Pulmonology · Medical Literature
Safety and efficacy of astegolimab for COPD with frequent exacerbations regardless of baseline blood eosinophil counts (ALIENTO and ARNASA): randomised, double-blind, placebo-controlled, phase 2b and 3 trials.
Abstract
Interleukin-33 and its receptor, ST2, are implicated in neutrophilic and eosinophilic inflammation during chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to assess the efficacy and safety of astegolimab, an anti-ST2 human IgG2 monoclonal antibody, which were evaluated in two COPD pivotal trials. In two randomised, double-blind, placebo-controlled trials (phase 2b ALIENTO and phase 3 ARNASA), current or former smokers with COPD and a history of frequent exacerbations, irrespective of baseline blood eosinophils, were randomly assigned (1:1:1; stratification by smoking status and region) to receive subcutaneous astegolimab 476 mg every 2 weeks, every 4 weeks, or placebo, alongside optimised inhaled maintenance therapy over 52 weeks. The primary endpoint (analysed in participants receiving one or more doses) was annualised rate of moderate or severe exacerbations. Missing data were considered similar to data from other participants in the same treatment group with the same baseline characteristics. The trials were registered with ClinicalTrials.gov (NCT05037929 and NCT05595642). In ALIENTO, 1301 participants (astegolimab every 2 weeks, n=433; astegolimab every 4 weeks, n=437; and placebo, n=431) initiated treatment between Oct 5, 2021, and Feb 19, 2024. In ARNASA, 1375 participants (astegolimab every 2 weeks, n=459; astegolimab every 4 weeks, n=459; and placebo, n=457) initiated treatment between Jan 9, 2023, and June 25, 2024. Adjusted rate ratios versus placebo for the primary endpoint were 0·85 (95% CI 0·72-1·00; p=0·049) for astegolimab every 2 weeks and 0·93 (0·79-1·10; p=0·38) for astegolimab every 4 weeks in ALIENTO, and 0·85 (0·72-1·01; p=0·068) for astegolimab every 2 weeks and 0·82 (0·70-0·98; p=0·024) for astegolimab every 4 weeks in ARNASA. Adverse events were balanced between treatments, with most participants experiencing one or more adverse events (1093 [84·0%] of 1301 participants in ALIENTO and 1176 [85·5%] of 1375 in ARNASA). The most common non-COPD adverse event was nasopharyngitis in ALIENTO and upper respiratory chest infection in ARNASA. Deaths occurred in 40 (3·1%) of 1301 participants in ALIENTO and in 44 (3·2%) of 1375 participants in ARNASA, and were balanced across treatment groups. Across both trials, a total of three deaths (0·1%) were considered to be related to treatment by investigators. In ALIENTO, astegolimab every 2 weeks was associated with a lower annual rate of exacerbations versus placebo in patients with COPD and a history of frequent exacerbations. In ARNASA, these findings did not meet statistical significance. Together, these findings suggest a role for targeting the ST2/IL-33 pathway to reduce the frequency of COPD exacerbations in patients with limited treatment options. Genentech, a member of the Roche Group, and F Hoffmann-La Roche.
Clinical relevance
Does subcutaneous astegolimab (anti-ST2 monoclonal antibody), added to optimised inhaled maintenance therapy, reduce the annualised rate of moderate or severe exacerbations in current or former smokers with COPD and a history of frequent exacerbations, irrespective of baseline blood eosinophil count? __SNAPSHOT__ {"studyDesign":"Two concurrent randomised, double-blind, placebo-controlled trials: phase 2b (ALIENTO; NCT05037929) and phase 3 (ARNASA; NCT05595642)","setting":"Multi-centre, international; specific countries not reported in abstract","sampleSize":"ALIENTO: n=1,301 (astegolimab Q2W n=433, Q4W n=437, placebo n=431); ARNASA: n=1,375 (astegolimab Q2W n=459, Q4W n=459, placebo n=457)","population":"Current or former smokers aged 40–90 years (ALIENTO) or 40–80 years (ARNASA) with moderate-to-very-severe COPD, a history of frequent exacerbations, and no minimum blood eosinophil count threshold required for enrolment","intervention":"Subcutaneous astegolimab 476 mg every 2 weeks (Q2W) or every 4 weeks (Q4W) added to optimised inhaled maintenance therapy (ICS+LABA, LAMA+LABA, or triple ICS+LAMA+LABA)","comparator":"Subcutaneous placebo on the same dosing schedules alongside optimised inhaled maintenance therapy","primaryOutcome":"Annualised rate of moderate or severe COPD exacerbations over 52 weeks (analysed in all participants receiving ≥1 dose)","followUp":"52 weeks of treatment","fundingSource":"Industry — Genentech (a member of the Roche Group) and F. Hoffmann-La Roche"}
Key findings
In ALIENTO (phase 2b), astegolimab Q2W produced an adjusted rate ratio (RR) of 0.85 (95% CI 0.72–1.00; p=0.049) versus placebo, corresponding to a 15% relative reduction in the annualised exacerbation rate (AER) — a borderline statistically significant result. The Q4W regimen did not reach significance (RR 0.93, 95% CI 0.79–1.10; p=0.38). In ARNASA (phase 3), astegolimab Q2W showed a nearly identical point estimate (RR 0.85, 95% CI 0.72–1.01; p=0.068), which did not meet the pre-specified significance threshold; the Q4W regimen showed RR 0.82 (95% CI 0.70–0.98; p=0.024), a nominally significant but paradoxically inconsistent result given its non-significance in the confirmatory arm. The absolute reduction in AER was approximately 15.4% for Q2W in ALIENTO and 14.5% for Q2W in ARNASA; exact absolute event rates were not reported in the abstract, precluding NNT calculation. Notably, total exacerbation counts were lower than prospectively anticipated in both trials, raising concerns about the studies being underpowered relative to the observed event rate. Adverse events were balanced between arms: 84.0% of ALIENTO participants and 85.5% of ARNASA participants experienced ≥1 adverse event across treatment groups. The most common non-COPD adverse events were nasopharyngitis (ALIENTO) and upper respiratory tract infection (ARNASA). Deaths occurred in 3.1% of ALIENTO participants and 3.2% of ARNASA participants, balanced across groups; across both trials, three deaths (0.1%) were considered treatment-related by investigators.
Practice implications
ALIENTO established a statistically significant, albeit borderline (p=0.049), reduction in COPD exacerbation rate with astegolimab Q2W in frequent exacerbators, regardless of eosinophil count — a noteworthy patient-selection innovation given prior biologics (e.g., dupilumab) required elevated eosinophils. However, ARNASA, the definitive phase 3 confirmatory trial, failed to replicate this finding for Q2W at conventional significance levels despite an essentially identical point estimate (RR 0.85), suggesting the programme was underpowered due to unexpectedly low event rates rather than true absence of effect. The 14–15% relative reduction in AER, if real, represents a modest effect size; most approved COPD biologics and pharmacological combinations achieve larger or comparably sized reductions. The phase 3 primary endpoint was not met, meaning regulatory approval based on these data alone would be unlikely without additional trial data or pooled analyses. Findings apply specifically to frequent exacerbators on maximal inhaled therapy; patients with rare exacerbations, those not on optimised background therapy, or non-smokers were not studied. The eosinophil-agnostic design is conceptually important given the IL-33/ST2 pathway's role in both neutrophilic and eosinophilic inflammation. Because only the abstract is available, subgroup analyses (by eosinophil count, smoking status, exacerbation severity, GOLD stage, or background therapy) cannot be evaluated, and no quality-of-life or lung function data are assessable. The inconsistency between ALIENTO (Q2W met primary) and ARNASA (Q4W met primary but Q2W did not) further complicates interpretation and raises questions about dose-response biology or chance findings across multiple comparisons. Practice should not change based on these results. __LIMITATIONS__ The phase 3 ARNASA trial failed to meet its pre-specified primary endpoint for the Q2W arm, the dose most likely to advance to approval, making this a formally negative phase 3 trial.,Total exacerbation counts were lower than prospectively anticipated in both trials, indicating the studies were likely underpowered due to event rate misestimation rather than an absence of biological effect.,The Q4W regimen showed statistical significance in ARNASA (p=0.024) but not in ALIENTO (p=0.38), yielding an inconsistent dose-response pattern across trials that is difficult to interpret biologically.,The absolute AER in each arm was not reported in the abstract, precluding calculation of absolute risk reduction and NNT.,Both trials were industry-funded (Genentech/Roche), with multiple investigators disclosing financial relationships with the sponsor, introducing risk of spin or selective emphasis.,Missing data were imputed by assuming they were similar to participants with matching baseline characteristics in the same treatment group — an assumption that may systematically favour the active arm if sicker patients discontinue at higher rates.,Eosinophil subgroup analyses, GOLD stage distribution, background therapy details, quality-of-life outcomes, spirometry changes, and hospitalisation data were not reported in the abstract.,Age ranges differed slightly between trials (ALIENTO: 40–90; ARNASA: 40–80), potentially affecting population comparability and generalisability to elderly patients.,The 52-week follow-up does not capture long-term durability of effect, sustained safety signals, or whether exacerbation suppression translates into mortality benefit.,Only the abstract is available for this summary; full publication review may alter interpretation of subgroup findings, sensitivity analyses, and secondary endpoints. __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ Astegolimab Q2W produced a borderline statistically significant 15% reduction in COPD exacerbation rate in the phase 2b ALIENTO trial but failed to meet the primary endpoint in the confirmatory phase 3 ARNASA trial, despite nearly identical point estimates — likely due to lower-than-anticipated exacerbation event rates in both studies. The safety profile was acceptable with no new signals identified. Astegolimab is not currently approvable based on these data, and practice should not change; further adequately powered trials or pooled regulatory analyses are needed before this agent can be recommended in clinical practice.