Journal Article

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

Watling, Mark I L, Glatt, Sophie, Griffiths, Meryn, Miossec, Pierre, Shaw, Stevan, Ionescu, Lucian, Yeremenko, Nataliya, Lawson, Alastair D G, Maroof, Ash, Baker, Terry, Baeten, Dominique, Vajjah, Pavan, Oliver, Ruth, Popa, Serghei, Strimenopoulou, Foteini

2018

Overview

ObjectiveInterleukin (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.MethodsPreclinical 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.ResultsIL-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.ConclusionsThese 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 numberNCT02141763; Results.

• Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism,Elsevier Limited,BMJ Publishing Group
• Subject: Adult / Antibodies, Monoclonal, Humanized - immunology / Antibodies, Monoclonal, Humanized - pharmacology / Antibodies, Neutralizing - immunology / Arthritis / Arthritis, Psoriatic - drug therapy / Arthritis, Psoriatic - immunology / autoimmune diseases / Chemokines / Chemotaxis / Clinical and Epidemiological Research / Clinical trials / Cytokines / Double-Blind Method / Female / Fibroblasts / Gene expression / Homology / Humans / Immunoglobulin G / Inflammation / Inflammation - drug therapy / Inflammation - immunology / Inflammatory diseases / Interleukin-17 - antagonists & inhibitors / Interleukin-17 - immunology / Male / Middle Aged / Monoclonal antibodies / Neutrophils / Pharmacokinetics / Proof of Concept Study / Psoriasis / Psoriatic arthritis / Rheumatology / Severity of Illness Index / Skin / Treatment Outcome / Tumor necrosis factor-TNF