CADTH Reimbursement Review

Bimekizumab (Bimzelx)

Sponsor: UCB Canada Inc.

Therapeutic area: Psoriasis, moderate to severe plaque

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Introduction

Plaque psoriasis is a chronic inflammatory skin disease characterized by erythematous inflammatory plaques that may be itchy or painful and are usually covered by silver, flaking scales.¹ In addition to the overt dermatological symptoms, plaque psoriasis is often associated with psychosocial symptoms and may affect various aspects of social functioning, including interpersonal relationships and performance at school or work. Treatments include topical therapy, phototherapy, non-biologic systemic drugs (e.g., methotrexate, cyclosporine), and biologic therapies (e.g., interleukin [IL]-17, IL-23, IL-12/23 inhibitors and tumour necrosis factor [TNF] alpha inhibitors). An estimated 1 million Canadians are living with psoriasis, 90% of whom have plaque psoriasis.²

Bimekizumab is a humanized monoclonal antibody that belongs to the IL-17 drug class.³ Bimekizumab is approved by Health Canada for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. It is available as a 160 mg/1 mL pre-filled syringe or autoinjector. The recommended dose is 320 mg, administered as 2 160 mg subcutaneous (SC) injections every 4 weeks for the first 16 weeks, followed by 320 mg SC every 8 weeks thereafter.³ The product monograph states that, at the prescriber’s discretion, discontinuation of treatment may be considered in patients who have shown no improvement after 16 weeks of treatment. The product monograph also states that, for patients with a body weight of 120 kg or more who do not achieve a complete skin response, a dosage of 320 mg every 4 weeks after week 16 may be considered.³

The objective of this report is to perform a systematic review of the beneficial and harmful effects of bimekizumab 160 mg/mL solution for SC injection for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

Stakeholder Perspectives

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

Patient Input

Two responses to CADTH’s call for patient input for the bimekizumab submission were received: a submission from the Psoriasis Society of Canada and a co-operative submission from the Canadian Association of Psoriasis Patients (CAPP) and the Canadian Psoriasis Network (CPN). The information used to inform the submissions was from phone calls from psoriasis patients as well as from a survey that was hosted on the CAPP and CPN websites and sent to clinics conducting bimekizumab trials to share with patients. A total of 95 survey responses were received, in addition to a telephone interview with a bimekizumab trial participant.

The patients described psoriasis as a chronic inflammatory condition that can present potentially debilitating challenges. Most patients reported living with psoriatic arthritis and about half of all survey respondents described their psoriasis as moderate or severe. Common symptoms, experienced by more than 2-thirds of patients, included flaking, itching, and redness, and more than half of patients experienced pain. Most patients reported that their psoriasis symptoms affected their social life, self-esteem, mental health, intimate life, sleep, and work. Many patients reported feeling that their symptoms are not effectively controlled with existing therapies. Most patients indicated that an improvement in their quality of life or a reduction in symptoms would be an important treatment outcome, in addition to the desire for a faster response to treatment, clear skin, or a cure. Moreover, a new treatment should have reduced adverse effects, be affordable, assist with persistent symptoms, and be easier to take.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

According to the clinical expert consulted for this review, none of the available treatments for plaque psoriasis provide a cure, and there remains an unmet need for highly effective and safe treatments that are accessible and easy to use. The clinical expert stated that the ideal treatment would produce a sustained Psoriasis Area and Severity Index (PASI) 100 response (a 100% improvement in PASI score) in all patients, with a low risk of adverse events; would minimize or eliminate the negative impact of psoriasis on health-related quality of life (HRQoL); and would benefit 1 or more of the comorbidities, particularly psoriatic arthritis.

In the clinical expert’s opinion, bimekizumab is unlikely to cause a shift in the treatment paradigm for moderate to severe plaque psoriasis, as it is anticipated that prior treatment with methotrexate or cyclosporine will be required for reimbursement. As the fourth IL-17 inhibitor approved for plaque psoriasis in Canada, bimekizumab is an additional efficacious drug in the treatment armamentarium, thus increasing the likelihood that the patient will find a drug that works well and is tolerated.

The expert stated that bimekizumab is appropriate for adult patients with moderate to severe plaque psoriasis who are suitable candidates for systemic therapy. Most payors would limit use to patients with a minimum PASI score of 12 and 10% or more of body surface area (BSA) affected. Patients least suitable for treatment with bimekizumab would be those with active Crohn disease or those who had failed 1 or more prior trials of an IL-17 inhibitor, according to the clinical expert.

In clinical practice, response to therapy is assessed based on the PASI score, with a PASI 75 response at 16 weeks considered a clinically meaningful improvement by the clinical expert. However, clinicians expect that patients will achieve a higher threshold of improvement with newer biologic drugs. According to the clinical expert consulted, discontinuation of bimekizumab would be warranted in patients who failed to reach or maintain PASI 75 response, in those with inadequate control of comorbid psoriatic arthritis, in those who developed a high-risk malignancy or significant infection, and in those undergoing elective surgery.

Clinician Group Input

No input was received from clinician groups.

Drug Program Input

The drug programs enquired about the place in therapy of bimekizumab and whether it may cause a shift in the treatment algorithm for plaque psoriasis. The clinical expert did not anticipate that bimekizumab would affect the treatment algorithm and stated that the initiation, renewal, and discontinuation criteria for bimekizumab should be aligned with other biologic drugs used for the treatment of patients with moderate to severe plaque psoriasis.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

The systematic review included 4 multi-centre, double-blind randomized controlled trials (RCTs) that evaluated the safety and efficacy of bimekizumab in patients with moderate to severe plaque psoriasis who were candidates for systemic therapy or phototherapy (studies PS0009, PS0008, PS0015, and PS0013). The studies randomized 435 to 743 patients to receive bimekizumab compared with placebo, ustekinumab, adalimumab, or secukinumab, for 48 to 56 weeks. The dosage of bimekizumab was either 320 mg SC every 4 weeks or 320 mg every 4 weeks for the first 16 weeks and then every 8 weeks thereafter. Study PS0013 used a randomized withdrawal design, and bimekizumab-treated patients who achieved a 90% improvement in their PASI score (PASI 90) at week 16 were randomized to either switch to placebo or to continue receiving bimekizumab every 4 weeks or bimekizumab every 8 weeks.

In studies PS0009, PS0008, and PS0013, the co-primary outcomes were the proportion of patients who achieved a PASI 90 response, and an Investigator’s Global Assessment (IGA) score of “clear” or “almost clear” (i.e., 0 or 1) with at least a 2-point change from baseline, at week 16. The IGA is a 5-point composite physician assessment of the overall severity of the patient’s psoriatic lesions at a given time point. The primary outcome in study PS0015 was the proportion of patients who achieved a PASI 100 response at week 16. 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 PASI response is the percentage improvement in PASI score. IGA 0/1, PASI 90, or PASI 100 response thresholds are generally accepted as representing clinically relevant improvements.

The mean age of the patients enrolled ranged from 43.5 years (standard deviation [SD] 13.1) to 49.7 years (SD 13.6) across treatment groups in the 4 trials. Most patients were male (64% to 73%) and White (74% to 94%), with psoriasis that was rated as moderate in severity based on their IGA score (59% to 72%). Most patients (69% to 83%) had received prior systemic therapy, which included prior biologic therapy for 31% to 44% of patients and prior IL-17 therapy for 11% to 24% of patients.

Efficacy Results

Initial Treatment Period

In Study PS0009, 85.0% of patients in the bimekizumab group achieved PASI 90 response at 16 weeks, compared with 49.7% for ustekinumab and 4.8% for placebo groups (Table 2). The between-group differences favoured bimekizumab versus ustekinumab (odds ratio [OR] 6.06; 95% confidence interval [CI], 3.87 to 9.47; P < 0.001) and versus placebo (OR 99.87; 95% CI, 34.02 to 293.18; P < 0.001), demonstrating that bimekizumab was superior to ustekinumab and placebo for the PASI 90 response at week 16. The results for the co-primary outcome of IGA 0/1 response at week 16 showed similar findings. At 16 weeks, 84.1%, 53.4%, and 4.8% of the bimekizumab, ustekinumab, and placebo groups, respectively, achieved an IGA score of 0 or 1 (OR 4.81 bimekizumab versus ustekinumab; 95% CI, 3.10 to 7.47; P < 0.001).

The proportion of patients who achieved PASI 90 response at 16 weeks in Study PS0008 was 86.2% and 47.2% for bimekizumab and adalimumab groups, respectively, and the OR favoured bimekizumab versus adalimumab (OR 7.46; 95% CI, 4.71 to 11.82; P < 0.001). Bimekizumab demonstrated superiority to adalimumab for the IGA 0 or 1 response at week 16 (85.3% versus 57.2%; OR 4.32; 95% CI, 2.79 to 6.77; P < 0.001).

The withdrawal study, PS0013, reported that 90.8% of patients in the bimekizumab group achieved PASI 90 response at week 16 compared with 1.2% of patients in the placebo group, with an OR of 496.32 (95% CI, 82.8 to 2,975.09; P < 0.001). The results were similar for the co-primary outcome IGA 0/1 response (92.6% versus 1.2% bimekizumab versus placebo; OR 657.3; 95% CI, 105.8 to 4,083.3; P < 0.001).

In Study PS0015, 61.7% and 48.9% of patients in the bimekizumab and secukinumab groups, respectively, achieved PASI 100 response at week 16 (primary outcome). On the relative scale, the differences favoured bimekizumab versus secukinumab (OR 1.72; 95% CI, 1.27 to 2.31; P < 0.001), demonstrating that bimekizumab was superior to secukinumab. At 16 weeks, 85.5% and 74.3% achieved PASI 90 response, and 85.5 and 78.6% achieved IGA 0/1 response in the bimekizumab and secukinumab groups, respectively. Between-group differences favoured bimekizumab versus secukinumab, but these outcomes were not controlled for type I error rate and should be interpreted as supportive evidence of the overall effect of bimekizumab.

In studies PS0009, PS0008, and PS0013, the proportion of patients who achieved PASI 100 response at 16 weeks (secondary outcome) ranged from 58.6% to 68.2% in the bimekizumab groups, compared with 23.9% for adalimumab, 20.9% for ustekinumab, and 0% to 1.2% for placebo groups. The between-group differences favoured bimekizumab versus adalimumab and placebo, and all comparisons were statistically significant (P < 0.001). The comparison in PS0009 also favoured bimekizumab versus ustekinumab. This analysis was not part of the statistical testing hierarchy to control the type I error rate; thus, these data should be interpretive as supportive evidence only.

For all studies, the sensitivity analyses for the primary or co-primary outcomes showed findings that were supportive of the primary analyses. Descriptive data for PASI 90 or PASI 100 response and IGA 0/1 response at week 16 were generally consistent between subgroups, based on prior biologic therapy (yes/no), prior systemic therapy (yes/no), and baseline PASI score (< 20 versus ≥ 20). Limited post hoc data were available for patients with body weight of 120 kg or more.

HRQoL was reported based on the Dermatology Life Quality Index (DLQI), a 10-item dermatology-specific questionnaire that covers 6 domains and is scored from 0 to 30, with lower scores indicating better HRQoL. The proportion of patients with a DLQI score of 0 or 1 at 16 weeks |||||||||||||| in the bimekizumab groups than placebo groups in PS0009 |||||||||||||||||||||||||||| and in Study PS0013 |||||||||||||||||||||||||||||||||||||||||| achieved a DLQI score of 0 or 1 in the bimekizumab than the ustekinumab group in PS0009 |||||||||||||||||||||||||||| and for bimekizumab versus adalimumab in PS0008 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. HRQoL outcomes were not controlled for type I error rate; thus, these data should be interpreted as supportive evidence only.

Maintenance Treatment Period

In Study PS0009, 81.9% of patients in the bimekizumab group and 55.8% in the ustekinumab group achieved PASI 90 response at week 52, with an OR of 3.80 (95% CI, 2.44 to 5.90; P < 0.001) favouring bimekizumab. IGA 0/1 response was reported for 78.2% and 60.7% in the bimekizumab and ustekinumab groups, respectively (OR 2.41; 95% CI, 1.57 to 3.70; P < 0.001).

In Study PS0015, the PASI 100 response at week 48 was 73.5%, 66.0%, and 48.3% in the bimekizumab every 4 weeks, bimekizumab every 4 weeks for 16 weeks then every 8 weeks, and secukinumab groups, respectively. The between-group differences favoured bimekizumab versus secukinumab for both the every 4 weeks maintenance dosage (OR 3.24; 95% CI, 2.10 to 5.00; P < 0.001) and the every 8 weeks maintenance dosage (OR 2.12; 95% CI, 1.48 to 3.04; P < 0.001). This analysis excluded 4% of patients who withdrew during the first 16 weeks and was based on patients in the bimekizumab group who were re-randomized at 16 weeks to every 4 or 8 weeks maintenance dosage regimens (maintenance set N = 716). For the analysis based on all randomized patients, the 48-week PASI 100 results were comparable (67.0% versus 46.2% for bimekizumab versus secukinumab, respectively; OR 2.46; 95% CI, 1.81 to 3.34; P < 0.001).

Descriptive data were reported at week 56 for Study PS0008. Among patients who remained on bimekizumab every 4 weeks throughout the study, 84.8% and 82.3% achieved PASI 90 and IGA 0/1 response at week 56. For patients who received bimekizumab every 4 weeks for 16 weeks, then every 8 weeks thereafter, 82.6% and 83.2% achieved PASI 90 and IGA 0/1 response at week 56.

Withdrawal Treatment Period

In Study PS0013, patients in the bimekizumab group who achieved PASI 90 response at week 16 were re-randomized to switch to placebo or to continue bimekizumab every 4 weeks or 8 weeks. At week 56, 88.8% of patients who continued on bimekizumab reported PASI 90 response, compared with 16.2% of patients who switched to placebo (OR 47.41; 95% CI, 22.09 to 101.75; P < 0.001).

Harms Results

The frequency of adverse events was generally similar between groups in Study PS0009 (initial treatment period [first 16 weeks]: 47% to 56%; total study period: 80% to 82%), Study PS0008 (70% to 77%), and Study PS0015 (81% to 86%) (Table 3). In Study PS0013, more patients who received bimekizumab reported adverse events than the placebo group during the initial treatment period (61% versus 41%), but the frequency was comparable during the withdrawal period (69% to 77%). Across the studies, infections were the most commonly reported adverse events, specifically fungal infections, of which oral candidiasis was the most commonly reported event. Across studies, the bimekizumab groups reported a higher frequency of fungal infections than the comparators. In the first 16 to 24 weeks of PS0009, PS0008, and PS0013, 12% to 16% of patients in the bimekizumab groups reported a fungal infection, compared with 0% to 2% of those who received placebo, ustekinumab, or adalimumab. In the total study period, 18% to 29% of patients who received bimekizumab experienced a fungal infection, versus 3% and 10% who received ustekinumab or secukinumab, respectively. No systemic fungal infections were reported, and the frequency of serious infections was generally low (0% to 3%).

The frequency of adverse events was generally similar between bimekizumab groups that received maintenance doses every 4 weeks compared with every 8 weeks. However, in PS0013, the frequency of fungal infections was higher among patients who continued on bimekizumab every 4 weeks (21%) than every 8 weeks (14%) or those switched from bimekizumab to placebo (7%).

Serious adverse events were reported by 3% to 6% of patients who received bimekizumab, 8% of patients who received ustekinumab, and 6% who received secukinumab during the total study period of PS0008, PS0009, and PS0015, and in 3% to 5% of patients who received bimekizumab or placebo during the withdrawal period of PS0013. Seven patients died during the 4 studies, including 3 patients (0% to 0.5%) in the bimekizumab groups, and 1 patient in each of the ustekinumab, adalimumab, secukinumab, and placebo groups (0% to 1.2%).

The number of patients who discontinued the study due to adverse events was generally low across trials, and similar between treatment groups within studies, during the overall treatment period (3% to 5%) or withdrawal period (0% to 3%).

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

ADA = adalimumab; AE = adverse event; AMS = active medication set; BKZ = bimekizumab; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SAE = serious adverse event; SECU = secukinumab; SS = safety set; USTE = ustekinumab; WDAE = withdrawal due to adverse event.

^aIncludes patients randomized to BKZ and those switched from placebo to BKZ after the first 16 weeks.

^bBKZ q.4.w. group includes all events that occurred during BKZ q.4.w. treatment for all 3 randomized treatment groups.

Source: Clinical Study Report for PS0009,⁴ Clinical Study Report for PS0008,⁵ Clinical Study Report for PS0015,⁶ Clinical Study Report for PS0013.⁷

Critical Appraisal

The risk of bias related to randomization and treatment allocation concealment was rated as low for all studies, and, in general, the patient characteristics appeared to be balanced between groups at baseline. However, in studies PS0009 and PS0008, some differences were observed in the median duration of disease and the proportion of patients with PASI score 20 and higher. However, the clinical expert consulted for this review did not anticipate that the differences noted would bias the results. The trials were double blind and took steps to maintain blinding of patients and investigators. However, nonidentical pre-filled syringes were used to administer the study drugs, which may have resulted in some patients being aware of treatment assignment. It is unclear whether unblinding may have introduced any bias into the results. The statistical analyses were based on a stratified Cochran-Mantel-Haenszel (CMH) test for the intention-to-treat population, with missing data imputed as nonresponders. While the PASI 90, PASI 100, or IGA 0/1 response outcome measures are generally accepted as representing clinically important improvement in psoriasis severity, the primary outcomes for this chronic condition were measured at 16 weeks. The longer-term outcome data were limited by the lack of control group (PS0008), were affected by failure to maintain randomization (maintenance set in PS0015), were restricted to patients with a demonstrated response to treatment (PS0013), or did not use a Health Canada–recommended dosage regimen (i.e., every 4 weeks maintenance dosage for patients with weight < 120 kg) (PS0009, PS0015, PS0013). In addition, there were important limitations to HRQoL data (such as lack of control of type I error, unknown extent of missing data, incomplete reporting of between-group differences), which limit the interpretation of these results.

The safety data available for bimekizumab were limited by the sample size and study duration of the trials, which may have been insufficient to detect infrequent adverse events or those that take a longer time to develop.

With respect to external validity, the characteristics of the patients enrolled in the trials were considered representative of patients in Canada with moderate to severe plaque psoriasis in Canada who may be treated with biologic drugs, according to the clinical expert consulted for this review. The trials, however, excluded patients with a history of nonresponse to IL-17 inhibitors or nonresponse to more than 1 biologic drug other than an IL-17 inhibitor. Thus, the treatment effects of bimekizumab in these patients in unknown. Moreover, concomitant use of topical therapies, phototherapy or non-biologic systemic drugs was prohibited during the trials, as was the titration of biologic drug dosages or dosing frequency to effect, which is common in clinical practice. Thus, the prescribing patterns of biologic controls or co-interventions used during the trial may not reflect clinical practice.

Indirect Comparisons

Description of Studies

The sponsor submitted an indirect treatment comparison (ITC) that evaluated the efficacy of bimekizumab in the treatment of moderate to severe chronic plaque psoriasis compared with other biologic and non-biologic systemic treatments. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Results

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Critical Appraisal

Several sources of heterogeneity were noted across the trials, including the proportion of patients with comorbid psoriatic arthritis, prior exposure to biologics or other non-biologic therapies, region, duration of disease, study years, timing of the outcome assessment, and placebo response rate. Due to this heterogeneity, the ITC was conducted ||||||||||||||||||||||||||||||||||||||||||; however, it is uncertain whether this approach is adequate to control for differences in patient characteristics that may bias results. The ITC did not assess other outcomes of interest to this review and was limited ||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Comparative indirect evidence is lacking on ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Other Relevant Evidence

Description of Studies

The aim of the ongoing extension study, PS0014, was to examine the longer-term efficacy and safety of bimekizumab in patients who had completed 1 of the 3 pivotal studies — PS0008, PS0009, or PS0013. Interim data up to 48 weeks of the extension study were available at the time this report was written. All patients received open-label bimekizumab 320 mg SC every 4 weeks or every 8 weeks. A total of 1,286 patients were enrolled, of which 3.5% had discontinued before week 24 of the extension study. Most patients (64%) were continuing in the study and had not completed the 48-week follow-up at the time of the interim analysis of PS0014.

Efficacy Results

The proportion of patients who achieved PASI or IGA response at week 24 in Study PS0014 was similar among those who received bimekizumab every 4 weeks and every 8 weeks. At 24 weeks, 89.2% and 90.1% of patients had achieved a PASI 90 response and 87.5% and 88.3% of patients had an IGA 0/1 response, among those who received bimekizumab every 4 weeks or every 8 weeks, respectively (nonresponder imputation). PASI 100 response was reported by 72.7% and 74.9% of patients who had received bimekizumab every 4 weeks or every 8 weeks, respectively. The proportion of patients who reported a DLQI score of 0 or 1 at 24 weeks was 82.5% and 81.2% among those who received bimekizumab every 4 weeks or every 8 weeks, respectively.

Harms Results

No new safety signals were reported, based on the 48-week interim safety data in PS0014. Adverse events were reported by 59% to 71% of patients, of which infections and infestations were common (41% to 53%). Fungal infections were reported in 229 patients (18%), including Candida infections in 174 patients (14%). Serious adverse events were reported in 66 patients (5.1%), as well as 8 serious infections (0.6%) and 3 deaths.

Critical Appraisal

Limitations of the extension study include selection bias, lack of a control group, and lack of blinding. Reporting of harms and subjective measures (such as those included in the PASI score) may be biased by knowledge of treatment received. Since only descriptive statistics were published in this interim report, and since there were no comparator groups, the interpretation of the results is limited. Moreover, there is potential for selection bias, as patients who discontinued the parent RCTs due to adverse events, lack of efficacy, or other reasons were excluded. The lack of systematic follow-up after discontinuation of bimekizumab in the extension study could have missed important information regarding the long-term adverse effects of the treatment. In addition, not all patients received a maintenance dosage regimen that was consistent with Health Canada recommendations.

Conclusions

Bimekizumab showed statistically and clinically important improvement in psoriasis disease severity versus placebo, adalimumab, ustekinumab, and secukinumab, measured as PASI 90, IGA response, or PASI 100 response at week 16, among patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. The 1-year data suggest that PASI response may be maintained in the majority of patients who continue bimekizumab therapy, with between-group differences that favour bimekizumab versus secukinumab or ustekinumab.

Short-term data suggest that patients who receive bimekizumab may be more likely to show improvements in HRQoL (measured using the DLQI) than those who receive placebo, adalimumab, and ustekinumab, but not secukinumab. However, HRQoL outcomes were outside the statistical testing procedure and should be interpreted as supportive evidence in view of the inflated risk of type I error.

The indirect evidence suggests that bimekizumab |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Several sources of heterogeneity were identified across the trials included in the ITC, and it is uncertain whether the methods used to control for potential bias were adequate, or whether the between-group differences for some comparisons were clinically important.

Infections were among the most commonly reported adverse events, and fungal infections were reported more frequently among patients who received bimekizumab than among those receiving the comparators. The incidence of serious adverse events or withdrawals due to adverse events was low among patients who received bimekizumab, and no new safety signals were identified in the interim extension study data. However, the RCTs were not designed or powered to detect rare adverse events or those with a longer lag time, and longer-term comparative safety data are lacking.

Introduction

Disease Background

Plaque psoriasis is a chronic inflammatory skin disease characterized by erythematous inflammatory plaques that may be itchy or painful and are usually covered by silver, flaking scales.¹ It is a complex immune-mediated disorder, in which dysregulation of components of the innate and adaptive immune systems, keratinocyte function, and vascular structure contribute to the manifestations of the disease.⁸

In addition to the overt dermatological symptoms, plaque psoriasis is often associated with psychosocial symptoms, including poor self-esteem, and may affect various aspects of social functioning, including interpersonal relationships and performance at school or work. These negative impacts on social and work life were described by most patients who provided input for this CADTH Common Drug Review. Psoriasis is associated with several comorbid conditions, including depressive symptoms, conditions associated with an increased risk of cardiovascular disease (such as type 2 diabetes, metabolic syndrome, and obesity), and psoriatic arthritis.^1,9

The severity of psoriasis may be classified as mild, moderate, or severe, based on the extent of BSA affected, with 10% or more of BSA affected generally considered more severe disease.¹⁰ However, for patients with involvement of the hands, feet, scalp, face, or genital area, or those experiencing significant physical discomfort or emotional impacts from the disease, psoriasis may also be considered severe, regardless of BSA affected.¹⁰ For most patients with moderate to severe plaque psoriasis, the disease cannot be adequately controlled with topical treatments or phototherapy alone.¹⁰

There are multiple forms of psoriasis, including plaque, guttate, inverse, pustular, and erythrodermic psoriasis, but plaque psoriasis is the most common form and represents approximately 90% of cases.² It is estimated that up to 1 million Canadians are living with a type of psoriasis.² In Ontario, the estimated the age- and sex-standardized cumulative prevalence of psoriasis in 2015 was 2.32%.¹¹ Up to 1-third of patients with psoriasis have moderate to severe disease.^12-15

Standards of Therapy

Plaque psoriasis requires lifelong treatment. Measures of treatment success include clearance (absence of signs of disease), control (satisfactory response to therapy as defined by the patient and/or physician), and remission (suppression of signs and symptoms over time). Clearance and symptom control have been identified as treatment outcomes that are important to patients, and treatment decisions depend largely on the patient’s perception of their disease.

In patients with mild psoriasis, topical treatments (such as corticosteroids, vitamin D₃ analogues, retinoids, anthralin, and tars) may be sufficient to control the disease; however, for those with moderate to severe psoriasis, systemic therapies are often required.^16,17 Traditional systemic drugs include cyclosporine and methotrexate, but long-term use may be limited by toxicity.¹⁷ In Canada, there are several biologic drugs approved for the treatment of psoriasis (Table 4). The first biologic drugs licensed to treat plaque psoriasis were TNF alpha inhibitors. While effective and associated with rapid disease control, TNF alpha inhibitors are associated with a number of safety concerns, including serious infections (e.g., sepsis, reactivated tuberculosis, viral infections), autoimmune conditions (e.g., lupus and demyelinating disorders), and malignancies such as lymphoma.^16,17 Other available biologic drugs include the IL-23 inhibitors risankizumab, guselkumab, and tildrakizumab; the IL-12/23 inhibitor ustekinumab; and IL-17 inhibitors secukinumab, ixekizumab, and brodalumab. These drugs have been associated with serious infections; potential activation of inflammatory bowel disease, in the case of IL-17 inhibitors; and suicidal ideation, in the case of brodalumab. According to the clinical expert consulted for this review, IL-17 and IL-23 inhibitors are now chosen more frequently by Canadian dermatologists over TNF alpha inhibitors as the first biologic for the treatment of plaque psoriasis.

Drug

Bimekizumab is a humanized monoclonal antibody that binds to the IL-17A, IL-17F, and IL-17AF cytokines and inhibits their interaction with the IL-17RA/IL-17RC receptor complex.³ Bimekizumab is approved by Health Canada for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. It is available as a 160 mg/1 mL pre-filled syringe or autoinjector. The recommended dose is 320 mg, administered as 2 160 mg SC injections (pre-filled single use syringe or autoinjector) every 4 weeks for the first 16 weeks, followed by 320 mg SC every 8 weeks thereafter.³ The product monograph states that, at the prescriber’s discretion, discontinuation of treatment may be considered in patients who have shown no improvement after 16 weeks of treatment. The product monograph also states that, for patients with a body weight of 120 kg or more who did not achieve a complete skin response, a dosage of 320 mg every 4 weeks after week 16 may be considered.³

Bimekizumab underwent a standard review by Health Canada. The drug has not previously been reviewed by CADTH. The sponsor is requesting reimbursement as per the anticipated indication.¹⁸

Table 4: Key Characteristics of Drugs for Psoriasis

IL = interleukin; IV = IV; SC = subcutaneous.

^aHealth Canada indication.

Source: Product monographs.^3,19-39

Stakeholder Perspectives

Patient Group Input

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

Two responses to CADTH’s call for patient input for the bimekizumab submission were received: a submission from the Psoriasis Society of Canada and a co-operative submission from the Canadian Association of Psoriasis Patients (CAPP) and the Canadian Psoriasis Network (CPN). The information used to inform the submissions was from phone calls from psoriasis patients as well as from a survey hosted on the CAPP and CPN websites and sent to clinics conducting bimekizumab trials to share with patients. A total of 95 survey responses were received, in addition to a telephone interview with a bimekizumab trial participant.

The patients described psoriasis as a chronic inflammatory condition that can present potentially debilitating challenges. Most patients reported living with psoriatic arthritis, and about half of all survey respondents described their psoriasis as moderate or severe. Common symptoms experienced by more than 2-thirds of patients included flaking, itching, and redness, and more than half of patients experienced pain. Most patients reported that their psoriasis symptoms affected their social life, self-esteem, mental health, intimate life, sleep, and work. Many patients reported feeling that their symptoms are not effectively controlled with existing therapies. Most patients indicated that an improvement in their quality of life or a reduction in symptoms would be an important treatment outcome, in addition to the desire for a faster response to treatment, clear skin, or a cure. Moreover, a new treatment should have reduced adverse effects, be affordable, assist with persistent symptoms, and be easier to take.

Clinician Input

Input from the Clinical Expert Consulted by CADTH

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

Unmet Needs

According to the clinical expert consulted for this review, none of the available treatments for plaque psoriasis provide a cure, and there remains an unmet need. The ideal treatment would produce a sustained PASI 100 response in all patients, with a low risk of adverse effects; would minimize or eliminate the negative impact of psoriasis on HRQoL; and would benefit 1 or more of the comorbidities, particularly psoriatic arthritis. Ideally, the medication would produce remission without the need for continuous long-term administration or could be administered intermittently, as required, when the patient reaches a predetermined PASI score after interruption of therapy. In addition, the treatment would be easily accessed by the patient and convenient to administer.

Place in Therapy

In the clinical expert’s opinion, bimekizumab is unlikely to cause a shift in the treatment paradigm for moderate to severe plaque psoriasis, as it is anticipated that prior treatment with methotrexate or cyclosporine will be required for reimbursement.

Bimekizumab is the fourth IL-17 inhibitor approved for the treatment of plaque psoriasis in Canada. As such, it does not have a completely unique mechanism of action compared to currently available drugs. It is the first drug in this class to inhibit both IL-17A and IL-17F.

At present, it is impossible to predict with certainty whether a patient will respond adequately to any of the available biologic drugs. In addition, not all drugs are suitable for all patients (e.g., Crohn disease is a contraindication to the IL-17 inhibitors, severe depression with suicidal ideation is a contraindication to brodalumab, and cardiac failure and multiple sclerosis are contraindications to TNF alpha inhibitors). The expert stated that bimekizumab will be an additional efficacious drug in the treatment armamentarium and will increase the likelihood that the patient will find a drug that works well and is well tolerated.

The expert indicated that dermatologists will likely favour IL-17 inhibitors, including bimekizumab, as the first biologic drugs of choice due to their high efficacy, along with IL-23 inhibitors. Bimekizumab (for patients less than 120 kg body weight) has the advantage of a longer maintenance dosage frequency (every 8 weeks), compared to ixekizumab and secukinumab (every 4 weeks), and brodalumab (every 2 weeks).

In regard to gaps in the evidence, the expert noted that the potential for intermittent therapy with bimekizumab, and its efficacy in psoriatic arthritis, are currently unknown.

The expert anticipated that it will be uncommon for dermatologists to combine bimekizumab with methotrexate or apremilast.

In general, if there are no contraindications (or reimbursement issues, in the case of apremilast) the expert recommended trials of methotrexate, cyclosporine, acitretin (in palmoplantar plaque psoriasis), and possibly apremilast before initiating bimekizumab. Trials of non-biologic drugs are required for public reimbursement for biologic drugs and for most third-party carriers, and many patients respond well without significant toxicity. As stewards of a publicly funded health care system, dermatologists are encouraged to offer these lower-cost alternatives before offering the biologic drugs.

Patient Population

According to the clinical expert, bimekizumab is appropriate for adult patients with moderate to severe plaque psoriasis who are suitable candidates for systemic therapy. Most payors would limit use to patients with a minimum PASI score of 12 and psoriasis affecting 10% or more of BSA.

The expert anticipates that most patients with moderate to severe plaque psoriasis are likely to show an improvement with bimekizumab. However, for patients with psoriatic arthritis, additional evidence is required, including data on the relative efficacy of the IL-23 inhibitors versus the IL-17 inhibitors for psoriatic arthritis. Currently, it is impossible to identify which patients are most likely to respond to bimekizumab. In general, patients who have failed multiple previous biologic therapies may be less likely to respond to subsequent therapies than patients who are biologic-naive. The expert foresees that patients who have experienced primary or secondary failure with 1 IL-17 inhibitor may be successfully treated with another member of the IL-17 class. However, additional evidence is required.

The expert expects there will be a small portion of patients who remain clear of psoriasis for a significant time after bimekizumab is discontinued. A review of treatment interruption data will be required so that start-stop therapy options can be explored.

Patients least suitable for treatment with bimekizumab would be those with active Crohn disease or those who had failed 1 or more prior trials of an IL-17 inhibitor, according to the clinical expert.

The diagnosis of psoriasis is made clinically and is not a challenging diagnosis for dermatologists, so misdiagnosis is unlikely. Basic laboratory testing before starting bimekizumab, as with all other biologic drugs, would include HIV serology, viral hepatitis screening, and screening for latent tuberculosis.

Assessing Response to Treatment

According to the clinical expert, response to therapy is assessed based on the PASI score (as a requirement for reimbursement); in some practices, the DLQI instrument may also be used. A PASI 75 response at 16 weeks would be considered a clinically meaningful response to treatment. However, clinicians expect that patients will achieve a higher threshold of improvement with newer biologic drugs.

The expert stated that patients who have achieved a PASI 90 or PASI 100 response at 16 weeks will be offered follow-up in 1 year but may be seen earlier if response wanes or the patient is concerned about a possible adverse event. If the patient has barely achieved a PASI 75 response at 16 weeks, a follow-up appointment would be booked in approximately 12 to 16 weeks to determine whether there has been additional improvement.

Discontinuing Treatment

According to the clinical expert, the following would be reasons to discontinue treatment:

• Failure to reach PASI 75 improvement at 16 weeks

• Failure to maintain PASI 75 response during the maintenance phase; in Canada, patients would typically receive a dosage increase and addition of topical therapy to see whether response can be recaptured

• Failure of the drug to control psoriatic arthritis in patients with concomitant arthritis

• Development of a high-risk malignancy, particularly if the patient’s oncologist is advising immunotherapy

• Elective surgery (orthopedic, gastrointestinal, genitourinary) and development of significant infections; in most cases, these result in temporary discontinuation followed by resumption of the drug.

Prescribing Conditions

Bimekizumab may be administered by the patient at home after appropriate training but could also be administered at a community infusion clinic or at the prescribing dermatologist’s office.

A dermatologist will be required to diagnose, treat, and monitor patients on bimekizumab. Patients may be co-managed by dermatology and rheumatology if they also have psoriatic arthritis.

Clinician Group Input

No input was received from clinician groups.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

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

Clinical Evidence

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

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of bimekizumab 160 mg/mL solution for SC injection for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

Methods

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

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.⁴⁰

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was bimekizumab. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

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

The initial search was completed on September 8, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on January 26, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.⁴¹ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

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

Findings from the Literature

A total of 4 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Four multi-centre, double-blind RCTs met the inclusion criteria for the systematic review (studies PS0009, PS0008, PS0015, and PS0013). Study schematics for the 4 trials are shown in Figure 2 to Figure 5.

The objective of Study PS0009 (BE VIVID) was to the compare the efficacy and safety of bimekizumab versus placebo or ustekinumab in the treatment of patients with moderate to severe chronic plaque psoriasis. The study randomized 567 patients (4:2:1) to bimekizumab every 4 weeks, ustekinumab (weight-based dosing), or placebo. After 16 weeks, patients in the placebo group were switched to receive bimekizumab every 4 weeks up to week 52.

The 56-week Study PS0008 (BE SURE) was designed to evaluate the efficacy and safety of bimekizumab versus adalimumab in patients with moderate to severe plaque psoriasis. Patients were randomized 1:1:1 to bimekizumab every 4 weeks, bimekizumab every 4 weeks for 16 weeks, then every 8 weeks, or adalimumab (with crossover to bimekizumab at 24 weeks) (N = 478).

The aim of Study PS0015 (BE RADIANT) was to evaluate the efficacy and safety of bimekizumab versus secukinumab in patients with moderate to severe plaque psoriasis. A total of 743 patients were randomized (1:1) to bimekizumab every 4 weeks or secukinumab for the first 16 weeks, after which, patients in the bimekizumab group were re-randomized (1:2) to receive maintenance therapy with bimekizumab every 4 weeks or every 8 weeks up to week 48. Patients in the secukinumab group continued to receive that drug until the end of the study at week 48.

Study PS0013 (BE READY) used a randomized withdrawal design to examine the efficacy and safety of bimekizumab versus placebo at 16 weeks, and the effects of treatment withdrawal on the efficacy and safety of bimekizumab over 56 weeks. A total of 435 patients were randomized (4:1) to bimekizumab every 4 weeks or placebo for the first 16 weeks. At 16 weeks, patients in the bimekizumab group who achieved PASI 90 response were re-randomized to bimekizumab every 4 weeks, bimekizumab every 8 weeks, or placebo (1:1:1). Patients in the placebo group with a PASI 90 response at week 16 remained on placebo, and patients in both groups who were nonresponders at week 16, or who relapsed at week 20 or later, received escape therapy with bimekizumab every 4 weeks for 12 weeks.

The trials were conducted between December 2017 and June 2020, and all included sites from Canada, US, Europe, and Australia. Two studies also included sites from Asia (PS0008, PS0013). The number of Canadian patients enrolled was 61 (11%), 77 (16%), 89 (21%), and 88 (12%) in studies PS0009, PS0008, PS0013, and PS0015, respectively. In all 4 studies, randomization was stratified by region and prior biologic drug exposure (yes/no), with patients allocated to treatments using an interactive response technology. Of note, the dosage frequency of some bimekizumab groups during the maintenance period of the trials was not consistent with the Canadian product monograph, which recommends every 8 weeks for most patients.

Patients who completed the PS009, PS0008, or PS0013 trials were eligible to enter the open-label extension study, PS0014 (BE BRIGHT) and receive bimekizumab 320 mg every 4 or 8 weeks. Patients who received escape therapy in PS0013 were also allowed to enter extension Study PS0014 if they achieved at least a PASI 50 response to rescue therapy. Patients who completed the double-blind period of PS0015 were eligible to enter a 96-week open-label extension period and continued to receive bimekizumab 320 mg every 4 or 8 weeks.

Figure 2: Study Schematic Diagram for PS0009

IGA = Investigator’s Global Assessment; PASI = Psoriasis Area and Severity Index; Q4W = every 4 weeks; SFU = safety follow-up.

Source: Clinical Study Report for PS000.⁴

Figure 3: Study Schematic Diagram for PS0008

IGA = Investigator's Global Assessment; PASI = Psoriasis Area and Severity Index; Q4W = every 4 weeks; Q8W = every 8 weeks; SFU = safety follow-up.

Source: Clinical Study Report for PS0008,⁵

Figure 4: Study Schematic Diagram for PS0015

PASI = Psoriasis Area and Severity Index; PBO = placebo; Q4W = every 4 weeks; Q8W = every 8 weeks SEC = secukinumab; SFU = safety follow-up.

Source: Clinical Study Report for PS0015.⁶

Figure 5: Study Schematic Diagram for PS0013

IGA = Investigator's Global Assessment; PASI = Psoriasis Area and Severity Index; Q4W = every 4 weeks; Q8W = every 8 weeks; SFU = safety follow-up.

Populations

Inclusion and Exclusion Criteria

All 4 trials used essentially the same inclusion and exclusion criteria. They enrolled adults who had had moderate or severe plaque psoriasis for at least 6 months, who had a baseline PASI score of at least 12 points, and who had at least 10% of their BSA affected. All patients had an IGA score of at least 3 points on a 5-point scale (i.e., moderate severity psoriasis) and were candidates for systemic treatment or phototherapy.

Key exclusion criteria were patients who had experienced primary failure (no response within 12 weeks) to an IL-17 biologic drug or to more than 1 biologic response modifier other than an IL-17; who had a recent infection or history of serious, opportunistic, recurrent, or chronic infection; and who had active suicidal ideation, moderate to severe depression, or history of lymphoproliferative disease or malignancy. Patients with inflammatory conditions other than psoriatic arthritis were also excluded. Those with Crohn disease or ulcerative colitis were allowed if they had no active symptomatic disease.

Baseline Characteristics

The mean age of the patients enrolled ranged from 43.5 years (SD 13.1) to 49.7 years (SD 13.6) across treatment groups in the 4 trials (Table 8, Table 9, and Table 10). Most patients were male (64% to 73%) and White (74% to 94%), with psoriasis that was rated at moderate severity based on their IGA score (59% to 72%). The proportion of patients with a PASI score greater than 20 at baseline ranged from 34% to 47% across treatment groups in all 4 studies. Most patients (69% to 83%) had received prior systemic therapy, which included prior biologic therapy for 31% to 44% of patients, and prior IL-17 therapy for 11% to 24% of patients.

The baseline characteristics were generally similar between trials except in a few instances, such as Study PS0009, that enrolled more Asian patients (22%) than other studies (2% to 7%), and fewer patients had received an IL-17 biologic drug in Study PS0015 (12%) than in other trials (approximately 22%). A few imbalances were noted between groups in studies PS0009 and PS0008, including the median duration of disease, the proportion of patients with PASI score of 20 or higher, and the mean age in PS0009. Other baseline patient characteristics appeared to be generally well balanced between groups within trials.

Table 8: Summary of Baseline Characteristics for Study PS0009 and PS0008

ADA = adalimumab; BKZ = bimekizumab; BMI = body mass index; BSA = body surface area; DLQI = Dermatology Life Quality Index; IGA = Investigator's Global Assessment; IL = interleukin; PASI = Psoriasis Area and Severity Index; PBO = placebo; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; RS = randomized set; SD = standard deviation; SS = safety set; TNF = tumour necrosis factor; USTE = ustekinumab.

Source: Clinical Study Report for PS0009,⁴ Clinical Study Report for PS0008,⁵ Clinical Study Report for PS0015,⁶ Clinical Study Report for PS0013.⁷

Table 9: Summary of Baseline Characteristics for Study PS0015 and PS0013

BKZ = bimekizumab; BMI = body mass index; BSA = body surface area; DLQI = Dermatology Life Quality Index; IGA = Investigator's Global Assessment; IL = interleukin; PASI = Psoriasis Area and Severity Index; q.4.w. = every 4 weeks; RS = randomized set; SD = standard deviation; SECU = secukinumab; TNF = tumour necrosis factor.

Source: Clinical Study Report for PS0015,⁶ Clinical Study Report for PS0013.⁷

Interventions

Table 10 provides a summary of the study treatments administered during the initial treatment period (first 16 weeks) and the maintenance or withdrawal period (week 16 up to week 56) of the included studies.

In Study PS0009, patients were randomized to receive placebo, bimekizumab 320 mg SC every 4 weeks, or ustekinumab 45 mg or 90 mg SC at week 0, week 4, and every 12 weeks up to week 52. Weight-based dosing of ustekinumab was used, with patients weighing 100 kg or less receiving 45 mg dose and those more than 100 kg receiving the 90 mg dose. After the 16-week initial treatment period, patients in the placebo group were switched to bimekizumab 320 mg SC every 4 weeks until the end of the trial.

In Study PS0008, patients were randomized to receive bimekizumab 320 mg SC every 4 weeks; bimekizumab 320 mg SC every 4 weeks for 16 weeks, then every 8 weeks; or adalimumab 80 mg SC at week 0, 40 mg at week 1, and 40 mg every 2 weeks until week 24, after which they were switched to bimekizumab 320 mg every 4 weeks until week 56.

In Study PS0015, patients were randomized to bimekizumab 320 mg SC every 4 weeks or secukinumab 300 mg SC at weeks 0, 1, 2, 3, 4, and every 4 weeks up to week 16 (initial treatment period). At 16 weeks, patients in the bimekizumab group were re-randomized to 1 of 2 maintenance dosages: bimekizumab 320 mg every 4 weeks or bimekizumab 320 mg every 8 weeks. Patients in the secukinumab group continued to receive 300 mg every 4 weeks up until week 48. Of note, the re-randomization of the bimekizumab-treated patients at week 16 was implemented after enrolment had started based on Protocol Amendment 1 (October 17, 2018) and was applied only to patients enrolled after the protocol amendment. Patients randomized to bimekizumab before implementation of Protocol Amendment 1 continued to receive every 4 week dosage up until the 48-week study visit.

Study PS0013 randomized patients to receive bimekizumab 320 mg SC every 4 weeks or placebo for the first 16 weeks. At 16 weeks, patients in the bimekizumab group who achieved PASI 90 response were re-randomized to bimekizumab 320 mg every 4 weeks, bimekizumab 320 mg every 8 weeks, or placebo during the 40-week withdrawal period. Patients in the placebo group who achieved a PASI 90 response continued on placebo. At 16 weeks, any patients who had not achieved PASI 90 response entered the escape arm and received open-label bimekizumab 320 mg SC every 4 weeks for 12 weeks. In addition, patients who relapsed at 20 weeks or later were also enrolled in the escape arm and received open-label bimekizumab.

All the sponsor’s personnel, study investigators, and patients were blinded to the randomized treatment group. The study drug was administered by unblinded study staff who were not otherwise involved in the conduct of the trial. All patients received 1 or 2 SC injections of active study drug and/or placebo at each study visit so that the number and timing of injections were the same for all treatment groups within each study. In all studies, bimekizumab was supplied as a 1 mL pre-filled syringe containing 160 mg/mL solution for SC injection. Pre-filled syringes with placebo contained 1 mL of 0.9% sodium chloride. The active control drugs were commercially available and were supplied as a pre-filled syringes containing 45 mg/0.5 mL ustekinumab in Study PS0009, adalimumab 40 mg/0.8 mL or 40 mg/0.4 mL in Study PS0008, or 150 mg/1 mL secukinumab for Study PS0015. The study drug was administered into the lateral abdominal wall, upper outer thigh, or upper arm in a manner that the syringe could not be seen by the patient (i.e., the patient wore eye coverings or was instructed to turn away during injection).⁴⁶

Concomitant use of topical moisturizers, over-the-counter shampoos for scalp psoriasis, and mild or low-potency topical steroids were allowed in all studies. The use of mild analgesics were allowed for treatment of arthritis pain, as were nonsteroidal anti-inflammatory drugs, if the dosages were stable before screening. Other treatments for psoriatic arthritis were not allowed. The following medications were prohibited during the trial and were required to be stopped before randomization (with a specific washout period): other topical treatments for psoriasis (2 weeks); systemic non-biologic treatments for psoriasis (e.g., immunosuppressants, systemic steroids, phototherapy) (1 month); anti-TNF biologic drugs (1 to 3 months); anti-IL-17 biologic drugs (3 months); and other biologic or systemic therapies (2 weeks to 12 months, depending on the drug).

Studies PS009, PS0008, and PS0015 had stopping rules for patients who did not respond to the randomized study drug. Patients who had a persistent IGA score of 3 or higher for at least 4 weeks despite continuous treatment with the study drug for a minimum of 12 weeks were considered nonresponders and were withdrawn from the study at 24 weeks (Study PS0009), week 28 (PS0015), or week 36 (PS0008), or any subsequent time points when these criteria were met. Other protocol-defined permanent or temporary stopping criteria that applied to all studies included active tuberculosis or untreated latent tuberculosis, newly diagnosed inflammatory bowel disease or disease flare, active suicidal ideation or behaviour, severe major depression, serious adverse events, and pregnancy. Patients were prohibited from receiving live or live-attenuated vaccines during the studies.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 11. These end points are further summarized below. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Psoriasis Area and Severity Index (PASI)

The PASI is widely used in psoriasis trials to grade the extent and severity of psoriatic lesions. It combines an assessment of the BSA affected in 4 anatomic regions (head, trunk, arms, and legs) and the severity of desquamation, erythema, and plaque induration or infiltration (thickness) in each region. Scores range from 0 to 72 points. In general, a PASI score more than 10 represents more severe disease.⁴⁷ The percent improvement in PASI score is calculated as the baseline PASI score minus post-baseline PASI score, divided by baseline PASI score, multiplied by 100. Patients with a 75%, 90%, or 100% improvement are categorized as achieving a PASI 75, PASI 90, or PASI 100 response. PASI scores have shown weak to moderate correlation with DLQI scores and good inter-rater and moderate intra-rater reliability.^48,49 Responsiveness may be weak, especially when the BSA affected is less than 10%.^50,51

In all trials, investigators had documented training on how to perform PASI and IGA assessments, and the same investigator assessed efficacy outcomes for a given patient at all study visits. PASI 90 or PASI 100 response was the primary or co-primary outcome in all 4 studies, and these responses are generally accepted as representing clinically relevant improvements (see Appendix 4). In Study PS0013, relapse was defined as not achieving a PASI 75 response at week 20 or later during the withdrawal period (i.e., among patients who had achieved PASI 90 response at week 16).

Investigator’s Global Assessment (IGA)

The IGA is a composite score of physician assessment of the overall severity of the patient’s psoriatic lesions. The static version of the IGA, which is a measurement of the disease severity at a given time point, was used in all included studies. The investigator assessed the overall severity of psoriasis based on 5-point scale, as described in Table 12. Higher scores indicate a more severe condition.

In 3 studies, the co-primary outcome of IGA response was defined as a IGA score of “clear” or “almost clear” (i.e., 0 or 1), with at least a 2-category improvement from baseline, which is generally accepted as a clinically meaningful score. The same definition was used for separate analyses in the subgroup of patients with scalp or palmoplantar psoriasis who had a baseline IGA score of at least 2 for these areas. The IGA has shown moderate correlation with DLQI, and strong correlation with PASI scores.^52,53 The IGA has shown acceptable test-retest reliability,⁵² but no information on responsiveness was found.

Health-Related Quality of Life

The DLQI is a dermatology-specific questionnaire that has been used to assess the impact of the disease on a patient’s HRQoL. It is a 10-item questionnaire that covers 6 domains: symptoms and feeling, daily activities, leisure, work and school, personal relationships, and bother with psoriasis treatment, each assessed over the past week. Each item is scored on a 4-point Likert scale: 0 (not at all affected/not relevant), 1 (a little affected), 2 (a lot affected), and 3 (very much affected). The overall DLQI score is a numeric score between 0 to 30, with lower scores indicating better quality of life.^54,55 The final numeric score translates to the effect of the patient’s disease on their quality of life, where 0 to 1 = no effect, 2 to 5 = small effect, 6 to 10 = moderate effect, 11 to 20 = very large effect, and 21 to 30 = extremely large effect.⁵⁶ The DLQI has shown strong correlation with the EuroQol 5-Dimensions questionnaire (EQ-5D) index score and the bodily pain and social functioning domains of the Short Form 36 Health Survey (SF-36).⁵⁵ It may, however, lack conceptual validity for the psychological impact of psoriasis. There is evidence of responsiveness and test-retest reliability.^54,55 Estimates of the minimal important difference (MID) range from 2.2 to 6.9.^55,57 The sponsor defined a 4-point improvement in the DLQI as the MID.

The EuroQol 5-Dimensions 3-Levels questionnaire (EQ-5D-3L) questionnaire is a generic, preference-based, HRQoL measure.⁵⁸ It includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is divided into 3 levels representing “no problems,” “some problems,” and “extreme problems” (1, 2, and 3, respectively). The 5 questions are scored and together contribute to the EQ-5D index (utility) score between 0 and 1, where 0 represents death, and 1 represents perfect health. Different utility functions are available that reflect the preferences of specific populations (e.g., US, UK). The EQ-5D also includes a visual analogue scale (VAS) of the patient’s self-rated health status on a vertical 20 cm scale that ranges from 0 (worst imaginable health status) to 100 (best imaginable health status). Estimates of the MID for the VAS range from 3.8 to 10.3 in patients with psoriasis.⁵⁵

The SF-36 version 2 is a 36-item, general health status instrument that consists of 8 health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health.^59,60 The SF-36 also provides 2 component summaries, the physical component summary and the mental component summary, derived from aggregating the 8 domains according to a scoring algorithm. All domain and component scores are based on a scale of 0 to 100, with higher scores indicating higher health status. Scores are standardized with a mean of 50 and SD of 10 points in the general US population. The sponsor defined a change of 2 points in the SF-36 physical component score and 3 points in the SF-36 mental component score as the MID, which was consistent with the literature, but are not specific to patients with psoriasis.⁶¹

Harms

For the included studies, an adverse event was any untoward medical occurrence that may or may not have a causal relationship with treatment. Serious adverse events included death, any event that was life-threatening or that resulted in significant disability or incapacity, a congenital anomaly, or an important medical event that may have jeopardized the patient, required medical or surgical intervention, or hospitalization. Confirmed active tuberculosis was also reported as a serious adverse event.

The trials pre-specified several adverse events of interest and conducted special monitoring, additional data collection activities and enhanced signal detection activities for the following events: infections (serious, opportunistic, fungal, and tuberculosis), neutropenia, hypersensitivity, suicidal ideation and behaviour, depression, major cardiovascular events, liver function test changes/enzyme elevations, malignancies, and inflammatory bowel diseases. Suicidal ideation and behaviour was assessed using the self-reported electronic Columbia Suicide Severity Rating Scale questionnaire.

Statistical Analysis

Studies PS0019 and PS0013 were designed to test the superiority of bimekizumab versus placebo for the co-primary outcomes of PASI 90 and IGA 0/1 response at week 16. Study PS0008 tested the noninferiority, and then superiority, of bimekizumab versus adalimumab for the co-primary outcomes of PASI 90 and IGA 0/1 response at week 16. Both co-primary outcomes in PS0009, PS0008, and PS0013 had to show a P value of less than 0.05 for noninferiority or superiority to be demonstrated. The primary outcome in PS0015 was PASI 100 response at week 16 for bimekizumab versus secukinumab, which was tested first for noninferiority, then superiority.

The primary and other binomial outcomes in all trials were analyzed using a stratified CMH test, with prior biologic drug exposure and region as stratification factors. Patients with missing data due to early study withdrawal or who had stopped the study drug were imputed as nonresponders. For the primary and secondary outcomes, superiority versus placebo or active control was based on the CMH test P value for general association, with the OR and 95% CI reported based on the Wald test. The assessment of noninferiority of bimekizumab versus ustekinumab, adalimumab, or secukinumab in studies PS0009, PS0008, and PS0015 was established if the lower 97.5% CI for the stratified Mantel-Haenszel absolute risk difference was greater than –10%. The sponsor stated the 10% noninferiority margin was selected because it was considered to be a clinically relevant difference that could influence the choice of treatments. No citations were provided to support the noninferiority margin selected. Of note, the 16-week outcomes comparing bimekizumab to adalimumab in Study PS0008 were analyzed based on the pooled bimekizumab groups, as both groups had received the same bimekizumab dose during the first 16 weeks of the study. Table 13 describes the statistical methods used in the trials and the planned sensitivity analyses.

In Study PS0015, the proportion of patients who achieved PASI 100 response at week 48 was analyzed based on 2 populations: first, patients initially randomized to either bimekizumab or secukinumab (regardless of re-randomization of bimekizumab-treated patients at week 16); and, second, patients re-randomized at week 16 to bimekizumab every 4 weeks or every 8 weeks (maintenance set) compared to secukinumab. The COVID-19 pandemic disrupted participation in Study PS0015 for 143 patients (19%) during the last few weeks of the maintenance treatment period, which resulted in some missing data, remote (telephone or video) assessment of outcomes, or out-of-window treatment assessments. Additional sensitivity and subgroup analyses were conducted to determine any the impact of the pandemic on the findings.

For all studies, the pre-planned subgroup analyses of interest to this review included patients with scalp or palmoplantar psoriasis at baseline, prior biologic drug exposure (yes/no), prior systemic therapy (yes/no), and baseline disease severity (PASI < 20, PASI ≥ 20). Of these subgroups, randomization was stratified by prior biologic drug exposure only. Efficacy results by subgroups were reported descriptively, with the exception of scalp IGA at 16 weeks in studies PS0009 and PS0013, which were part of the fixed-sequence statistical testing procedure. No pre-planned subgroup analyses were reported based on prior biologic drug class or by body weight less than 120 kg or 120 kg or more. However, the sponsor provided post hoc pooled data by body weight.

The change from baseline in the EQ-5D VAS was reported descriptively, and no between-group comparisons were reported. The change from baseline in SF-36 mental and physical component scores were analyzed using an analysis of covariance (ANCOVA) model that included covariates for treatment, region, prior biologic drug exposure, and the baseline values. Multiple imputation methods were used to impute missing data (Table 13). The proportion of patients who achieved a DLQI score of 0 or 1 was analyzed using a stratified CMH test, with prior biologic drug exposure and regions as stratification factors. Other analyses of DLQI data have not been summarized in this report.

All studies used a fixed-sequence testing procedure to control the family-wise type I error rate. Superiority was tested based on a 2-sided alpha of 0.05, and noninferiority was tested based on a 1-sided alpha of 0.025 and a 10% noninferiority margin. In studies PS0009, PS0008, and PS0013, both of the co-primary end points had to show statistical significance for the alpha to be passed to the next comparison and for the statistical testing to proceed. Details of the testing procedure and order of testing are presented in Table 14. For any outcomes or subgroup analyses outside of these lists, there was no control of the type I error rate.

Study PS0009 was powered for superiority of bimekizumab versus placebo and ustekinumab for the co-primary outcomes of PASI 90 and IGA 0/1 response at 16 weeks. The planned sample size of 560 patients was based on a 4:2:1 randomization to the bimekizumab, ustekinumab, and placebo groups, respectively, and assumed a 16-week PASI 90 response rate of 75%, 58%, and 2%, and IGA 0/1 response rate of 85%, 68%, and 5%. Response rates were based on data from the bimekizumab phase II study PS0010⁶² and the CLEAR study⁶³ for ustekinumab. The estimated power was greater than 99% for superiority versus placebo for both outcomes, and 95% and 98% for superiority versus ustekinumab for PASI 90 and IGA 0/1, based on 2-sided significance level of 0.05. The study had greater than 99% power for noninferiority of both outcomes, based on a 1-sided significance of 0.025 and a 10% noninferiority margin.

The planned sample size in Study PS0008 was 150 patients per treatment group, assuming PASI 90 and IGA 0/1 response rates of 75% and 85% in the bimekizumab groups and 50% and 68% in the adalimumab group (based on Study PS0010 and VOYAGE-1 and VOYAGE-2 trials).^62,64,65 The trial had 97% or higher power to detect a significant difference between the bimekizumab groups and the adalimumab group for each of the co-primary outcomes at 16 weeks (2-sided significance level of 0.05 for superiority). The projected power was greater than 99% for each outcome to test for noninferiority based on a 1-sided significance level of 0.025 and 10% noninferiority margin.

The estimated sample size for Study PS0015 was 700 patients, based on which the study had 98% power to detect the superiority of bimekizumab versus secukinumab for the PASI 100 response at 16 weeks. These estimates assumed a PASI 100 response rate of 60% and 44% for bimekizumab and secukinumab, respectively (based on Study PS0010⁶² and CLEAR⁶³). The study had greater than 99% power for the noninferiority comparison, based on a 10% noninferiority margin.

Study PS0013 had greater than 99% power to detect superiority versus placebo for the co-primary outcomes at 16 weeks. The estimated sample size of 400 patients (randomized 4:1 to bimekizumab and placebo) was based on the same PASI 90 and IGA0/1 response rates as in Study PS0009. No power estimates were provided for outcomes tested during the withdrawal period.

Table 14: Sequence of Statistical Testing

IGA = Investigator's Global Assessment; MS = maintenance set; PASI = Psoriasis Area and Severity Index; PSD = patient symptom diary; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; RS = randomized set.

Source: Clinical Study Report for PS0009,⁴ Clinical Study Report for PS0008,⁵ Clinical Study Report for PS0015,⁶ Clinical Study Report for PS0013.⁷

Analysis Populations

In studies PS0009, PS0008, and PS0015, efficacy analyses were based on the randomized set, which included all patients randomized. The maintenance set included all randomized patients who received at least 1 dose of study drug during the maintenance period of these trials.

The efficacy analysis populations in study PS0013 included the randomized set (all patients randomized) and the week 16 responder set (all patients who achieved a PASI 90 response at week 16 and received at least 1 dose of study drug in the withdrawal period). The escape study set included patients who were either nonresponders at week 16 (i.e., did not achieve PASI 90) or who experienced a relapse during the withdrawal period, and had received at least 1 dose of bimekizumab as escape therapy.

In all trials, the safety set included all patients randomized who received at least 1 dose of study drug. Study PS0009 also reported safety data for the active medication set, which included all patients who received at least 1 dose of bimekizumab or ustekinumab. The bimekizumab set in Study PS0008 included all patients who received at least 1 dose of bimekizumab.

Results

Patient Disposition

The number of patients screened ranged from 576 to 1,005, of which 73% to 78% were randomized to 1 of the included studies (Table 15, Table 16, Table 17). The main reason for screening failure was that patients did not meet study eligibility criteria.

During the initial treatment period (first 16 weeks), the proportion of patients who discontinued the study drug ranged from 5% to 11% in the placebo groups, 3% to 5% in the bimekizumab groups, and 4% to 6% in the active control groups. The proportion of discontinuations was generally similar between groups within studies, with the exception of Study PS0009, in which the frequency of study drug discontinuation was higher for placebo (11%) than ustekinumab or bimekizumab (4% and 5%, respectively).

During the maintenance treatment period, the proportion of patients who stopped the study drug ranged from 3% to 11% and was generally similar between groups within trials.

Table 15: Patient Disposition for Study PS0009 and PS0008

ADA = adalimumab; BKZ = bimekizumab; MS = maintenance set; PBO = placebo; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; RS = randomized set; USTE = ustekinumab.

^aFirst 16 weeks.

^bStudy PS009 reasons for screen failure were as follows: study ineligibility (n = 151, 21%), consent withdrawn (n = 8, 1%), or other (n = 9, 1%)

^cStudy PS008 reasons for screen failure were as follows: study ineligibility (n = 123, 20%), consent withdrawn (n = 11, 2%), or other (n = 2, 0.3%)

^dWeek 16 to week 52 for Study PS0009; week 16 to week 56 for Study PS0008.

Source: Clinical Study Report for PS0009,⁴ Clinical Study Report for PS0008.⁵

Table 16: Patient Disposition for Study PS0015

BKZ = bimekizumab; MS = maintenance set; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; RS = randomized set; SECU = secukinumab.

^aFirst 16 weeks.

^bStudy PS015 reasons for screen failure were as follows: study ineligibility (n = 247, 25%) or other (n = 15, 2%)

^cWeek 16 to week 48.

Source: Clinical Study Report for PS0015.⁶

Table 17: Patient Disposition for Study PS0013

BKZ = bimekizumab; NA = not applicable; PBO = placebo; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; RS = randomized set.

^aFirst 16 weeks.

^bStudy PS013 reasons for screen failure were as follows: study ineligibility (n = 129, 22%), consent withdrawn (n = 7, 1%), or other (n = 5, 1%)

^cWeek 16 to week 56.

Source: Clinical Study Report for PS0013.⁷

Exposure to Study Treatments

During the initial treatment period, the mean duration of study drug exposure was similar between groups and ranged from 106.6 days (SD 19.5) to 110.4 days (SD 8.5) across the studies. The mean study drug exposure for the total treatment period was 321.3 days (SD 76.4) and 337.6 days (SD 74.6) for bimekizumab and ustekinumab groups in study PS0009, and 321.2 days (SD 53.4) and 315.6 days (SD 63.9) for bimekizumab and secukinumab groups in Study PS0015 (Table 18). For the patients who received bimekizumab every 4 weeks or every 8 weeks in Study PS0008, the mean treatment duration during the maintenance period was 270.9 days (SD 34.9) and 265.0 days (SD 50.3), respectively. For the total study period of PS0008, the mean total treatment duration was 230.5 days (SD 119.3) for all patients who received bimekizumab every 4 hours at any point during the trial (including those who were switched from adalimumab to bimekizumab).

For the withdrawal period of Study PS0013, patients who were switched from bimekizumab to placebo had a shorter treatment duration (192.1 days; SD 74.4) than patients who continued on bimekizumab every 4 weeks (260.0 days; SD 57.9) or every 8 weeks (268.7 days; SD 39.8) (Table 19).

Table 18: Treatment Exposure in Studies PS0009, PS0008, and PS0015

ADA = adalimumab; BKZ = bimekizumab; NA = not applicable; NR = not reported; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SD = standard deviation; SECU = secukinumab; SS = safety set; USTE = ustekinumab.

^aIncludes bimekizumab q.4.w. study drug taken in all 3 treatment groups.

^bPatients in the adalimumab group were switched to bimekizumab after 24 weeks. The mean treatment exposure at 24 weeks was 163.1 days (SD 22.7) for the bimekizumab groups and 162.2 days (SD 28.8) for the adalimumab group.

Source: Clinical Study Report for PS0009,⁴ Clinical Study Report for PS0008,⁵ Clinical Study Report for PS0015.⁶

Table 19: Treatment Exposure in Study PS0013

BKZ = bimekizumab; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SD = standard deviation; SS = safety set.

Source: Clinical Study Report for PS0013.⁷

Efficacy

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

Skin Clearance or Psoriasis Score

Initial Treatment Period

The key 16-week outcomes for all trials are shown in Table 20 to Table 22. PASI 90 and IGA 0/1 response were co-primary outcomes in studies PS0009, PS0008, and PS0013, and PASI 100 response was the primary outcome in Study PS0015. Patients with missing data were imputed as nonresponders.

In Study PS0009, 85.0% of patients in the bimekizumab group achieved PASI 90 response at 16 weeks compared with 49.7% for ustekinumab and 4.8% for placebo (Table 20). Bimekizumab every 4 weeks demonstrated noninferiority to ustekinumab as the lower limit of the 95% CI for the absolute risk difference exceeded the –10% noninferiority margin (absolute risk difference 35.2%, 95% CI, 27.0% to 43.4%). On a relative scale, bimekizumab was superior to ustekinumab (OR 6.06; 95% CI, 3.87 to 9.47; P < 0.001) and to placebo (OR 99.87; 95% CI, 34.02 to 293.18; P < 0.001). The results for the co-primary outcome of IGA 0/1 response at week 16 showed similar findings (Table 21). At 16 weeks, 84.1%, 53.4%, and 4.8% in the bimekizumab, ustekinumab, and placebo groups, respectively, achieved an IGA score of 0 or 1 (OR 4.81 bimekizumab versus ustekinumab; 95% CI, 3.10 to 7.47; P < 0.001).

The 16-week co-primary outcomes of study PS0008 were analyzed based on the pooled bimekizumab groups, as all patients received bimekizumab every 4 weeks for the initial 16 weeks, as per the statistical analysis plan. The proportion of patients who achieved PASI 90 response at 16 weeks was 86.2% and 47.2% for bimekizumab and adalimumab groups, respectively, and noninferiority was demonstrated (absolute risk difference 39.3%; 95% CI, 30.9% to 47.7%). The OR favoured bimekizumab versus adalimumab, which was statistically significant (OR 7.46; 95% CI, 4.71 to 11.82; P < 0.001). Bimekizumab also demonstrated superiority to adalimumab for the IGA 0 or 1 response at week 16 (85.3% versus 57.2%; OR 4.32; 95% CI, 2.79 to 6.77; P < 0.001).

The withdrawal study, PS0013, reported that 90.8% of patients in the bimekizumab group achieved PASI 90 response at week 16 compared with 1.2% of patients in the placebo group, with an OR of 496.32 (95% CI, 82.8 to 2,975.09; P < 0.001). The results were similar for the co-primary outcome IGA 0/1 response (92.6% versus 1.2%; OR 657.3 for bimekizumab versus placebo; 95% CI, 105.8 to 4,083.3; P < 0.001).

In Study PS0015, 61.7% and 48.9% of patients in the bimekizumab and secukinumab groups, respectively, achieved PASI 100 response at week 16 (primary outcome). The study demonstrated noninferiority of bimekizumab, as the lower limit of the 95% CI for the absolute risk difference exceeded the –10% noninferiority margin (absolute risk difference 12.7%; 95% CI, 5.8% to 19.6%). On the relative scale, the differences favoured bimekizumab versus secukinumab, demonstrating superiority (OR 1.72; 95% CI, 1.27 to 2.31; P < 0.001). At 16 weeks, 85.5% and 74.3% achieved PASI 90 response, and 85.5 and 78.6% achieved IGA 0/1 response in the bimekizumab and secukinumab groups, respectively. Between-group differences favoured bimekizumab versus secukinumab, but these outcomes were not controlled for type I error rate and should be interpreted as evidence supportive of the overall effect of bimekizumab.

In studies PS0009, PS0008, and PS0013, the proportion of patients who achieved PASI 100 response at 16 weeks (secondary outcome) ranged from 58.6% to 68.2% in the bimekizumab groups, compared with 23.9% for adalimumab, 20.9% for ustekinumab, and 0% to 1.2% for placebo groups (Table 22) The between-group differences favoured bimekizumab versus adalimumab and placebo, and all comparisons were statistically significant (P < 0.001). The comparison between bimekizumab and ustekinumab in PS0009 also favoured bimekizumab but was not part of the statistical testing hierarchy to control the type I error rate. Thus, these data should be interpretive as supportive evidence only.

For all studies, the sensitivity analyses for the primary or co-primary outcomes showed findings that were supportive of the primary analyses. The results of the per-protocol set were aligned with the randomized set (intention-to-treat population) and demonstrated noninferiority of bimekizumab versus active controls in studies PS0009, PS0008, and PS0015. Additional analyses of PASI 100 PASI 90, and IGA 0/1 response at week 24 in PS0008 (before adalimumab patients switching to bimekizumab), were comparable to results at week 16 (Appendix 3, Table 37). Across the trials, the proportion of patients who achieved PASI 75 response at week 4 ranged from 71.0% to 76.9% in the bimekizumab groups, 15.3% for ustekinumab, 31.4% for adalimumab, 47.3% in secukinumab, and 1.2% to 2.4% for placebo groups (Appendix 3, Table 38). All comparisons favoured bimekizumab versus active controls or placebo, with P values less than 0.001.

Subgroup data of interest to this review are presented in Appendix 3, Table 39 to Table 43. Descriptive data for PASI 90 or PASI 100 response and IGA 0/1 response at week 16 were generally consistent between subgroups, based on prior biologic therapy (yes/no), prior systemic therapy (yes/no), and baseline PASI score less than 20 versus 20 or higher. No data were available for subgroups based on treatment history according to biologic drug class. The European Public Assessment Report described post hoc subgroup data for patients weighing 120 kg or more that was pooled from studies PS0009, PS0008, and PS0015 (N = 88).¹² Patients weighing 120 kg or more who received maintenance dosing of bimekizumab every 4 weeks (N = 51) showed greater improvement in PASI 100 response from week 16 (39.2%) to week 48 (68.6%), compared with patients who received bimekizumab every 8 weeks (week 16: 45.9%; week 48: 51.4%; N = 37).¹² Additional sponsor-submitted post hoc subgroup data according to body weight less than 120 kg or 120 kg or more are presented in Appendix 3, Table 44.⁶⁶

The IGA response for patients with psoriasis of the scalp and palmoplantar regions is described in Appendix 3, Table 39. Across the trials, 84% to 92% of patients in bimekizumab groups achieved an IGA score of 0 or 1 of the scalp at week 16, with at least a 2-point decrease from baseline. The proportion of patients with an IGA 0/1 response of the scalp was 71% for ustekinumab, 67% for adalimumab, 87% for secukinumab, and 7% to 15% for placebo groups. In studies PS0009 and PS0013, the comparison between bimekizumab and placebo for scalp IGA response showed OR point estimates of 37.70 and 158.0, respectively, and P values less than 0.0001, favouring bimekizumab. The between-group difference in scalp IGA response favoured bimekizumab versus ustekinumab and adalimumab in studies PS0009 and PS0008, but these comparisons were not part of the statistical testing hierarchy and should be viewed as supportive evidence. No difference was detected between bimekizumab and secukinumab in terms of scalp IGA 0/1 response at week 16 in Study PS0015.

Across the studies, the proportion who achieved IGA 0/1 response at week 16 for the palmoplantar region was 81% to 94% for bimekizumab groups, 83% for ustekinumab, 71% for adalimumab, 89% for secukinumab, and 24% to 32% for placebo. No between-group comparisons were reported.

Maintenance Treatment Period

In Study PS0009, 81.9% of patients in the bimekizumab group and 55.8% in the ustekinumab group achieved PASI 90 response at week 52, with an OR of 3.80 (95% CI, 2.44 to 5.90; P < 0.001) favouring bimekizumab. IGA 0/1 response was reported for 78.2% and 60.7% in the bimekizumab and ustekinumab groups, respectively (OR 2.41; 95% CI, 1.57 to 3.70; P < 0.001) (Table 23).

Descriptive data were reported at week 56 for Study PS0008 (Table 23). Among patients who remained on bimekizumab every 4 weeks throughout the study, 84.8% and 82.3% achieved PASI 90 and IGA 0/1 response, respectively, at week 56. For patients who received bimekizumab every 4 weeks for 16 weeks, then every 8 weeks thereafter, 82.6% and 83.2% achieved PASI 90 and IGA 0/1 response at week 56, respectively.

In Study PS0015, PASI 100 response at week 48 was reported by 67.0% of patients initially randomized to bimekizumab 320 mg every 4 weeks, and 46.2% of patients randomized to secukinumab (randomized set N = 743) (Table 24). Based on the randomized set, the between-group difference favoured bimekizumab over secukinumab (OR 2.46; 95% CI, 1.71 to 3.34; P < 0.001). At 16 weeks, patients in the bimekizumab group were re-randomized to 2 maintenance dosages: bimekizumab 320 mg every 4 weeks, or bimekizumab 320 mg every 8 weeks. The 48-week results were reported based on the maintenance set, which included all patients who received at least 1 dose of study drug during the maintenance period (N = 716, 96.4%), according to the 16-week randomized treatment groups. The PASI 100 response at week 48 was 73.5%, 66.0%, and 48.3% in the bimekizumab every 4 weeks, bimekizumab every 4 weeks/every 8 weeks, and secukinumab groups, respectively. The between-group differences favoured bimekizumab versus secukinumab for both the every 4 week maintenance dosage (OR 3.24; 95% CI, 2.10 to 5.00; P < 0.001) and the every 8 week maintenance dosage (OR 2.12; 95% CI, 1.48 to 3.04; P < 0.001).

Withdrawal Treatment Period

In Study PS0013, patients in the bimekizumab group who achieved PASI 90 response at week 16 were re-randomized to switch to placebo or to continue bimekizumab every 4 weeks or 8 weeks. At week 56, 88.8% of patients in the pooled bimekizumab group reported PASI 90 response, compared with 16.2% of patients who switched to placebo (OR 47.41; 95% CI, 22.09 to 101.75; P < 0.001) (Table 25).

Relapse

Patients considered responders at week 16 in PS0013 were followed to assess the proportion who relapsed (i.e., did not achieved PASI 75 response at week 20 or later). At week 56, 77 of 105 patients (73%) who were switched from bimekizumab to placebo had relapsed, compared with 9 of 100 (9%) of patients who received maintenance dosages of bimekizumab every 8 weeks, and 12 of 106 patients (11%) who received bimekizumab every 4 weeks (no between-group statistical testing was reported).

Health-Related Quality of Life

HRQoL measures were defined as “other” outcomes by the sponsor and were not part of the planned statistical testing hierarchy in any of the studies.

Data from the proportion of patients who achieved a DLQI score of 0 or 1 at 16 weeks are summarized in Table 26. A DLQI score of 0 or 1 was considered clinically relevant and has been characterized as the condition having no impact on HRQoL.⁵⁶ The proportion of patients with a DLQI score of 0 or 1 at 16 weeks |||||||||||||| in the bimekizumab groups than placebo groups in PS0009 |||||||||||||||||||||||||||| and in study PS0013 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| a DLQI score of 0 or 1 in the bimekizumab than the ustekinumab group in PS0009 ||||||||||||||||||||||||||||||||| and for bimekizumab versus adalimumab in PS0008 ||||||||||||||||||||||||||||||||||||||||||||||||||||| However, these differences should be interpreted as supportive evidence due to the inflated family-wise risk of type I error. |||||||||||||||||||||||||||| between bimekizumab and secukinumab in PS0015 ||||||||||||||||||||||||||||||||||||||||||

Table 26: Proportion of Patients With DLQI Score 0 or 1 at Week 16 (RS)

ADA = adalimumab; BKZ = bimekizumab; DLQI = Dermatology Life Quality Index; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SECU = secukinumab; USTE = ustekinumab.

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Source: Clinical Study Report for PS0009,⁴ Clinical Study Report for PS0008,⁵ Clinical Study Report for PS0015,⁶ Clinical Study Report for PS0013.⁷

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Harms

Only those harms identified in the review protocol are reported below. See Table 27 to Table 30 for detailed harms data.

Adverse Events

In Study PS0009, 47%, 56%, and 51% of patients experienced an adverse event in the placebo, bimekizumab, and ustekinumab groups, respectively, during the initial treatment period, and 82% and 80% of patients had an adverse event in the bimekizumab and ustekinumab groups during the total study period (Table 27).

The frequency of events was similar between bimekizumab and adalimumab groups during the first 24 weeks of PS0008 (70% to 72%, respectively) and for the 2 bimekizumab maintenance dosage groups during the total study period (73% and 77%, respectively) (Table 28). Study PS0015 also reported a comparable frequency of adverse events in the bimekizumab (86%) and secukinumab groups (81%) during the total study period, as well as between bimekizumab every 4 weeks and bimekizumab every 8 week dosage groups (81% and 75%, respectively) during the maintenance period (Table 29).

In Study PS0013, 41% of patients in the placebo group and 61% in the bimekizumab group reported an adverse event in the initial treatment period. During the withdrawal period, 69% of patients who were switched from bimekizumab to placebo reported an adverse event, compared with 77% and 74% of patients who remained on bimekizumab (Table 30).

Across the studies, nasopharyngitis, oral candidiasis, and upper respiratory tract infections were the most commonly reported adverse events.

Table 27: Summary of Harms in Study PS0009

AMS = active medication set; BKZ = bimekizumab; IR = incidence rate; NA = not applicable; PY = patient-year; q.4.w. = every 4 weeks; SAE = serious adverse event; SOC = system organ class; SS = safety set; USTE = ustekinumab.

Note: IR reported as the number of patients with treatment-emergent adverse event per 100 PYs follow-up.

^aIncludes patients randomized to BKZ and those switched from placebo to BKZ after the first 16 weeks.

^bFrequency > 5%.

^cReported in 2 or more patients per treatment group.

Source: Clinical Study Report for PS0009.⁴

Table 28: Summary of Harms in Study PS0008

ADA = adalimumab; IR = incidence rate; BKZ = bimekizumab; NA = not applicable; PY = patient-year; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SAE = serious adverse event; SOC = system organ class; SS = safety set.

Note: IR reported as the number of patients with treatment-emergent adverse event per 100 PYs follow-up.

^aBKZ q.4.w. group includes all events that occurred during BKZ q.4.w. treatment for all 3 randomized treatment groups.

^bFrequency > 5%.

^cReported in 2 or more patients per treatment group.

Source: Clinical Study Report for PS0008.⁵

Table 29: Summary of Harms in Study PS0015

BKZ = bimekizumab; IR = incidence rate; MS = maintenance set; NR = not reported; PY = patient-year; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SAE = serious adverse event; SECU = secukinumab; SOC = system organ class; SS = safety set.

Note: IR reported as the number of patients with treatment-emergent adverse event per 100 PYs follow-up.

^aFrequency > 5%.

^bReported in 2 or more patients per treatment group.

Source: Clinical Study Report for Clinical Study Report for PS0015.⁶

Table 30: Summary of Harms in Study PS0013

BKZ = bimekizumab; IR = incidence rate; NR = not reported; PY = patient-year; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SAE = serious adverse event; SOC = system organ class; SS = safety set; USTE = ustekinumab.

Note: IR reported as the number of patients with treatment-emergent adverse event per 100 PYs follow-up.

^aFrequency > 5%.

^bReported in 2 or more patients.

Source: Clinical Study Report for PS0013.⁷

Serious Adverse Events

The frequency of serious adverse events was similar between groups during the initial treatment period and ranged from 1% to 3% across the placebo, bimekizumab, and active control groups. During the withdrawal period of Study PS0013, 3% to 5% of patients who switched from bimekizumab to placebo or who remained on bimekizumab experienced a serious adverse event. For the total study period, serious adverse events were reported by 3% to 6% of patients who received bimekizumab, 8% of patients who received ustekinumab, and 6% who received secukinumab across studies PS0008, PS0009, and PS0015. Specific serious adverse events reported in 2 or more patients in the bimekizumab groups included myocardial infarction, appendicitis, road traffic accident, and diarrhea.

Withdrawals Due to Adverse Events

During the initial treatment period of PS0009, 2% of patients in the bimekizumab and ustekinumab groups discontinued the study due to adverse events, compared with 7% in the placebo group. The frequency of discontinuations was similar for bimekizumab groups (2% and 4%) and adalimumab (3%) during the initial treatment period of PS0008. In Study PS0013, no patients in the placebo group and 1% in the bimekizumab group discontinued due to adverse events during the first 16 weeks, and none to 3% discontinued during the withdrawal period.

The number of patients who discontinued the study due to adverse events during the overall treatment period was generally low across trials and similar between treatment groups within studies PS0009 (bimekizumab 5%, ustekinumab 4%), PS0008 (bimekizumab 3%), and PS0015 (bimekizumab 4%, secukinumab 3%). Specific events that led to discontinuation in 2 or more patients in the bimekizumab groups were psoriasis, oral candidiasis, and increased hepatic enzyme levels.

Mortality

Seven patients died during the 4 studies, including 3 patients (0% to 0.5%) in the bimekizumab groups and 1 patient in each of the ustekinumab, adalimumab, secukinumab, and placebo groups (0% to 1.2%). The cause of death in the bimekizumab-treatment patients was cardiac arrest (PS0009), unknown cause (PS0009), and road traffic accident (PS0015). The cause of death in other groups was esophageal carcinoma (placebo), heart injury and cardiac arrest (ustekinumab), squamous cell carcinoma (adalimumab), and asphyxia and aspiration (secukinumab).

Notable Harms

Infections were a commonly reported adverse event in all studies. No cases of active tuberculosis, systemic fungal infections, or systemic opportunistic infections were reported in any of the trials.

In Study PS0009, the incidence rate of infections was higher in the bimekizumab versus placebo group (137 versus 83 patients with a treatment-emergent adverse event per 100 person-years [PYs]) during the initial treatment period, and higher versus ustekinumab in the overall study period (116 versus 74 patients per 100 PYs). However, the frequency of serious or opportunistic infections was generally low and ranged from 0% to 3% across the treatment groups. More patients in the bimekizumab group reported fungal infections compared with placebo (14% versus 0%; first 16 weeks) and compared with ustekinumab (23% versus 3%; 52 weeks). Oral candidiasis infections were the most common fungal infection reported in the overall study period (bimekizumab 15% versus ustekinumab 1%). Six patients in the bimekizumab group withdrew from the study due to fungal infections, including 1 patient with a serious esophageal candidiasis infection.

The incidence rate of infections ranged from 155 to 180 patients per 100 PYs in the bimekizumab groups compared with 151 patients per 100 PYs in the adalimumab group during the first 24 weeks of PS0008. More patients who received bimekizumab experienced a fungal infection compared with adalimumab (16% versus 1%), of which oral candidiasis was the most commonly reported fungal infection (11% versus 0%). No fungal infections led to study discontinuation. One patient in the bimekizumab and 1 in the adalimumab group experienced a serious infection during the first 24 weeks, and 8 patients who received bimekizumab had a serious infection in the overall study period. The incidence of infections in the overall study period was similar among patients who received bimekizumab every 4 weeks versus every 8 weeks (141 to 145 patients per 100 PYs).

In the total study period of PS0015, the incidence of infections was 140 patients per 100 PYs in the bimekizumab group compared with 104 patients per 100 PYs in the secukinumab group. Fungal infections were reported in 29% versus 10% of patients in the bimekizumab versus secukinumab groups, respectively, including 19% versus 3% of patients reporting oral candidiasis. The frequency of serious infections was 2% per group and of opportunistic infections was 1% or less per group. A skin candidiasis infection led to study discontinuation for 1 patient in the bimekizumab group. During the maintenance period, the incidence of infections was similar in the bimekizumab every 4 weeks and the every 8 weeks dosage groups (138 to 142 patients per 100 PYs).