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The first anniversary of the MASH “market”: looking back and ahead
Markus Gores, Vice President, EMEA Thought Leadership
Kirstie Scott, Senior Consultant, EMEA Thought Leadership
Mar 13, 2025

On March 14, 2024, Madrigal made history when the FDA approved its oral, thyroid hormone receptor beta agonist Rezdiffra (resmetirom) as the first therapy for metabolic dysfunction-associated steatohepatitis (MASH), formerly known as NASH. With its approval, Rezdiffra put an end to the industry’s long history of unsuccessful MASH drug development which became a notorious graveyard for innovators [1].

At the first anniversary of this important milestone, we take a look at how Rezdiffra has fared commercially and what lies ahead. In this blog, we will also review the late-stage MASH pipeline and its implications for the emerging treatment landscape as new competitors are lining up to make a play for the MASH opportunity.

Marking one year of Rezdiffra on the market

Madrigal surprised many industry observers and investors alike with Rezdiffra’s promising early launch performance despite facing formidable challenges as a small company introducing the first-ever, MASH-specific therapy; for example, limited disease awareness, low diagnosis rates and the absence of established care pathways, as we discussed in more detail elsewhere [2]. Yet, Rezdiffra delivered revenue ahead of consensus expectations for each of its three quarters on the market (see Figure 1).

This notable early performance is the result of Madrigal’s extensive market shaping activities, including:

  • Identifying 14,000 target physicians in total, with a primary focus on engaging 6,000 hepatologists and gastroenterologists, who treat the majority of the 315,000 diagnosed F2-F3 stage MASH patients. This initial focus on liver specialists was aimed at capturing patients already diagnosed and under care.
  • Educating top-tier hepatologists and gastroenterologists, as well as payers, on MASH, about Madrigal’s new therapy and non-invasive diagnostics.
  • Creating treatment pathways, broadening access and supporting practices with administrative requirements for securing reimbursement or acquiring imaging diagnostics.
  • Supporting patients along their MASH treatment journey.

The impact of these activities is reflected in a number of key metrics [3], e.g., achieving 80% coverage of commercially insured lives in the U.S. after just two quarters post launch; over 11,800 patients being treated with Rezdiffra by the end of 2024, with 60% of its top target physicians having written a prescription for Rezdiffra; while payers accepted over 95% of covered patients based on a MASH diagnosis using non-invasive tests instead of demanding a liver biopsy, thus defying expectations given the requirement of biopsy-confirmed MASH for phase 3 trials.

Looking ahead, Madrigal may need to accelerate expansion of its prescriber base to sustain its early momentum. Targeting a subset of liver specialists was an effective strategy during the early launch period for capturing pent-up demand from patients already under care, however, future growth will require broader engagement.

Building on its positive start in the U.S., Madrigal is planning to launch Rezdiffra in Europe in the second half of 2025, pending EMA approval.

The FDA’s approval of Rezdiffra was conditional and based on histopathological assessments of liver biopsies as surrogate endpoints. For full approval, Madrigal needs to provide confirmatory evidence on clinical outcomes. This is being generated in the ongoing extension of its MAESTRO-NASH phase 3 trial which measures a composite clinical outcome up to 54 months, comprising all-cause mortality, liver transplant, significant hepatic events, including hepatic decompensation, and histological progression to cirrhosis.

Furthermore, Madrigal is pursuing indication expansion beyond Rezdiffra’s current label which covers MASH patients with moderate or severe liver scarring, equating to fibrosis stage F2 and F3 disease.

Its ongoing MAESTRO-NASH OUTCOMES phase 3 trial focuses on compensated MASH cirrhosis (fibrosis stage F4c patients) and, if successful, could make Rezdiffra the first approved therapy for F2-F4c MASH. Madrigal recently reported promising two-year results from the open-label part of its MAESTRO-NAFLD-1 phase 3 trial, where Rezdiffra demonstrated a marked reduction in liver stiffness as measured by vibration-controlled transient elastography in patients with compensated MASH cirrhosis (F4c). This readout supports Rezdiffra’s potential benefit in the F4c patient population.

The late-stage MASH pipeline: several competitors are lining up

While Madrigal is enjoying its head start for the time being as the first-to-market entrant, it will face competition in the not too distant future, as several assets progress through the late-stage MASH pipeline.

There are currently six other late-stage MASH assets in development with confirmed, ongoing or completed phase 3 trials that focus on Rezdiffra’s label population of MASH patients with fibrosis stage F2 and F3 (see Figure 2). These assets represent four mechanisms of action (MoAs):

  • Incretin mimetics, including GLP-1 receptor agonist semaglutide (Novo Nordisk) and dual glucagon/GLP-1 receptor agonist survodutide (Boehringer Ingelheim)
  • Fibroblast growth factor 21 (FGF21) analogues pegozafermin (89bio) and efruxifermin (Akero Therapeutics)
  • Pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor (Inventiva)
  • Fatty acid synthase (FASN) inhibitor denifanstat (Sagimet)

Novo Nordisk’s MASH programme is the most advanced, making it the likely first competitor Madrigal will face in the next 12 months. In November 2024, Novo Nordisk reported positive results for semaglutide from part 1 of the ESSENCE phase 3 trial which hit both its histological primary endpoints, demonstrating statistically significant resolution of MASH with no worsening of fibrosis, and improvement of fibrosis by at least one stage with no worsening of MASH. Novo Nordisk expects to file for regulatory approvals in the first half of 2025, setting up a future showdown with Rezdiffra.

Meanwhile, part 2 of the ESSENCE phase 3 trial continues with focus on measuring liver-related clinical events at 240 weeks, which regulators will require as confirmatory outcomes data for full approval.

Outside its current label of F2 and F3 stage MASH patients, Rezdiffra is also facing competition in its efforts to expand into F4 stage cirrhotic patients, which several late-stage assets are targeting in their respective phase 3 trials (see Figure 2):

  • Dual glucagon/GLP-1 receptor agonist survodutide (LIVERAGE-Cirrhosis)
  • FGF21 analogues pegozafermin (ENLIGHTEN-Cirrhosis) and efruxifermin (SYNCHRONY-Outcomes). In January 2025, Akero Therapeutics reported impressive long-term data for efruxifermin from its SYMMETRY phase 2b trial, showing reversal of cirrhosis without worsening of MASH in 39% of treated, F4 stage cirrhotic MASH patients vs. 15% for placebo after 96 weeks.

Looking beyond the current late-stage MASH pipeline, two notable competitors, Viking and Lilly, have yet to commit to conducting phase 3 trials, despite their assets, Viking’s THR-β agonist VK2809 and Lilly’s dual GLP-1/GIP receptor agonist tirzepatide, delivering positive clinical data in 2024 from their respective phase 2b trials, VOYAGE and SYNERGY-NASH.

Outlook: The emerging competitive landscape in MASH

A competitive field of potential, future MASH therapies is emerging that have reported compelling data on key histopathological endpoints in F2/F3 patients which regulators accept for conditional approval: resolution of MASH with no worsening of fibrosis, and improvement of fibrosis by at least one stage with no worsening of MASH (see Figure 3). The caveat of cross-trial comparisons applies, with assets in different trial phases, while differences in trial designs, trial populations, treatment duration and a highly variable placebo response across MASH trials represent additional confounders.

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
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