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

Abstract

Background and 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. We evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering small interfering RNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis.

Approach and results: NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the United States. Patients with HCV-SVR (for ≥ 1 year) and advanced fibrosis received once-weekly i.v. infusions of placebo or BMS-986263 (45 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.

FIGURE 1

NCT03420768 study design. Eligible patients were randomized 1:1:2 to receive placebo or BMS‐986263 (45 mg or 90 mg) i.v. QW for 12 weeks. ^aLiver biopsies were performed within 8 weeks prior to or during the screening period

FIGURE 2

METAVIR stage change from baseline to Week 12. Patients with ≥ 1 METAVIR stage improvement at Week 12 stratified by (A) arm or (B) baseline fibrosis stage. ^aOR and difference in response rates are shown for each arm compared with placebo. ^bOne F2 patient had an inadequate Week 12 biopsy specimen and was considered to have no fibrosis improvement

FIGURE 3

Ishak score change from baseline to Week 12. Patients with ≥ 2 Ishak score improvement at Week 12 stratified by study arm and baseline fibrosis stage. ^aOne F2 patient had an inadequate Week 12 biopsy specimen and was excluded from the analysis

FIGURE 4

Liver HSP47 mRNA and protein change from baseline to Week 12. (A) Percentage of patients per arm with reduced HSP47 mRNA at Week 12. (B,C) Median percentage change in HSP47 mRNA (B) and HSP47 protein (C). ^aMissing data, n = 1. ^bMissing data, n = 2

FIGURE 5

Geometric mean BMS‐986263 plasma concentration. Figure shows the mean concentration time profile following administration of all infusions in the study. PK samples were collected at preinfusion, midinfusion, and postinfusion at Weeks 0, 1, 4, 6, and 11. Trough PK samples were collected preinfusion at Weeks 2, 5, 7, and 8. Samples during a dosing interval were collected at 72 h postinfusion following the doses at Weeks 0 and 6. Additional postinfusion PK samples were collected at 1 and 3 weeks following the Week 11 dose