Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial.

BACKGROUND

Genetic data implicate IL-33 in asthma susceptibility. Itepekimab, a monoclonal antibody targeting IL-33, demonstrated clinical activity in asthma, with potential in chronic obstructive pulmonary disease (COPD). In this study we first aimed to test the hypothesis that genetic variants in the IL-33 pathway were also associated with COPD. On the basis of the strong association of IL-33 pathway genes with pulmonary diseases like asthma and COPD, we conducted this phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy.

METHODS

In this two-part study, genetic analyses of loss-of-function and gain-of-function variants in the IL-33 pathway, previously associated with asthma risk, were initially characterised for COPD. We then did a double-blind, phase 2a trial comparing itepekimab with placebo in patients with moderate-to-severe COPD despite standard therapy, at 83 study sites in ten countries. Patients aged 40-75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy, were randomly assigned (1:1) to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24-52 weeks. The primary endpoint of the phase 2a trial was annualised rate of moderate-to-severe acute exacerbations of COPD during the treatment period. The key secondary outcome was change in prebronchodilator FEV

FINDINGS

Genetic analyses demonstrated association of loss of function in IL33 with reduced COPD risk, and gain of function in IL33 and IL1RL1 variants with increased risk. Subsequent to this, in the phase 2 trial, 343 patients were randomly assigned to placebo (n=171) or itepekimab (n=172) from July 16, 2018, to Feb 19, 2020. Annualised rates of acute exacerbations of COPD were 1·61 (95% CI 1·32-1·97) in the placebo group and 1·30 (1·05-1·61) in the itepekimab group (relative risk [RR] 0·81 [95% CI 0·61-1·07], p=0·13), and least squares mean prebronchodilator FEV

INTERPRETATION

The primary endpoint in the overall population was not met, subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD.

FUNDING

Sanofi and Regeneron Pharmaceuticals.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests KFR reports consulting and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Roche, and Sanofi, and federal funding of the German Ministry for Research and Technology for the German Center for Lung Research. BRC reports consulting and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Pulmonx, Regeneron, and Sanofi. MEW reports personal fees from Boehringer Ingelheim, Cohero Health, Equillium, Gala Therapeutics, Genentech, Genzyme, GlaxoSmithKline, Novartis, Pulmatrix, Regeneron Pharmaceuticals, resTORbio, and Sentien Biotechnologies; and grants and personal fees from AstraZeneca, Sanofi, and Teva. JEH, AB, MAF, MKR, MCN, NA, DMW, and GDY report employment by and are shareholders of Regeneron Pharmaceuticals. RMA, XL, MMB, HS, and HG report employment by and might hold stock or stock options in Sanofi.