The FINANCIAL -- Gilead Sciences, Inc. and Novo Nordisk A/S announced results from a phase 2 proof-of-concept trial. The five-arm trial evaluated combinations of Novo Nordisk’s semaglutide, a GLP-1 receptor agonist, with Gilead’s investigational FXR agonist cilofexor and/or Gilead’s investigational ACC inhibitor firsocostat over 24 weeks in 108 people with non-alcoholic steatohepatitis (NASH). The results were presented at The Liver Meeting Digital Experience (TLMdX), 13–16 November 2020 (Late Breaker #L02).
The trial met its primary endpoint by demonstrating that in people with NASH and mild to moderate fibrosis all regimens were well tolerated. The most common adverse events (AEs) were gastrointestinal. Minimal pruritus (itching) was observed in people treated with cilofexor. Across all groups, 5–14% of people discontinued any trial treatment due to AEs.
Exploratory efficacy endpoints assessing biomarkers of liver health at 24 weeks in post-hoc analyses showed statistically significant improvements in hepatic steatosis (measured by magnetic resonance imaging proton density fat fraction; MRI-PDFF) and liver injury (measured by serum alanine aminotransferase; ALT) in the combination arms versus semaglutide alone. Although liver stiffness measured by vibration-controlled transient elastography (VCTE) and enhanced liver fibrosis (ELF) score declined in all groups, statistically significant differences between groups were not observed.
“These results offer novel insights around the multiple mechanisms that drive NASH and demonstrate the potential of combination approaches for patients in significant need of a treatment option for this condition,” said Naim Alkhouri, MD, director of the Fatty Liver Program, Chief of Transplant Hepatology, Arizona Liver Health, Chandler. “We are encouraged that these data showcase the potential for combination approaches to elicit improvements in liver fat content, liver biochemistry, and certain non-invasive tests of fibrosis, all of which have been associated with meaningful histologic improvement in NASH.”
“Gilead is focused on delivering scientific advances that can improve the lives of people with liver disease, both through our own innovation and in partnership with companies with complementary expertise, such as Novo Nordisk,” said Mark Genovese, MD, Senior Vice President, Inflammation Clinical Development at Gilead Sciences. “These data offer new insights into potential therapeutic approaches to treating NASH, a disease which currently has limited treatment options.”
“This trial brings together Gilead and Novo Nordisk’s respective expertise and science to provide important insights into potential new combination therapies involving semaglutide to help people living with NASH,” said Martin Holst Lange, senior vice president, Global Development at Novo Nordisk. “We are now carefully evaluating next steps together based on a thorough assessment of data.”
The companies are also presenting preclinical data supporting the development of combination approaches in NASH. In the preclinical trial, semaglutide alone and in combination with cilofexor and/or GS-834356 (an analogue of firsocostat) were administered daily for 12 weeks in a murine model of diet-induced NASH (n=15-16/group). The results demonstrated that while semaglutide significantly improved NASH and fibrosis-related endpoints, the addition of either cilofexor or the firsocostat analogue further improved liver fat reduction. The combination of all three agents had the greatest impact on changes in the NAFLD Activity Score (NAS).
The safety and efficacy of firsocostat, GS-834356 and cilofexor have not been established. Firsocostat, GS-834356 and cilofexor are investigational compounds and are not approved by the FDA or any other regulatory authority. Semaglutide has not been approved by the FDA or any other regulatory authority for the treatment of people living with NASH but has been approved for the treatment of type 2 diabetes.