AIR – an open-label, 36-week, clinical trial of buloxibutid – investigating the disease modifying potential of a novel angiotensin II type 2 receptor agonist in IPF

The unmet medical need in idiopathic pulmonary fibrosis (IPF) remains monumental with multiple trials failing to show stabilization or improvement. Buloxibutid (C21) is an oral, selective angiotensin II type 2 (AT2) receptor agonist with disease modifying potential. Buloxibutid drives an upstream pathway that improves alveolar epithelial type 2 cell survival, reduces fibrosis, and resolves vascular remodeling. AIR is an open-label, single-arm, 36-week, phase 2a trial investigating safety and efficacy of 100 mg BID of buloxibutid in treatment-naïve participants with centrally confirmed IPF. The primary efficacy endpoint is change in forced vital capacity (FVC), normalized to a 24-week rate of decline. Plasma levels of TGF-β1 and the collagenase MMP-13 are measured to further characterize the mechanism of action. The fully recruited study consists of 52 patients. In a 46 patient prefinal analysis the FVC increased from baseline by 47 mL (90% CI -108, +203 mL) at 24 weeks (n=27) and increased by 235 mL (90% CI +8, +389), normalized, at 36 weeks (n=19). TGF-β1 was reduced by 57% and MMP-13 levels increased by 67%. FVC stabilization at 24 weeks and improvement at 36 weeks, combined with a reduction of plasma TGF-β1 and increase of MMP-13, are consistent with the proposed disease modifying mechanism of action of buloxibutid. Buloxibutid was well tolerated with no signals of gastrointestinal adverse reactions or serious adverse reactions. Ten individuals reported reversible, mild to moderate hair thinning. The efficacy and safety of buloxibutid in IPF will be confirmed in the global, 52-week, phase 2b ASPIRE trial.