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

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.

Author information

1
Global Exploratory Development, UCB Pharma, Slough, UK.
2
Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands.
3
Immunology Patient Value Unit, UCB Pharma, Brussels, Belgium.
4
Structural Biology, UCB Pharma, Slough, UK.
5
New Medicines, UCB Pharma, Slough, UK.
6
Department of Rheumatology and Nephrology, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova.
7
Department of Clinical Immunology and Rheumatology, University of Lyon, Lyon, France.

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

Conflict of interest statement

Competing interests: DB, TB, MG, SG, LI, ADGL, AM, RO, SS, FS, PV, MILW are employees of UCB Pharma. DB, TB, ADGL, PV hold stocks and/or stock options in UCB Pharma. DB is a part-time employee of UCB Pharma and holds a part-time position at the Academic Medical Center/University of Amsterdam. DB received a grant from UCB Pharma to conduct preclinical experiments; DB received grants and/or consultant or investigator fees from the following organizations outside of the submitted work: AbbVie, Pfizer, MSD, Roche, BMS, Novartis, Eli Lilly, Boehringer Ingelheim and Glenmark. MG is a paid contractor for UCB working in a consulting capacity. PM is a scientific advisor to UCB Pharma and received associated fees outside of the submitted work. SP, NY declare no relevant conflicts of interest.

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