B77-06 Inhibition of Hedgehog Signaling With Taladegib Reduces Fibrogenesis in a Scar in a Jar Model of Pulmonary Fibrosis

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and fatal interstitial lung disease with limited therapeutic options. Fibroblast activation and excessive extracellular matrix (ECM) deposition play central roles in the development and progression of IPF. Therefore, targeting fibrogenesis and ECM accumulation represents a key strategy in the development of anti-fibrotic therapies. Type VI collagen (COL6) synthesis, measured by the PRO-C6 biomarker, has been reported to be elevated in patients with progressive IPF (Organ et al., Respir. Res. 2019; Jessen et al., BMC Pulm. Med. 2021). Fibrosis is driven by multiple pro-fibrotic mediators that collectively promote ECM remodeling. In this study, we utilized a pro-fibrotic cytokine cocktail to induce fibrogenesis and investigated the ability of Taladegib, a Hedgehog pathway inhibitor currently in Phase 2b clinical development for IPF, to suppress type VI collagen synthesis. Our findings demonstrate that Hedgehog pathway inhibition with Taladegib attenuates fibrogenesis induced by the cytokine cocktail in primary normal human lung fibroblasts and decreases matrix turnover in a human fibroblast “Scar-in-a-Jar” assay. Methods Primary lung fibroblasts were cultured in the Scar-in-a-jar model, and fibroblasts were exposed to a pro-fibrotic cytokine cocktail (FC) for 12 days. Cell culture supernatants were collected at day 12 for quantification of type VI collagen synthesis using the clinically relevant biomarker nordicPRO-C6TM. This study examined the impact of Taladegib (0.3-10 µM) and standard of care (Nintedanib 0.03-1 µM) on PRO-C6 levels in the presence of the FC compared to vehicle control. The FC, Taladegib, Nintedanib and treatment controls were administered on days 0, 4 and 8. Results Stimulating fibroblasts with the FC significantly (p 0.0001) increased PRO-C6 (2.8-fold) levels on day 12 compared to cells without stimulation. Taladegib (1-10 µM) and Nintedanib (0.03-1 µM) significantly (p = 0.0192 - p 0.0001) reduced levels of PRO-C6 (1.1 to 2.3-fold and 1.2 to 2.2-fold at day 12 compared to vehicle control. Conclusions Our findings show that the in vitro model employed is highly responsive to alterations in fibrogenesis, and that Hedgehog pathway inhibition with Taladegib significantly suppresses cytokine-induced fibrotic activity, highlighting its potential as a therapeutic strategy for idiopathic pulmonary fibrosis (IPF). This abstract is funded by: Nordic Bioscience