Breakthrough Phase II Trial Data Reinforces Potential of Survodutide as Leading MASH Treatment

(IN BRIEF) In a significant stride towards combating metabolic dysfunction-associated steatohepatitis (MASH), Boehringer Ingelheim unveils groundbreaking results from a Phase II trial sub-analysis of survodutide. Demonstrating impressive efficacy, up to 64.5% of adults with moderate to advanced fibrosis stages F2 and F3 experienced improved liver scarring without worsening MASH, compared to 25.9% with placebo after 48 weeks of treatment. These findings, presented at the European Association for the Study of the Liver Congress (EASL) 2024 and published concurrently in The New England Journal of Medicine, underline survodutide’s potential as a best-in-class MASH therapy. With plans to swiftly advance into Phase III trials, Boehringer Ingelheim aims to address the pressing need for innovative treatments in MASH and associated comorbidities.

(PRESS RELEASE) INGELHEIM, 7-Jun-2024 — /EuropaWire/ — Boehringer Ingelheim today unveiled groundbreaking findings from a sub-analysis of the Phase II trial of survodutide, showcasing remarkable improvements in fibrosis among adults with metabolic dysfunction-associated steatohepatitis (MASH). The results, presented at the European Association for the Study of the Liver Congress (EASL) 2024 and concurrently published in The New England Journal of Medicine, highlight the potential of survodutide as an advanced treatment for MASH and associated fibrosis.

The study revealed that up to 64.5% of adults with moderate to advanced fibrosis (F2 and F3) experienced a significant enhancement in fibrosis without exacerbating MASH, compared to only 25.9% with placebo after 48 weeks of treatment. This difference in response underscores the promising efficacy of survodutide in addressing the complex interplay between MASH and fibrosis, particularly in patient populations at heightened risk of liver-related complications.

These findings complement previously announced data from the trial, which demonstrated that survodutide led to statistically significant improvements in MASH compared to placebo, with up to 83.0% of adults experiencing positive outcomes.

Survodutide, a dual agonist targeting glucagon and GLP-1 receptors, represents a novel approach to addressing MASH and associated fibrosis. Dr. Arun Sanyal, Principal Investigator of the trial, expressed enthusiasm about the potential of survodutide to revolutionize treatment paradigms for individuals grappling with MASH and clinically significant fibrosis.

Moreover, the Phase II trial revealed significant improvements in secondary endpoints, including reductions in liver fat content and Non-alcoholic Fatty Liver Disease Activity Score (NAS), further validating the therapeutic potential of survodutide.

Carinne Brouillon, Head of Human Pharma at Boehringer Ingelheim, emphasized the urgency of developing effective treatments for MASH, a condition intricately linked with cardiovascular, renal, and metabolic disorders such as obesity. Brouillon affirmed Boehringer Ingelheim’s commitment to advancing survodutide into Phase III trials to address this unmet medical need.

Survodutide, licensed from Zealand Pharma, has garnered regulatory support, including FDA Fast Track Designation and EMA access to the Priority Medicine (PRIME) Scheme for MASH with fibrosis. Additionally, ongoing Phase III studies are exploring the potential of survodutide in overweight and obese populations, further underscoring its multifaceted therapeutic potential.

In conclusion, the latest findings underscore the promise of survodutide as a best-in-class treatment for MASH and associated fibrosis, heralding a new era of therapeutic possibilities for individuals affected by these conditions.

Notes to editors:

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).1 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).1

Use of MASH terminology

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.27 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).27

To reflect these recommendations, Boehringer Ingelheim has adopted the use of MASH to describe this Phase II trial.

About metabolic dysfunction-associated steatohepatitis (MASH)

MASH is a chronic and progressive liver disease caused by a build-up of fat in the liver,13,28 and is a more severe form of metabolic dysfunction-associated steatotic liver disease (MASLD).29 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.16 MASH is a disease closely associated with connected cardiovascular, renal, and metabolic diseases,30,31 and it is estimated that 34% of people living with obesity also have MASH.25

MASH severity is assessed using a scale that ranges from F0 to F4, which measures the level of fibrosis (scarring):32

• F0-F1: indicates no or mild fibrosis
• F2-F3: indicates moderate or advanced fibrosis
• F4: indicates cirrhosis

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.10

The primary endpoint of trial is the percentage of participants achieving histological improvement of MASH without worsening of fibrosis after 48 weeks of treatment.10 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.10 The NAS represents the sum of scores for steatosis (a build-up of fat in the liver33), lobular inflammation (inflammatory cells34) and ballooning (a type of liver cell degeneration35).

Secondary outcome measures include:10

• 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.10

About survodutide (BI 456906)

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.6

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 U.S. FDA Fast Track Designation in May 2021 for the treatment of MASH and fibrosis,21 and it was accepted to the EMA PRIME scheme in November 2023.22

Boehringer also studied survodutide in a 2-part Phase I trial among people with cirrhosis (F4) and varying degrees of liver dysfunction.36 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.36

Survodutide is also being evaluated in five Phase III studies for people living with overweight and obesity.2,23,24 SYNCHRONIZE-1 and SYNCHRONIZE-2 include sub-populations of patients with comorbidities, without and with type 2 diabetes, respectively.2 SYNCHRONIZE-CVOT includes a sub-population of patients with cardiovascular disease, chronic kidney disease, or with risk factors for cardiovascular disease.2 SYNCHRONIZE-JP in Japan and SYNCHRONIZE-CN in China are exploring survodutide for sub-populations of people living with obesity.23,24 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.24

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.26 The double-blind 48-week, placebo-controlled trial initiated enrollment in March this year.26

About Boehringer Ingelheim

Boehringer Ingelheim is working on breakthrough therapies that transform lives, today and for generations to come. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term, sustainable perspective. More than 53,000 employees serve over 130 markets in the two business units Human Pharma and Animal Health. Learn more at www.boehringer-ingelheim.com/uk (UK and Ireland) or www.boehringer-ingelheim.com (rest of world).

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