The AIR Phase 2 Trial of the Angiotensin II Type 2 Receptor Agonist, Buloxibutid, in Individuals With Idiopathic Pulmonary Fibrosis: A Responder Analysis

Abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal interstitial lung disease lacking well tolerated and effective pharmacological therapies. Untreated, the proportion of patients showing a positive trajectory in lung function is very small. In the pivotal trials of nintedanib and pirfenidone, forced vital capacity percent predicted (FVCpp) increased by ≥5% in 6-11% of patients and by ≥10% in 0-3% of patients after 48-52 weeks of treatment1,2. Buloxibutid (also known as C21) is an orally available, selective angiotensin II type 2 receptor (AT2R) agonist. By activating AT2R on alveolar epithelial type 2 cells, buloxibutid triggers a cascade of signaling pathways that inhibit fibrosis, promote alveolar integrity and function, and reduce disease-associated vascular remodeling. Here, we report lung function responder patterns to buloxibutid treatment over 36 weeks in the AIR trial. Methods: AIR (NCT04533022) was a 36-week multicenter, open-label, single-arm, phase-2 trial investigating safety and efficacy of buloxibutid in participants with centrally confirmed IPF who were not receiving anti-fibrotic therapy. Participants received oral buloxibutid 100 mg twice daily and the primary efficacy endpoint was change in FVC from baseline. Responder analyses were conducted to investigate the number of participants who improved in FVCpp by >0%, >5%, and >10% at week 36. Results: The trial included 52 participants (mean age 67.3 years [SD 9.4], 77% males, with a mean percent predicted FVC 76.1% [SD 14.2]). Mean observed FVC improved during 36 weeks of buloxibutid treatment. In the full analysis set (n=48), 19 participants (40%) showed an increase in FVCpp above baseline at week 36. The percentage of participants with an improvement in FVC increased over the trial period. By week 36, 12 participants (25%) had an improvement in FVCpp >5%, and 9 participants (19%) had improved by >10%. Responders were observed across HRCT patterns of both typical and probable UIP. Conclusions: The selective AT2R agonist buloxibutid was associated with a high proportion of FVC responders. Importantly, the percentage of patients experiencing more than 5% or 10% increase in FVCpp compared favorably with reported rates for licensed antifibrotic therapies. Buloxibutid's efficacy and safety as a treatment for IPF is now being further evaluated in ASPIRE, a global, 52-week, phase-2b, randomized, double-blind, placebo-controlled trial. References:1 Brown KK, et al. Respiratory Medicine 2019;146:42-48. 2 Noble PW, et al. Eur Respir J 2016;47:243-253.