Switching to twice-yearly depemokimab from mepolizumab/benralizumab in severe asthma: A multicenter, randomized, double-blind, Phase 3A Clinical Trial (NIMBLE)
Geoffrey Chupp, HIROYUKI NAGASE, D Skowasch, Gilles Devouassoux, ANDRÉANNE CÔTÉ, Daniel J Jackson, David J Jackson, Michael E Wechsler, Varsha Imber, John E. McGinniss, Sherine O K, P. Howarth, Ian D. Pavord, NIMBLE Study Investigators
Abstract
RATIONALE: Depemokimab is the first ultra-long-acting biologic with high IL-5 binding affinity, high potency, and an extended half-life enabling twice-yearly dosing. OBJECTIVES: Investigate the efficacy and safety of switching to depemokimab in participants with severe asthma already managed with and responsive to short-acting biologic therapies targeting IL-5 or its receptor. METHODS: NIMBLE (NCT04718389) was a multicenter, randomized, double-blind, double-dummy, parallel-group, phase 3A noninferiority study. Participants were ≥12 years old with asthma and documented clinical benefit on mepolizumab 100 mg subcutaneously every 4 weeks or benralizumab 30 mg subcutaneously every 8 weeks for ≥12 months. Participants were randomized 1:1 to depemokimab 100 mg subcutaneously every 26 weeks or maintained on their prior biologic (mepolizumab or benralizumab). The primary endpoint was annualized rate of clinically significant exacerbations over 52 weeks, with predefined noninferiority margin set at 1.28. Safety endpoints included adverse events. MEASUREMENTS AND MAIN RESULTS: Annualized rates (95% confidence intervals [CIs]) of clinically significant exacerbations over 52 weeks were 0.57 (0.50 to 0.64) with depemokimab (n = 848) and 0.49 (0.43 to 0.55) with active comparator (n = 839); the rate ratio (95% CI) was 1.16 (0.98 to 1.38). Since the upper bound of the 95% CI exceeded 1.28, noninferiority was not met. Most participants in both treatment arms experienced no clinically significant exacerbations. Health-related quality of life, asthma control, and lung function outcomes were stable throughout the study. Adverse events were comparable between treatment groups. CONCLUSIONS: While statistical noninferiority was not met, exacerbation rates were low and symptom control/lung function were maintained in both groups. This first randomized, controlled switch trial in severe asthma suggests that participants with severe asthma on mepolizumab or benralizumab may safely switch to twice-yearly depemokimab.