Bimekizumab for the treatment of moderate-to-severe plaque psoriasis: efficacy, safety, pharmacokinetics, pharmacodynamics and transcriptomics from a phase IIa, randomized, double-blind multicentre study

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.

Figure 1

Study design. Study visits occurred at week 0 (baseline), and weeks 2, 4, 8, 12, 16, 20, 28 and 36 (safety follow‐up). The bimekizumab plus placebo (BKZ+PBO) group received two doses of bimekizumab 320 mg, at weeks 0 and 4, with placebo at week 16; the BKZ group received three doses of bimekizumab 320 mg, at weeks 0, 4 and 16. ^aOnly patients who achieved a 25% improvement from baseline Psoriasis Area and Severity Index score (PASI 25) in the first 16 weeks were eligible for entry to the extension study (NCT03230292) after the safety follow‐up visit; if these patients failed to achieve PASI 25 at weeks 20, 24 or 28 they were permitted to enter the extension study early, receiving the first dose of study drug at that visit.

Figure 2

Patient disposition. The bimekizumab plus placebo (BKZ+PBO) group received two doses of bimekizumab 320 mg at weeks 0 and 4, with placebo at week 16; the BKZ group received three doses of bimekizumab 320 mg, at weeks 0, 4 and 16. ^aStudy completion was defined as completing week 28 or completing the visits at weeks 20, 24 or 28 and entering the extension study early.

Figure 3

Psoriasis Area and Severity Index (PASI) response to week 16 for the combined treatment groups (nonresponder imputation). PASI 75/90/100, ≥ 75%/90%/100% improvement from baseline PASI.

Figure 4

Psoriasis Area and Severity Index (PASI) score and Investigator’s Global Assessment (IGA) 0/1 responses at weeks 16, 20 and 28 (nonresponder imputation); and bimekizumab (BKZ) plasma concentration from baseline to week 36. The bimekizumab plus placebo (BKZ+PBO) group received two doses of BKZ 320 mg at weeks 0 and 4, with placebo at week 16; the BKZ group received three doses of bimekizumab 320 mg, at weeks 0, 4 and 16. (a) 90% improvement in PASI (PASI 90) responses. (b) PASI 100 responses (total clearance). (c) IGA 0/1 responses: score of 0 (clear) or 1 (almost clear) with ≥ 2‐category improvement relative to baseline IGA, scored on a 5‐point scale. (d) Bimekizumab plasma concentration. See Figure S1 (Supporting Information) for the bimekizumab plasma concentration target range rationale.

Figure 5

Molecular resolution of the psoriasis (PsO) transcriptome by bimekizumab (BKZ). (a) Scatter plot comparing the fold change (FC) at baseline and after treatment for each probeset significantly dysregulated at baseline. Probesets are coloured by their direction at baseline. Violin plot insert of percentage improvements of psoriasis probesets. (b) Results of principal component analysis used to project the sample transcriptomes onto two dimensions (together explaining 35% of global variance in the data). (c) Heat map of expression profiles for probesets in the psoriasis transcriptome at baseline and after treatment. Expression values are scaled by row, and probesets are split first by direction and then clustered using hierarchical clustering. Samples are arranged in ascending order of Psoriasis Area and Severity Index (PASI) scores at baseline. Bars signify the percentage PASI response at week 12, with PASI 100 responders (those with 100% improvement from baseline PASI) further highlighted in orange.

Figure 6

Relative expression of key genes in T helper (Th)17‐stimulated keratinocytes. Human keratinocytes were stimulated with Th17 supernatant, with anti‐interleukin (IL)‐16 blocking antibodies, or without (control). Expression relative to unstimulated cells (shown as a horizontal line) is reported. BKZ, bimekizumab.

Figure 7

Expression of 12 key genes in treated lesional tissue at week 8 relative to baseline nonlesional (NL) and lesional tissue. Log2 normalized expression of probesets corresponding to specific marker genes that underpin psoriasis pathology, in baseline lesional and nonlesional samples and treated lesional samples at week 8. Hashed red horizontal lines correspond to the median baseline expression of a probeset in nonlesional tissue. Log fold change (FC) and false discovery rate (FDR)‐adjusted P‐values are calculated using the limma moderated t‐test. IL, interleukin. BKZ, bimekizumab; CXCL, C‐X‐C motif chemokine ligand 1; CCL, C‐C motif chemokine; KRT, keratin. ***FDR < 0·001.

Figure 8

Drivers of plaque formation in psoriasis. Proinflammatory chemotactic factors: CXCL1 (C‐X‐C motif chemokine ligand 1), interleukin (IL)‐8 (encoded by CXCL8) and CCL20 (C‐C motif chemokine 20); upstream cytokines: IL‐17A, IL‐17F, IL‐23A and IL‐12B; markers of epithelial stress: IL‐19, IL‐36γ and IL‐36α; proliferation: KRT16; antimicrobial peptide: S100A7. TNF, tumour necrosis factor. The T17 cell represents IL‐17‐producing T cells (including cytotoxic T cells and T helper cells).