protocol deviations was similar between the treatment groups in each trial and sensitivity analyses using the per-protocol set were performed to investigate the impact of important protocol deviations, whose results supported the primary analysis. Adherence was greater than 97% during the 16-week DB treatment period for the trials and more than 95% during the BE OPTIMAL trial’s active treatment–blind period. After the 16-week DB period in the BE OPTIMAL trial, patients randomized to placebo began bimekizumab treatment for the remaining 36 weeks. During this time, all patients were permitted to use rescue therapy, which was used by 4.8% of patients and 7.0% of patients in the bimekizumab and placebo groups, respectively. Patients who accessed rescue therapy remained in the trial and there was no indication if their data were handled differently (e.g., imputed as nonresponders). As a result, the longer-term efficacy and harms results may be confounded by the lack of placebo group and by any rescue medication that was used. The use of stable concomitant therapies was permitted in the trials and the minimum stable duration ranged from 2 weeks to 8 weeks. These medications (particularly the cDMARDs) could take more time than the aforementioned minimum durations to reach full efficacy, making it difficult to attribute treatment effects and harms to either bimekizumab or a concomitant drug.

The risk of bias due to missing outcome data was low. Conservative data imputation methods were used in the trials. The number of discontinuations was low and balanced (1.4%) between the bimekizumab and placebo groups in the BE OPTIMAL trial. In the BE COMPLETE trial, 1 (0.4%) patient in the bimekizumab group withdrew by choice compared to 4 (3.0%) patients in the placebo group. Although the numbers are small and it is unlikely to be an important source of bias, it may suggest that data were not missing at random and/or treatment assignment may have been unblinded. There were 4 outcomes relevant to the CADTH review that did not use the full randomized populations. PASI 90 assessments included patients with at least 3% BSA affected by psoriasis at baseline for each trial and IGA response included patients who had at least 3% BSA affected by psoriasis and an IGA score of 2 or higher at baseline for each trial. The LEI and LDI outcomes included pooled data from the 2 trials for patients with enthesitis and dactylitis, respectively, at baseline. Because these 4 outcomes used subsets of the randomized population, it is uncertain if the known and unknown treatment effect modifiers were still balanced between the groups and there may have been unmeasurable bias that influenced the results.

There was likely a low risk of bias resulting from the measurement of outcomes. Outcomes in the trials were prespecified and physicians were blinded to treatment assignments. Assignment to adalimumab could have been unblinded due to the smaller injection volume (0.4 mL or 0.8 mL) compared to bimekizumab or placebo (1 mL), but the impact on the results was likely low because adalimumab was not included in the statistical comparisons.

The risk of bias resulting from selective reporting of results is low. The statistical analysis plan, protocol, and statistical testing hierarchy to control for type I error were prespecified in both trials. Subgroups were also prespecified but were not adjusted for multiplicity in the trials. Furthermore, 2 of the subgroups (patients with an inadequate response to 2 TNFis and patients with an intolerance to TNFis) had fewer patients, making it challenging to draw conclusions from these analyses with certainty.

External Validity

There were 9 patients in each of the trials who were from Canada and received either bimekizumab or placebo. There was limited racial diversity in the trials with most patients being white, which the clinical expert consulted by CADTH indicated does not reflect the diversity of patients with PsA across Canada. Patients were either biologic-naive (the BE OPTIMAL trial) or had a history of inadequate response or intolerance to 1 TNFi or 2 TNFis (the BE COMPLETE trial). Patients with experience with other bDMARDs (e.g., interleukin inhibitors) were not included and there were few patients with prior tsDMARD use; thus, it is uncertain if the results from the trials would be generalizable to patients who have experience with these targeted treatments. Patients were also excluded if they had active, symptomatic IBD (including Crohn disease and ulcerative colitis) or forms of psoriasis other than chronic plaque type (e.g., pustular, erythrodermic, and guttate psoriasis, drug-induced psoriasis). The clinical expert agreed that bimekizumab would be avoided in patients with a history of or current IBD; however, they noted that patients with other forms of psoriasis could be treated with bimekizumab in practice. Based on the reported baseline characteristics, the expert indicated that the patients in the trials were generally similar to those who are treated in clinical practice and could receive bimekizumab in Canada.

Patients could continue using other medications for PsA if they were on a stable dose before baseline. The clinical expert confirmed that the types of medications and doses are reasonable for treating PsA, and noted that methotrexate, sulfasalazine, and leflunomide are cDMARDs commonly used in practice while NSAIDs, COX-2 inhibitors, and corticosteroids are for immediate symptom relief (and are not disease-modifying). The expert also indicated that hydroxychloroquine is rarely used in Canadian practice and apremilast is a targeted therapy typically accessed after cDMARDs.

According to the clinical expert, treatment response is often assessed using TJC, SJC, enthesitis, dactylitis, and skin psoriasis improvement, and may include composite outcomes such as MDA or DAPSA. Although the other outcomes in the trials are not commonly used in practice, they may provide information important to clinicians, patients, and decision-makers. There was evidence of validity, reliability, and responsiveness for some outcome measures and only the patient-reported outcomes (HAQ-DI, SF-36 PCS, and PtAAP) had MIDs identified in the literature (though it was unclear if these were for between-group differences). The expert also noted that treatment response can be assessed at 3 months, suggesting that there should have been adequate time to observe a response for most outcomes relevant to the CADTH review during the first 16 weeks of the trials.

Although bimekizumab was administered in a clinic during the trials, it may be possible for patients to self-administer the drug at home after proper training and if the physician determines it is appropriate, as is described in the Health Canada product monograph for bimekizumab for the treatment of adults with moderate-to-severe plaque psoriasis.²

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^22,23

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of an important effect based on thresholds identified in the literature for HAQ-DI, SF-36 PCS, and PtAAP. The target of the certainty of evidence assessment was the presence or absence of an important effect based on thresholds informed by the clinical expert consulted for this review for ACR, MDA, LEI, LDI, SJC, PASI 90, and IGA.

For the GRADE assessments, findings from the BE OPTIMAL and BE COMPLETE trials were assessed together per outcome because these studies were similar in population, intervention, design, and outcome measures.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for bimekizumab versus placebo for patients with PsA.

Long-Term Extension Studies

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

The sponsor submitted 2 long-term extension studies that evaluated bimekizumab for the treatment of adult patients with PsA. The BE ACTIVE 2 study²⁵ is a now-completed, 104-week, phase II OLE study that aimed to assess the long-term safety, tolerability, and efficacy of bimekizumab in 184 adults with PsA who completed the preceding phase IIb BE ACTIVE study. The BE ACTIVE study,²⁶ not included in the systematic review, was a 48-week, randomized, DB, placebo-controlled, parallel-group, dose-ranging study that included adults with PsA who had previously been exposed to 1 TNFi. Patients were randomized to receive placebo or 1 of several bimekizumab dosing regimens for the initial 12-week placebo-controlled period, and then rerandomized to receive bimekizumab 160 mg every 4 weeks or 320 mg every 4 weeks up to week 48; during the BE ACTIVE 2 trial,²⁵ all patients received the same bimekizumab 160 mg every 4 weeks dosing regimen used in the BE OPTIMAL²⁰ and BE COMPLETE trials.¹⁹

The BE VITAL study^27,28 is an ongoing, phase III OLE study of the BE COMPLETE and BE OPTIMAL trials that is evaluating the long-term efficacy (up to week 140) and long-term safety (up to week 212) of bimekizumab in 1,131 patients with PsA who received bimekizumab 160 mg every 4 weeks. This study is ongoing (the estimated completion date is May 25, 2026); therefore, the summary within this CADTH report will only cover data up to week 52 from 377 patients who completed 16 weeks of treatment in the BE COMPLETE trial.

Populations

The inclusion and exclusion criteria for the BE ACTIVE 2²⁵ and BE VITAL^27,28 studies were consistent with those of the preceding trials (the BE ACTIVE,²⁶ BE OPTIMAL,²⁰ and BE COMPLETE¹⁹ trials). Namely, the studies included adults aged 18 years or older who had a clinical diagnosis of active PsA with symptom duration of at least 6 months at baseline, and baseline values of at least 3 of 68 for TJC and at least 3 of 66 for SJC. Patients who met the withdrawal criteria for the preceding trials were excluded from the extension studies. In cases with an ongoing SAE or history of serious infection, the medical monitor was consulted before patients were allowed to enrol in the extension studies.

Interventions

In both the BE ACTIVE 2 and BE VITAL studies, bimekizumab 160 mg every 4 weeks was administered subcutaneously. Patients were not allowed to use concomitant biologics while receiving bimekizumab but were permitted to use concomitant NSAIDs and/or cDMARDs at the discretion of the investigator; only 1 NSAID or COX-2 inhibitor was permitted at a given time. Steroid tapers were permitted for disease activity or disease-related symptoms (up to 20 mg prednisone or the equivalent for a maximum of 14 days). One injection per joint for up to 3 discrete joints was permitted per 12-month period.

Outcomes

The safety outcomes for the BE ACTIVE 2²⁵ and BE VITAL^27,28 studies included incidences of TEAEs, SAEs, and withdrawal due to TEAEs. The efficacy outcomes for the BE ACTIVE 2 and BE VITAL studies were generally consistent with those of the preceding studies (i.e., the BE ACTIVE,²⁶ BE OPTIMAL,²⁰ and BE COMPLETE¹⁹ studies). The efficacy outcomes summarized in this section include:

• measures of ACR50 and ACR70 response at various time points

• measures of MDA response

• measures of PASI 75, PASI 90, and PASI 100 response at various time points for patients with psoriasis affecting at least 3% BSA at the preceding study’s baseline

• change from baseline in LDI and LEI (LEI was only evaluated in the BE VITAL study)

• change from baseline in SF-36 PCS scores.

Measures of response and change from baseline values were calculated during the extension studies using the baseline values from the preceding studies. IGA response data were only collected during the BE VITAL study and have not yet been reported.

Statistical Analysis

All data from the extension studies were analyzed descriptively using summary statistics. No formal sample size calculations were performed. Analyses were based on a safety set (patients who received at least 1 dose of bimekizumab) and a full analysis set (patients who received at least 1 dose of bimekizumab and had at least 1 valid efficacy measurement).

Intermittent missing data were imputed using the Markov chain Monte Carlo method, followed by regression for monotone missing data. For the multiple imputation procedures, it was assumed that data were missing at random.

Results

Baseline Characteristics

Demographic and disease characteristics based on the baseline of the preceding studies for patients enrolled in the BE ACTIVE 2 and BE VITAL studies are presented in Table 25 and Table 26, respectively.

In the BE ACTIVE 2 study, the study population had a mean age of 49 (SD = 12.2) years, with 52.5% of patients being male and 47.5% being female. The mean time since PsA diagnosis was 8.0 years. Thirteen (7.1%) patients had psoriasis affecting at least 3% BSA. Additionally, the mean TJC of 68 joints was 4.9 (SD = 9.0) joints and the mean SJC of 66 joints was 1.7 (SD = 4.1) joints.

In the BE VITAL study, the study population had a mean age of 50.5 (SD = 12.5) years, with 47.5% males and 52.5% females. The mean time since PsA diagnosis was 9.5 years. Overall, 76.8% of patients had an inadequate response to 1 TNFi, 11.0% of patients had an inadequate response to 2 TNFis, and 12.3% of patients had an intolerance to TNFis. Additionally, 66.0% of patients had psoriasis affecting at least 3% BSA. The mean TJC was 18.7 (SD = 13.8) joints and the mean SJC was 9.9 (SD = 7.7) joints.

Table 25: Summary of Demographic Characteristics at Baseline of Preceding Studies (Safety Set)

BMI = body mass index; NR = not reported; q.4.w. = every 4 weeks; SD = standard deviation.

Sources: BE ACTIVE 2 Clinical Study Report²⁵ and BE COMPLETE Clinical Study Report.¹⁹

Table 26: Summary of Baseline Clinical Characteristics at Entry Into Extension Studies (Safety Set)

BSA = body surface area; DMARD = disease-modifying antirheumatic drug; NR = not reported; NSAID = nonsteroidal anti-inflammatory drug; PsA = psoriatic arthritis; q.4.w. = every 4 weeks; SD = standard deviation; SJC = swollen joint count; TJC = tender joint count; TNFi = tumour necrosis factor inhibitor.

Sources: BE ACTIVE 2 Clinical Study Report²⁵ and BE COMPLETE Clinical Study Report.¹⁹

Patient Disposition

The patient disposition of the BE ACTIVE 2 and BE VITAL studies is summarized in Table 27. Among 184 patients who completed the BE ACTIVE trial and subsequently enrolled in the BE ACTIVE 2 study, 1 patient discontinued due to an AE (tongue fungal infection). Among the 183 patients who were dosed with bimekizumab in the BE ACTIVE 2 study (i.e., the safety set), most patients completed the study (88.0%). Discontinuation was reported for 12.0% of patients; the reason for discontinuation was most commonly related to TEAEs or consent withdrawal.

Among 388 patients who completed 16 weeks in the BE COMPLETE trial, 377 patients entered the BE VITAL long-term extension study. In total, 347 (86.8%) patients remained in the study at week 52. As per the protocol, patients withdrawn from study treatment could return for all remaining study visits. Of the patients who remained in the study at week 40 and week 52, 4 (1.0%) patients were not on randomized treatment. Ten patients discontinued due to TEAEs in the BE VITAL study. Discontinuation was reported in 18 patients; the reason for discontinuation was most commonly related to TEAEs or consent withdrawal.

Table 27: Patient Disposition for BE ACTIVE and BE VITAL Studies

NR = not reported; q.4.w. = every 4 weeks.

Sources: BE ACTIVE 2 Clinical Study Report²⁵ and Coates et al. (2024).²⁷

Concomitant Medications and Cointerventions

The concomitant use of nonbiologic medication for PsA was permitted and common during the BE ACTIVE 2 study (90.2% of patients). The concomitant use of nonbiologic medication for PsA was not reported in the BE VITAL study. Biologic treatments for PsA were not permitted in either study. In the BE ACTIVE 2 study, the most common treatments were folic acid and methotrexate, and concomitant rescue therapy was reported for 24 (13.1%) patients (Table 28).

Exposure to Study Treatments

The total time at risk was 392.7 years in the BE ACTIVE 2 study (Table 29).

Because some patients switched from placebo in the BE COMPLETE trial to bimekizumab in the BE VITAL study, exposure is reported separately for patients randomized to bimekizumab or with any exposure to bimekizumab. The total time at risk was 259.5 years among 267 patients who were originally randomized to receive bimekizumab during the BE COMPLETE trial, and this time increased to 339.8 years among the 388 patients who received bimekizumab during the BE VITAL study (Table 29).

Table 29: Patient Exposure During the Extension Studies (Safety Set)

NR = not reported; q.4.w. = every 4 weeks; SD = standard deviation.

Note: Data were not reported for the subgroups categorized according to previous treatment in the BE ACTIVE study.

Sources: BE ACTIVE 2 Clinical Study Report²⁵ and Coates et al. (2024).²⁷

Efficacy

ACR Response

ACR20, ACR50, and ACR70 response rates in the BE ACTIVE 2 study at various study time points relative to the baseline values from the BE ACTIVE study are summarized in Table 30. Rates of ACR20, ACR50, and ACR70 response were similar at baseline and at week 104 with continued bimekizumab treatment in the BE ACTIVE 2 study.

During the BE VITAL trial, patients originally randomized to bimekizumab showed an ACR50 response of 51.7% at week 52, by NRI analysis (Table 31). Patients who were initially randomized to placebo showed an ACR50 response of 40.6% at week 52 (Table 31). ACR20 and ACR70 similarly improved over time for these groups.

Table 30: ACR Response Rates in BE ACTIVE 2 Study Relative to BE ACTIVE Study Baseline (Full Analysis Set, NRI and OC)

ACR = American College of Rheumatology; ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; EV = entry visit; NRI = nonresponder imputation; Nsub = N subgroup; OC = observed case; q.4.w. = every 4 weeks.

Note: In the n (%) row (primary analysis), patients for whom ACR could not be derived due to missing data were counted as nonresponders, as this row corresponds to the NRI analysis. In the n of Nsub (%) row (OC sensitivity analysis), Nsub represented the number of patients with a nonmissing measurement at the given week, and percentages were calculated accordingly.

Source: BE ACTIVE 2 Clinical Study Report.²⁵

Table 31: Efficacy Results in BE VITAL Study at Week 16 and Week 52 (Full Analysis Set, NRI and OC)

ACR20 = American College of Rheumatology 20% improvement in rheumatoid arthritis; ACR50 = American College of Rheumatology 50% improvement in rheumatoid arthritis; ACR70 = American College of Rheumatology 70% improvement in rheumatoid arthritis; BSA = body surface area; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MDA = minimal disease activity; NRI = nonresponder imputation; OC = observed case; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PASI 100 = 100% reduction in Psoriasis Area Severity Index score; q.4.w. = every 4 weeks.

Note: Table 31 has been adapted from “Table 2 Efficacy outcomes at week 16 and week 52” Coates et al. (2024)²⁷ under the Creative Commons license agreement CC BY-NC 4.0 (https://creativecommons.org/licenses/by-nc/4.0/). Adaptations consist of the inclusion and reordering of only the rows present (e.g., ACR20, PASI 100) and removal of rows from the original table (e.g., VLDA response).

^aACR50 at week 16 was the primary end point in the BE COMPLETE trial.

^bPatients with enthesitis at baseline defined by LEI greater than 0.

^cPatients with dactylitis at baseline defined by LDI greater than 0.

^dIn patients with psoriasis affecting at least 3% BSA at baseline.

Source: Coates et al. (2024).²⁷

MDA Response

The proportion of patients who had attained an MDA response was 58.6% at week 104 of the BE ACTIVE 2 study, and similar results were observed in secondary analyses using observed case data (Table 32).

In the BE VITAL study, the proportion of bimekizumab-randomized patients attaining the MDA composite measures of disease activity was 47.2% at week 52. Of initial placebo-randomized patients, after switching to bimekizumab, 33.1% of patients attained MDA (NRI) at week 52 (Table 31).

Table 32: MDA Response Rates by Visit in BE ACTIVE 2 Study Relative to BE ACTIVE Study Baseline (Full Analysis Set, NRI and OC)

EV = entry visit; MDA = minimal disease activity; NRI = nonresponder imputation; Nsub = N subgroup; OC = observed case; q.4.w. = every 4 weeks.

Note: In the n (%) row (primary analysis), patients for whom MDA could not be derived due to missing data were counted as nonresponders, as this row corresponds to the NRI analysis. In the n of Nsub (%) row (OC sensitivity analysis), Nsub represented the number of patients with a nonmissing measurement at the given week, and percentages were calculated accordingly.

Source: BE ACTIVE 2 Clinical Study Report.²⁵

PASI Response

According to the sponsor summary, an error in the original protocol resulted in a limited number of patients being assessed for PASI response at select midstudy time points. However, this error was addressed in a protocol amendment and nearly all patients had PASI data available for the week 104 visit.

The BE ACTIVE 2 study evaluated PASI 75, PASI 90, and PASI 100 response rates at various time points, which were calculated relative to the baseline values from the BE ACTIVE study (Table 33). At week 104, the proportion of patients who attained PASI 75, PASI 90, and PASI 100 was 79.2%, 73.3%, and 65.8%, respectively.

For the BE VITAL trial, the proportions of patients attaining PASI 75, PASI 90, and PASI 100 increased out to week 52 in both those who were initially placebo-randomized patients and those who were bimekizumab-randomized patients with psoriasis affecting at least 3% BSA at baseline (Table 31).

Table 33: PASI Response Rates in BE ACTIVE 2 Study Relative to BE ACTIVE Study Baseline in Patients With Psoriasis Affecting At Least 3% BSA at Baseline (Full Analysis Set, NRI and OC)

BSA = body surface area; EV = entry visit; NRI = nonresponder imputation; Nsub = S nubgroup; OC = observed case; PASI = Psoriasis Area Severity Index; PASI 75 = 75% reduction in Psoriasis Area Severity Index score; PASI 90 = 90% reduction in Psoriasis Area Severity Index score; PASI 100 = 100% reduction in Psoriasis Area Severity Index score.

Note: In the n (%) row (primary analysis), patients for whom PASI could not be derived due to missing data were counted as nonresponders as this row corresponds to the NRI analysis. In the n of Nsub (%) row (OC sensitivity analysis), Nsub represented the number of patients with a nonmissing measurement at the given week, and percentages were calculated accordingly.

Source: BE ACTIVE 2 Clinical Study Report.²⁵

LEI and LDI Response

Data regarding the LEI were only collected during the BE VITAL study among patients with enthesitis at baseline. For patients who switched from placebo to bimekizumab, the enthesitis resolution rate for LEI was 58.3% at week 52. Of the patients originally randomized to bimekizumab, 56.6% had enthesitis resolution for LEI at week 52 (Table 31).²⁷

Due to the low number of patients with dactylitis in the BE ACTIVE 2 study, and the corresponding low number of data points for analysis, convergence issues were observed with the multiple imputation model. Therefore, analysis of LDI scores was only based on observed case data (Table 34). Compared to the baseline from the BE ACTIVE study, the mean change from baseline for LDI scores was –47.2 (SD = 78.2) at patients’ entry visit for the BE ACTIVE 2 study and was sustained to week 104 (–60.7 [SD = 71.5]) with continued bimekizumab treatment.

Among patients with dactylitis at baseline in the BE VITAL study, for patients who switched from placebo to bimekizumab, the rate of dactylitis resolution was 85.7% at week 52. For patients originally randomized to bimekizumab, the rate of dactylitis resolution was 85.3% at week 52 (Table 31).²⁷

Table 34: Changes in LDI Scores by Visit in Extension Studies Relative to Preceding Study Baseline (Full Analysis Set, OC Data, No Imputation)

CFB = change from baseline; EV = entry visit; LDI = Leeds Dactylitis Index; OC = observed case; q.4.w. = every 4 weeks; SD = standard deviation.

Source: BE ACTIVE 2 Clinical Study Report.²⁵

SF-36

The mean SF-36 PCS change score was sustained with continued bimekizumab treatment up to week 104, with mean PCS change of 9.5 (SE = 0.8) (Table 35).

In the BE VITAL study, data regarding the SF-36 PCS were only reported up to week 40. The mean SF-36 PCS change from baseline was 7.3 (SE = 0.9) at week 40 for patients who switched from placebo to bimekizumab. For those who were originally randomized to bimekizumab, the mean SF-36 PCS change from baseline was 8.4 (SE = 0.6) at week 40 (Table 36).²⁷

Table 35: Changes in SF-36 Scores by Visit in Extension Studies Relative to Preceding Study Baseline (Full Analysis Set, MI)

CFB = change from baseline; EV = entry visit; MI = multiple imputation; PCS = physical component summary; q.4.w. = every 4 weeks; SE = standard error; SF-36 = Short Form (36) Health Survey.

Note: Missing values were replaced by 1 of a set of plausible values, where each value is a Bayesian draw from the conditional distribution of the missing data given the observed data. This was performed 100 times and summaries of the resulting datasets were combined for reporting.

Source: BE ACTIVE 2 Clinical Study Report.²⁵

Table 36: Efficacy Results in BE VITAL Study at Week 16 and Week 40 (Full Analysis Set)

CFB = change from baseline; MI = multiple imputation; PCS = physical component summary; q.4.w. = every 4 weeks; SE = standard error; SF-36 = Short Form (36) Health Survey.

Note: Table 36 has been adapted from “Table 2 Efficacy outcomes at week 16 and week 52” Coates et al. (2024)²⁷ under the Creative Commons license agreement CC BY-NC 4.0 (https://creativecommons.org/licenses/by-nc/4.0/). Adaptations consist of the inclusion and reordering of only the rows present (e.g., SF-36 PCS) and removal of rows from the original table (e.g., ACR20 response).

Source: Coates et al. (2024).²⁷

Harms

Harms results for the BE ACTIVE 2 and BE VITAL studies are displayed in Table 37 and Table 38, respectively. The total time at risk was 392.3 patient-years during the BE ACTIVE 2 study. Most patients reported TEAEs (80.9%), which were most commonly infections and infestations (55.2%). The proportion of patients who reported SAEs was 7.7%. The discontinuation of bimekizumab treatment due to TEAEs occurred among 4.9% of patients, mainly due to oral fungal infection (1.6%). No deaths were reported.

In the BE VITAL study, at least 1 TEAE was reported by 243 of 388 (62.6%) patients while receiving bimekizumab up to week 52. The most frequently reported TEAEs were hypersensitivity (4.9%), SARS-CoV-2 (COVID-19) infections (7.2%), fungal infections (9.5%), nasopharyngitis (5.9%), and urinary tract infection (5.9%). Serious infections occurred among 1.8% of patients, and 1.3% of patients had neutropenia. The proportion of patients who reported SAEs was 5.9%. The discontinuation of bimekizumab treatment due to TEAEs occurred among 4.1% of patients. One death was reported and deemed unrelated to study treatment.

Table 37: Summary of Harms in BE ACTIVE 2 Study (Safety Set)