BMS‐986263 in patients with advanced hepatic fibrosis: 36‐week results from a randomized, placebo‐controlled phase 2 trial

Background & aims Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. Here, we evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering siRNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis. Approach & results NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the USA. Patients with HCV-SVR (for ≥1 year) and advanced fibrosis received once-weekly intravenous infusions of placebo or BMS-986263 (45 mg or 90 mg) for 12 weeks. The primary endpoint was ≥1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment and 2/15 (13%; placebo), 3/18 (17%; 45 mg), and 6/28 (21%; 90 mg) had METAVIR improvements of ≥1 stage at Week 12. Five patients in the 90 mg arm had Ishak improvements by ≥2 stages. BMS-986263 plasma concentrations increased in a generally dose-proportional fashion between BMS-986263 doses, with no notable accumulation with weekly dosing. All adverse events (AEs) were mild or moderate in intensity; most treatment-related AEs were infusion-related reactions in the BMS-986263 arms. At baseline, collagen levels were low, indicating low levels of fibrogenesis in these patients. Conclusions In patients with HCV-SVR, BMS-986263 administration was generally well tolerated through Week 36 and resulted in METAVIR and Ishak score improvements. Further evaluation of BMS-986263 in patients with active fibrogenesis is warranted.