Survodutide Receives FDA Breakthrough Therapy Designation for MASH, Phase III Trials Begin
Key Insights
The FDA has granted Breakthrough Therapy designation to Boehringer Ingelheim's survodutide for adults with non-cirrhotic MASH (search) and moderate to advanced fibrosis (search).
Survodutide's designation is based on clinical data demonstrating potential improvement over existing therapies for MASH (search) and advanced fibrosis (search).
Boehringer Ingelheim has initiated two Phase III trials, LIVERAGE and LIVERAGE-Cirrhosis (search), to evaluate the efficacy and safety of survodutide in MASH (search) patients.
Boehringer Ingelheim's survodutide (BI 456906), a dual glucagon/GLP-1 receptor (search) agonist, has received Breakthrough Therapy designation from the FDA for the treatment of adults with non-cirrhotic metabolic dysfunction-associated steatohepatitis (search) (MASH (search)) and moderate to advanced fibrosis (search). This designation, announced on October 8, 2024, aims to expedite the development and review of survodutide, acknowledging its potential to offer significant improvement over existing treatments for MASH. Concurrently, Boehringer Ingelheim has initiated two Phase III clinical trials, LIVERAGE and LIVERAGE-Cirrhosis (search), to further evaluate the efficacy and safety of survodutide in patients with MASH. These trials represent a crucial step in addressing the urgent need for novel therapeutic options for this prevalent and serious liver disease. The Breakthrough Therapy designation underscores the potential for this therapy to fundamentally change how MASH is treated.
Clinical Significance and Trial Design
The FDA's decision to grant Breakthrough Therapy designation was based on preliminary clinical data suggesting that survodutide could offer a substantial improvement over current treatment options. In light of this designation, Boehringer Ingelheim has commenced two Phase III trials to comprehensively assess survodutide's impact on MASH (search). The LIVERAGE trial will enroll approximately 1,800 adults with MASH and fibrosis (search) stages 2 or 3, while the LIVERAGE-Cirrhosis (search) trial will include around 1,590 adults with compensated MASH cirrhosis. Participants in both studies will be randomized to receive weekly injections of either survodutide, up to a maximum dose of 6 mg, or a placebo.
The LIVERAGE trial is structured in two parts. The primary endpoints for the first part, spanning 52 weeks, are the proportion of patients achieving MASH (search) resolution without worsening of fibrosis (search), and at least a one-point improvement in fibrosis without worsening of MASH. The primary endpoint for the second part, which will continue for approximately seven years, is the time to first occurrence of liver-related events or all-cause mortality. The LIVERAGE-Cirrhosis (search) trial, with a duration of approximately four and a half years, has a primary endpoint of time to first occurrence of all-cause mortality or liver-related events.
Expert Commentary
"Given the significant burden of MASH (search) and the limited therapeutic options, novel approaches are urgently needed," said Arun Sanyal, MD, professor of medicine at Virginia Commonwealth University School of Medicine, and director, VCU’s Stravitz-Sanyal Institute for Liver Disease and Metabolic Health. "The Phase III LIVERAGE studies represent an exciting opportunity to investigate whether survodutide, with its dual glucagon and GLP-1 receptor (search) agonist mechanism of action, can help address this significant medical need."
Shashank Deshpande, head of human pharma at Boehringer Ingelheim, noted the innovative design of the Phase III program, which specifically targets advanced fibrosis (search), including patients living with cirrhosis (search) due to MASH (search). "The Breakthrough Therapy designation underscores that this potential best-in-class therapy has an opportunity to fundamentally change how MASH is treated," Deshpande stated.
MASH Disease Burden and Current Landscape
Metabolic dysfunction-associated steatohepatitis (search) (MASH (search)) is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD (search)), affecting approximately 250 million people globally. In the United States, cases are projected to increase by 63% between 2015 and 2030, rising from 16.5 million to 27.0 million. MASH is closely associated with cardiovascular, renal, and metabolic diseases, with an estimated 34% of obese individuals also having MASH. The disease is a leading cause of liver transplants in women and individuals over 65 in the U.S.
Survodutide Mechanism of Action and Development
Survodutide, licensed to Boehringer Ingelheim from Zealand Pharma, functions as a dual glucagon/GLP-1 receptor (search) agonist. It activates both glucagon and GLP-1 receptors, which play a role in controlling metabolic functions. The drug is also under evaluation for the treatment of obesity in the SYNCHRONIZE studies. Zealand Pharma retains co-promotion rights in the Nordic countries, while Boehringer Ingelheim is solely responsible for global development and commercialization.