Summary Basis of Decision for Bimzelx

 

Clinical Pharmacology

The medicinal ingredient of Bimzelx, bimekizumab, is a recombinant humanized full‑length monoclonal antibody of the immunoglobulin G subclass 1 kappa. Bimzelx has two identical antigen binding regions that bind and neutralize interleukin (IL)‑17A, IL‑17F, and IL‑17AF cytokines, blocking their interaction with the IL‑17RA/IL‑17RC receptor complex. Elevated concentrations of IL‑17A and IL‑17F have been shown to be implicated in several immune mediated inflammatory diseases, such as plaque psoriasis. In vitro, dual neutralization of both IL‑17A and IL‑17F with Bimzelx suppresses the expression of inflammation related genes and proteins to a greater extent than inhibition of IL‑17A alone. The availability of a novel biologic targeting a different angle of the IL‑17 inflammatory pathway (i.e., IL‑17A in conjunction with IL‑17F, and IL‑17AF) offers a potential clinical benefit compared to other available IL‑17 therapies and provides patients exhibiting treatment dissatisfaction or loss of efficacy to current available plaque psoriasis therapies with an alternate treatment option.

The clinical pharmacology data for Bimzelx were derived from six early Phase studies, and two Phase III sub‑studies. Pharmacokinetic parameter estimates of bimekizumab exposure were based on a population pharmacokinetic model derived from data obtained in the Phase III studies (described in the Clinical Efficacy section).

The standard recommended dosing regimen for Bimzelx is 320 mg every 4 weeks (Q4W) up to Week 16 and 320 mg every 8 weeks (Q8W) thereafter. For patients with a body weight ≥120 kg and who did not achieve a complete skin response, continuing with dosing Q4W after Week 16 may be considered. In order to obtain the 320 mg recommended dose, patients must take two separate 160 mg injections, using either a prefilled syringe or autoinjector presentation. Bimekizumab exposure from the prefilled syringe and prefilled autoinjector has been shown to meet the pre‑specified Health Canada bioequivalence criteria for exposure. Self-administration of Bimzelx into either the abdomen or upper thigh is supported by exposure data from two Phase III sub‑studies showing consistent bimekizumab exposure following either self‑administration, or administration by a healthcare provider. No data were provided for self-administration into the upper arm; this is reflected in the current labeling.

The most parsimonious population pharmacokinetic model for bimekizumab was a one compartment model with first order absorption and elimination kinetics. Goodness‑of‑fit and visual predictive check plots suggest that the model was appropriately parameterized and provided a good fit with the observed data. The population pharmacokinetic model predicted an absolute bioavailability of approximately 70%, consistent with observed data, and dose proportionality was observed across the dosage range 64 mg to 480 mg administered subcutaneously.

Body weight was a significant covariate for bimekizumab exposure in the population pharmacokinetic model which showed that exposure decreased as body weight increased. The average bimekizumab plasma concentration in adult patients weighing ≥120 kg was predicted to be at least 30% lower than in adult patients weighing 90 kg. Exposure-response modeling suggests that the switch in dosing regimen to Q8W after Week 16 was associated with a decrease in efficacy (as measured by Psoriasis Area and Severity Index or Investigator’s Global Assessment score) in this patient population. Therefore, a dosing regimen of Q4W after Week 16 (i.e., during the maintenance phase) may be considered for patients with a body weight ≥120 kg who did not achieve a complete skin response.

For further details, please refer to the Bimzelx Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Bimzelx for the treatment of moderate to severe plaque psoriasis in adult patients is based on clinical data from three multicentre, randomized, double‑blind, active-comparator and/or placebo controlled studies, PS0008 (adalimumab), PS0009 (ustekinumab and placebo), and PS0013 (placebo). The studies enrolled a total of 1,480 patients 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10% or more, an Investigators Global Assessment (IGA) score of ≥3 and a Psoriasis Area and Severity Index (PASI) score of ≥12, and who were candidates for phototherapy or systemic therapy. Patients with other chronic inflammatory conditions (with the exception of psoriatic arthritis) were excluded from these studies.

All three studies assessed the superiority of Bimzelx compared to an active-comparator and/or placebo based on changes from baseline to Week 16 using the following two co‑primary endpoints:

• the proportion of patients who achieved at least a 90% reduction from baseline in the Psoriasis Area and Severity Index score (PASI 90);
• the proportion of patients with an IGA of 0 (clear) or 1 (almost clear) with at least a two‑category improvement relative to baseline.

Study PS0008 evaluated 478 patients for 56 weeks. Patients were randomized to receive either Bimzelx 320 mg Q4W through Week 56, Bimzelx 320 mg Q4W through Week 16 followed by Bimzelx 320 mg Q8W through Week 56, or adalimumab as per local labeling recommendation through Week 24 followed by Bimzelx 320 mg Q4W through Week 56.

Study PS0009 evaluated 567 patients for 52 weeks where patients were randomized to receive either Bimzelx 320 mg Q4W, ustekinumab (45 mg or 90 mg, depending on patient weight, at baseline, Week 4, and then every 12 weeks), or placebo for an initial 16 weeks followed by Bimzelx 320 mg Q4W. 

Study PS0013 evaluated 435 patients for 56 weeks. Patients were randomized to receive Bimzelx 320 mg Q4W or placebo. At Week 16, patients who achieved a PASI 90 response entered the 40‑week randomized withdrawal period. Patients initially randomized to Bimzelx 320 mg Q4W were re‑randomized to either Bimzelx 320 mg Q4W or Bimzelx 320 mg Q8W or a placebo (i.e., withdrawal of Bimzelx). Patients initially randomized to placebo continued to receive placebo provided they were PASI 90 responders. Patients who did not achieve a PASI 90 response at Week 16 entered an open‑label escape arm and received Bimzelx 320 mg Q4W for 12 weeks. Patients who relapsed (did not achieve PASI 75 response) during the randomized withdrawal period also entered the 12‑week escape arm.

Across the three studies, the majority of patients enrolled were predominantly male (70.7%) and white (84.1%), with a mean age of 45.2 years (age range: 18 to 83 years). Patients had a median baseline PASI score of 18.4 and a median affected body surface area of 20%. The baseline IGA score was severe in 33.4% of study participants. A total of 38.2% of patients had received a prior biologic therapy; 23.0% had received at least one anti‑interleukin (IL)‑17 agent, and 13.2% had received at least one tumor necrosis factor‑antagonist. Overall, 22.4% of patients were naïve to any systemic therapy (including non‑biologics and biologics) and 39.3% had received prior phototherapy or chemotherapy.

The results from all three studies showed that Bimzelx treatment was associated with a statistically significant and clinically meaningful improvement in PASI 90 and IGA 0/1 responses compared to placebo, adalimumab, and ustekinumab. In Study PS0008, PASI 90 was 39.0% higher and IGA 0/1 was 28.1% higher in Bimzelx treated patients compared to adalimumab treated patients. In Study PS0009, PASI 90 was 80.2% and 35.3% higher and IGA 0/1 was 79.3% and 30.7% higher in the Bimzelx treated patients compared to patients treated either with a placebo or ustekinumab, respectively. In Study PS0013, PASI 90 was 89.6% higher and IGA 0/1 was 91.4% higher in the Bimzelx treated patients compared to patients who received a placebo. In addition, Bimzelx treatment effects were often observed within the first four weeks (i.e., PASI 75 was often achieved after a single‑dose), and by Week 16 a complete plaque psoriasis clearance was observed (i.e., PASI 100 and IGA 0) in the majority of patients. Additionally, high levels of response were sustained through Weeks 52/56 with no notable difference between dosing regimens Q4W and Q8W for maintenance, except in patients weighing ≥120 kg. When evaluating the odds ratios of complete response (i.e., IGA 0 or PASI 100) in patients weighing ≥120 kg who had not achieved complete response at Week 16, there was a notable increased likelihood of these patients achieving a complete response at Week 48 when dosed Q4W compared to Q8W for the maintenance phase. Therefore, the recommended maintenance dosing regimen for patients weighing <120 kg is Q8W, while for those weighing ≥120 kg who did not achieve a complete response at Week 16, the option of maintaining a dosing regimen of Q4W may be considered.

Other secondary endpoints measuring complete response, overall disease symptoms and severity, patient‑perceived symptoms, health‑related quality of life, and plaque psoriasis on areas of high impact were all supportive of a favourable benefit associated with Bimzelx treatment.

Overall, the efficacy data provided in this submission support the approval of Bimzelx for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

For more information, refer to the Bimzelx Product Monograph, approved by Health Canada and available through the Drug Product Database.

Indication

The New Drug Submission for Bimzelx was filed by the sponsor with the following indication, which Health Canada subsequently approved:

• Bimzelx (bimekizumab injection) is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

Clinical Safety

The safety data for Bimzelx injection was derived from the Phase III clinical studies PS0008, PS0009, and PS0013 previously described in the Clinical Efficacy section. A longer‑term extension study, PS0014, as well as two Phase II studies PS0010 and PS0016 and their longer‑term extensions (PS0011 and PS0018) were also included as part of the safety data. Overall, the safety of Bimzelx has been characterized in 1,789 patients, with 1,073 exposed to Bimzelx for at least one year. 

During the 16-week placebo-controlled period of studies PS0009 and PS0013, 670 patients received Bimzelx 320 mg Q4W compared to 169 patients in the placebo group. Adverse events were reported in 58.8% of patients receiving Bimzelx and 43.8% of patients receiving placebo. The most frequently reported treatment‑emergent adverse events (TEAE) were nasopharyngitis (7.9% Bimzelx vs. 6.5% placebo), oral candidiasis (7.3% Bimzelx vs. 0.0% placebo), upper respiratory tract infection (3.4% Bimzelx vs. 5.3% placebo), and headache (3.3% Bimzelx vs. 0.0% placebo). The frequency of serious adverse events was low and consistent between the Bimzelx (1.6%) and placebo (2.4%) treated patients. Discontinuation due to TEAE were low during the placebo‑controlled period, and were slightly lower in Bimzelx treated patients (1.6%) compared to placebo treated patients (4.1%).

In the combined safety results from Phase II and III studies, TEAEs were reported in 81.9% of patients treated with Bimzelx. The most common TEAEs were nasopharyngitis (20.8%), oral candidiasis (15.1%), and upper respiratory tract infection (10.4%). Based on the mechanism of action of Bimzelx, infections were considered adverse events which were pre-specified safety topics of interest. The exposure adjusted incident rate (EAIR) was used to compare adverse events for pre-specified safety topics of interest due to the imbalance in exposure between Bimzelx and comparator treated patients. The frequency of infections was largely driven by fungal infections, which were reported in 22.6% (EAIR 26.0) of the Bimzelx treated patients compared to 2.5% (EAIR 2.6) of ustekinumab or 0.6% (EAIR 1.4) of adalimumab treated patients. Of the fungal infections, candida infections (largely oral candidiasis) affected 17.0% (EAIR 18.7) of Bimzelx treated patients compared to 1.2% (EAIR 1.3) of ustekinumab and 0.0% (EAIR 0) of adalimumab treated patients. The majority of infections in the Bimzelx treated patients were mild or moderate, however, in the first year of treatment (0-52 weeks), recurrent fungal infections occurred in 8.5% of Bimzelx patients and 82.4% of fungal infections were considered resolved at the time of data‑cut off for the study report. The risk of infections has been included in the Bimzelx Product Monograph. There were no clinically meaningful differences in the frequency of serious infections (Bimzelx 1.4% [EAIR 1.4], ustekinumab 2.5% [EAIR 2.6], adalimumab 0.6% [EAIR 1.4]) between treatments. Other adverse events which were pre-specified safety topics of interest included malignancy and major adverse cardiac events (MACEs). In the Phase II and III studies, malignancy was observed at low frequency in patients treated with Bimzelx (0.8%, EAIR 0.8), ustekinumab (0.6%, EAIR 0.6), and adalimumab (0.6, EAIR 1.4), respectively. Major cardiac events were also observed at low frequency in the Bimzelx treated patients (0.7%, EAIR 0.66) compared to ustekinumab or adalimumab treated patients (both 0%, EAIR 0). Rare or uncommon adverse events may not have been adequately captured in the active comparator groups due to the small number of patients enrolled in these groups. Based on data available at the time of this submission, the potential long‑term risk of malignancy or MACE associated with Bimzelx exposure has not been fully elucidated; however, these risks are considered mitigated through routine pharmacovigilance.

A total of five deaths were reported in the Phase II and III studies in Bimzelx treated patients; no trend was observed in the identified cause of deaths (two deaths were adjudicated as MACE) and the incidence of deaths were consistent with the background rate of the psoriasis population.

Based on the clinical data available at the time of authorization, the safety profile of Bimzelx was considered acceptable. The observed increased risk of infection is considered to be mitigated through labelling and post-market pharmacovigilance.

For more information, refer to the Bimzelx Product Monograph, approved by Health Canada and available through the Drug Product Database.