• Michael E Wechsler, Marcella K Ruddy, Ian D Pavord, Elliot Israel, Klaus F Rabe, Linda B Ford, Jorge F Maspero, Raolat M Abdulai, Chih-Chi Hu, Renata Martincova, Andreas Jessel, Michael C Nivens, Nikhil Amin, David M Weinreich, George D Yancopoulos, and Helene Goulaouic.
• From the Department of Medicine, National Jewish Health, Denver (M.E.W.); Regeneron Pharmaceuticals, Tarrytown, NY (M.K.R., M.C.N., N.A., D.M.W., G.D.Y.); NIHR Oxford Respiratory Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom (I.D.P.); Harvard Medical School and Brigham and Women's Hospital, Boston (E.I.); the Department of Medicine, Christian Albrechts University Kiel, Kiel, and LungenClinic Grosshansdorf and the Airway Research Center North at the German Center for Lung Research, Grosshansdorf - all in Germany (K.F.R.); the Asthma and Allergy Center, Bellevue, NE (L.B.F.); Fundación CIDEA (Centro de Investigación de Enfermedades Alérgicas y Respiratorias), Buenos Aires (J.F.M.); Sanofi, Cambridge, MA (R.M.A.); Sanofi, Bridgewater, NJ (C.-C.H., A.J.); Sanofi, Prague, Czech Republic (R.M.); and Sanofi, Chilly-Mazarin, France (H.G.).
• N. Engl. J. Med. 2021 Oct 28; 385 (18): 1656-1668.

BackgroundMonoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear.MethodsIn a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety.ResultsA total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups.ConclusionsInterleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.).Copyright © 2021 Massachusetts Medical Society.

28 keywords...

hide…