Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: UCB Pharma S.A., Allée de la Recherche 60, B-1070 Bruxelles, Belgium
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors
ATC code: L04AC21
Bimekizumab is a humanised IgG1/κ monoclonal antibody that selectively binds with high affinity to 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 implicated in the pathogenesis of several immune-mediated inflammatory diseases including plaque psoriasis. Bimekizumab inhibits these proinflammatory cytokines, resulting in the normalization of skin inflammation and as a consequence improvement in clinical symptoms associated with psoriasis. From in vitro models, bimekizumab was shown to inhibit psoriasis-related gene expression and cytokine production to a greater extent than inhibition of IL-17A alone.
The safety and efficacy of bimekizumab was evaluated in 1,480 patients with moderate to severe plaque psoriasis in three Phase 3 multicenter, randomised, placebo and/or active comparatorcontrolled studies. Patients were at least 18 years of age, had a Psoriasis Area and Severity Index (PASI) score ≥12 and Body Surface Area (BSA) affected by psoriasis (PSO) ≥10%, an Investigators Global Assessment (IGA) score ≥3 on a 5-point scale and were candidates for systemic psoriasis therapy and/or phototherapy. The efficacy and safety of bimekizumab were evaluated versus placebo and ustekinumab (BE VIVID – PS0009), versus placebo (BE READY – PS0013) and versus adalimumab (BE SURE – PS0008).
The BE VIVID study evaluated 567 patients for 52 weeks where patients were randomised to receive either bimekizumab 320 mg every 4 weeks, ustekinumab (45 mg or 90 mg, depending on patient weight, at baseline and week 4 and then every 12 weeks), or placebo for an initial 16 weeks, followed by bimekizumab 320 mg every 4 weeks.
The BE READY study evaluated 435 patients for 56 weeks. Patients were randomised to receive bimekizumab 320 mg every 4 weeks or placebo. At week 16, patients who achieved a PASI 90 response entered the 40-week randomised withdrawal period. Patients initially randomised to bimekizumab 320 mg every 4 weeks were re-randomised to either bimekizumab 320 mg every 4 weeks or bimekizumab 320 mg every 8 weeks or placebo (i.e. withdrawal of bimekizumab). Patients initially randomised 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 bimekizumab 320 mg every 4 weeks for 12 weeks. Patients who relapsed (did not achieve PASI 75 response) during the randomised withdrawal period also entered the 12-week escape arm.
The BE SURE study evaluated 478 patients for 56 weeks. Patients were randomised to receive either bimekizumab 320 mg every 4 weeks through week 56, bimekizumab 320 mg every 4 weeks through week 16 followed by bimekizumab 320 mg every 8 weeks through week 56 or adalimumab as per labeling recommendation through Week 24 followed by bimekizumab 320 mg every 4 weeks through week 56.
Baseline characteristics were consistent across all 3 studies: patients were predominantly male (70.7%) and white (84.1%), with a mean age of 45.2 years (18 to 83 years), and 8.9% were ≥65 years of age. The median baseline BSA was 20%, the median baseline PASI score was 18 and the baseline IGA score was severe in 33% of patients. The median baseline scores for Patient Symptoms Diary (PSD) pain, itch and scaling items ranged between 6 and 7 on a 0-10 points scale and the median baseline Dermatology Life Quality Index (DLQI) total score was 9.
Across all 3 studies, 38% of patients had received a prior biologic therapy; 23% had received at least one anti-IL17 agent (primary anti-IL17 failures were excluded) and 13% had received at least one TNF-antagonist. Twenty-two percent were naïve to any systemic therapy (including non-biologic and biologic) and 39% of patients had received prior phototherapy or photochemotherapy.
The efficacy of bimekizumab was evaluated with respect to impact on skin disease overall, specific body locations (scalp, nails, palms and soles), patient reported symptoms and impact on quality of life. The two co-primary endpoints in all 3 studies were the proportion of patients who achieved 1) a PASI 90 response and 2) an IGA “clear or almost clear” (IGA 0/1with at least two points improvement from baseline) response at week 16. PASI 100, IGA 0 response at week 16 and PASI 75 response at week 4 were secondary endpoints in all 3 studies.
Treatment with bimekizumab resulted in significant improvement across efficacy endpoints compared to placebo, ustekinumab or adalimumab at week 16. The main efficacy results are shown in Table 2.
Table 2. Summary of clinical responses in BE VIVID, BE READY and BE SURE:
| BE VIVID | BE READY | BE SURE | |||||
|---|---|---|---|---|---|---|---|
| Placebo (N=83) n (%) | Bimekizumab 320 mg Q4W (N=321) n (%) | Ustekinumab (N=163) n (%) | Placebo (N=86) n (%) | Bimekizumab 320 mg Q4W (N=349) n (%) | Bimekizumab 320 mg Q4W (N=319) n (%) | Adalimumab (N=159) n (%) | |
| PASI 100 Week 16 | 0 (0.0) | 188 (58.6)a | 34 (20.9) | 1 (1.2) | 238 (68.2)a | 194 (60.8)a | 38 (23.9) |
| PASI 90 Week 16 | 4 (4.8) | 273 (85.0)a,b | 81 (49.7) | 1 (1.2) | 317 (90.8)a | 275 (86.2)a | 75 (47.2) |
| PASI 75 Week 4 Week 16 | 2 (2.4) 6 (7.2) | 247 (76.9)a,b 296 (92.2) | 25 (15.3) 119 (73.0) | 1 (1.2) 2 (2.3) | 265 (75.9)a 333 (95.4) | 244 (76.5)a 295 (92.5) | 50 (31.4) 110 (69.2) |
| IGA 0 Week 16 | 0 (0.0) | 188 (58.6)a | 36 (22.1) | 1 (1.2) | 243 (69.6)a | 197 (61.8) | 39 (24.5) |
| IGA 0/1 Week 16 | 4 (4.8) | 270 (84.1)a,b | 87 (53.4) | 1 (1.2) | 323 (92.6)a | 272 (85.3)a | 91 (57.2) |
| Absolute PASI ≤2 Week 16 | 3 (3.6) | 273 (85.0) | 84 (51.5) | 1 (1.2) | 315 (90.3) | 280 (87.8) | 86 (54.1) |
| PSD Pain improvement ≥4 (N) Week 16 | (N=48) 5 (10.4) | (N=190) 140 (73.7) | (N=90) 54 (60.0) | (N=49) 0 (0.0) | (N=209) 148 (70.8) | (N=222) 143 (64.4) | (N=92) 43 (46.7) |
| PSD Itch improvement ≥4 (N) Week 16 | (N=53) 6 (11.3) | (N=222) 151 (68.0) | (N=104) 57 (54.8) | (N=60) 0 (0.0) | (N=244) 161 (66.0) | (N=248) 153 (61.7) | (N=107) 42 (39.3) |
| PSD Scaling improvement ≥4 (N) Week 16 | (N=56) 6 (10.7) | (N=225) 171 (76.0) | (N=104) 59 (56.7) | (N=65) 1 (1.5) | (N=262) 198 (75.6) | (N=251) 170 (67.7) | (N=109) 42 (38.5) |
Bimekizumab 320 mg Q4W=bimekizumab every 4 weeks. Non-Responder Imputation (NRI) is used.
IGA 0/1 response was defined as Clear (0) or Almost Clear (1) with at least a 2-category improvement from Baseline at week 16. IGA 0 response was defined as Clear (0) with at least a 2-category improvement from Baseline at week 16.
PSD is a Patient Symptoms Diary, also referred to as Psoriasis Symptoms and Impacts Measure (P-SIM), measuring psoriasis symptom severity on a scale from 0 (no symptoms) to 10 (very severe symptoms). Response is defined as a decrease ≥4 from baseline to week 16 for pain, itch and scaling on a scale from 0 to 10.
a p <0.001 versus placebo (BE VIVID and BE READY), versus adalimumab (BE SURE), adjusted for multiplicity.
b p <0.001 versus ustekinumab (BE VIVID), adjusted for multiplicity.
Bimekizumab was associated with a rapid onset of efficacy. In BE VIVID, at week 2 and week 4, PASI 90 response rates were significantly higher for bimekizumab-treated patients (12.1% and 43.6% respectively) compared to placebo (1.2% and 2.4% respectively) and ustekinumab (1.2% and 3.1% respectively).
In the BE VIVID study, at week 52, bimekizumab-treated patients (every 4 weeks) achieved significantly higher response rates than the ustekinumab-treated patients on the endpoints of PASI 90 (81.9% bimekizumab vs 55.8% ustekinumab, p<0.001), IGA 0/1 (78.2% bimekizumab vs 60.7% ustekinumab, p<0.001) and PASI 100 (64.5% bimekizumab vs 38.0% ustekinumab).
Figure 1. PASI 90 responder rates over time in BE VIVID:
BKZ 320 mg Q4W=bimekizumab every 4 weeks; Uste=ustekinumab. NRI is used.
In the BE SURE study at week 24, a significantly higher percentage of patients treated with bimekizumab (Q4W/Q4W and Q4W/Q8W combined dosing arms) achieved PASI 90 and IGA 0/1 responses as compared with adalimumab (85.6% and 86.5% respectively vs 51.6% and 57.9% respectively, p<0.001). At week 56, 70.2% of patients treated with bimekizumab Q8W achieved a PASI 100 response. Among the 65 adalimumab non-responders at week 24 (< PASI 90), 78.5% achieved a PASI 90 response after 16 weeks of treatment with bimekizumab. The safety profile observed in patients who switched from adalimumab to bimekizumab without a wash-out period was similar to patients who initiated bimekizumab after wash out of prior systemic therapies.
Figure 2. PASI 90 responder rates over time in BE SURE:
BKZ 320 mg Q4W = bimekizumab every 4 weeks; BKZ 320 mg Q8W = bimekizumab every 8 weeks; ADA= adalimumab.
Patients in the BKZ Q4W/Q8W group switched from Q4W to Q8W dosing at week 16. Patients in the ADA/BKZ 320 mg Q4W group switched from ADA to BKZ Q4W at week 24. NRI is used.
The efficacy of bimekizumab was demonstrated regardless of age, gender, race, disease duration, body weight, PASI baseline severity and previous treatment with a biologic. Bimekizumab was efficacious in prior biologic exposed patients, including anti-TNF / anti IL-17 and in systemic treatment-naïve patients. Efficacy in patients with primary failure to anti-IL17 has not been investigated.
Based on population PK/ PD analysis and supported by clinical data, patients with higher body weight (≥120 kg) who did not achieve complete skin clearance at week 16 benefited from continued bimekizumab 320 mg every four weeks (Q4W) after the initial 16 weeks of treatment. In the BE SURE study, patients received bimekizumab 320 mg Q4W through week 16, followed by either Q4W or every eight weeks (Q8W) dosing through week 56, regardless of responder status at week 16. Patients in the ≥120 kg group (N=37) on the Q4W maintenance regimen showed greater improvement in PASI100 between week 16 (23.5%) and week 56 (70.6%) compared to those on the Q8W maintenance regimen (week 16: 45.0% vs week 56: 60.0%).
Improvements were observed in psoriasis involving the scalp, nails, palms and soles in patients treated with bimekizumab at week 16 (see Table 3).
Table 3. Scalp, palmoplantar and nail responses in BE VIVID, BE READY and BE SURE at week 16:
| BE VIVID | BE READY | BE SURE | |||||
|---|---|---|---|---|---|---|---|
| Placebo | Bimekizumab 320 mg Q4W | Ustekinumab | Placebo | Bimekizumab 320 mg Q4W | Bimekizumab 320 mg Q4W | Adalimumab | |
| Scalp IGA (N)a Scalp IGA 0/1, n (%) | (72) 11 (15.3) | (285) 240 (84.2)b | (146) 103 (70.5) | (74) 5 (6.8) | (310) 286 (92.3)b | (296) 256 (86.5) | (138) 93 (67.4) |
| pp-IGA (N)a pp-IGA 0/1, n (%) | (29) 7 (24.1) | (105) 85 (81.0) | (47) 39 (83.0) | (31) 10 (32.3) | (97) 91 (93.8) | (90) 75 (83.3) | (34) 24 (70.6) |
| mNAPSI 100 (N)a mNAPSI 100, n (%) | (51) 4 (7.8) | (194) 57 (29.4) | (109) 15 (13.8) | (50) 3 (6.0) | (210) 73 (34.8) | (181) 54 (29.8) | (95) 21 (22.1) |
Bimekizumab 320 mg Q4W= bimekizumab every 4 weeks. Non responder imputation (NRI) is used. Scalp IGA 0/1 and pp-IGA 0/1 responses were defined as Clear (0) or Almost Clear (1) with ≥2 category improvement relative to Baseline.
a Include only patients with a scalp Investigator Global Assessment (IGA) of 2 or greater, a palmoplantar IGA of 2 or greater and a modified Nail Psoriasis and Severity Index (mNAPSI) score >0 at baseline.
b p <0.001 versus placebo, adjusted for multiplicity
Scalp IGA and palmoplantar IGA responses in bimekizumab-treated patients were maintained through week 52 / 56. Nail psoriasis continued to improve beyond week 16. In BE VIVID, at week 52, 60.3% of patients treated with bimekizumab 320 mg every 4 weeks achieved complete nail clearance (mNAPSI 100). In BE READY, at week 56, 67.7% and 69.8% of week 16 PASI 90 responders achieved complete nail clearance with bimekizumab 320 mg every 8 weeks and bimekizumab 320 mg every 4 weeks respectively.
Table 4. Maintenance of responses with bimekizumab at week 52 in PASI100, PASI90, IGA 0/1 and Absolute PASI ≤2 responders at week 16*:
| PASI 100 | PASI 90 | IGA 0/1 | Absolute PASI ≤2 | ||||
|---|---|---|---|---|---|---|---|
| 320mg Q4W (N=355) n (%) | 320mg Q8W (N=182) n (%) | 320mg Q4W (N=516) n (%) | 320mg Q8W (N=237) n (%) | 320mg Q4W (N=511) n (%) | 320mg Q8W (N=234) n (%) | 320mg Q4W (N=511) n (%) | 320mg Q8W (N=238) n (%) |
| 295 (83.1) | 161 (88.5) | 464 (89.9) | 214 (90.3) | 447 (87.5) | 214 (91.5) | 460 (90.0) | 215 (90.3) |
* Integrated analysis of BE VIVID, BE READY and BE SURE. NRI is used.
320 mg Q4W: bimekizumab 320 mg every 4 weeks followed by bimekizumab 320 mg every 4 weeks from week 16.
320 mg Q8W: bimekizumab 320 mg every 4 weeks followed by bimekizumab 320 mg every 8 weeks from week 16.
Figure 3. PASI 90 responder rates over time for PASI 90 responders at week 16 – Randomized withdrawal period in BE READY:
In BE READY, for PASI 90 responders at week 16 who were re-randomised to placebo and withdrawn from bimekizumab, the median time to relapse, defined as loss of PASI 75, was approximately 28 weeks (32 weeks after the last bimekizumab dose). Among these patients, 88.1% regained a PASI 90 response within 12 weeks of restarting treatment with bimekizumab 320 mg every 4 weeks.
Across all 3 studies, a greater proportion of patients treated with bimekizumab experienced no impact of psoriasis on their quality of life as measured by the Dermatology Life Quality Index (DLQI) compared to placebo and active comparator-treated patients at week 16 (Table 5).
Table 5. Quality of life in study BE VIVID, BE READY and BE SURE:
| BE VIVID | BE READY | BE SURE | |||||
|---|---|---|---|---|---|---|---|
| Placebo (N=83) n (%) | Bimekizumab 320 mg Q4W (N=321) n (%) | Ustekinumab (N=163) n (%) | Placebo (N=86) n (%) | Bimekizumab 320 mg Q4W (N=349) n (%) | Bimekizumab 320 mg Q4W (N=319) n (%) | Adalimumab (N=159) n (%) | |
| DLQI 0/1a Baseline | 3 (3.6) | 16 (5.0) | 5 (3.1) | 4 (4.7) | 11 (3.2) | 10 (3.1) | 13 (8.2) |
| DLQI 0/1a Week 16 | 10 (12.0) | 216 (67.3) | 69 (42.3) | 5 (5.8) | 264 (75.6) | 201 (63.0) | 74 (46.5) |
a DLQI absolute score of 0 or 1 indicates no impact of the disease on health-related quality of life. NRI is used.
DLQI 0/1 responses continued to increase beyond week 16 and then were maintained through week 52 / 56. In BE VIVID, DLQI 0/1 response rate at week 52 was 74.8% in patients treated with bimekizumab 320 mg every 4 weeks. In BE SURE at week 56, 78.9% and 74.1% of patients had a DLQI 0/1 with bimekizumab 320 mg every 8 weeks and bimekizumab 320 mg every 4 weeks, respectively.
The European Medicines Agency has deferred the obligation to submit the results of studies with Bimzelx in one or more subsets of the paediatric population in psoriasis (see section 4.2 for information on paediatric use).
Based on population pharmacokinetic analysis, following a single subcutaneous dose of 320 mg in plaque psoriasis patients, bimekizumab reached a median (2.5th and 97.5th percentile) peak plasma concentration of 25 (12-50) μg/mL, between 3 and 4 days post dose.
Population pharmacokinetic analysis showed that bimekizumab was absorbed with an average absolute bioavailability of 70.1% in healthy volunteers.
Based on simulated data, the median (2.5th and 97.5th percentile) peak and trough concentration at steady-state following subcutaneous administration of 320 mg every 4 weeks are 43 (20-91) µg/mL and 20 (7-50) µg/mL respectively and steady-state is reached after approximately 16 weeks with every 4 weeks dosing regimen. Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 1.74-fold increase in peak plasma concentrations and area under the curve (AUC) following repeated four weekly dosing.
After switching from the 320 mg every 4 weeks dosing regimen to 320 mg every 8 weeks dosing regimen at week 16, steady-state is achieved approximately 16 weeks after the switch. Median (2.5th and 97.5th percentile) peak and trough plasma concentrations are 30 (14-60) μg/mL and 5 (1-16) μg/mL respectively.
Based on population pharmacokinetic analyses, the median (coefficient of variation ) volume of distribution (V/F) at steady state was 11.2 (30.5) L in plaque psoriasis patients.
Bimekizumab is a monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous immunoglobulins.
Based on population pharmacokinetic analyses, the median (coefficient of variation ) apparent clearance (CL/F) of bimekizumab was 0.337 L/day (32.7) and the mean terminal elimination halflife of bimekizumab was 23 days in clinical studies in patients with plaque psoriasis.
Bimekizumab exhibited dose-proportional pharmacokinetics in patients with plaque psoriasis over a dose range from 64 mg to 480 mg following multiple subcutaneous administrations, with apparent clearance (CL/F) being independent of dose.
A population pharmacokinetic/pharmacodynamic model was developed using all available data in moderate to severe plaque psoriasis patients. The analysis showed that higher bimekizumab concentrations are related to better Psoriasis Area and Severity Index (PASI) and Investigators Global Assessment (IGA) response. A dose of 320 mg every 4 weeks was shown to be an appropriate dose for the initial treatment period and 320 mg every 8 weeks thereafter is appropriate for the maintenance period for the majority of moderate to severe plaque psoriasis patients (see Special Populations, Body weight).
Population pharmacokinetic modelling indicated that exposure decreased as body weight increased. The average plasma concentration in adult patients weighing ≥120 kg following a 320 mg subcutaneous injection was predicted to be at least 30% lower than in adult patients weighing 90 kg. Dose adjustment may be appropriate in some patients (see section 4.2).
Based on population pharmacokinetic analysis with a limited number of elderly patients (n=110 for age ≥65 years and n=14 for age ≥75 years), apparent clearance (CL/F) in elderly patients and patients less than 65 years of age was similar. No dose adjustment is required (see section 4.2).
No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of bimekizumab. The renal elimination of intact bimekizumab, an IgG monoclonal antibody, is expected to be low and of minor importance. Similarly, IgGs are mainly eliminated via intracellular catabolism and hepatic impairment is not expected to influence clearance of bimekizumab. Based on population pharmacokinetic analyses, hepatic function markers (ALT/bilirubin) did not have any impact on bimekizumab clearance in patients with plaque psoriasis.
No clinically meaningful differences in bimekizumab exposure were observed in Japanese subjects compared to Caucasian subjects in a clinical pharmacokinetic study. No dose adjustment is required.
Population pharmacokinetic modelling indicated females may have 10% faster apparent clearance (CL/F) compared to males and it is not clinically meaningful. No dose adjustment is required.
Non-clinical data revealed no special hazard for humans based on tissue cross-reactivity testing, repeat-dose toxicity studies (including safety pharmacology endpoints and assessment of fertilityrelated endpoints) and evaluation of pre- and postnatal development in the cynomolgus monkey.
In cynomolgus monkeys, bimekizumab-related effects were limited to mucocutaneous changes consistent with pharmacologic modulation of commensal microflora.
No mutagenicity or carcinogenicity studies were conducted with bimekizumab. However monoclonal antibodies are not expected to damage DNA or chromosomes. In a 26-week chronic toxicology study in cynomolgus monkeys there were no pre-neoplastic or neoplastic lesions observed at a dose resulting in 109 times the human exposure at 320 mg every 4 weeks.
In a peri- and postnatal development study in the cynomolgus monkey, bimekizumab showed no effects on gestation, parturition, infant survival, foetal and postnatal development when administered throughout organogenesis until parturition at a dose resulting in 27 times the human exposure at 320 mg every 4 weeks based on AUC. At birth, serum bimekizumab concentrations in infant monkeys were comparable to those of mothers.
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