ALIENTO and ARNASA were randomised, double-blind, placebo-controlled trials of astegolimab, an anti-ST2 monoclonal antibody, in patients with COPD and frequent exacerbations. Crucially, they enrolled irrespective of blood eosinophil count and irrespective of chronic bronchitis — the two criteria that have defined every successful COPD biologic to date. Participants were randomised to astegolimab every two weeks, every four weeks, or placebo for 52 weeks on top of optimised maintenance therapy. The prespecified pooled intention-to-treat population was 2,682.
Annualised moderate and severe exacerbations fell by 15% with fortnightly dosing (rate ratio 0.85, interval 0.76 to 0.96) and 12% with four-weekly (0.88, 0.78 to 0.99). Severe exacerbations specifically fell by 32% on the fortnightly schedule (0.68, 0.52 to 0.87), described as nominally significant. Tolerability was good.
The effect sizes are modest and the drug is not licensed. What matters is the population: if ST2 blockade works in COPD unselected for type 2 inflammation, it addresses the majority of patients that eosinophil-directed biologics leave out. The hierarchical testing plan is also worth noting — secondary endpoints were only formally tested because the primary succeeded, which is what keeps the severe-exacerbation result from being a fishing expedition.
- Enrolled regardless of eosinophil count — the important design choice here
- 15% relative reduction is modest; the absolute rate matters more for an individual
- Fortnightly dosing outperformed four-weekly on both endpoints
- The severe exacerbation result is labelled nominally significant, not confirmatory
- Not licensed; this is a pooled analysis of two pivotal trials, not approval
The statistics, in plain English
A rate ratio of 0.85 with an interval from 0.76 to 0.96 excludes no effect but sits close to it — the reduction could be as little as 4%. Hierarchical testing means the severe-exacerbation endpoint was only examined because the primary succeeded, which controls the false-positive rate that testing many endpoints would otherwise inflate. The authors still call it nominally significant, which is the appropriately cautious label.
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