Randomized, Double-Blind, Placebo-controlled Study of Brodalumab, a Human Anti–IL-17 Receptor Monoclonal Antibody, in Moderate to Severe Asthma

Abstract

Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).

Interleukin-17 cytokine signalling in patients with asthma

“…In further support of conducting new studies, an anticipated increase in local infections was observed in the clinical trial by BUSSE et al [80], and this side-effect is in need of further evaluation prior to developing this new pharmacotherapeutic principle.…”

“…BUSSE et al [80] recently published a report of a clinical trial of an IL-17RA monoclonal antibody in patients with various types of asthma. Interestingly, a beneficial clinical effect was claimed for patients with inadequately controlled asthma who displayed high reversibility in response to a bronchodilator.…”

“…In particular, due to the lack of critical mechanistic evidence from patients it is not yet possible to make a firm conclusion with reference to the causative involvement of cytokine signalling via IL-17A and IL-17F in the mobilisation of neutrophils in asthma. This being said, it is very promising that a recent interventional [39] and a recent descriptive study [80] identified patients with moderateto-severe asthma and high reversibility as a clinical phenotype of particular interest. Even though these two important studies leave several important questions unanswered, this particular finding warrants further study.…”

Targeting cytokines in asthma therapy: could IL-37 be a solution?

“…Surprisingly, a number of attempts to neutralize the activity of these factors with antibodies like canakinumab, brodalumab [17], adalimumab, golimumab [18], and infliximab did not produce convincing results in clinical trials [19]. None of these agents reduced inflammatory cell counts or produced significant improvements of the clinical outcomes, but raised serious concerns over the safety of TNF-α-blockade and an increased susceptibility to respiratory infections.…”

T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

“…Although many T-cell populations contribute to the spectrum of allergic asthma phenotypes (2), cytokine-secreting T-helper 2 (T H 2) cells have the capacity to induce allergen-specific IgE (atopy) and invoke many of the pathophysiological manifestations associated with asthma, including airway eosinophilia, mucus hypersecretion, airway remodeling, and airway hyperreactivity. Targeting specific cytokinesignaling pathways in allergic asthma has had mixed efficacy (3)(4)(5), suggesting that additional targets and more focused approaches should be considered (6). Several T H 2 cell lineage-promoting transcriptional regulators, including GATA binding protein 3 (GATA-3) (7), , , and avian musculoaponeurotic fibrosarcoma (cMAF) (10), have been identified in T H 2 cells; however, it is unclear whether other transcriptional regulators are required for T H 2 cell-mediated responses.…”