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 onceweekly 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

The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application

“…In a Phase 1 trial on healthy persons (n = 20), ND-LO2-s0201, a lipid nanoparticle that targets hepatic stellate cells and is capable of reversibly suppressing HSP47, was shown to be well tolerated and may be investigated further in Phase II trials. A randomized, double-blind, placebo-controlled Phase II study evaluated the safety and efficacy of BMS-986263 in patients with advanced hepatic fibrosis after virologic cure of hepatitis C (an infection caused by a virus that attacks the liver and leads to inflammation, NCT03420768) [ 62 ]. BMS-986263 is a lipid nanoparticle delivering siRNA designed to degrade HSP47 mRNA.…”

Regulation of Progression and Resolution of Liver Fibrosis by Immune Cells

“…Currently, numerous clinical trials for the treatment of NASH have been conducted, however, no therapeutic agents have been approved except for Saroglitazar, peroxisome proliferatoractivated receptor (PPAR) agonist, approved in India [112], suggesting that the development of therapeutic agents for NASH is challenging. Therapeutic agents for NASH fibrosis under investigation include farnesoid X receptor (FXR) agonists [113], fibroblast growth factor (FGF) modifiers [114,115], Glucagon-like peptide-1 receptor (GLP1R) agonists [116], PPAR agonists [117], inflammatory regulators [118], stellate function control [119], and stellate ablation [120,121]. Among drugs involved in inflammation control via effects on immune cells, the CCR2/CCR5 antagonist [122], the TLR4 antagonist [123], and the galectin-3 inhibitor[124] have been discontinued due to insufficient efficacies.…”

“…or the elimination of stellate cells targeted by immune cells during the exacerbation or recovery phase of fibrosis are considered to be the most promising, next to bile acid signaling-targeting therapies, such as FXR agonists. In particular, the specific removal of stellate cells using the vitamin A-liposomal siRNA against Heat shock protein (HSP) 47 system suggests that it is possible to lower the stage of fibrosis [120]. The development of new therapeutic strategies inferred from the mechanism underlying recovery from fibrosis via immune cells is also important.…”

“…In particular, the specific removal of stellate cells using the vitamin A–liposomal siRNA against heat shock protein (HSP) 47 system suggests that it is possible to lower the stage of fibrosis. 120 The development of new therapeutic strategies inferred from the mechanism underlying recovery from fibrosis via immune cells is also important. For example, in the CCl4 model, macrophages exhibit conversion to a fibrolytic phenotype by modification with relaxin peptide or miR-30a-5p, and drugs utilizing this strategy may be effective.…”

Measure twice, cut once

“…[1] In this month's issue, Lawitz et al report on the use of BMS-986263, a retinoid-conjugated lipid nanoparticle containing HSP47 siRNA delivered as a weekly infusion. [2] Participants in the study had a history of HCV and were ~3-4 years after sustained virological response. It is a small phase 2 study intended to focus on fibrosis regression after 12 weekly infusions with BMS-986263 in participants with METAVIR F3 or F4 fibrosis at baseline.…”