The emergence of incretin-modulating therapies has transformed the way healthcare providers are tackling the obesity pandemic. With groundbreaking drugs such as Wegovy (semaglutide) and Zepbound (tirzepatide) now revolutionising chronic weight management, emerging evidence is shedding light on their broader impact—not just on weight, but on vital organs like the heart, kidneys, and liver. These advancements are opening new doors in the fight against comorbidities, offering hope for a more holistic treatment approach in patients suffering from metabolic dysfunction-associated steatohepatitis (MASH). Given its high prevalence and overlap with other metabolic conditions such as obesity and type 2 diabetes (T2D), there is a critical need to find effective solutions to address the significant economic and health burdens MASH imposes on society.

Although the treatment landscape for MASH is still in its early stages, with no therapies available until the recent approval of Madrigal’s Rezdiffra, incretin-modulating assets are now emerging as a promising option and are poised to become a cornerstone of MASH therapy. This is evident in the recently published clinical practice guidelines by the EASL-EASD-EASO societies, where the use of GLP-1 receptor agonists and co-agonists is very much encouraged for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH comorbidities. Thus far, however, these therapies have not been recommended for the more severe and challenging condition of moderate to severe (F2-3) fibrotic MASH, where they are now progressing in clinical development. Novo Nordisk’s semaglutide, is perhaps the most awaited GLP-1 receptor agonist candidate in MASH, as it is the only asset in its class currently being investigated in a Phase III trial, with results expected from this much-anticipated study in Q4 2024.

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However, semaglutide has faced challenges in improving liver fibrosis in the past, as it failed to achieve this endpoint in previous Phase IIb trials. Consequently, MASH stakeholders are shifting their focus towards more promising therapies that employ a dual agonism approach. This includes Zepbound, Eli Lilly’s GLP-1/GIP receptor agonist, as well as Boehringer Ingelheim’s GLP-1/glucagon receptor agonist, survodutide, both of which touted impressive Phase IIb results at the recent EASL 2024 conference and are anticipated to be the next significant advancements in incretin-modulating treatments for MASH. The trial arm of survodutide 6.0mg demonstrated up to 64.5% of adults with F2-3 fibrosis achieving an improvement in fibrosis ≥1-stage without a worsening of MASH, versus 25.9% with placebo after 48 weeks of treatment. At the same time, tirzepatide achieved 1 stage or greater of fibrosis improvement without a 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, which appear to be slightly lower rates when indirectly compared to the placebo-adjusted results for survodutide.  

What distinguishes these dual receptor agonists from each other? Gastric inhibitory polypeptide (GIP), an incretin hormone secreted by the intestine, enhances insulin secretion in a glucose-dependent manner and primarily boosts insulin sensitivity. On the other hand, glucagon, secreted by the pancreas in response to low glucose levels, acts directly on the liver through various mechanisms. This distinction may explain why GLP-1/GIP agonists are more effective for T2D than for MASH, making GLP-1/glucagon receptor agonists a potentially more promising option for treating fibrotic MASH. Nevertheless, in the absence of Phase III and head-to-head trials, it remains difficult to make true efficacy comparisons between these assets. Both Eli Lilly and Boehringer Ingelheim are planning to initiate their Phase III trials for MASH in 2024. While survodutide will be a new entrant to the GLP-1 space, Eli Lilly’s tirzepatide is expected to benefit from significant physician familiarity, having been approved for the treatment of T2D in May 2022 and chronic weight management in November 2023, for which sales are expected to reach over $29.6bn by 2033, according to GlobalData.

Other GLP-1/glucagon agonists are also poised to enter the market, including Altimmune’s promising pemvidutide and efinopegdutide, a joint venture between MSD and Hanmi Pharmaceuticals. In a rapidly growing and highly competitive field, these companies are keen to distinguish their therapies. Altimmune, for instance, is emphasising the potential of its pemvidutide to preserve lean mass. Meanwhile, MSD and Hanmi have begun exploring a bi-weekly dosing regimen and are using semaglutide as an active comparator in their Phase IIb MASH trial, aiming to secure a competitive edge. Looking ahead, there’s also the potential disruption from GLP-1/GIP/glucagon triple receptor agonists on the horizon, in particular Eli Lilly’s retatrutide, which showed a promising MASLD sub-group analysis that was presented at last year’s AASLD conference. However, the company has yet to provide further updates on retatrutide’s development for MASH. Moreover, Hanmi has a GLP-1/glucagon/GIP triple agonist in development, which it claims has a direct anti-fibrotic effect. This could in theory combine the strengths of both tirzepatide and survodutide, making it a potentially formidable MASH asset.

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The MASH treatment pipeline is becoming increasingly competitive, with a growing number of contenders leveraging diverse mechanisms of action to capture a share of this potentially vast market. As advancements in non-invasive diagnostics reveal a previously overlooked patient pool for this “silent killer,” new opportunities will emerge for potential MASH therapies. Among these, incretin-modulating treatments—whether used alone or in combination—are expected to play a pivotal role in shaping the future of MASH management.

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