Late Breaking Abstract - ND-L02-s0201 treatment leads to efficacy in preclinical IPF models

Background: ND-L02-s0201/BMS-986263 is a lipid nanoparticle encapsulating a siRNA which inhibits expression of heat shock protein 47 (HSP47), a collagen-specific chaperone. ND-L02-s0201 is being evaluated for the treatment of hepatic fibrosis. IPF patient data show elevated HSP47 lung expression and linkage to poor prognosis. Our objective was to test ND-L02-s0201 efficacy in preclinical lung fibrosis models. Methods: We developed aggressive and sustained bleomycin (BLM) and silica induced rat lung fibrosis models. These therapeutic models ensure treatment of established disease that is maintained through-out the study. Key endpoints included lung weights, hydroxyproline (measure of collagen formation), histology and fibrosis (Trichrome) score. Lung function was evaluated using a 7 minute treadmill test. Utilizing the BLM model, myofibroblasts, epithelia, endothelia and macrophage cell populations were enriched, counted and characterized. Results: In the BLM model, we demonstrated dose-dependent and statistically significant reduction in lung weight, collagen deposition and histology and fibrosis scores following ND-L02-s0201 treatment. As a functional measure, statistically significant improvement in lung function determined by running endurance capacity was noted. Following cell enrichment, myofibroblasts contained the highest HSP47 mRNA expression. BLM led to a >5-fold increase in myofibroblasts and ND-L02-s0201 treatment reduced the myofibroblasts to sham levels. Comparable anti-fibrotic efficacy utilizing the endpoints was also observed in the silica model. Conclusions: Given the significant unmet medical need and our results, the safety and efficacy of ND-L02-s0201 warrants evaluation in IPF clinical trials.