Survodutide Wins FDA Breakthrough Therapy Designation for Noncirrhotic MASH Treatment in Adults

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The US FDA today granted Breakthrough Therapy designation to survodutide (BI 456906), a dual glucagon/glucagon-like peptide-1 (GLP-1) receptor agonist, for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and moderate or advanced fibrosis (stages 2 or 3).

In its October 8, 2024, press release, Boehringer Ingelheim also announced the initiation of a pair of global phase 3 clinical trials that will examine the safety and efficacy of survodutide in adults with MASH and moderate or advanced fibrosis (stages 2 or 3) as well as those with MASH and cirrhosis, LIVERAGE and LIVERAGE-Cirrhosis.

“Given the significant burden of MASH and the limited therapeutic options, novel approaches are urgently needed,” Arun Sanyal, MD, a professor of medicine at Virginia Commonwealth University (VCU) School of Medicine and director of VCU’s Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, said in the press release. “The Phase III LIVERAGE studies represent an exciting opportunity to investigate whether survodutide, with its dual glucagon and GLP-1 receptor agonist mechanism of action, can help address this significant medical need.”

In September 2024, topline results from a phase 2 study assessing survodutide in 295 adults with MASH presented at the 2024 European Association for the Study of the Liver (EASL) Congress in Milan, Italy, showed that the novel dual glucagon/GLP-1 RA improved MASH without worsening fibrosis after 48 weeks of treatment. Specifically, the study’s primary endpoint was met, with up to 83% of survodutide-treated participants showing improvement in MASH with no worsening in fibrosis.

Survodutide will now progress to the global LIVERAGE and LIVERAGE-Cirrhosis studies. According to the release, the LIVERAGE trial will consist of approximately 1800 adults with MASH and fibrosis stages 2 or 3 and the LIVERAGE-Cirrhosis study will enroll approximately 1590 adults with compensated MASH cirrhosis (stage 4). Participants in each trial will be randomly assigned to receive weekly injections of either survodutide, reaching a maximum dose of 6 mg, or placebo.

As described in the press release, LIVERAGE will consist of 2 parts. For part 1, the primary endpoints are the proportion of adults achieving MASH resolution without worsening of fibrosis, and at least a 1-point improvement in fibrosis without worsening of MASH, after 52 weeks. The primary endpoint of part 2, which will continue for approximately 7 years, is the time to first occurrence of liver-related events or all-cause mortality.

LIVERAGE-Cirrhosis will continue for approximately 4 and a half years and the primary endpoint is the time to first occurrence of all-cause mortality or liver-related events, according to the press release.

"With the number of MASH patients expected to rise worldwide in the coming years, advancing our understanding of this condition is more crucial than ever," Shashank Deshpande, head of Human Pharma at Boehringer Ingelheim, said in the release. "Our Phase III trial program with survodutide is one of the largest of its kind in terms of countries and sites involved. Notably, the program’s innovative design, which specifically targets advanced fibrosis including patients living with cirrhosis due to MASH – the most in-need population, is set to redefine the treatment landscape. The Breakthrough Therapy designation underscores that this potential best-in-class therapy has an opportunity to fundamentally change how MASH is treated."

Survodutide is also being examined among individuals living with overweight or obesity and without type 2 diabetes in the phase 2 SYNCHRONIZE clinical trial. Findings from the study presented last year at the 83rd Scientific Sessions of the American Diabetes Association (ADA), in San Diego, CA, showed that survodutide was associated with weight loss of up to 18.7% among 387 participants with a body mass index of 27 kg/m² or higher.

Reference: Boehringer receives U.S. FDA Breakthrough Therapy designation and initiates two phase III trials in MASH for survodutide. News release. Boehringer Ingelheim. October 8, 2024. Accessed October 8, 2024. https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/survodutide-us-fda-breakthrough-therapy-phase-3-trials-mash