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

Ann Rheum Dis. 2018 Apr;77(4):523-532. doi: 10.1136/annrheumdis-2017-212127. Epub 2017 Dec 23.

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibodies, Neutralizing / immunology*
  • Arthritis, Psoriatic / drug therapy*
  • Arthritis, Psoriatic / immunology
  • Double-Blind Method
  • Female
  • Humans
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Interleukin-17 / antagonists & inhibitors
  • Interleukin-17 / immunology*
  • Male
  • Middle Aged
  • Proof of Concept Study
  • Severity of Illness Index
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • IL17A protein, human
  • IL17F protein, human
  • Interleukin-17
  • bimekizumab

Associated data

  • ClinicalTrials.gov/NCT02141763