Astegolimab Trial Readout In Frequent-Exacerbator COPD

Key Takeaways

• ALIENTO favored the every-2-week regimen, whereas ARNASA favored the every-4-week regimen on the primary exacerbation endpoint.
• Participants were current or former smokers with COPD and frequent exacerbations, enrolled regardless of baseline eosinophil count and treated with optimized inhaled maintenance therapy for 52 weeks.
• Adverse events and deaths were balanced across groups, and investigators considered three deaths across both trials treatment-related.

Across the ALIENTO and ARNASA trials, astegolimab produced a mixed readout in frequently exacerbating COPD, with one ALIENTO regimen reaching significance versus placebo and ARNASA showing significance for the every-4-week comparison but mixed results across dose schedules overall. ALIENTO was phase 2b, and ARNASA was phase 3. Both enrolled current or former smokers regardless of baseline blood eosinophil counts, a feature that shaped how the studies were framed. Both trials tested the antibody alongside optimized inhaled treatment. Together, the two randomized, placebo-controlled trials showed a mixed efficacy signal across dose schedules.

Investigators randomly assigned participants in a 1:1:1 ratio, stratified by smoking status and region, to subcutaneous astegolimab 476 mg every 2 weeks, every 4 weeks, or placebo. All groups continued optimized inhaled maintenance therapy for 52 weeks in these randomized, double-blind, placebo-controlled studies. ALIENTO enrolled 1301 participants, with 433, 437, and 431 assigned to the every-2-week, every-4-week, and placebo groups, while ARNASA enrolled 1375, with 459, 459, and 457 in those groups. Treatment initiation ran from Oct. 5, 2021, to Feb. 19, 2024, in ALIENTO and from Jan. 9, 2023, to June 25, 2024, in ARNASA. The primary endpoint was the annualized rate of moderate or severe exacerbations among participants who received one or more doses.

For the primary endpoint in ALIENTO, adjusted rate ratios versus placebo were 0.85 (95% CI 0.72-1.00; p=0.049) with every-2-week dosing and 0.93 (0.79-1.10; p=0.38) every 4 weeks. In ARNASA, the corresponding rate ratios were 0.85 (0.72-1.01; p=0.068) for every 2 weeks and 0.82 (0.70-0.98; p=0.024) for every 4 weeks. The favored schedule differed between ALIENTO and ARNASA rather than moving in one direction across the program. Enrollment was irrespective of baseline blood eosinophil counts, and the efficacy signal differed by regimen across the two studies.

Most participants had at least one adverse event, affecting 1093 of 1301 participants in ALIENTO and 1176 of 1375 in ARNASA, with overall events balanced between groups. Deaths were also balanced across treatment arms, occurring in 40 of 1301 participants in ALIENTO and 44 of 1375 in ARNASA, with three deaths across both trials considered treatment-related. The most common non-COPD adverse event was nasopharyngitis in ALIENTO and upper respiratory chest infection in ARNASA. The authors linked the ALIENTO every-2-week result to a lower annual exacerbation rate and described ARNASA as not meeting statistical significance. They also suggested a role for ST2/IL-33 pathway targeting in reducing exacerbation frequency in patients with limited treatment options.