Survodutide shows breakthrough improvement in liver fibrosis with no worsening of MASH in 64.5% of patients with F2 and F3 fibrosis.- Boehringer + Zealand Pharma.

The full data results were presented at the European Association for the Study of the Liver Congress (EASL) 2024 and published simultaneously in The New England Journal of Medicine. The secondary endpoint shows that up to 52.3% of adults treated with survodutide (BI 456906) achieved a significant improvement in liver scarring (fibrosis) stages F1, F2 and F3 (mild to moderate or advanced scarring), versus 25.8% with placebo after 48 weeks of treatment [response difference: 26.5% (95% CI 8.37% – 44.66%), p<0.01].>

This news follows data announced earlier this year when the trial met its primary endpoint. These results demonstrated that up to 83.0% of adults achieved a statistically significant improvement of MASH versus placebo (18.2%), reinforcing the potential of survodutide as a best-in-class treatment [response difference: 64.8% (95% CI 51.1% – 78.6%), p<0.0001]. survodutide is a glucagon glp-1 receptor dual agonist with a novel mechanism of action, and the first to show this level of fibrosis benefit in a phase ii mash trial after 48 weeks of treatment. the glucagon agonist component in survodutide has the potential to increase energy expenditure and has a direct impact in the liver, which could contribute to the improvement of fibrosis. the glp-1 agonist component decreases appetite while increasing fullness and satiety.>

“I am particularly excited about the findings of the Phase II trial in survodutide, which demonstrate the potential for glucagon agonism, in addition to GLP-1, to both improve MASH and shift the needle on fibrosis,” said Dr. Arun Sanyal, M.D., Professor of Medicine, Physiology and Molecular Pathology at Virginia Commonwealth University School of Medicine, and Principal Investigator of the trial. “These data position survodutide as a leading glucagon/GLP-1 receptor dual agonist that could be a game-changer for people living with MASH and clinically significant fibrosis.”

An improvement was measured as a decrease of at least one stage in fibrosis after 48 weeks of treatment in this trial. Fibrosis is a measurement of the progression of MASH, a progressive disease impacting more than 115 million people worldwide. MASH is caused by inflammation of the liver that can lead to fibrosis, and severe tissue scarring (cirrhosis) can substantially increase the risk of end-stage liver disease and liver cancer. Liver transplant may be the only treatment option at this stage, which can place significant financial strain on healthcare systems. Liver fibrosis typically worsens slowly, and it is easy to go undetected if the fibrosis is not extensive. The reversal of liver fibrosis is often challenging for advanced stages of scarring and may not be possible for cirrhosis.

In this Phase II trial , survodutide also demonstrated significance versus placebo for all other secondary endpoints after 48 weeks of treatment. Actual treatment results showed that up to 87.0% of adults achieved at least a 30% relative reduction in liver fat versus 19.7% with placebo, as well as a relative reduction in liver fat content of up to 64.3% versus 7.3% with placebo. The absolute change from baseline in Non-alcoholic Fatty Liver Disease Activity Score (NAS, which is used to measure improvement in MASH) in actual treatment results was up to -3.3 with survodutide versus -0.4 with placebo.

Survodutide is licensed to Boehringer Ingelheim from Zealand Pharma, with Boehringer solely responsible for development and commercialization globally. Zealand has a co-promotion right in the Nordic countries.

In this trial, survodutide demonstrated safety data consistent with GLP-1 based molecules, with no new safety data concerns. Survodutide was granted FDA Fast Track Designation in 2021, and the European Medicines Agency (EMA) granted access to the Priority Medicine (PRIME) Scheme for MASH with fibrosis in November last year.

Survodutide is also being explored in five Phase III studies for people living with overweight and obesity, both of which are associated with MASH. An additional Phase III trial is evaluating if survodutide helps people living with overweight or obesity, with a confirmed or presumed diagnosis of MASH, reduce liver fat and lose weight.

About the data :Boehringer Ingelheim’s Phase II study in MASH and fibrosis stages F1, F2 and F3 included two analyses: planned (assigned dose at randomization) and actual (dose at the end of treatment). This press release reports on actual data results for participants (295 patients were randomized, and 293 received at least one dose of treatment and were analyzed) across both the primary and secondary endpoints. The additional sub-analysis among people with fibrosis F2 and F3 was conducted among patients with paired biopsies (223 of 293 patients had fibrosis F2 and F3 at baseline (76.2%) of which 170 had paired biopsies).

Boehringer Ingelheim’s Phase II trial is registered on clinicaltrials.gov as ‘A Study to Test Safety and Efficacy of BI456906 in Adults With Non-alcoholic Steatohepatitis (NASH) and Fibrosis (F1-F3)’ .This trial was registered prior to a 2023 update in nomenclature made by a number of multinational liver societies including EASL, AASLD and ALEH,.Their recommendation was to update non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD), and to update non-alcoholic steatohepatitis (NASH) with metabolic dysfunction-associated steatohepatitis (MASH).To reflect these recommendations, Boehringer Ingelheim has adopted the use of MASH to describe this Phase II trial.

About the trial (NCT04771273) :This is a Phase II, randomized double-blind placebo-controlled dose-finding trial of 295 participants that evaluates weekly subcutaneous injections of survodutide in people living with MASH and fibrosis (F1, F2 and F3) among adults both with and without type 2 diabetes. The primary endpoint of trial is the percentage of participants achieving histological improvement of MASH without worsening of fibrosis after 48 weeks of treatment. A histological improvement of MASH is defined as a decrease of greater than 2 points on the Non-alcoholic Fatty Liver Disease Activity Score (NAS – total score ranges from 0-8), including greater than 1 point decrease in NASH sub-score for lobular inflammation or ballooning, and no increase in fibrosis stage. The NAS represents the sum of scores for steatosis (a build-up of fat in the liver), lobular inflammation (inflammatory cells) and ballooning (a type of liver cell degeneration).

Secondary outcome measures include:: i. At least 30% relative reduction in liver fat content after 48 weeks of treatment compared to baseline. ii. Absolute and relative change of liver fat content from baseline after 48 weeks of treatment. iii. Improvement of fibrosis, defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment. iv. Absolute change from baseline in total score for NAS after 48 weeks of treatment. The trial consisted of dose escalation to either 2.4mg, 4.8mg and 6.0mg treatment groups for up to 24 weeks, and dose maintenance for 24 weeks.

See-JUN 07, 2024; "A Phase II Randomized Trial of Survodutide in MASH and Fibrosis"; A.J. Sanyal and Others10.1056/NEJMoa2401755.