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Indication: The treatment of adult patients with active ankylosing spondylitis who have responded inadequately or are intolerant to conventional therapy
CADTH recommends that bimekizumab (Bimzelx) should be reimbursed by public drug plans for the treatment of adult patients with active ankylosing spondylitis (AS) who have responded inadequately or are intolerant to conventional therapy if certain conditions are met.
Bimzelx should only be covered to treat adult patients with active AS based on the criteria used by each public drug plan for reimbursement of biologic disease-modifying antirheumatic drugs (bDMARDs).
Bimzelx should only be reimbursed if prescribed by a rheumatologist or a clinician with experience in the treatment of adult patients with active AS who are not undergoing treatment with other bDMARDs or targeted synthetic DMARDs. The cost of Bimzelx should not exceed the least expensive bDMARD reimbursed for treating AS.
AS is a type of arthritis that mainly affects the spine. It is a chronic condition that causes inflammation in the spinal joints, leading to back pain, stiffness, and sometimes eye problems. AS can lead to disability if left untreated. Approximately 300,000 people living in Canada have AS, although the actual number may be higher due to diagnosis challenges.
Given the limited availability of target therapies, current treatments becoming less effective over time, and the unequal response of patients with AS to available treatment options, there is an unmet need for treatments with sustained effectiveness that are safe and work well for all patients with active AS.
Treatment with Bimzelx is expected to cost approximately $21,198 per patient annually.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that bimekizumab be reimbursed for the treatment of adult patients with active AS who have responded inadequately or are intolerant to conventional therapy only if the conditions listed in Table 1 are met.
Evidence from a double-blind, placebo-controlled, randomized phase III trial (BE MOBILE 2 [N = 332]) demonstrated that treatment with bimekizumab resulted in added clinical benefit for adult patients with active moderate to severe AS who had failed to respond to 2 different NSAIDs or had contraindication/intolerance to NSAID compared to placebo. Specifically, assessment after the 16-week double-blind period showed that the adjusted ASAS 40 rate was 41.5% for patients treated with bimekizumab compared with 19.8% for those who received placebo, with a between-group difference: 21.8%; (95% CI, 11.4% to 32.1%). The corresponding odds ratio (OR) was 2.88 (95% CI, 1.71 to 4.87; P < 0.001) in favour of bimekizumab, indicating that treatment with bimekizumab led to a statistically significant improvement in ASAS 40 response rate. Although a minimal clinically important difference (MID) threshold was not identified for ASAS 40, CDEC agreed with the clinical expert that the difference is likely to be clinically meaningful. Assessment of other disease activity and symptom outcomes such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), nocturnal spinal pain (NSP), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) also showed least square (LS) mean differences in favour of bimekizumab that were statistically significant and reached the respective MID thresholds for the outcomes.
CDEC noted that the BE MOBILE 2 trial lacked long-term comparative evidence of bimekizumab versus placebo beyond 16 weeks. The sponsor submitted another study (Be AGILE 2 trial, N = 255) to address this gap. However, CDEC discussed that it was a single-arm phase II open-label study with potential selection bias and insufficient evidence to conclude any long-term comparative efficacy and safety advantages of bimekizumab over other treatments for AS.
CDEC acknowledged clinicians- and patients-identified unmet needs such as effective and safe treatment that work well for all patients, a limited availability of targeted therapies, waning effectiveness of current therapies over time, and a continuing need for effective treatment options for AS patients who do not respond adequately to currently available treatments. Based on the results from the BE MOBILE 2 trial, bimekizumab may address some of these unmet needs.
At the sponsor submitted price for bimekizumab and publicly listed price for all relevant comparators, bimekizumab was more costly than several relevant comparators used in the treatment of adults with active AS who have responded inadequately or are intolerant to conventional therapy. Given the lack of direct comparative evidence and the findings from the indirect treatment comparisons (ITCs) suggesting bimekizumab was no more effective than available biologic disease-modifying antirheumatic drugs (bDMARDs), there is insufficient evidence to justify a cost premium over the least expensive bDMARDs reimbursed for the treatment of active AS.
Reimbursement Conditions and Reasons.
AS is a chronic, inflammatory, and heterogeneous disease with significant burden to patients driven by pain, fatigue, and stiffness. Axial spondyloarthritis (axSpA) encompasses radiographic axial spondyloarthritis (r-axSpA, also known as AS) and nonradiographic axial spondyloarthritis (nr-axSpA). Although nr-axSpA shares several features with AS, advanced sacroiliac (SI) joint damage and spine ankylosis are absent. Patients with uncontrolled inflammation may progress to irreversible axial structural damage, spinal fractures, and severe spinal cord injury. Patients may also experience extramusculoskeletal manifestations, such as uveitis. A population-based study of the incidence and prevalence of AS in year 2010 using Ontario provincial health administrative databases found an age- and sex-standardized prevalence and incidence rates of 0.213% and 0.015%, respectively. AS was estimated to affect 300,000 patients in Canada in 2019.
NSAIDs are the first-line treatment for adult patients with active AS. After NSAIDs, advanced therapy consists of biologic or targeted disease-modifying antirheumatologic drugs (bDMARDs or tDMARDs, respectively). There are currently 2 classes of bDMARDs available in Canada for AS: TNF inhibitors and interleukin-17A (IL-17A) inhibitors. Janus kinase (JAK) inhibitors are the only class of tDMARD available for the treatment of AS in Canada, and they are indicated after a patient has experienced inadequate response to a bDMARD. Many patients with AS receiving advanced therapy will experience treatment failure. When failure of advanced therapies occurs, it is recommended to switch to another advanced therapy either within the same class or to another class. There is very little evidence to guide switching between advanced therapies. Therefore, guidelines recommend any switch within or between treatment classes when treatment failure occurs.
Bimekizumab has been approved by Health Canada for the treatment of adult patients with active AS. Bimekizumab is a humanized IgG1/κ monoclonal antibody that neutralizes IL-17A, IL-17F and IL-17AF cytokines. It is available as 160 mg/mL, solution for subcutaneous injection and the dosage recommended in the product monograph is 160 mg given as 1 subcutaneous injection every 4 weeks.
To make its recommendation, the committee considered the following information:
A total of 2 inputs were submitted for this review. One came from ACE, and the other was a joint submission by 4 patient groups: The CSA, CAPA, ASC, and CJ. ACE conducted an online survey between 2019 and 2022 to gather information from patients with AS (n = 4). The joint input by 4 patient groups was prepared based on an online survey conducted from September – October 2023 among patients with AS (n = 109).
According to the joint input by 4 patient groups, the majority of patients with AS experience back pain (90.48%), joint stiffness (79.05%), fatigue (77.14%), and hip pain (71.43%), have difficulties in exercising or being active (80.77%), challenges with sleep (73.08%), as well as impaired ability to work (57.69%) and make social connections (53.85%). Besides, patients living with AS require help with daily activities and emotional support from caregivers. Input by ACE echoes the patient experiences provided by the joint input and added flare-ups, deconditioning, anxiety, and mood changes as the impact of AS on their daily lives. Outcomes of interest to patients mentioned in the joint input were improved symptoms (71%) such as less fatigue, pain, and stiffness, better quality of life (67%) including ability to socialize more and better mental well-being, affordability to manage AS (66%), reduced side effects of medications (48%), and convenience (36%) in terms of drug dosing schedules, route of administration or formulations. The ACE input agrees with these outcomes of interest and added that ease of movement, ability to exercise more, control of back spasms and inflammation, less weight gain are other outcomes of interest.
The joint input emphasized that approximately half of patients become resistant to their treatments within 5 years, therefore, access to new treatment options is essential. Of note, the 4 patient groups pointed out that for Canadians it takes on average 7 to 10 years from the onset of symptoms to be diagnosed with AS. Delayed diagnosis and treatment then lead to irreversible damage and negative impact on mental health. According to the input, patients with AS experience a significantly impacted quality of life and frustration during this time.
The clinical expert consulted by CADTH indicated that the goals of treatment are to control pain and inflammation and prevent radiographic damage and disability related to AS. The clinical expert stated that the treatment of AS is tailored according to current manifestations of the disease (axial, peripheral, entheseal, extra-articular symptoms and signs), level of current symptoms, clinical findings, and prognostic indicators, disease activity, pain, physical function, structural damage (joint especially hip involvement, spinal deformities), comorbidity, concomitant drugs, and the wishes and expectations of the patient. The clinical expert consulted by CADTH indicated that unmet needs in the management of AS included some patients not responding to available treatments once initiated (primary failure), many patients developing active disease after initially responding to treatment (secondary failure), limited access to early diagnosis and treatment; choosing the right drug for the right patient at the right time (precision medicine) due to the availability of relatively few targeted therapies (TNFi, IL17Ai, and JAKi); and safety concerns for most DMARDs as well as NSAIDs. According to the clinical expert, these safety concerns include infections with most drugs, new onset or worsening of associated diseases (uveitis, inflammatory bowel disease [IBD], and psoriasis) and comorbidities, thus, treatments that are safe, effective for all manifestations and well tolerated by most patients are needed. Though the efficacy of various drugs on the musculoskeletal manifestations are similar, no drug is equally effective for all manifestations and their effect on associated diseases may vary as per feedback from the clinical expert.
The clinical expert consulted by C”DTH indicated that bimekizumab would fit after failure of NSAIDs either by itself or in combination with NSAIDs in clinical practice. The clinical expert would not reserve bimekizumab for patients with refractory disease or patients who are intolerant to other therapies as there are no other drugs targeting both IL17A and F cytokines. The clinical expert stated that given bimekizumab’s efficacy in both musculoskeletal and skin disease, it may be the drug of choice following treatment with NSAIDs in patients with severe skin psoriasis and who do not have IBD.
Patients with a previous personal or family history of IBD may not be candidates for treatment with bimekizumab. This is because, according to the clinical expert consulted by CADTH, the use of IL17 inhibitors would increase the risk of IBD flares based on the experience with using DMARDs targeting IL17A in patients with IBD. The clinical expert consulted by CADTH stated that patients having inadequate response to currently available DMARDs are most in need of an additional treatment option. The clinical expert indicated that patients best suited for treatment with bimekizumab are generally identified by clinician examination and judgment.
According to the clinical expert consulted by CADTH, clinical response is determined by change in severity of back pain as assessed by patient-reported questionnaires including total back pain score and the BASDAI. More objective measures, such as the Ankylosing Spondylitis Disease Activity Score (ASDAS), are used in tertiary care centres. Other measures include improvement in enthesitis counts, joint counts (tender and swollen), as well as improvement in skin psoriasis. These measures aligned with the assessments used in clinical trials. The clinical expert consulted by CADTH indicated that BASDAI score at 3 to 6 months would be used to assess response. At least a 50% reduction in BASDAI score or at least 2 absolute point reduction in BASDAI score is usually required to suggest clinically significant improvement.
According to the clinical expert consulted by CADTH, a lack of response in back pain (given that other causes of back pain are excluded) and secondary failure (relapse) are the most important factors to consider when deciding to discontinue treatment with bimekizumab. The clinical expert indicated that recurrent infections, and the occurrence of IBD would require discontinuation of bimekizumab. The clinical expert indicated that discontinuing the treatment with bimekizumab is determined by clinical evaluation by a rheumatologist, sometimes involving imaging by MRI.
The clinical expert stated that rheumatologists are trained to identify inflammatory sacroiliitis and spondylitis; therefore, the diagnosis should be made by them. According to the clinical expert consulted by CADTH, patients with AS are usually treated in an outpatient setting both in community clinics and clinics attached to community and academic hospitals. In rare instances severe disease including skin, eye and bowel disease may warrant admission to a hospital. A rheumatologist is required to diagnose, treat, and monitor patients with AS. Since uveitis, IBD and skin psoriasis are present with AS, ophthalmologists, gastroenterologists and dermatologists are also relevant to disease management.
The clinical expert consulted by CADTH stressed that the treatment options for patients with active AS are limited and thus bimekizumab provides an additional treatment option for such patients.
No clinician group input was submitted for this review.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions from the Drug Programs.
One pivotal trial (BE MOBILE 2) was included in the sponsor’s systematic review. The BE MOBILE 2 trial was a phase III, multicentre, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of bimekizumab in patients with active AS compared to placebo. This study enrolled adults who had active AS (i.e., radiographic axial spondyloarthritis [axSpA]) and fulfilled the modified New York (mNY) criteria. Eligible study participants (N = 332) were randomized 2:1 to receive bimekizumab (n = 221) 160 mg/mL or placebo (n = 111) subcutaneously every 4 weeks (Q4W). The mean age of all study participants was 40.4 years with a range of 19 to 80 years. Treatment groups were generally well balanced with respect to AS-related and other baseline disease characteristics. At baseline, the majority of all study participants were using NSAID therapies (79.8%) and prior anti-TNF therapy was used by 16.3% of all study participants. The primary objective of the BE MOBILE 2 trial was to demonstrate the efficacy of bimekizumab administered subcutaneously Q4W compared to placebo in the treatment of patients with active AS. The primary end point of the study was Assessment of SpondyloArthritis International Society 40% (ASAS 40) and secondary end points included BASDAI, BASFI, NSP; based on numeric rating scale (NRS), MASES, and HRQoL using the ASQoL and Work Productivity and Activity Impairment Questionnaire-specific health problem [WPAI-SHP]) scales.
At week 16 of the double-blind treatment period, patients in the bimekizumab group reported a higher adjusted ASAS 40 response rate compared with the placebo group (41.5% vs, 19.8% for bimekizumab versus placebo; between-group difference: 21.8%; 95% CI, 11.4% to 32.1%). This corresponded to an OR of 2.88 (95% CI, 1.71 to 4.87; P < 0.001) in favour of bimekizumab. No estimate of a between-group MID was identified by CADTH, but clinical expert input suggested the absolute difference between groups was clinically important based on a 15% threshold. The ASAS 40 response in the bimekizumab group was also observed at weeks 24, 36, and 52. Prespecified subgroup analyses of ASAS 40 response rate at week 16 were generally consistent with the primary analysis. At week 16 of the double-blind treatment period, patients who were TNF alpha inhibitor-naive or experienced in the bimekizumab group reported a higher adjusted ASAS 40 response rate compared with those in the placebo group (45.7% and 40.5% versus 23.4% and 17.6% for bimekizumab versus placebo). The results of sensitivity and supportive analyses, including the tipping point analyses, were in line with the primary efficacy results.
At week 16, patients in the bimekizumab group had a greater LS mean reduction (reductions reflect improvement) from baseline in BASDAI score compared with patients in the placebo group (LS means, –2.7 versus –1.7 for bimekizumab versus placebo). An estimated median MID of 1.4 points (range = 0.9 to 1.8) was identified in the literature. The clinical expert consulted by CADTH indicated that they would consider a 1-point difference between groups as clinically meaningful. The difference in LS means between treatment groups was –1.04 (95% CI, –1.5 to –0.6; P < 0.001) in favour of bimekizumab. Generally, the treatment effects of bimekizumab on the BASDAI were observed at weeks 24, 36, and 52.
At week 16, patients in the bimekizumab group had a greater LS mean reduction (reductions reflect improvement in physical function) from baseline in BASFI score compared with patients in the placebo group which worsened (LS means, –1.9 versus –1.0 for bimekizumab versus placebo). An estimated median MID of 1.1 points (range = 1.0 to 1.4) was identified in the literature. The difference in LS means between treatment groups was –1.1 (95% CI, –1.5 to –0.6; P < 0.001) in favour of bimekizumab. The clinical expert consulted by CADTH suggested a MID of 1 point for between-group difference. Generally, the treatment effects of bimekizumab on the BASFI were observed at week 24, 36, and 52.
At week 16, patients in the bimekizumab group had a greater LS mean reduction (reductions reflect improvement) from baseline in NSP (based on NRS) score compared with patients in the placebo group which worsened (LS means, –3.2 versus –1.7 for bimekizumab versus placebo). An estimated median MID of 1.5 points (range = 1.1 to 2.3) was identified in the literature. The difference in LS means between treatment groups was –1.5 (95% CI, –2.0 to –1.0; P < 0.001) in favour of bimekizumab. The clinical expert consulted by CADTH identified a MID of 1 point for between-group difference. Generally, the treatment effects of bimekizumab on the NSP were observed at week 24, 36, and 52.
At week 16 of the double-blind treatment period, patients with enthesitis at baseline in the bimekizumab group reported a higher adjusted enthesitis-free rate compared with those in the placebo group (43.8% versus 23.9% for bimekizumab versus placebo; between-group difference: 19.8%; 95% CI, 6.3% to 33.4%). This corresponded to an OR of 2.47 (95% CI, 1.30 to 4.68) in favour of bimekizumab. No estimate of a between-group MID was identified by CADTH, but clinical expert input suggested a 15% difference would be clinically important, therefore, the absolute difference between groups was clinically important. Generally, the treatment effects of bimekizumab on the enthesitis-free rate were observed at week 24 and 52. The enthesitis-free state outcome was not controlled for type I error rate and thus these data should be interpreted as supportive evidence only.
At week 16, patients in the bimekizumab group had a greater LS mean reduction (reductions reflect improvement) from baseline in ASQoL score compared with patients in the placebo group which worsened (LS means, –4.6 versus –3.1 for bimekizumab versus placebo). A MID of 1 unit of worsening (i.e., + 1) or 2 units improvement (i.e., −2) was identified in the literature. The difference in LS means between treatment groups was –1.5 (95% CI, –2.4 to –0.7; P < 0.001) in favour of bimekizumab. The clinical expert consulted by CADTH identified a MID of 2 points for between-group difference. Generally, the treatment effects of bimekizumab on the ASQoL were observed at week 24, 36, and 52.
At week 16, the bimekizumab group compared with the placebo group had a greater mean reduction (improvement) from baseline in WPAI-SHP score for percent time missed due to disease-related problems (–5.5 versus –1.2; between-group difference: –2.9; 95% CI,–6.9 to 1.1), percent impairment while working due to disease-related problems (–20.8 versus –6.1; between-group difference: –12.5; 95% CI,–18.2 to –6.9), percent overall work impairment due to disease-related problems (–22.2 versus–6.7; between-group difference: –12.8; 95% CI,–18.7 to –6.9), and percent activity impairment due to disease-related problems (–23.3 versus –14.4; between-group difference: –9.4; 95% CI,–13.9 to –4.9). No MIDs for WPAI-SHP were identified in the literature. Generally, the treatment effects of bimekizumab on the WPAI-SHP domains were observed at week 24, 36, and 52 except for percent activity impairment due to disease-related problems where patients reported similar results between groups. The WPAI-SHP outcome was not controlled for type I error rate and thus these data should be interpreted as supportive evidence only.
Any adverse event (AE) was reported among 54.3% of patients in the bimekizumab group and 43.2% of patients in the placebo group at week 16. The most commonly reported adverse events (i.e., reported by ≥ 5% of patients in either group) were: infections and infestations (28.1% versus 22.5% for bimekizumab versus placebo), gastrointestinal disorders (13.1% versus 9.9%), nervous system disorders (8.1% versus 4.5%), upper respiratory tract infection (2.7% versus 7.2%), and eye disorders (2.3% versus 6.3%).
Serious adverse events (SAEs) were reported among 2.3% of patients in the bimekizumab group and 0.9% of patients in the placebo group at week 16. The following SAEs were commonly reported in the bimekizumab group but no patients in the placebo group: Goitre (0.5%), colitis ulcerative (0.5%), Crohn disease (0.5%) cholelithiasis (0.5%), and hepatitis A (0.5%).
Discontinuation due to AEs was reported among 2.7% of patients in the bimekizumab group but no patients in the placebo group at week 16. The commonly reported AEs that led to study discontinuation in the bimekizumab group were psychiatric evaluation abnormal (0.9%), lymphoid tissue hyperplasia (0.5%), Crohn disease (0.5%), oral candidiasis (0.5%), and rash (0.5%). No deaths due to AEs were reported during the double-blind treatment period in the BE MOBILE 2 trial.
Serious infections, fungal infections, opportunistic infection, malignancies, major adverse cardiac event, neutropenia, suicidal ideation and behaviour, IBD, hypersensitivity reactions, and liver injury or disorders were considered notable harms by the sponsor and/or the clinical expert consulted by CADTH. The commonly reported notable harms were hypersensitivity reactions (7.7% versus 1.8 for bimekizumab versus placebo), fungal infections (6.3% versus 0), liver injury or disorders (4.5% versus 3.6%), IBD (1.8% versus 0), neutropenia (0.5% versus 0), and serious infections (0.5% versus 0.9).
The CADTH review team noted that there were no comparative data available beyond week 16 as patients in the placebo group were reallocated to receive bimekizumab during the 36-week maintenance period after finishing all assessments at the end of the 16-week double-blind treatment period. Therefore, it is uncertain what the direct comparative efficacy and safety of bimekizumab are after week 16. For the analysis of the primary and key secondary end points, a fixed sequence testing procedure was employed to adjust for multiple comparisons across multiple end points, thereby controlling the type I error. The CADTH review team noted that the analyses of enthesitis-free state based on MASES index was not included in the fixed sequence testing hierarchy and thus the results should be considered as supportive evidence. Although the subgroup analyses were prespecified, the BE MOBILE 2 trial was not powered to detect any change in the ASAS 40 response rate between bimekizumab and placebo in subgroup analyses except for the subgroup of patients who are TNFi-naive, additionally, no formal statistical tests for interaction between subgroups were conducted. There were 2 protocol amendments regarding eligibility criteria made after the enrolment of the first patient (April 25, 2019). The CADTH review team considered these 2 protocol amendments may increase patient heterogeneity and introduce bias. The direction of the bias is uncertain as there were no data reported on the numbers of patients with psoriatic arthritis and patients who had failed to more than 2 NSAIDs included in the trial. HRQoL is considered a relevant outcome by patients with active AS and the clinical expert consulted by CADTH. However, the assessment of the ability of returning to normal activities and/or functioning using WPAI-SHP was not controlled for multiplicity and thus should be considered as exploratory and supportive.
The BE MOBILE 2 trial used placebo as the comparator group. According to the clinical expert consulted by CADTH, an anti-TNF biosimilar monoclonal antibody would be an appropriate comparator to bimekizumab. The clinical expert indicated placebo is not an appropriate comparator, head-to-head studies with an active drug would be ideal. The BE MOBILE 2 trial excluded patients with more than 1 TNF alpha inhibitor and/or more than 2 additional non-TNF alpha biological response modifiers, or any IL-17 biological response modifier at any time. The clinical expert indicated that those patients should be considered eligible for bimekizumab, although the response rate might be lower, some patients do respond to bDMARDs after failure to TNF inhibitors and IL17 inhibitors, therefore, the clinical expert would switch treatments within the same class due to relatively limited treatment options. According to the clinical expert, the study results would not be generalizable to those prior mentioned patients as it is expected that the response rates will be lower in this patient population, which tends to have lower response rates with subsequent treatments in clinical practice. In addition, there was no study site in Canada in the BE MOBILE 2 trial, which may compromise the generalizability of the study results to the clinical practice in Canada.
For the pivotal BE MOBILE 2 trial identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group. Following the GRADE approach, evidence from randomized controlled trial (RCTs) started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: ASAS 40, BASDAI, BASFI, NSP, MASES, HRQoL (ASQoL and WPAI-SHP), and SAEs.
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of a clinically important effect based on thresholds informed by the clinical expert consulted by CADTH for this review for ASAS 40, BASDAI, BASFI, NSP, MASES, ASQoL, and SAEs. For WPAI-SHP, there is no established MID and the clinical expert consulted by CADTH could not provide a threshold of important difference so the target of the certainty of evidence assessment was the presence or absence of any (non-null) effect.
Summary of Findings for Bimekizumab Versus Placebo for Patients With Active Ankylosing Spondylitis.
One single-arm, phase II, OLE study, BE AGILE 2, was submitted by the sponsor as supporting evidence. Patients who had been enrolled in and completed BE AGILE trial were rolled over to BE AGILE 2 (N = 255), which was conducted in European countries and the US All patients in BE AGILE 2 received open-label bimekizumab 160 mg every 4 weeks for up to 204 weeks, i.e., a total possible exposure of 252 weeks for those who have taken bimekizumab in the parent trial, BE AGILE.
ASAS 40 response was sustained up to week 208 in BE AGILE 2 (147/249 [59%] by nonresponder imputation (NRI), 147/201 [73.1%] by observed case data). The mean BASDAI score decreased from baseline value and was sustained by week 208 (n = 249, −4.01, standard error [SE] = 0.13 versus an MID range of 0.9 to 1.8 points). The mean BASFI score decreased from baseline and sustained at week 208 (n = 249, −3.1 [SE = 0.15]). Relative to baseline, the NSP score decreased and maintained at week 208 (n = 249, −4.55 [SE = 0.16] versus an MID range of 1.1 to 2.3 points). Also, the mean ASQoL score decreased from baseline and was maintained through week 208 (n = 249, −5.9 [SE = 0.3] versus an MID range of + 1 [worsening] to −2 [improvement] units). Among patients with enthesitis at baseline, the mean MASES score decreased and maintained improvement up to week 208 in BE AGILE 2 (n = 164, −0.37 [SE = 0.23]). WPAI-SHP was not assessed in BE AGILE 2 study.
A total of 237 (92.9%) study participants reported any treatment-emergent adverse event (TEAE) during BE AGILE 2. Most commonly reported TEAEs were nasopharyngitis (18%), upper respiratory tract infection and corona virus infection (12.9% each), and bronchitis (8.6%). There were 46 (18.0%) patients who experienced at least 1 SAE, with corona virus infection and pneumonia being the most common (1.2% each). Twenty-one (8.2%) patients discontinued study treatment due to TEAE mostly due to ALT (1.2%) and AST (0.8%) elevation. Two fatal TEAEs were reported during the study: 1 incident due to road traffic accident and another incident due to cardiorespiratory arrest. Fungal infection (18.4%) and hypersensitivity (11.4%) were the most common adverse events of special interest reported during BE AGILE 2, where vast majority of fungal infections did not lead to treatment discontinuation (a single patient discontinued due to perirectal abscess).
A lack of a control group, open-label design, and selective patient population are the major limitations of BE AGILE 2 extension study. Open-label design without comparator arm could overestimate results for efficacy outcomes, especially the patient-reported outcomes. Moreover, a risk of selection bias was noted for BE AGILE 2 since patients who have responded to bimekizumab and tolerated side effects are more likely to continue the extension period.
The network meta-analyses (NMAs) were performed to determine the clinical efficacy and safety of bimekizumab, compared with other relevant interventions at week 12 to 16, for the treatment of patients with AS. The NMAs were conducted on 3 different networks: purely naive (100% bDMARD-naive, 24 studies, 4,145 patients), predominantly naive (~90% bDMARD-naive, 26 studies, 5,271 patients), and purely experienced (100% bDMARD-experienced, 9 studies, 1,048 patients).
The unanchored matching-adjusted indirect comparisons (MAIC) were performed to establish long-term relative clinical efficacy of bimekizumab compared to other IL-17A inhibitors in patients with AS at week 52.
In the bDMARD pure naive network, for most comparisons between bimekizumab versus TNFis, IL-17i’s or JAKis, there were no clear differences observed. The exceptions to this were 2 findings in which bimekizumab showed statistically significant improvement in SF-36 PCS results compared to adalimumab and compared to secukinumab but the differences observed were not clinically significant and the credible intervals were wide, indicating uncertainty.
In the bDMARD predominantly naive network, for most comparisons between bimekizumab versus TNFis, IL-17i’s or JAKis, there were no clear differences observed. There were some exceptions to this general observation which were statistically significant differences, but these were not clinically significant and credible intervals were wide, indicating uncertainty. Bimekizumab showed improvement in SF-36 PCS and Assessment of SpondyloArthritis International Society (ASAS-PR) results compared to secukinumab. Results favoured etanercept compared to bimekizumab for BASDAI 50 and BASFI. Results favoured golimumab IV compared to bimekizumab for BASFI and ASQoL. Results favoured adalimumab and certolizumab over bimekizumab for Ankylosing Spondylitis Disease Activity Score – inactive disease (ASDAS-ID). Results favoured tofacitinib over bimekizumab for Bath Ankylosing Spondylitis Metrology Index (BASMI). Results favoured upadacitinib over bimekizumab for ASDAS-ID.
In the bDMARD-experienced network, for most comparisons between bimekizumab versus TNFis, IL-17i’s or JAKis, there were no clear differences observed. The exceptions to this were 2 findings in which results favoured certolizumab over bimekizumab for ASQoL and SF-36 PCS. In these 2 instances, the difference may be clinically significant, but the credible intervals were wide, indicating uncertainty, and these results were not confirmed in the other networks.
MAIC analyses suggested that bimekizumab 160 mg Q4W had statistically significantly better results at week 52 compared with ixekizumab 80 mg Q4W for ASAS 20, ASAS 40 and BASDAI-Change from baseline and BASDAI 50. Results also favoured bimekizumab over secukinumab 150 mg Q4W for ASAS 40 and BASDAI-Change from baseline. However, there were significant limitations to the MAIC that preclude making claims of superiority of bimekizumab over comparators.
The sponsor conducted NMAs of bimekizumab compared to other medications in the context of axial spondyloarthritis for 2 harms outcomes: discontinuation due to any reason and SAEs. The comparators of interest with data available for this NMA were IL-17A inhibitors ixekizumab and secukinumab, tumour necrosis factor-alpha inhibitors adalimumab, certolizumab pegol, etanercept, golimumab (subcutaneous (SC) or IV routes) and infliximab (IV), Janus kinase inhibitors tofacitinib and upadacitinib.
The network for analysis of discontinuation due to any reason contained 18 studies. Study discontinuation rates were low in all trials (range: 0 to 14 patients per treatment arm). Time points between 12 and 16 weeks were used for this analysis. Credible intervals were very wide for most estimates. There were no clear differences seen between bimekizumab and any other treatment. There was 1 finding in which bimekizumab had a higher risk of study discontinuation compared to tofacitinib, however, the uncertainty around this estimate was high as reflected by a wide credible interval.
The network for analysis of SAE’s contained 18 studies. SAE rates were low in all studies (range 0 to 10 SAE’s per treatment arm). Time points between 12 and 16 weeks were used for this analysis. Credible intervals were very wide for most estimates. There were no clear differences between bimekizumab and any other treatments in the network.
There were no harms outcomes assessed in the MAIC.
The sponsor conducted an NMA using a Bayesian approach. This was a reasonable method to apply given the common comparator of placebo. The sponsor’s decision to perform 3 separate NMA analyses based on the potential effect modifier of prior exposure to bDMARDs was appropriate. Some networks had a large number of trials and a large number of patients which were considered a strength of the NMA analyses. The sponsor did not perform sensitivity analyses in the NMA and did not attempt to identify and adjust for effect modifiers despite the availability of a large number of trials for some of the networks. The time point of 12 to 16 weeks that was selected for outcome analyses was reasonable and clinically relevant for efficacy but not as meaningful for harms since an assessment of long-term harms was lacking.
Confidence intervals and credible intervals were wide for many estimates in the NMA. Despite the large number of trials, the number of patients and events in some analyses were small, precluding the possibility of detecting a difference between treatments. For example, the incidence of harms outcomes was small, resulting in very wide credible intervals around the estimates. For this reason, the results of the harms analyses were not informative and did not serve to illuminate the risk of harms for bimekizumab relative to other treatments.
The sponsor performed an unanchored MAIC because of the lack of a placebo arm beyond week 16 for bimekizumab and comparators. This was an adequate justification for performing a MAIC. The selection of comparators from the same pharmacologic group (IL-17A inhibitors) was a rational approach, but comparisons to other biologics would also have been of interest. The MAIC allowed a comparison of 52 weeks of clinical data. The MAIC analyses suggested there were some differences favouring bimekizumab compared to secukinumab and ixekizumab for ASAS 20, ASAS 40 BASDAI-Change from baseline and BASDAI 50 but several limitations of the MAIC prevent drawing strong conclusions regarding the comparative effectiveness of bimekizumab. For example, there were important differences between the studies included in the MAIC that did not account for several of the prognostic factors that were deemed important by the authors of the MAIC, were not used in the weighting adjustments of the MAIC. There were notable differences in study populations before and after adjustment. In the MAIC analyses, the ESS for the bimekizumab group was reduced to 80% for the comparison to secukinumab 150 mg, 51% for the comparison to secukinumab 300 mg, and 20% for the comparison to ixekizumab. Not all matching variables that were deemed important were used in the weighting adjustments of the MAIC analyses. Regarding the MAIC analyses, the sponsor noted that “the amount of bias in the indirect comparisons are likely to be substantial” and CADTH reviewers agree with this assessment.
Results of the sponsor’s NMA did not show consistent differences between bimekizumab and comparators in the networks for efficacy or harms outcomes. While differences were reported in a small number of comparisons in some populations, these were associated with wide 95% CrIs for many of the comparisons, indicating imprecision of the results.
Results of the sponsor’s MAIC favoured bimekizumab for some outcomes but there were significant limitations. The limitations include differences in study design and providing models with partial adjustments of prognostic and effect modifiers rather than fully adjusted. These limitations, in addition to the substantial reduction in effective sample sizes, undermine any claims of superior performance of bimekizumab over comparators in the MAIC.
Neither the NMA nor the MAIC provided clear evidence of a difference in efficacy or harms outcomes for bimekizumab versus comparators.
The BE MOBILE 1 trial was a phase III, multicentre, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of bimekizumab in patients with active nr-axSpA. The sponsor identified the BE MOBILE 1 study as the study addressing the gap in efficacy and safety of bimekizumab in patients with active nr-axSpA. The CADTH review team considered the BE MOBILE 1 trial not relevant to this review as patients with active nr-axSpA are different than patients with active AS for whom the indication is being reviewed. Therefore, the CADTH review team notes that no studies addressing gaps in the systematic review evidence were identified for this review.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis: the total number of eligible patients was inaccurately estimated, the Non-Insured Health Benefits population was inappropriately calculated, the total population size is uncertain given the trial eligibility criteria, and the proportion of adult patients with AS requiring biologic and advanced therapies is uncertain. Based on the CADTH reanalysis, the three-year budget impact to public drug plans of introducing bimekizumab for the treatment of adult patients with AS is expected to be $1,464,006 (-$533,456 in year 1, $473,163 in year 2, and $1,524,299 in year 3). In a scenario analysis exploring the impact of reimbursing bimekizumab for the treatment of adult patients with moderate to severe AS, the 3-year budget impact is expected to be $1,601,864.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Dr. Peter Jamieson, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Ms. Alicia McCallum, Dr. Srinivas Murthy, Dr. Danyaal Raza, Dr. Edward Xie, and Dr. Peter Zed.
Meeting date: March 27, 2024
Regrets: Two of the expert committee members did not attend.
Conflicts of interest: None
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Indication: The treatment of adult patients with active ankylosing spondylitis who have responded inadequately or are intolerant to conventional therapy
Sponsor: UCB Canada Inc.
Final recommendation: Reimburse with conditions
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