Several trial readouts during 2024 have strengthened the case for incretin-based MASH therapies by dispelling doubts about their ability to improve fibrosis. These earlier concerns stemmed from the GLP-1 MoA lacking a direct effect on the liver.

For example, in the ESSENCE phase 3 trial, semaglutide demonstrated improvement of fibrosis by ≥1 stage with no worsening of MASH in 37% of treated F2/F3 patients vs. 22.5% for placebo; 59.1% of MASH F2/F3 patients treated with tirzepatide in the SYNERGY-NASH phase 2 trial achieved this endpoint vs. 32.8% for placebo; whereas 64.5% of MASH F2/F3 patients treated with survodutide in a phase 2 trial saw improvement of fibrosis by one or more stages vs. 25.9% for placebo.

Incretin dual-agonists tirzepatide (GLP-1/GIP) and survodutide (glucagon/GLP-1) have also shown impressive resolution of MASH with no worsening of fibrosis, at a placebo-adjusted rate of 60.1% and 54.2%, respectively. This positions these dual-agonists favourably among emerging MASH therapies across both key histopathological endpoints.

Rezdiffra also faces potential intra-class competition from fellow THR-β agonist VK2809, which demonstrated notable MASH resolution and antifibrotic efficacy in the VOYAGE 2b trial, of 46% and 23% placebo-adjusted rates, respectively, while FGF21 analogue efruxifermin is leading the field with 51% of placebo-adjusted fibrosis improvement of ≥1 stage.

Importantly, future competitive dynamics and adoption of different MASH therapies will be driven by multiple considerations, beyond efficacy demonstrated against histopathological endpoints:

• Tolerability: MASH as a chronic liver disease requires long-term treatment, making a clean tolerability profile an important differentiator as it impacts adherence and persistence, and in turn patient outcomes. For example, gastrointestinal, treatment-emergent adverse events (GI-TEAEs), such as nausea, vomiting or diarrhoea, are commonly observed side effects among incretin mimetics, at different degrees of severity, and are known causes for treatment discontinuation.
• Route of administration: Patients typically prefer oral therapies over injectables, assuming no significant trade-off in efficacy or tolerability between those two modalities. The emerging treatment landscape for MASH comprises both: oral therapies Rezdiffra, VK2809, denifanstat and lanifibranor; injectable therapies including incretin mimetics (semaglutide, survodutide, tirzepatide), and pegozafermin and efruxifermin. Dosing frequency is another important factor, e.g., potential, future long-acting injectables with monthly or even less frequent dosing could sway patient preference.
• Cardiometabolic benefits: One of the defining features of cardiometabolic diseases is the substantial overlap between different patient populations. Multiple indications often manifest themselves as co-morbidities in the same patient, e.g., MASH, type 2 diabetes, cardiovascular disease or chronic kidney disease. Incretin mimetics have shown favourable effects on multiple risk factors, e.g., BMI, glycaemic control, blood pressure, lipids and kidney function, with the potential to transform the management of overall cardiometabolic risk.
  These broader benefits may give incretin mimetics an advantage as potential ‘backbone agents’ over ‘MASH only therapies’, with a risk to the latter of being relegated within the MASH treatment algorithm. Moreover, incretin mimetics may even shrink the long-term MASH opportunity, for example, if an upstream intervention targeting obesity or diabetes prevents the downstream manifestation of MASH in the first place.

In addition to differentiation between product profiles, commercial success will depend on securing broad market access. As more players enter the market, payers will focus on how different MASH therapies are priced. This will become even more important with payers increasingly concerned about budget impact as innovators seek to significantly expand the MASH market. For example, incretin mimetics, at current list prices for diabetes or obesity, would look more competitive to payers compared to Rezdiffra’s list price point.

Price competition in the MASH market will accelerate when off patent semaglutide becomes available, which in some countries could be as early as 2026. In this scenario, incumbents and future entrants will face a MASH market where payer expectations are anchored around low(er) cost semaglutide versions. Furthermore, off patent semaglutide could give a boost to MASH combination therapies by emerging as the low(er) cost backbone agent of choice, used, for example, in conjunction with a fibrosis-targeting MASH drug.

While Madrigal’s first-to-market status has given it a head start in creating awareness and building relationships with hepatologists and gastroenterologist, the key prescriber specialties for MASH F2/F3 patients, market expansion will require engagement of a broader HCP universe, including endocrinologists, possibly cardiologists, nephrologists, and even GPs.

Even though these additional HCP specialties are not the primary prescribers for MASH therapies, they see patients with various cardiometabolic co-morbidities, including those at risk of developing MASH. As such, they will play a key role in identifying high-risk patients who should be screened for MASH and referred to liver specialists, given the asymptomatic nature of MASH until its advanced stages. This gives an advantage to competitors already embedded with those HCP specialties, such as Novo Nordisk, Lilly or Boehringer Ingelheim.

Furthermore, commercial scale matters too in reaching these much larger HCP universes to drive awareness and improve screening, referrals and diagnosis rates, the prerequisites for expanding the pool of MASH patients available for treatment.

The MASH market is still under-developed and has a lot of untapped potential. By 2030, there will be an estimated ~14 million F2-F4 patients in the U.S. alone [4], compared to just 11,800 F2-F3 U.S. patients treated with a MASH-specific therapy by the end of 2024. With unmet need remaining high, there will be room in the near- to medium-term for multiple therapies that target specific mechanisms within the complex pathogenesis of MASH, possibly deployed as combinations, to address its different disease manifestations.

As the MASH market enters its second year, we should expect key battlelines to be drawn between future competitors.

References

1. Drenth, J. P. H., & Schattenberg, J. M. (2020). The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success. Expert Opinion on Investigational Drugs, 29(12), 1365–1375. https://doi.org/10.1080/13543784.2020.1839888
2. IQVIA white paper, January 2024: Emerging from the Shadows: A New Era for NASH - IQVIA
3. Madrigal quarterly earnings reports, Q2-Q4/2024: https://ir.madrigalpharma.com/events-and-presentations
4. 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 Jan;67(1):123-133. https://doi.org/10.1002/hep.29466