An Active-comparator-controlled, Open-label, Parallel Group Study to Evaluate the Effect of Survodutide on Energy Expenditure and Fatty Acid Oxidation in Subjects With Obesity

This study is open to adults between 18 and 65 years of age who have obesity. People can join the study if they have a body mass index (BMI) between 30 and 45 km/m². The purpose of this study is to find out whether a medicine called survodutide improves how the body uses energy and breaks down fat. This study compares survodutide with another medicine called semaglutide. Survodutide is being developed to treat people with obesity.
Semaglutide is already used to treat people with obesity.
Participants are put into 2 groups by chance. One group gets survodutide and the other group gets semaglutide. Participants get survodutide or semaglutide as an injection under the skin once a week. Participants are in the study for about 8 months. During this time, they visit the study site weekly. Some of the visits may also be done at the participant's home instead of the study site.
At some of the visits, doctors test how much energy a participant's body uses. This is done in a special room where they measure the oxygen that is breathed in and the carbon dioxide that is breathed out by the participant. The results are compared between the 2 groups to see whether the treatment works. The doctors also regularly check participants' health and take note of any unwanted effects.

Start Date17 Jan 2025

Sponsor / Collaborator

Boehringer Ingelheim GmbH

NCT06632457 / RecruitingPhase 3

A Phase III Double-blind, Randomised, Placebo-controlled Trial to Evaluate Liver-related Clinical Outcomes and Safety of Once Weekly Injected Survodutide in Participants With Compensated Non-alcoholic Steatohepatitis/Metabolic Dysfunction Associated Steatohepatitis (NASH/MASH) Cirrhosis

This study is open to adults who are at least 18 years old and have:
* A confirmed liver disease called non-alcoholic steatohepatitis (NASH) or
* A confirmed liver disease called metabolic-associated steatohepatitis (MASH)
* BMI of 27 kg/m2 or more or
* 25 kg/m2 or more if the participant is Asian.
People with a history of other chronic liver diseases or high alcohol intake cannot take part in this study. The purpose of this study is to find out whether a medicine called survodutide helps people with NASH or MASH improve their liver function.
Participants are put into 2 groups randomly, which means by chance. 1 group gets survodutide and 1 group gets placebo. Placebo looks like survodutide but does not contain any medicine. Each participant has twice the chance of getting survodutide. Participants and doctors do not know who is in which group. Participants inject survodutide or placebo under their skin once a week. All participants regularly receive counselling to make changes to their diet and to exercise regularly.
Participants are in the study for up to 4 and a half years. During this time, they visit the study site or have a remote visit by video call every 2, 4 or 6 weeks for about a 1 year and 5 months. After this time participants visit the trial site or have a remote visit every 3 months until the end of the study.
The doctors check participants' health and take note of any unwanted effects. The participants' body weight is regularly measured. At some visits the liver parameters are measured using different imaging methods. The participants also fill in questionnaires about their symptoms. The results are compared between the groups to see whether the treatment works.

Start Date12 Nov 2024

Sponsor / Collaborator

Boehringer Ingelheim GmbH

NCT05202353 / RecruitingPhase 1

Open-label, Randomised, 4 Parallel-group, Phase I Clinical Trial to Investigate BI 456906 Occupancy of Glucagon Receptors in Liver and Glucagon-like Peptide 1 Receptors in Pancreas in Comparison With Semaglutide After Administration of Radiolabeled Tracer in Male and Female Subjects With Obesity Using PET and MRI

This study is open to adults with obesity. People with a body mass index (BMI) in the range from 30 to 40 kg/m2 and a body weight of 70 to 150 kg can participate in the study. The purpose of this study is to find out whether treatment with a medicine called BI 456906 changes the occupancy of receptors in the liver and in the pancreas. These receptors are involved in appetite and weight regulation. To measure the occupancy of these receptors, doctors use injectable tracers. Doctors visualise the binding of the tracers to these receptors with imaging methods.
Participants are put into 4 groups randomly, which means by chance. 2 groups get BI 456906 and 2 groups get semaglutide. Semaglutide is an approved medicine for body weight reduction. For 17 weeks, participants get injections under the skin. They either get BI 456906 twice a week or semaglutide once a week. The injected doses increase in small steps. Before and after 17 weeks of treatment, the receptor occupancy is determined.
Participants are in the study for up to 6 months. At the beginning and at the end of the treatment participants stay at the study site with an overnight stay. At the beginning, the study staff trains participants how to inject the study treatment at home. Participants who get BI 456906 visit the study site 18 times and have 19 visits at home. Participants who get semaglutide visit the study site 15 times and have 6 home visits. The doctors also regularly check participants' health and take note of any unwanted effects.

Start Date01 Nov 2024

Sponsor / Collaborator

Boehringer Ingelheim GmbH

100 Clinical Results associated with Survodutide

100 Translational Medicine associated with Survodutide

100 Patents (Medical) associated with Survodutide

Literatures (Medical) associated with Survodutide

01 Dec 2024·JACC-Heart Failure

Survodutide for the Treatment of Obesity

Review

Author: Kosiborod, Mikhail N ; le Roux, Carel W. ; Platz, Elke ; Kaplan, Lee M ; Unseld, Anna ; Startseva, Elena ; Kaplan, Lee M. ; Brueckmann, Martina ; le Roux, Carel W ; Kosiborod, Mikhail N. ; Wharton, Sean ; Ajaz Hussain, Samina

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors may be more effective than GLP-1 receptor agonism alone in reducing body weight, but the cardiovascular (CV) effects are unknown. The authors describe the rationale and design of SYNCHRONIZE-CVOT, a phase 3, randomized, double-blind, parallel-group, event-driven, CV safety study of survodutide, a dual glucagon and GLP-1 receptor agonist, administered subcutaneously once weekly compared with placebo in adults with a body mass index ≥27 kg/m² and established CV disease or chronic kidney disease, and/or at least 2 weight-related complications or risk factors for CV disease. The primary endpoint of SYNCHRONIZE-CVOT is time to first occurrence of the composite adjudicated endpoint of 5-point major adverse CV events. This global CV outcomes trial is currently enrolling, with a target recruitment of 4,935 participants. SYNCHRONIZE-CVOT is the first trial that will determine the CV safety and efficacy of survodutide in people with obesity and increased CV risk. (A Study to Test the Effect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity [SYNCHRONIZE-CVOT]; NCT06077864).

01 Nov 2024·DIABETES CARE

Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity

Review

Author: Drucker, Daniel J.

The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits of GLP-1RA in select patient populations. In ongoing trials investigators are interrogating the efficacy of these agents for new indications, including metabolic liver disease, peripheral artery disease, Parkinson disease, and Alzheimer disease. The success of GLP-1–based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide block the GIP and activate the GLP-1 receptor, whereas retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors. Here I highlight evidence establishing the efficacy of GLP-1–based medicines, while discussing data that inform safety, focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer. Rapid progress in development of highly efficacious GLP-1 medicines, and anticipated differentiation of newer agents in subsets of metabolic disorders, will provide greater opportunities for use of personalized medicine approaches to improve the health of people living with cardiometabolic disorders.

01 Nov 2024·JOURNAL OF HEPATOLOGY

Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis

Article

Author: Schmid, Bernhard ; Noureddin, Mazen ; Fraessdorf, Mandy ; Alkhouri, Naim ; Andrews, Charles P ; Hosseini-Tabatabaei, Azadeh ; Neff, Guy W ; Schattenberg, Jörn M ; Gane, Edward J ; Sanyal, Arun J ; Mazo, Daniel F ; Fenske, Wiebke K ; Lawitz, Eric J ; Younes, Ramy ; Hussain, Samina Ajaz ; Takács, István

BACKGROUND & AIMS:

Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis.

METHODS:

This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC_0-∞) and maximal plasma concentration (C_max). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored.

RESULTS:

In the single-dose cohorts (n = 41), mean AUC_0-∞ and C_max were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment.

CONCLUSIONS:

Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis.

IMPACT AND IMPLICATIONS:

Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

CLINICALTRIALS:

GOV IDENTIFIER:

NCT05296733.

102

News (Medical) associated with Survodutide

05 Nov 2024

·endpts.com

Zealand’s ‘aspirational’ mission for its amylin drug to be first-line in obesity

SAN ANTONIO — Zealand Pharma, hoping to create the next “foundational” therapy for obesity, detailed more Phase 1 data on its amylin analog that was the backbone of a $1 billion raise this summer. Researchers said Zealand’s drug, dubbed petrelintide, led to up to 8.6% mean weight loss in an early-phase trial. Also, all gastrointestinal disorders observed in the study were mild, save for a moderate case of nausea and a moderate incidence of vomiting. The data were presented Tuesday at the annual ObesityWeek conference in Texas. Zealand initially toplined the data in June and quickly raised $1 billion for the “ crown jewel .” Analysts have predicted petrelintide could reach peak sales of $10 billion. At week 16 in the Phase 1, patients on 2.4 mg petrelintide lost a mean 4.8% body weight. The middle-dose group, 4.8 mg, lost the most at 8.6%, and the 9 mg group saw 8.3% reductions, the researchers said. The drop was 1.7% for the placebo cohort. Petrelintide could potentially have GLP-1-like weight loss of 15% to 20% in larger studies, Zealand chief medical officer David Kendall told Endpoints News on the sidelines of the conference. It also believes amylin agonists could help preserve lean muscle mass, an issue that has come up with the GLP-1 class. The company will dose the first patient in a Phase 2 trial in the coming days or weeks, Kendall said. The study will “elucidate” the differences between the 4.8 mg and 9 mg doses, he said. Zealand is positioning the drug as a potential standalone replacement for GLP-1s or as the first medicine that patients go to for obesity, but the company isn’t excluding the opportunity to combine with GLP-1s or other mechanisms, Kendall said. Novo Nordisk and Eli Lilly have dominated the field so far, but their GLP-1-based medicines carry GI tolerability baggage, among other challenges. Rather than suppress appetite and give patients a “food aversion” signal like the GLP-1s, amylin emphasizes the satiety signal, Kendall said. In his career, he’s worked in both the amylin field at Amylin Pharmaceuticals and on GLP-1s and other mechanisms at Lilly. “If you’ve had a meal here in Texas, you know what satiety feels like. That sense of, I’ve had enough, maybe a little bit too much,” Kendall said. “It actually enhances that signal so you don’t have that same food aversion, the lack of interest. So people tend to eat.” Petrelintide has a 240-hour half-life, or about 10 days, Kendall said. Novo, Lilly, AstraZeneca and multiple other drugmakers are also working on amylin. The field awaits a key Phase 3 readout this quarter from Novo’s CagriSema, a combination of the amylin asset cagrilintide and its blockbuster semaglutide. Novo’s amylin drug “will always be tied to semaglutide,” Kendall said. “We see petrelintide as the next potentially foundational class of therapies going forward. I know it seems maybe aspirational to say over and above what is a pretty successful GLP-1-based therapeutic class.” Structure Therapeutics, which plans to start testing its amylin candidate in humans next year, is looking up to Zealand’s progress. “Zealand is probably the pioneer in terms of pushing the monotherapy as part of their strategy,” Structure CEO Raymond Stevens said in an interview on the sidelines of the conference. “Some of the hypothesis is: amylin has the potential for better tolerability by itself, amylin alone, versus GLP-1.” As Zealand works on the Phase 2, it is looking for a large pharma to help carry petrelintide into Phase 3 and make it a standalone drug. With a fresh $1 billion, though, Zealand is “not backs-against-the-wall,” Kendall said. “The most important thing is not just to find someone with lots of people and deep pockets, but someone who believes in the positioning we’ve talked about.” Zealand already has a partner for its lead obesity drug, the Boehringer Ingelheim-allied survodutide, a glucagon/GLP-1 receptor dual agonist.

Phase 1Clinical ResultPhase 3Phase 2

08 Oct 2024

·pipelinereview.com

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

October 08, 2024 I 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 agonist 2 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: Survodutide’s potential to treat adults with MASH and fibrosis has also been recognized by: 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 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 . References 1 Sanyal 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. 2 Zimmermann 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. 3 U.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. 4 Kumar R, Kumar S, Prakash SS. Compensated liver cirrhosis: Natural course and disease-modifying strategies. World J Methodol. 2023;13(4):179-193. 5 Boehringer 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. 6 Clinicaltrials.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. 7 Clinicaltrials.gov. A Study to Test Whether BI 456906 Helps Japanese People Living With Obesity Disease (SYNCHRONIZE™JP). Available at: clinicaltrials.gov/study/NCT06176365 . Accessed September 2024. 8 Clinicaltrials.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 (NASH) to Reduce Liver Fat and to Lose Weight. Available at: https://clinicaltrials.gov/study/NCT06309992 . Accessed September 2024. 9 Boehringer 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. 10 European 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. 11 Ramai D, Facciorusso A, Vigandt E, et al. Progressive Liver Fibrosis in Non-Alcoholic Fatty Liver Disease. Cells . 2021;10(12):3401. 12 National Institute of Diabetes and Digestive and Kidney Diseases. Nonalcoholic Fatty Liver Disease (NAFLD) and NASH. Available at: www.niddk.nih.gov/health-information/liver-disease/nafld-nash . Accessed September 2024 13 American Liver Foundation. Nonalcoholic steatohepatitis (NASH): Symptoms & complications (2023). Available at: liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/ . Accessed September 2024. 14 Estes 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. 15 Musso, 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. 16 Schnell. 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. 17 Quek 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. 18 Kleiner 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. SOURCE: Boehringer Ingelheim

Phase 2Phase 3Breakthrough TherapyFast Track

08 Oct 2024

·www.globenewswire.com

Zealand Pharma announces that Boehringer receives U.S. FDA Breakthrough Therapy designation and initiates two Phase III trials in MASH for survodutide

Company announcement – No. 47 / 2024 Zealand Pharma announces that 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 study Boehringer launches two Phase III studies of survodutide, LIVERAGE in adults with MASH and moderate or advanced fibrosis (stages 2 or 3), and LIVERAGE-Cirrhosis in those with MASH and cirrhosis (stage 4) Copenhagen, Denmark, October 8, 2024 – Zealand Pharma A/S (Nasdaq: ZEAL) (CVR-no. 20045078), a biotechnology company focused on the discovery and development of innovative peptide-based medicines, reports that Boehringer Ingelheim today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for survodutide (BI 456906), a dual glucagon/GLP-1 receptor agonist for the treatment of adults living with non-cirrhotic 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. In addition, Boehringer announced the initiation of two Phase III clinical trials for survodutide for the treatment of adults living with metabolic dysfunction-associated steatohepatitis (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 approximately 1,800 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 approximately 1,590 adults living with MASH and compensated cirrhosis (fibrosis stage 4), a condition where the liver presents severe scarring. “Representing one of the most serious and fastest-growing obesity-related co-morbidities with limited treatment options available today, we are both pleased and excited to see Boehringer Ingelheim advance survodutide into two Phase III trials in MASH in both F2/F3 patients (moderate to advanced fibrosis) as well as F4 patients (cirrhosis),” said David Kendall, M.D., Chief Medical Officer of Zealand Pharma. “The U.S. FDA Breakthrough Therapy Designation follows the impressive and groundbreaking Phase II data with survodutide in MASH and fibrosis presented earlier this year which provided evidence of clear differentiation that position survodutide as a potentially leading incretin-based therapy for obesity and MASH in the future.” For additional information, please refer to Boehringer Ingelheim’s press release from today available at Survodutide US FDA Breakthrough Therapy phase 3 trials MASH | Boehringer Ingelheim (boehringer-ingelheim.com). About LIVERAGE and LIVERAGE-CirrhosisLIVERAGE 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. 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. 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 2021 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 2023 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 (subject to Zealand's co-promotion right in the Nordic countries). About metabolic dysfunction-associated steatohepatitis (MASH) 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 increase 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 fibrosisF2-F3: indicates moderate or advanced fibrosisF4: indicates cirrhosis About Zealand PharmaZealand Pharma A/S (Nasdaq: ZEAL) ("Zealand") is a biotechnology company focused on the discovery and development of peptide-based medicines. More than 10 drug candidates invented by Zealand have advanced into clinical development, of which two have reached the market and three candidates are in late-stage development. The company has development partnerships with a number of pharma companies as well as commercial partnerships for its marketed products. Zealand was founded in 1998 and is headquartered in Copenhagen, Denmark, with a presence in the U.S. For more information about Zealand’s business and activities, please visit www.zealandpharma.com. Forward looking statementsThis company announcement contains “forward-looking statements”, as that term is defined in the Private Securities Litigation Reform Act of 1995 in the United States, as amended, even though no longer listed in the United States this is used as a definition to provide Zealand Pharma’s expectations or forecasts of future events regarding the research, development and commercialization of pharmaceutical products, the timing of the company’s pre-clinical and clinical trials and the reporting of data therefrom. These forward-looking statements may be identified by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would” and other words and terms of similar meaning. You should not place undue reliance on these statements, or the scientific data presented. The reader is cautioned not to rely on these forward-looking statements. Such forward-looking statements are subject to risks, uncertainties and inaccurate assumptions, which may cause actual results to differ materially from expectations set forth herein and may cause any or all of such forward-looking statements to be incorrect, and which include, but are not limited to, unexpected costs or delays in clinical trials and other development activities due to adverse safety events, patient recruitment or otherwise; unexpected concerns that may arise from additional data, analysis or results obtained during clinical trials; our ability to successfully market both new and existing products; changes in reimbursement rules and governmental laws and related interpretation thereof; government-mandated or market-driven price decreases for our products; introduction of competing products; production problems at third party manufacturers; dependency on third parties, for instance contract research or development organizations; unexpected growth in costs and expenses; our ability to effect the strategic reorganization of our businesses in the manner planned; failure to protect and enforce our data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; regulatory authorities may require additional information or further studies, or may reject, fail to approve or may delay approval of our drug candidates or expansion of product labeling; failure to obtain regulatory approvals in other jurisdictions; exposure to product liability and other claims; interest rate and currency exchange rate fluctuations; unexpected contract breaches or terminations; inflationary pressures on the global economy; and political uncertainty, including the ongoing military conflict in Ukraine and the uncertainty surrounding upcoming elections in the US. If any or all of such forward-looking statements prove to be incorrect, our actual results could differ materially and adversely from those anticipated or implied by such statements. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from our expectations in any forward-looking statement. All such forward-looking statements speak only as of the date of this company announcement and are based on information available to Zealand Pharma as of the date of this announcement. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice. ContactsAdam Lange (Investors)Investor Relations OfficerZealand PharmaEmail: alange@zealandpharma.com Anna Krassowska, PhD (Investor and Media)Vice President, Investor Relations & Corporate CommunicationsZealand PharmaEmail: akrassowska@zealandpharma.com

Phase 2Phase 3Fast TrackBreakthrough Therapy

100 Deals associated with Survodutide

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis, Liver	Phase 3	US	Boehringer Ingelheim GmbH	14 Oct 2024
Fibrosis, Liver	Phase 3	CN	Boehringer Ingelheim (China) Investment Co., Ltd.	14 Oct 2024
Fibrosis, Liver	Phase 3	JP	Boehringer Ingelheim GmbH	14 Oct 2024
Fibrosis, Liver	Phase 3	AR	Boehringer Ingelheim (China) Investment Co., Ltd.	14 Oct 2024
Liver Cirrhosis	Phase 3	CN	Boehringer Ingelheim (China) Investment Co., Ltd.	14 Oct 2024
Liver Cirrhosis	Phase 3	AR	Boehringer Ingelheim (China) Investment Co., Ltd.	14 Oct 2024
Cicatrix	Phase 3	-	Boehringer Ingelheim GmbH	08 Oct 2024
Nonalcoholic Steatohepatitis	Phase 3	US	Boehringer Ingelheim GmbH	02 Apr 2024
Diabetes Mellitus, Type 2	Phase 3	US	Boehringer Ingelheim GmbH	27 Nov 2023
Diabetes Mellitus, Type 2	Phase 3	US	Boehringer Ingelheim (China) Investment Co., Ltd.	27 Nov 2023

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04771273 (1404-0043, CTgov)	Phase 2	Nonalcoholic Steatohepatitis \| Fibrosis	295	Survodutide (Survodutide 2.4 mg - Planned Maintenance Treatment)	fvehtnnekh(ckgmzmjylp) = wrtowodwez uubeqckiyq (nlamavupwu, snuavppwzt - xtpnukeftw) View more	-	03 Dec 2024
				Survodutide (Survodutide 4.8 mg - Planned Maintenance Treatment)	fvehtnnekh(ckgmzmjylp) = jnyeywrcyr uubeqckiyq (nlamavupwu, dorkneiteo - uaclthorql) View more
phase 2 trial (ESC2024)	Phase 2	Obesity	387	Survodutide 4.8 mg	ntndbmwmxi(woyecpdhwn) = ygkxwobmkx vlsjftwntz (ycysfxquba )	Positive	01 Sep 2024
NCT04153929 \| NCT03591718 \| NCT04667377 (1665-P, ADA2024)	Phase 1/2	Diabetes Mellitus, Type 2 \| Obesity HbA1c \| insulin sensitivity \| glucose biomarkers ... View more	-	Survodutide	mgnzpmyfwd(vnoczusfgv) = 0.4 vs 0.0 ltqrfxfzml (jycxvnzqwv ) View more	Positive	14 Jun 2024
				Placebo
ADA2024	Not Applicable	Obesity	-	Survodutide 20 nmol/kg	jwtsormktj(rulyvdylwt) = 75% reduction ybedvmyyhw (tlbezffjwo ) View more	-	14 Jun 2024
NCT04771273 (1404-0043, Pubmed)	Phase 2	Nonalcoholic Steatohepatitis	293	Survodutide 2.4 mg	zbsbhlnszb(cuuvquwzug) = pkqzpuwmea wzrckxfvma (ydnrbxfjss ) View more	Positive	07 Jun 2024
				Survodutide 4.8 mg	zbsbhlnszb(cuuvquwzug) = olffmufsgg wzrckxfvma (ydnrbxfjss ) View more
ENDO2024	Not Applicable	-	-	Semaglutide 15 nmol/kg	zkaxjwozjx(rduvugfbai) = xjopqlgsdl oelvihltix (bopegeszwc )	-	01 Jun 2024
				Survodutide 15 nmol/kg	zkaxjwozjx(rduvugfbai) = hsrtlpmjay oelvihltix (bopegeszwc )
NCT04667377 (Phase II Trial, ENDO2024)	Phase 2	-	384	Survodutide 4.8 mg	kfrtbyjlzn(gshzivycdm) = irumzlxbke vfkrwnxdhr (lhkubtodcb )	Positive	01 Jun 2024
				Placebo	kfrtbyjlzn(gshzivycdm) = xyhgraokej vfkrwnxdhr (lhkubtodcb )
NCT04771273 (Corporate Publications) Manual	Phase 2	Metabolic dysfunction-associated steatotic liver disease	295	Survodutide	aqgqffjnla(usuoympxgq) = ryaqvoncno qbxmhzibym (wnqzetpetj ) Met	Positive	26 Feb 2024
				placebo	aqgqffjnla(usuoympxgq) = ahchddsjjf qbxmhzibym (wnqzetpetj ) Met
NCT04771273 (GlobeNewswire) Manual	Phase 3	Nonalcoholic Steatohepatitis	-	survodutide	dstdwcvrvt(uzhqpaeeva) = udkxiegihl uxwqsnoedu (nsmnagtcyp ) Met	Positive	26 Feb 2024
				Placebo	dstdwcvrvt(uzhqpaeeva) = brljuumomi uxwqsnoedu (nsmnagtcyp ) Met
NCT04667377 (Phase II Trial, CTgov)	Phase 2	Obesity	387	BI 456906 (0.6 mg BI 456906 - Planned Maintenance Treatment (Maintenance Dose Assigned at Randomisation))	rsvghpizzo(dkjspwadrt) = azvrlwnpfc nyncshlflh (yjxnnocuex, wpxjsmombs - miwfpogqvr) View more	-	02 Nov 2023
				BI 456906 (2.4 mg BI 456906 - Planned Maintenance Treatment)	rsvghpizzo(dkjspwadrt) = xpdcsapvsg nyncshlflh (yjxnnocuex, vjhiklaipy - vxjhmbvsmj) View more

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