Boehringer Ingelheim: Boehringer receives U.S. FDA Breakthrough Therapy designation and initiates two phase III trials in MASH for survodutide

• The U.S. FDA Breakthrough Therapy designation is for the treatment of adults with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and moderate or advanced fibrosis, based on survodutide's groundbreaking results from Phase II study¹
• Boehringer launches two Phase III studies of survodutide, LIVERAGE in adults with MASH and moderate or advanced fibrosis, and LIVERAGE-Cirrhosis in those with MASH and cirrhosis

Boehringer Ingelheim announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for survodutide (BI 456906), a dual glucagon/GLP-1 receptor agonist² for the treatment of adults living with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and moderate or advanced fibrosis (stages 2 or 3). The Breakthrough Therapy designation expedites the development and review of medicines for serious or life-threatening diseases that have shown preliminary clinical evidence indicating substantial improvement over available treatments.³

In addition, Boehringer announced the initiation of two Phase III clinical trials for survodutide for the treatment of adults living with MASH and fibrosis (scarring).

LIVERAGE will examine whether survodutide can improve MASH and/or fibrosis after 52 weeks of treatment and reduce the risk of end-stage liver disease outcomes after approximately seven years of treatment in adults living with MASH and moderate or advanced liver fibrosis (stages 2 or 3). LIVERAGE-Cirrhosis will examine whether survodutide can reduce the risk of end-stage liver disease outcomes after approximately four and a half years of treatment in adults living with MASH and compensated cirrhosis (fibrosis stage 4), a condition where the liver presents severe scarring.⁴

"Given the significant burden of MASH and the limited therapeutic options, novel approaches are urgently needed," said Dr. Arun Sanyal, M.D., Professor of Medicine at Virginia Commonwealth University School of Medicine and Director of 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 agonist mechanism of action, can help address this significant medical need."

"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," said Shashank Deshpande, Head of Human Pharma at Boehringer Ingelheim. "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 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.

About LIVERAGE and LIVERAGE-Cirrhosis

LIVERAGE and LIVERAGE-Cirrhosis are global Phase III clinical trials investigating the efficacy and safety of survodutide in adults with MASH and fibrosis stages 2 or 3 and in those with compensated MASH cirrhosis (stage 4), respectively. LIVERAGE will enroll approximately 1,800 adults, and LIVERAGE-Cirrhosis will enroll approximately 1,590 adults. In each trial, participants will be randomized to receive weekly injections of either survodutide, reaching a maximum dose of 6 mg, or placebo.

LIVERAGE consists of two parts. The two primary endpoints of part one are proportion of patients achieving MASH resolution without worsening of fibrosis, and at least a 1-point improvement in fibrosis without worsening of MASH, after 52 weeks of treatment. The primary endpoint of part two, which will continue for approximately seven years, is time to first occurrence of liver-related events or all-cause mortality.

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

About survodutide (BI 456906)

Survodutide is a glucagon/GLP-1 receptor dual agonist that activates both the glucagon and GLP-1 receptors, which play a role in controlling metabolic functions.² Survodutide is being evaluated in a robust Phase III clinical development program, including the LIVERAGE studies for people living with MASH and fibrosis and the SYNCHRONIZE studies for people living with overweight or obesity.^5,6,7,8

Survodutide's potential to treat adults with non-cirrhotic MASH and moderate or advanced fibrosis (stages 2 or 3) has been recognized by the U.S. FDA, which granted it:

• Fast Track designation in May 2021⁹ and;
• Breakthrough Therapy designation in September 2024.

Survodutide's potential to treat adults with MASH and fibrosis has also been recognized by:

• the European Medicines Agency (EMA), through acceptance to its PRIME scheme in November 2023¹⁰ and;
• the Center for Drug Evaluation of China's National Medical Products Administration (NMPA), which granted it Breakthrough Therapy designation in June 2024.

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.

About metabolic dysfunction-associated steatohepatitis (MASH)

MASH is a chronic and progressive liver disease caused by a build-up of fat in the liver,^11,12 and is a more severe form of metabolic dysfunction-associated steatotic liver disease (MASLD).¹³ In the U.S., cases of MASH are predicted to rise by 63% between 2015 and 2030, from 16.5 million to 27.0 million cases.¹⁴ MASH is a disease closely associated with interconnected cardiovascular, renal and metabolic conditions,^15,16 and it is estimated that 34% of people living with obesity also have MASH.¹⁷

MASH severity is assessed using a scale that ranges from F0 to F4, which measures the level of fibrosis (scarring):¹⁸

• 0-1: indicates no or mild fibrosis
• 2-3: indicates moderate or advanced fibrosis
• 4: indicates cirrhosis

About Boehringer Ingelheim

Boehringer Ingelheim is a biopharmaceutical company active in both human and animal health. As one of the industry's top investors in Research and Development, the company focuses on developing innovative therapies in areas of high unmet medical need. Independent since its foundation in 1885, Boehringer takes a long-term perspective, embedding sustainability along the entire value chain. More than 53,500 employees serve over 130 markets to build a healthier, more sustainable, and equitable tomorrow. Learn more at https://www.boehringer-ingelheim.com.

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References

¹Sanyal AJ, Bedossa P, Fraessdorf M, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. 2024;391(4):311-319.

²Zimmermann T, Thomas L, Baader-Pagler T, et al. BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Mol Metab. 2022;66:101633.

³U.S. Food & Drug Administration. Breakthrough Therapy. Available at: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy.Accessed September 2024.

⁴Kumar R, Kumar S, Prakash SS. Compensated liver cirrhosis: Natural course and disease-modifying strategies. World J Methodol. 2023;13(4):179-193.

⁵Boehringer Ingelheim. Phase III studies to investigate survodutide for people living with obesity and overweight, with and without diabetes, cardiovascular disease and chronic kidney disease. Available at: www.boehringer-ingelheim.com/phase-3-studies-survodutide-obesity-and-overweight. Accessed September 2024.

⁶Clinicaltrials.gov. A Study to Test Whether BI 456906 Helps Chinese People Living With Overweight or Obesity to Lose Weight. Available at: clinicaltrials.gov/study/NCT06214741. Accessed September 2024.

⁷Clinicaltrials.gov. A Study to Test Whether BI 456906 Helps Japanese People Living With Obesity Disease. Accessed September 2024.

⁸Clinicaltrials.gov. A Study to Test Whether Survodutide Helps People Living With Obesity or Overweight and With a Confirmed or Presumed Liver Disease Called Non-alcoholic Steatohepatitis. Accessed September 2024.

⁹Boehringer Ingelheim. Boehringer Ingelheim and Zealand Pharma Receive FDA Fast Track Designation for Investigational Treatment for NASH. Available at: www.boehringer-ingelheim.com/us/press-release/boehringer-ingelheim-and-zealand-pharma-receive-fda-fast-track-designation. Accessed September 2024.

¹⁰European Medicines Agency. List of medicines currently in PRIME scheme. Available at: www.ema.europa.eu/en/documents/other/list-medicines-currently-prime-scheme_en.xlsx. Accessed September 2024.

¹¹Ramai D, Facciorusso A, Vigandt E, et al. Progressive Liver Fibrosis in Non-Alcoholic Fatty Liver Disease. Cells. 2021;10(12):3401.

¹²National Institute of Diabetes and Digestive and Kidney Diseases. Nonalcoholic Fatty Liver Disease. Accessed September 2024

¹³American Liver Foundation. Nonalcoholic steatohepatitis. Accessed September 2024.

¹⁴Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133.

¹⁵Musso, Giovanni, et al. "Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis." PLoS Medicine. Vol. 11, no. 7, July 2014, p. E1001680. doi: 10.1371/journal.pmed.1001680.

¹⁶Schnell. Oliver, et al. "CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes." Cardiovascular Diabetology. Vol. 23, no. 1, Mar. 2024. doi: 10.1186/s12933-024-02180-8.

¹⁷Quek J, Chan KE, Wong ZY, et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(1):20-30.

¹⁸Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321.