A110-06 Buloxibutid Stabilizes and Improves Lung Function in Idiopathic Pulmonary Fibrosis and Elevates Plasma Mmp-13, Linking AT2 Receptor Activation in Alveolar Epithelial Type 2 Cells to Resolution of Fibrosis

Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive extracellular matrix accumulation. Buloxibutid, a selective angiotensin II type 2 receptor (AT2R) agonist, stabilized and improved lung function in the 36-week Phase 2a AIR trial in patients with IPF. The increase in lung function could be the result of fibrolytic activity, for example by collagenase matrix metalloproteins (MMPs) such as MMP-13 which has been suggested to promote fibrosis resolution in IPF (Craig et al., Am J Respir Cell Mol Biol 2015; 53: 585). The AT2R is primarily expressed on alveolar epithelial type II cells (AEC2) highlighting the potential role of AEC2 in mediating resolution of fibrosis. Identifying the cellular source of MMP-13 and the role of AT2R in the process of collagen homeostasis is important for understanding the mechanism of action of buloxibutid. Methods In the clinical 36-week Phase 2a AIR trial, plasma MMP-13 concentrations were measured repeatedly in IPF patients treated orally with buloxibutid (100 mg twice daily). In a mechanistic preclinical study, lung tissue from healthy and bleomycin treated rats was analyzed by RNAscope to assess expression of surfactant protein C (SPC; an established marker of alveolar epithelial type II cells) and MMP-13. Results In the AIR trial, plasma MMP-13 increased from baseline by 33% (p < 0.01), 34% (p < 0.001) and 31% (p < 0.01) at weeks 12, 24 and 36, respectively. In rat lungs, SPC and MMP-13 co-localized exclusively to AEC2 cells, and bleomycin equally reduced SPC- and MMP-13-positive cells. Conclusions These findings indicate that AEC2 are a primary source of MMP-13 in the lungs and that activation of AT2R promotes AEC2 survival and function in pulmonary fibrosis. This is supported by data showing that buloxibutid protects human AEC2 from bleomycin-induced cell death (Nalbandyan et al., FASEB J 2018; 32(S1): 829.7). The increased plasma MMP-13 observed in IPF patients treated with buloxibutid may thus reflect AEC2-mediated resolution of fibrosis and serve as a biomarker of alveolar epithelial viability. This abstract is funded by: Vicore Pharma