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.
Keywords: anti-asthmatic agents; biological therapy; noninferiority trial.
People with severe asthma may be treated with injectable biologic medicines to reduce inflammation in the bronchial tubes of the lungs. These medicines (aka biologics) can reduce asthma flare-ups (ie, exacerbations) and improve asthma symptoms; they are considered safer than long-term steroid use. Depemokimab is a newly developed biologic that has been shown to reduce severe exacerbations versus placebo in patients with severe asthma (SWIFT-1/-2 studies). Once injected under the skin, depemokimab works for a 6-month period, so injections are only needed twice a year. Currently available biologics for severe asthma, such as mepolizumab and benralizumab, require injections every 4 to 8 weeks. Since people with asthma may prefer fewer injections and find it easier to stay on less frequent treatment, it is of clinical interest to find out whether those who have previously improved with mepolizumab/benralizumab therapy maintain that improvement when their treatment is switched to depemokimab therapy. This study compared outcomes after 1 year in people with severe asthma who either switched to depemokimab or continued with mepolizumab/benralizumab. A statistical threshold was set to determine whether switching to depemokimab was noninferior (ie, not worse) than continuing mepolizumab/benralizumab. While the study did not meet this threshold for noninferiority, switching to depemokimab was linked to only a marginally higher number of exacerbations per year compared with continuing mepolizumab/benralizumab, and most people in all treatment groups did not experience any exacerbations. Additionally, other outcomes, such as asthma symptoms, lung function, and adverse events were similar between all the treatments. These results indicate that most people with severe asthma can safely and effectively switch from a current short-acting biologic to a twice-yearly treatment regimen with depemokimab.
© The Author(s) 2026. Published by Oxford University Press on behalf of the American Thoracic Society.