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2020-11-17| Trials & Approvals

Gilead and Novo Nordisk Present Proof-of-Concept Data for the First Possible NASH Treatment

by Daniel Ojeda
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On November 15th, Gilead Sciences and Novo Nordisk presented results for the Phase 2 proof-of-concept trial for their triple-drug regimen to treat non-alcoholic steatohepatitis (NASH), the most severe form of non-alcoholic fatty liver disease. The results showed that the three-drug regimen, which consisted of Semaglutide, Cilofexor, and Firsocostat, was well tolerated, and it led to significant improvement in hepatic steatosis and liver injury.

NASH is the most severe form of non-alcoholic liver disease. It is characterized by the accumulation of fat in the liver, inflammation, and liver cell damage, which can cause fibrosis and progress to cirrhosis in severe cases. Around 25% of adults suffer from non-alcoholic fatty liver disease in the US, with 5% suffering from NASH.

The underlying cause of NASH is still unknown. However, people suffering from obesity, insulin resistance, high levels of triglycerides, metabolic syndrome, and type 2 diabetes are more likely to develop NASH. Currently, there are no pharmacotherapies available, and the most common treatment is gradual weight loss. Although this can reduce inflammation and fat in the liver, treatments aiding with liver recovery and preventing further injury are necessary.

Validating Triple-Drug Regimen to Treat NASH

Gilead Sciences and Novo Nordisk also presented pre-clinical data validating the use of Semaglutide, in combination with Cilofexor and/or Firsocostat, to treat NASH. For these experiments, a murine model of diet-induced NASH was used. Here, treatment with Semaglutide alone resulted in the reduction in liver fat and improvement of fibrosis-related endpoints. Combination of Semaglutide with Cilofexor or Firsocostat further improves positive outcomes, and treatment with all three drugs had the greatest improvements. The results were presented during the scientific conference “The Liver Meeting Digital Experience that took place from November 13th to 16th.

Phase 2 Clinical Trial

The 24-week long, proof-of-concept trial evaluated the safety and efficacy of Novo Nordisk’s GLP-1 receptor inhibitor, Semaglutide, combined with Gilead’s FXR agonist, Cilofexor, and/or Gilead’s ACC inhibitor, Firsocostat in people with NASH and mild to moderate fibrosis. The results showed that all the different combinations were well tolerated, with only around 5-14% of patients dropping out of the trial due to adverse events. The most common adverse events were gastrointestinal. Additionally, combination therapies resulted in significant improvement in hepatic steatosis and liver injury compared to Semaglutide alone.

“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.”

Competitors

With their collaboration with Novo Nordisk, Gilead aims to have better results than with their last drug candidate to treat NASH, Selonsertib. The Phase 3 trial for this drug was terminated earlier this year due to a lack of efficacy. In addition to Gilead, multiple companies are currently testing therapeutic candidates to treat NASH. Of these, Genfit with their PPAR agonist, Elafibranor, Tobira Therapeutics with their CCR2/5 antagonist, Cenicriviroc, and Intercept with their synthetically modified analog of chenodeoxycholic acid, Ocaliva, are currently in Phase 3 clinical trials. Although, it is important to point out that Ocaliva was recently rejected for approval by the FDA because the predicted benefit of Ocaliva does not sufficiently outweigh the potential risks, and the agency recommended further analysis of efficacy and safety data. This rejection further emphasizes the need for additional therapeutic candidates to treat NASH.

By Daniel Ojeda, Ph.D.

Related Article: With NASH Drug Rejected, Intercept CEO Lambasts FDA’s Evolving Guidelines

References
  1. https://www.gilead.com/news-and-press/press-room/press-releases/2020/11/gilead-and-novo-nordisk-present-new-data-from-proof-of-concept-trial-in-nash
  2. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/nonalcoholic-steatohepatitis-information-center/nash-definition-prevalence/
  3. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/symptoms-causes
  4. https://clinicaltrials.gov/ct2/show/NCT03053050
  5. https://www.genfit.com/pipeline/elafibranor/
  6. https://clinicaltrials.gov/ct2/show/NCT02217475
  7. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32963-0/fulltext
  8. https://ir.interceptpharma.com/news-releases/news-release-details/intercept-receives-complete-response-letter-fda-obeticholic-acid
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