Bristol-Myers Squibb Company has announced data from a phase 2 study of BMS-986036, an investigational pegylated analogue of human fibroblast growth factor 21 (FGF21), a key regulator of metabolism, in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) (F1-F3). The study achieved its primary endpoint of significant reduction in liver fat versus placebo. Statistically significant improvements were also seen in prespecified exploratory endpoints including biomarkers of fibrosis, metabolic parameters and markers of liver injury. These data were presented at a late-breaking oral presentation at EASL: The International Liver Congress on April 22 in Amsterdam.

“These data suggest that BMS-986036 may be effective in patients with NASH, many of whom will experience disease progression due to the lack of available treatment options,” said Arun Sanyal, MBBS, M.D., professor, Departments of Medicine, Physiology, and Molecular Pathology, Virginia Commonwealth University. “The results of this study show that BMS-986036 had beneficial effects on three important components in the treatment of NASH: liver fat, liver injury and fibrosis.”

“We are encouraged by the improvements these data showed across multiple aspects of NASH, and that patients could be effectively evaluated through imaging rather than through invasive liver biopsy,” said Mike Burgess, head of Cardiovascular, Fibrosis and Immunoscience Development, Bristol-Myers Squibb. “These data, along with previously announced Phase 2 data in patients with type 2 diabetes, support further clinical research of BMS-986036 as a potential treatment for NASH. We look forward to sharing these data with health authorities to determine next steps for further study of this asset.”

Bristol-Myers Squibb exclusively licensed the rights to research, develop and commercialize BMS-986036 from Ambrx.

This was a multicenter, randomized (1:1:1), double-blind, placebo-controlled study in adults with body mass index =25 kg/m2, biopsy-confirmed NASH (F1-F3), and hepatic fat fraction =10%, assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF), a noninvasive measurement of liver fat. Randomization was stratified by diabetes status. Patients received subcutaneous injections of BMS-986036 10 mg daily (n=25), BMS-986036 20 mg weekly (n=23), or placebo (n=26) daily for 16 weeks. The primary efficacy endpoint was absolute change in MRI-PDFF at Week 16. Exploratory endpoints included serum Pro-C3 (N-terminal type III collagen propeptide, a fibrosis biomarker), enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and, in a subset of patients, liver stiffness, assessed by MR elastography (MRE).

Among the 74 patients treated, 68 were assessed by MRI-PDFF at both Baseline and Week 16. Liver biopsy was conducted to confirm NASH at Baseline. At Week 16, both dosing regimens of BMS-986036 (10 mg daily or 20 mg weekly) significantly reduced liver fat as measured by MRI-PDFF versus placebo (6.8% and 5.2%, respectively, vs. 1.3%, p=0.0004 and p=0.008). The 10 mg daily dose resulted in 57% of patients (13/23) reaching =30% relative risk reduction. The 20 mg weekly dose resulted in 52% of patients (11/21) reaching =30% relative risk reduction. Both dosing regimens also improved Pro-C3 (a serum biomarker of fibrosis), magnetic resonance elastography (MRE, a measure of liver stiffness), as well as adiponectin, ALT and AST (markers of liver injury). Improvements in triglycerides, low density lipoprotein (LDL), and high density lipoprotein (HDL) were also observed in the treatment groups.

Overall, BMS-986036 had a favorable safety profile, with no deaths or serious adverse events related to treatment, and no discontinuations due to adverse events. The most frequent adverse events were diarrhea (13% and 22%, respectively, vs. 8% in placebo), nausea (16% and 13%, respectively, vs. 8%), and frequent bowel movements (20% and 0%, respectively, vs. 0%), none of which were severe.