Abstract and Introduction
Abstract
Background: Bimekizumab is a monoclonal antibody that selectively inhibits both interleukin (IL)-17A and IL-17F, which is currently under investigation for treatment of moderate-to-severe plaque psoriasis. Maintenance dosing every 4 weeks is well established with IL-17 inhibitors for psoriasis.
Objectives: To investigate the possible dosing interval during bimekizumab maintenance therapy to maintain clear skin, to inform phase III studies.
Methods: Forty-nine patients with moderate-to-severe plaque psoriasis received bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg (n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity and biopsy transcriptomic analyses were assessed to week 28.
Results: At week 8, 47% of patients achieved a 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12 (8 weeks after the second dose) before decreasing. In those who received bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week 8 transcriptional signature observed in lesional psoriatic skin rapidly normalized to levels consistent with nonlesional skin, resulting in molecular remission. Keratinocyte-related gene products such as CXCL1 (C-X-C motif chemokine ligand 1), IL-8 (encoded by the CXCL8 gene), CCL20 (C-C motif chemokine 20), IL-36γ and IL-17C were profoundly normalized to levels associated with nonlesional skin.
Conclusions: Here, inhibition of IL-17F in addition to IL-17A resulted in rapid, deep clinical responses. Additionally, profound normalization of keratinocyte biology and the psoriatic transcriptome was observed, including normalization of both IL17 and IL23 gene expression by week 8. These data provide evidence to support evaluation of bimekizumab maintenance dosing both every 8 and every 4 weeks in phase III clinical trials.
Introduction
The introduction of biologics that target tumour necrosis factor (TNF) or interleukin (IL)-12/23 has enabled the majority of patients with plaque psoriasis to achieve a 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75).[1] More recently, biologics targeting IL-23 and IL-17A have further raised treatment expectations, with PASI 90 becoming a realistic goal, and many patients also achieving PASI 100 (complete skin clearance).[2–5]
IL-17A, the signature cytokine of T helper (Th)17 cells, is a proinflammatory cytokine overexpressed in psoriatic tissue.[6] There is significant clinical evidence that IL-17A inhibition leads to rapid clinical, histological and molecular resolution of psoriasis. IL-17F is a close family member of IL-17A, and while it has been shown to be around 100-fold less potent than IL-17A in inducing proinflammatory cytokines such as CXCL1 (C-X-C motif chemokine ligand 1), IL-8 (encoded by the CXCL8 gene) and IL-6, it is much more abundant in psoriatic skin.[7,8] Increasing evidence highlights the central role of both IL-17A and IL-17F in the underlying disease pathobiology of psoriasis, by driving aberrant keratinocyte biology. Both keratinocyte proliferation and release of factors such as IL-36γ and IL-17C amplify inflammation and plaque chronicity.[9–11]
IL-17A and IL-17F are principally produced by activated Th17 cells and exist in dimeric isoforms (homodimers IL-17A/A and IL-17F/F, and heterodimer IL-17A/F).[6,12] Each dimer binds an IL receptor complex, IL-17RA/IL-RC, and therefore can transduce similar signalling and activation of target genes.[12] It has been found that all IL-17 isoforms are produced in active plaques of psoriasis vulgaris, and thus each has potential to stimulate 'downstream' activation of keratinocytes and other cell types that ultimately create visible psoriasis lesions.[7]
A significant challenge in chronic diseases such as psoriasis is the need for patients to receive medication over long periods of time. Less frequent treatment administration may increase treatment adherence and quality of life.[13–15] The commonly used IL-17A inhibitors, secukinumab and ixekizumab,[16,17] both require dosing every 4 weeks (Q4W) during maintenance treatment, and loss of response with these agents has driven efforts to optimize response with more frequent intervals,[5,18] as already used with the IL-17 receptor inhibitor, brodalumab.[19] There remains an unmet need for a treatment that provides both high rates of complete skin clearance and less frequent dosing.[20]
Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits both IL-17A and IL-17F.[21–23] Preclinical studies in human in vitro assays have shown that dual inhibition of IL-17A and IL-17F with bimekizumab leads to a greater inhibitory effect than blockade of either cytokine alone.[11] Phase II studies in patients with moderate-to-severe plaque psoriasis demonstrated high rates of skin clearance with bimekizumab, which were well-maintained with Q4W maintenance dosing.[24,25]
Here, we present results from a phase II exploratory trial designed to investigate whether high rates of skin clearance can be achieved with a prolonged bimekizumab maintenance dosing interval, and whether bimekizumab treatment is associated with the molecular resolution of psoriasis and other inflammatory markers.
The British Journal of Dermatology. 2022;186(4):652-663. © 2022 Blackwell Publishing
