Boehringer links dual glucagon/GLP-1 agonist to improvements in MASH scarring

Boehringer Ingelheim has made progress with its metabolic dysfunction-associated steatohepatitis (MASH) treatment, linking the Zealand Pharma-partnered candidate to improvements in disease activity and liver scarring in a phase 2 trial.

Investigators randomized 295 people with MASH and between mild and advanced scarring of the liver to receive weekly subcutaneous injections of survodutide at one of three doses or placebo. After 48 weeks, more people on survodutide than placebo had a biopsy-proven improvement in MASH without worsening of scarring, causing the study to hit its primary endpoint.

Boehringer reported that up to 83% of adults treated with survodutide achieved a statistically significant improvement of MASH. The placebo-adjusted difference was 64.8%. Notably, the trial also met all its secondary endpoints, including a statistically significant improvement in liver fibrosis.

Talking at a Goldman Sachs investor event last month, Zealand CEO Adam Steensberg described a potential improvement in scarring after 48 weeks a “blue sky scenario.” After Boehringer revealed that blue sky, investors sent shares in Zealand up 30% to almost 624 Danish kroner in trading Monday morning from a Friday closing price of 478 kroner.

Studies of bariatric surgery have shown that it is possible to create an environment that allows the liver to heal itself. The survodutide clinical trial suggests medicines that reduce fat levels in the liver can help to create that environment.

At an obesity R&D day in December, Steensberg predicted multiple GLP-1 drugs will achieve weight loss of 20% to 25%. The effect of the molecules on comorbidities such as MASH will give companies chances to differentiate their products from other treatments that provide similar levels of weight loss. Because survodutide acts on glucagon, which targets the liver, it may be better in MASH than plain GLP-1 drugs.

That idea is being put to the test. Novo Nordisk’s semaglutide, which it sells as Ozempic and Wegovy, failed a phase 2 MASH study in 2022 but the company continued enrolling patients in its pivotal trial. Eli Lilly is closing in on phase 2 data on its rival GLP-1 drug, tirzepatide. Madrigal Therapeutics is leading the way in MASH with its THR-beta selective agonist, which could win FDA approval in the next three weeks.

Tolerability is an area of focus. More than 20% of people dropped out of Boehringer and Zealand’s phase 2 obesity trial, although Steensberg has told investors “careful titration” can reduce tolerability issues, as Lilly and Novo showed with their GLP-1 drugs. The MASH trial tested a higher, and therefore potentially less tolerable, survodutide dose than obesity study but saw no unexpected issues.

Boehringer will provide a clearer look at how survodutide matches up to the competition when it shares the full phase 2 data. But the company has seen enough to paint the molecule as a potential best-in-class treatment for MASH and start five phase 3 trials across a range of subpopulations of people living with overweight and obesity, including cardiovascular and chronic kidney disease patients.

In a statement, Carinne Brouillon, head of human pharma at Boehringer, said the company “will move forward as quickly as possible in MASH” to bring survodutide “to the more than 1 billion people affected by interconnected cardiovascular, renal, metabolic diseases.”