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ND-L02-s0201 Treatment Leads to Efficacy in Preclinical IPF Models
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A2352 - ND-L02-s0201 Treatment Leads to Efficacy in Preclinical IPF Models
Author Block: J. Liu, Y. Liu, J. Zhang, F. Xia, A. Quimbo, J. Yao, J. Clamme, S. Zabludoff, W. Ying; Nitto BioPharma, Inc., San Diego, CA, United States.
RATIONALE: 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 and identify biomarkers that could be evaluated clinically. 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. In order to identify potential biomarkers of response, isolated lung mRNA from vehicle, ND-L02-s0201 and sham treated samples were profiled using RT2 Profiler™ PCR rat fibrosis array. 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. RT2 Profiler™ PCR rat fibrosis array results demonstrated that 11 out of 84 genes were downregulated more than 4-fold. 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, serum biomarker response and efficacy of ND-L02-s0201 warrants evaluation in IPF clinical trials.
Author Block: J. Liu, Y. Liu, J. Zhang, F. Xia, A. Quimbo, J. Yao, J. Clamme, S. Zabludoff, W. Ying; Nitto BioPharma, Inc., San Diego, CA, United States.
RATIONALE: 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 and identify biomarkers that could be evaluated clinically. 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. In order to identify potential biomarkers of response, isolated lung mRNA from vehicle, ND-L02-s0201 and sham treated samples were profiled using RT2 Profiler™ PCR rat fibrosis array. 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. RT2 Profiler™ PCR rat fibrosis array results demonstrated that 11 out of 84 genes were downregulated more than 4-fold. 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, serum biomarker response and efficacy of ND-L02-s0201 warrants evaluation in IPF clinical trials.
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