Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation

Abstract

Objective: Interleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone.

Methods: Preclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated.

Results: IL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals.

Conclusions: These data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions.

Trial registration number: NCT02141763; Results.

Keywords: autoimmune diseases; cytokines; inflammation; psoriatic arthritis.

Figure 1

IL-17F contributes to inflammation and bimekizumab demonstrates superior efficacy relative to inhibition of IL-17A or IL-17F alone. Recombinant IL-17A and IL-17F, with or without TNF, were used to activate either (A) PsA synoviocytes (n=2) or (B) NHDFs (n=4), and IL-8 release was assessed following overnight culture. To evaluate the individual and collective influence of IL-17A and IL-17F, (C) PsA synoviocytes (n=4), (D, F, G) primary NHDFs (n=4) or (E) normal synoviocytes (n=5) were stimulated with Th17 supernatant with or without IL-17-specific blocking antibodies. Following overnight culture, either (C, D) inhibition of IL-8 production, (E, F) gene transcriptional changes or (G) inhibition of chemotactic potential was evaluated. For transcriptional analysis (E, F), genes were normalised to GAPDH mRNA and expressed as relative fold changes compared with unstimulated cells. For primary NHDFs, the panel presents genes that had a fold change ≥3 for Th17 stimulation under IgG conditions. Values were subject to conditional formatting (three colour scale: maximum value—red, minimum value—green, median value—yellow) for each target gene across groups. The same genes were analysed for normal synoviocytes and the conditional formatting was applied for genes expressing a fold change ≥3. Data are mean ±SEM. Figures are representative of three independent experiments. *represents a significant reduction versus IgG control, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. † represents a significant reduction versus anti-IL-17A, †P<0.05, ††P<0.01, ††††P<0.0001. IL, interleukin; NHDF, normal human dermal fibroblasts; PsA, psoriatic arthritis.

Figure 2

Pharmacokinetic parameters of bimekizumab (PK-PPS). (A) GeoMean plasma concentration–time profile of bimekizumab (PK-PPS) and (B) table of pharmacokinetic variables of bimekizumab. PK-PPS, pharmacokinetic per-protocol set. Note: Means, SDs and CVs were only calculated if at least one-third of the concentrations were quantified at a respective time point. CV, coefficient of variation.

Figure 3

ACR and PASI response rates by treatment group (PD-PPS). (A–C) ACR response rates (%, with 95% CI) and (D-E) PASI response rates (%, with 95% CI). Dashed vertical lines indicate drug intake (weeks 0, 3 and 6). Note: top three doses of bimekizumab (160 mg/80 mg/80 mg, 240 mg/160 mg/160 mg, 560 mg/320 mg/320 mg); PASI75 and PASI100 were only calculated for patients with BSA ≥3% psoriasis involvement at baseline. Modifications in concomitant therapy were permitted post week 8. Subject 003–00320 was excluded from the analyses for all time points after week 8 due to receiving an increased dose of naproxen, adalimumab and leflunomide for control of worsening disease. ACR20, American College of Rheumatology 20% response criteria; ACR50, American College of Rheumatology 50% response criteria; ACR70, American College of Rheumatology 70% response criteria; PASI75, Psoriasis Area and Severity Index 75% response criteria; PASI100, Psoriasis Area and Severity Index 100% response criteria; PD-PPS, pharmacodynamic per-protocol set.