Journal Article Ahead of print 1 citation
PubMed: 42150581 DOI: 10.1016/S0140-6736(26)00637-9
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.
Lancet
Authors: Alberto Papi, Neil J Greening, Surya P Bhatt, Nicolas Roche, Bartolome Celli, Jadwiga A Wedzicha, Àlvar Agustí, Ruth Tal-Singer, MeiLan K Han, Wim Janssens, Nicola A Hanania, Parameswaran Nair, Peter Bremner, Konstantinos Porpodis, Yoko Shibata, Stephanie Korn, Ting Yang, Oliver Gordon, Rebecca Saenz, Julie Ng, Dorothy S Cheung, Jacob Devine, Michele A Grimbaldeston, Wenhui Zhang, Xiaoying Yang, Divya Mohan, Claus F Vogelmeier, Christopher E Brightling
Affiliations
- Pulmonary Division, University of Ferrara, St Anna University Hospital, Ferrara, Italy.
- Institute for Lung Health, Department of Respiratory Sciences, University of Leicester, Leicester, UK.
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
- Université Paris Cité, APHP Centre, Hôpital et Institut Cochin, Paris, France.
- Mass General Brigham Hospital, Harvard University Medical School, Boston, MA, USA.
- National Heart and Lung Institute, Imperial College London, London, UK.
- University of Barcelona, Barcelona, Spain; Respiratory Institute, Hospital Clinic, Barcelona, Spain; FCRB-IDIBAPS, Barcelona, Spain; CIBER Enfermedades Respiratorias, ISCIII, Spain.
- Global Allergy & Airways Patient Platform, Vienna, Austria.
- University of Michigan, Ann Arbor, MI, USA.
- Department of Chronic Diseases and Metabolism (CHROMETA), University Hospital Leuven, KU Leuven, Belgium.
- Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA.
- Department of Medicine, McMaster University, Hamilton, ON, Canada; Research Institute of St Joe's Hamilton, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
- University of Notre Dame, Fremantle, WA, Australia.
- Pulmonology Department, G Papanikolaou Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
- Fukushima Medical University, Fukushima, Japan.
- IKF Pneumologie Mainz, Mainz, Germany; Thoraxklinik Heidelberg, Heidelberg, Germany.
- China-Japan Friendship Hospital, Beijing, China.
- Roche Products, Welwyn Garden City, Hertfordshire, UK.
- Genentech, South San Francisco, CA, USA.
- Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg, German Center for Lung Research (DZL), Marburg, Germany.
Abstract
BACKGROUND
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.
METHODS
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).
FINDINGS
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.
INTERPRETATION
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.
FUNDING
Genentech, a member of the Roche Group, and F Hoffmann-La Roche.
MeSH
Safety, Blood, Eosinophils, Drug-Related Side Effects And Adverse Reactions, Pulmonary Disease, Chronic Obstructive, Therapeutics, Interleukin-33, History