The landscape of metabolic dysfunction-associated steatohepatitis (MASH) treatment is evolving, with incretin-modulating therapies gaining prominence. Drugs like semaglutide and tirzepatide, initially developed for obesity and type 2 diabetes, are now being investigated for their potential to address MASH and its associated comorbidities, offering a more holistic approach to treatment. Given the high prevalence of MASH and its overlap with conditions like obesity and type 2 diabetes, the need for effective solutions is critical to alleviate the significant economic and health burdens it imposes.
GLP-1 Therapies in MASH Treatment
While the treatment landscape for MASH has been limited, with Madrigal’s Rezdiffra being the first approved therapy, incretin-modulating assets are emerging as promising options. Recent clinical practice guidelines from the EASL-EASD-EASO societies encourage the use of GLP-1 receptor agonists and co-agonists for treating MASLD/MASH comorbidities. However, these therapies are now progressing in clinical development for the more severe condition of moderate to severe (F2-3) fibrotic MASH.
Novo Nordisk’s semaglutide is a highly anticipated GLP-1 receptor agonist candidate in MASH, currently in Phase III trials, with results expected in Q4 2024. However, previous Phase IIb trials showed that semaglutide failed to achieve the endpoint of improving liver fibrosis. This has led to increased interest in dual agonism approaches.
Dual Agonists: Survodutide and Tirzepatide
MASH stakeholders are shifting their focus towards therapies that employ a dual agonism approach. Boehringer Ingelheim’s GLP-1/glucagon receptor agonist, survodutide, and Eli Lilly’s GLP-1/GIP receptor agonist, tirzepatide, both presented positive Phase IIb results at the recent EASL 2024 conference.
The trial arm of survodutide 6.0mg demonstrated that 64.5% of adults with F2-3 fibrosis achieved an improvement in fibrosis ≥1-stage without worsening of MASH, compared to 25.9% with placebo after 48 weeks of treatment. Tirzepatide achieved ≥1 stage of fibrosis improvement without worsening of MASH in 59.1%, 53.3%, and 54.2% of participants taking 5mg, 10mg, and 15mg of the drug, respectively, compared to 32.8% of participants on placebo.
Mechanisms of Action
Gastric inhibitory polypeptide (GIP) enhances insulin secretion in a glucose-dependent manner and primarily boosts insulin sensitivity. Glucagon, secreted by the pancreas in response to low glucose levels, acts directly on the liver through various mechanisms. This may explain why GLP-1/GIP agonists are more effective for T2D, while GLP-1/glucagon receptor agonists are potentially more promising for treating fibrotic MASH. However, without Phase III and head-to-head trials, efficacy comparisons remain challenging. Both Eli Lilly and Boehringer Ingelheim plan to initiate their Phase III trials for MASH in 2024.
Competitive Landscape and Future Directions
Other GLP-1/glucagon agonists are also poised to enter the market, including Altimmune’s pemvidutide and efinopegdutide, a joint venture between MSD and Hanmi Pharmaceuticals. Altimmune is emphasizing pemvidutide’s potential to preserve lean mass, while MSD and Hanmi are exploring a bi-weekly dosing regimen and using semaglutide as an active comparator in their Phase IIb MASH trial.
Looking ahead, triple receptor agonists like Eli Lilly’s retatrutide, a GLP-1/GIP/glucagon triple receptor agonist, may offer further advancements. Hanmi also has a GLP-1/glucagon/GIP triple agonist in development, which it claims has a direct anti-fibrotic effect.
The MASH treatment pipeline is becoming increasingly competitive, with a growing number of contenders leveraging diverse mechanisms of action. As advancements in non-invasive diagnostics reveal a previously overlooked patient pool, new opportunities will emerge for potential MASH therapies. Incretin-modulating treatments are expected to play a pivotal role in shaping the future of MASH management.
