Ryan D. Gotesman, BHSc1 and Ron Vender, MD, FRCPC2
1University of Ottawa, Faculty of Medicine, Ottawa, ON, Canada
2Dermatrials Research Inc. & Venderm Innovations in Psoriasis, Hamilton, ON, Canada
Conflict of interest:
Ryan Gotesman has no conflicts of interest to disclose. Ron Vender has been a consultant, and/or scientific advisor, and/or investigator, and/or speaker for Amgen, AbbVie, Astellas, Bausch Health/Valeant, BMS, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GSK, Janssen, Leo Pharma, Merck (MSD), Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda and UCB.
Psoriasis is an immune-mediated inflammatory skin disease that affects about 2% of the population and is associated with many comorbidities. Recent advances have demonstrated interleukin (IL)-17 signaling plays a crucial role in the pathogenesis of psoriasis. Bimekizumab is a novel monoclonal antibody treatment for psoriasis that uses a single binding site to inhibit IL-17A and IL-17F. Here we will discuss the safety and efficacy of bimekizumab in the treatment of moderate-to-severe plaque psoriasis.
plaque psoriasis, IL-17, interleukin-17A, interleukin-17F, bimekizumab
Table of Contents:
Psoriasis is a chronic, auto-immune inflammatory skin condition with a worldwide prevalence of about 2%.1 The most common manifestation is plaque psoriasis, presenting as well-delineated, erythematous, scaly and itchy plaques that may appear anywhere on the body but are usually found on the extensor surfaces of the elbows and knees.2 Plaque psoriasis may be described as moderate-to-severe when it covers 3% or more of the body’s surface or has a significant effect on a patient’s quality of life. About 1 in 5 psoriasis patients report moderate or severe disease.3
The systemic inflammation in psoriasis can affect multiple systems beyond the skin. Psoriatic arthritis is an erosive arthritis that develops in about 30% of psoriatic patients and causes joint pain as well as stiffness.4 Psoriasis has also been linked with cardiovascular disease, diabetes, lymphoma and depression.5-7 The prevalence of comorbidities increases with disease severity, and men and women with severe psoriasis experience a 3.5 and 4.4 year reduction in life-expectancy, respectively.8
Multiple therapies are available for treating psoriasis. The mainstay for combating mild psoriasis is topical therapy composed of corticosteroids, vitamin D3 analogues, retinoids, anthralin and coal tar.9 Topical treatments are ineffective in managing moderate-to-severe disease though they may be used as adjuncts. Instead, moderate-to-severe psoriasis is treated using systemic therapy that includes phototherapy, corticosteroids, retinoids, methotrexate, cyclosporine, and biologics.10 Biologic agents target specific inflammatory molecules implicated in the pathogenesis of psoriasis and have proven particularly effective. Biologics have been developed against tumor necrosis factor-alpha (TNF-α), interleukin (IL)-12, IL-23, IL-17 and the IL-17 receptor.11 Recent advances have revealed the fundamental role that IL-17 pathways play in the development of psoriasis.
IL-17 in Psoriasis
The IL-17 family is comprised of six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F.12 Among the members, IL-17A and IL-17F share the greatest structural similarity and are secreted as homodimers or IL-17A/F heterodimers. IL-17 plays an essential part in defending against microbial invaders at mucosal and epithelial sites by stimulating production of inflammatory cytokines that attract neutrophils, monocytes and lymphocytes. T helper 17 (Th17) T cells are a major source of IL-17, as are gamma delta (γδ) T cells in the skin, neutrophils, natural killer cells and mast cells.13 IL-17 signaling is dysregulated in psoriasis.
The trigger for psoriasis is thought to be a foreign antigen, perhaps introduced through infection or trauma.14 Activated inflammatory cells release IL-23, which stimulates the production of inflammatory cytokines, including IL-17A, IL-17F and IL-17A/F. The activity of the IL-17A homodimer is about 30 times more than the IL-17F homodimer, with the activity of the IL-17A/F heterodimer lying somewhere in-between.15 All three induce the keratinocyte and vascular hyperproliferation underlying psoriasis. Indeed, IL-17A and IL-17F, along with their receptors, are highly expressed in psoriatic plaques.16 In addition, IL-17 can attract inflammatory cells to infiltrate psoriatic lesions and further contribute to the inflammatory state. Moreover, IL-17 can act in concert with TNF-α to create a positive feedback loop that maintains and exacerbates inflammation of the dermis.17
Biologics aimed at the IL-17 pathway have demonstrated impressive efficacy in treating moderate-to-severe psoriasis. Two of the three currently approved biologics, secukinumab and ixekizumab, inhibit IL-17A, while the remaining, brodalumab, antagonizes the IL-17 receptor A subunit. These inhibitors have proven to be more effective in clearing psoriasis than TNF-α inhibitors and many of the new IL-23 targeted therapies, thereby cementing IL-17 as a key component of plaque pathogenesis.18,19 Bimekizumab is a novel monoclonal antibody treatment for psoriasis that distinguishes itself by using a single binding site to neutralize two members of the IL-17 family, IL-17A and IL-17F.20 A number of Phase I, II and III trials have evaluated the efficacy and safety of bimekizumab.
Phase I Trials
In 2016, the first in-human double-blind, placebo-controlled study of bimekizumab randomized 39 patients with mild-tomoderate plaque psoriasis to receive a single dose of intravenous infusion of bimekizumab or placebo.21 The primary objective was to investigate the safety of bimekizumab and secondary objectives were to characterize the drug’s pharmacokinetic profile and clinical benefit. The tested doses of bimekizumab were 8mg, 40mg, 160mg, 480mg or 640mg and patients were evaluated over a 20-week period. Treatment emergent adverse events (TEAEs) were observed in 84.6% of those receiving bimkezumab compared to 76.9% on placebo. Most of the TEAEs were classified as mild, 61.5% in the bimekizumab cohort and 53.8% in the placebo group.
The TEAEs experienced by 10% or more of those on bimekizumab were headache, oropharyngeal pain, nasopharyngitis and site reactions from using medical devices. Only one serious adverse event, vomiting, was reported and not thought to be related to the medication. There were no severe TEAEs or deaths and no patients left the study due to an adverse event. Bimekizumab’s plasma concentration increased with dose in a linear fashion and the half-life ranged from 17-26 days. Five patients developed antibodies against bimekizumab during the trial, but they had no effect on pharmacokinetic parameters.
Bimekizumab elicited a dose-dependent improvement in disease severity. The biologic’s impact was most rapid at the higher doses of 480mg and 640mg, reducing baseline scores by over 65% at week 2. Maximal effect in all measures of disease activity were observed between weeks 8-12 in subjects receiving 160mg-640mg of the drug and the effect was maintained up to weeks 12-20. Focusing on Psoriasis Area and Severity Index (PASI) scores, the 160mg group experienced a maximal effect of over 85% reduction in PASI at week 6. Maximal effect of over 94% reduction in PASI score was reached by week 6 in the 480mg group and week 4 in the 640mg group, and the effect was maintained through weeks 12-20.
Phase II Trials
Soon after, bimekizumab was evaluated in the multicenter, double-blind, placebo-controlled Phase IIb BE ABLE I trial.22 The 250 patients with moderate-to-severe plaque psoriasis were randomized (1:1:1:1:1:1) to receive subcutaneous bimekizumab every 4 weeks at doses of 64mg, 160mg, 160mg with 320mg loading dose, 320mg, 480mg, or placebo. The primary endpoint was achieving PASI90 (90% reduction in PASI) at week 12.
Secondary endpoints were reaching PASI90 at week 8, PASI75 (75% reduction in PASI) at week 2, and PASI100 (complete skin clearance) at week 2, as well as achieving an Investigator’s Global Assessment (IGA) score of clear or almost clear skin (IGA0/1) with two or more categories of improvement from baseline. Bimekizumab elicited a swift clinical response, significantly improving disease activity across all doses by week 4. By week 8, substantially more patients on bimekizumab reached PASI90 (41%-86% vs. 0%, p<0.0001) and IGA0/1 (46%-86% vs. 5%, p≤0.0003) across doses compared with placebo. The primary endpoint, PASI90 response at week 12, was significantly related to bimekizumab dose (p<0.0001) and was reached by 46% of patients using 64mg, 67% using 160mg, 75% using 160mg and 320mg loading dose, 79% using 320mg and 72% using 480mg of bimekizumab compared to 0% on placebo (Figure 1).
Significantly more patients also achieved PASI75 (62%-93% vs. 5%, p<0.0001), PASI100 (28%-60% vs. 0%, p≤0.0002) and IGA0/1 (51%-86% vs. 5%, p≤0.0001) at week 12 across all doses compared to placebo.
The safety profile of bimekizumab did not change with dose, though TEAEs were more frequently reported in patients treated with bimekizumab than placebo (61% vs. 36%). The common TEAEs that occurred in 5% or more of patients in any treatment group were nasopharyngitis, upper respiratory tract infection, arthralgia, γ-glutamyltransferase increase, neutropenia, rhinitis, tonsillitis, oral candidiasis, headache, leukopenia and vomiting. Worth highlighting, 4.3% of bimekizumab patients developed fungal infections compared to no cases in the placebo group.
In addition, adverse events led to 4.8% of bimekizumab patients and 2.4% in the placebo group leaving the study; however, no serious events were thought to be related to the treatment. Importantly, no cases of anaphylactic reactions, inflammatory bowel disease, neuropsychiatric complications or systemic infections were reported.
Phase III Trials
Full results for the Phase III clinical trials BE VIVID and BE READY were published in early 2021 and confirmed bimekizumab to be a safe, effective therapy for moderate-to-severe plaque psoriasis. BE VIVID, was a 52-week trial that randomized 567 patients in a ratio of 4:2:1 to receive bimekizumab 320mg every 4 weeks, ustekinumab 45mg or 90mg (baseline weight-dependent dosing) at weeks 0 and 4, then every 12 weeks or placebo every 4 weeks.23 At week 16, the placebo group was switched to bimekizumab 320mg every 4 weeks. In BE VIVID, 85% of patients receiving bimekizumab reached PASI90 after 16 weeks of therapy, far more than the 50% of patients receiving ustekinumab and 5% of patients taking placebo.23 By the 52nd week, 82% of patients treated with bimekizumab had achieved PASI90 relative to 56% in the ustekinumab group.
Safety of the drug corresponded to the Phase II BE ABLE I trial. The safety profiles of bimekizumab and ustekinumab were comparable, with 6% of patients on bimekizumab experiencing serious TEAEs compared to 7% of those on ustekinumab.
Data from BE READY demonstrated bimekizumab’s impressive long-term efficacy. BE READY spanned 55 weeks and randomized 435 patients in a ratio of 4:1 to receive bimekizumab 320mg every 4 weeks or placebo every 4 weeks.24 Bimekizumab-treated patients who achieved PASI90 at week 16 were re-allocated (1:1:1) to receive bimekizumab 320mg every 4 weeks, every 8 weeks or placebo until week 56. At week 16, 91% of patients receiving bimekizumab 320mg every 4 weeks achieved PASI90 relative to 1% in the placebo arm. As well, IGA0/1 was achieved in 93% of patients receiving bimekizumab 320mg every 4 weeks relative to 1% in the placebo arm.
Patients randomized to placebo following the initial 16 weeks of therapy only relapsed after a median time of 32 weeks had elapsed since their last treatment. In addition, doubling the period between bimekizumab treatments did not reduce the drug’s effectiveness: About 91% of patients randomized to receive bimekizumab every 8 weeks following week 16 reached PASI90 by the end of the study, relative to the 87% in the group that received monthly bimekizumab for the entirety of the trial. With respect to safety, there were two cases of malignancy, one a basal cell carcinoma detected in the 320mg every 4 weeks group during the initial treatment phase, and a case of prostate cancer in the placebo group during the randomized withdrawal period. There were no serious hypersensitivity reactions across any of the bimekizumab groups.
Hepatic events occurred in 3% of the bimekizumab 320mg every 4 weeks group and 1% of the placebo group in the initial treatment period, and in 8% of the bimekizumab 320mg every 4 weeks group and 3% of the bimekizumab 320mg every 8 weeks group in the randomized withdrawal period. The majority of these cases were transient elevated liver function tests that self resolved without dose adjustment and none led to treatment discontinuation. Three serious infections (enterovirus, pneumonia, otitis media chronic) occurred in the bimekizumab 320mg every 4 weeks group and no opportunistic infections or active tuberculosis were reported.
A third Phase III clinical trial, BE SURE, randomized 478 patients to receive bimekizumab or adalimumab through an active-controlled initial treatment period of 24 weeks followed by a dose-blind maintenance treatment period until week 56.25 At week 16, bimekizumab was superior to adalimumab in achieving PASI90 and IGA0/1.26 Bimekizumab was also better at reaching PASI100 at weeks 16 and 24 and led to a more rapid response. High levels of skin clearance were achieved with bimekizumab during the dose-blind maintenance period through week 56 and no new safety concerns were identified. Importantly, BE SURE results have yet to be published in a peer-reviewed journal and are expected in 2021.
Bimekizumab is a novel treatment for moderate-to-severe plaque psoriasis that has shown promising efficacy and safety in clinical trials. By simultaneously targeting two components of the IL-17 pathway, IL-17A and IL-17F, the biologic can downregulate proinflammatory signaling and rapidly improve patients’ skin.
Based on strong Phase III trial results, 2020 saw the US Food and Drug Administration accept a biologics licence application and the European Medicine Agency accept a marketing authorization application for bimekizumab as a treatment of adults with moderate-to-severe plaque psoriasis. Though no serious adverse events were associated with the drug, its long-term safety must still be demonstrated. Due to IL-17’s role in preventing microbial invasion, particular attention should be paid to any increase in opportunistic infection. Further investigations are warranted to compare bimekizumab against biologics like secukinumab or ixekizumab that only target a single component of the IL-17 pathway.
Given the drug’s impressive efficacy, bimekizumab may become first-line therapy for moderate-to severe plaque psoriasis and the dermatology community eagerly awaits its approval.
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