Dual inhibition of the pro-inflammatory cytokines interleukin (IL)-17A and IL-17F by the humanized monoclonal antibody bimekizumab appears to have a positive effect on patients with psoriatic arthritis (PsA), according to the results of a randomized, proof-of-concept clinical trial (ClinicalTrials.gov identifier: NCT02141763) published in the Annals of the Rheumatic Diseases.
The investigators hypothesized that IL-17F combined with IL-17A contributes to chronic tissue inflammation and sought to examine whether dual neutralization might lead to more profound suppression of inflammation compared with the inhibition of IL-17A alone. The pharmacokinetics, clinical efficacy, and safety of multiple doses of bimekizumab used to neutralize both IL-17A and IL-17F were explored.
Patients were randomly assigned to 1 of 5 treatment regimens, which included intravenous administration on 3 separate occasions at 0, 3, and 6 weeks. Treatment regimens included bimekizumab 240 mg/160 mg/160 mg (n=21), bimekizumab 80 mg/40 mg/40 mg (n=6), bimekizumab 160 mg/80 mg/80 mg (n=6), bimekizumab 560 mg/320 mg/320 mg (n=6), or matched placebo (n=14). Study inclusion criteria were age ≥18 years at screening; diagnosis of adult-onset PsA ≥6 months before screening, according to the Classification Criteria for PsA; active psoriatic lesions or history of skin psoriasis; active arthritis with ≥3 tender joints and ≥3 swollen joints at screening and at baseline; presence of inflammatory markers; and inadequate response to ≥1 nonbiologic disease-modifying antirheumatic drug (DMARD) or 1 approved biologic DMARD.
IL-17F induced similar inflammatory responses as IL-17A in skin and joint cells. Neutralization of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis compared with inhibition by IL-17A or IF-17F alone. Both prespecified efficacy success criteria were met in the proof-of-concept trial and revealed rapid, profound responses in both joint and skin (pooled top 3 doses vs placebo at 8 weeks): Patients receiving bimekizumab had greater American College of Rheumatology 20% response rates compared with placebo (80.0% vs 16.7%) and Psoriasis Area and Severity Index 100% response criteria (86.7% vs 0%). Responses were sustained through 20 weeks, with no unexpected safety signals reported.
The investigators concluded that IL-17F plays a key role in chronic tissue inflammation beyond that of IL-17A. The rapid, sustained joint and skin responses reported in the proof-of-concept trial in patients with active PsA warrant additional research on dual inhibition of IL-17F and IL17A in immune-mediated inflammatory disorders.
Glatt S, Baeten D, Baker T, et al. 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;77(4):523-532.