Boehringer Ingelheim announced breakthrough results from a survodutide phase II trial sub-analysis that demonstrate up to 64.5% of adults with fibrosis stages F2 and F3 (moderate to advanced scarring) achieved an improvement in fibrosis without worsening of metabolic dysfunction-associated steatohepatitis (MASH), versus 25.9% with placebo after 48 weeks of treatment [response difference: 38.6% (95% CI 18.1% - 59.1%), p=0.0005]. F2 and F3 patient populations are at increased risk of developing liver-related complications.
The full data results were presented today 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. A 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.
“Today’s breakthrough fibrosis results further reinforce survodutide’s potential as a best-in-class treatment for people living with MASH. We will advance quickly into phase III trials,” said Carinne Brouillon, Head of Human Pharma, Boehringer Ingelheim. “New treatments are urgently needed for MASH, a disease connected with cardiovascular, renal and metabolic conditions like obesity, and we are excited to continue these important discussions with healthcare authorities.”
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 US Food and Drug Administration (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.
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.
MASH is a chronic and progressive liver disease caused by a build-up of fat in the liver, and is a more severe form of metabolic dysfunction-associated steatotic liver disease (MASLD). In the US, cases of MASH are predicted to rise by 63% between 2015 and 2030, from 16.5 million to 27.0 million cases. MASH is a disease closely associated with connected cardiovascular, renal, and metabolic diseases, and it is estimated that 34% of people living with obesity also have MASH.
MASH severity is assessed using a scale that ranges from F0 to F4, which measures the level of fibrosis (scarring): F0-F1: indicates no or mild fibrosis; F2-F3: indicates moderate or advanced fibrosis; F4: indicates cirrhosis.
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 =2 points on the Non-alcoholic Fatty Liver Disease Activity Score (NAS – total score ranges from 0-8), including =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: At least 30% relative reduction in liver fat content after 48 weeks of treatment compared to baseline; Absolute and relative Change of liver fat content from baseline after 48 weeks of treatment; Improvement of fibrosis, defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment; 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.
Survodutide is a glucagon/GLP-1 receptor dual agonist that activates both the glucagon and GLP-1 receptors, which are critical to controlling metabolic functions.
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. Survodutide is part of Boehringer Ingelheim’s research and development portfolio in the cardiovascular, renal, and metabolic disease areas.
Survodutide was granted US FDA Fast Track Designation in May 2021 for the treatment of MASH and fibrosis, and it was accepted to the EMA PRIME scheme in November 2023.
Boehringer also studied survodutide in a 2-part phase I trial among people with cirrhosis (F4) and varying degrees of liver dysfunction. The purpose of Part 1 was to find out whether cirrhosis (F4) and varying degrees of liver dysfunction influences how survodutide is taken up in the body, and the purpose of Part 2 was to find out whether having cirrhosis (F4) and varying degrees of liver dysfunction influences how people with overweight and obesity tolerate survodutide treatment for 28 weeks.
Survodutide is also being evaluated in five phase III studies for people living with overweight and obesity. SYNCHRONIZE-1 and SYNCHRONIZE-2 include sub-populations of patients with comorbidities, without and with type 2 diabetes, respectively. SYNCHRONIZE-CVOT includes a sub-population of patients with cardiovascular disease, chronic kidney disease, or with risk factors for cardiovascular disease. SYNCHRONIZE-JP in Japan and SYNCHRONIZE-CN in China are exploring survodutide for sub-populations of people living with obesity. SYNCHRONIZE-JP explores the relative change in liver fat from baseline to week 76 when treated with survodutide versus placebo, as a key secondary endpoint.
An additional phase III trial called SYNCHRONIZE-MASLD 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. The double-blind 48-week, placebo-controlled trial initiated enrollment in March this year.
