MASH in 2025: New Therapies, New Challenges
- The expected approval of the GIP/GLP1 dual agonist tirzepatide (OZEMPIC) late 2025-early 2026
- Additional drugs with new mechanisms of action
- Indication expansions to earlier and later stages of the disease
These developments mark a step forward for patients who up to this moment have had no therapeutic options other than lifestyle adjustments.
Given the high level of unmet need and large addressable population, MASH has been seen as an attractive therapeutic area for pharmaceutical developers. However, the approval of WEGOVY has disrupted the outlook, with its significantly lower price point relative to REZDIFFRA, as well as its differentiated metabolic therapeutic positioning. We explore these consequences in this article, particularly with relation to market access and pricing.
MASH: a slow but potentially devastating disease
MASH is a progressive liver disease characterized by hepatic steatosis with inflammation and hepatocellular injury, which can lead to fibrosis, cirrhosis, liver failure, or even hepatocellular carcinoma (HCC). It affects 1.5–6.5% of adults in the US and yet remains underdiagnosed due to its asymptomatic nature in the early stages. Disease progression is usually slow, with an average of seven years required to progress one fibrosis stage. [1,2]
Crucially, MASH is a heterogeneous disease, influenced by metabolic syndrome, obesity, type 2 diabetes, genetics, age, and ethnicity. This heterogeneity complicates treatment decisions and reimbursement frameworks.
Despite the significant public health burden, MASH has historically suffered from low awareness, stigmatisation (patients' fear of being associated with alcohol or drug abuse), and a lack of effective therapies. Diagnosis is increasingly reliant on non-invasive methods like vibration-controlled transient elastography and magnetic resonance elastography; which represents a huge improvement from diagnosis by liver biopsy.
The clinical trials for MASH have focused on measuring effectiveness typically along two types of intermediary outcomes which have been the basis of the conditional approvals in the US and EU:
- MASH resolution: Mild or no inflammation, no hepatocyte ballooning
- Stopping or reversing liver fibrosis: formation of scar tissue in the liver
These intermediate outcomes have enabled faster approvals and reimbursement. Regulators are expected to only move from conditional to full approval once the longer-term outcomes from the ongoing clinical trials become known. These outcomes are composite measures of liver function and survival.
Recent breakthroughs: REZDIFFRA and WEGOVY
The characteristics of the two recently approved drugs are summarised in table below:
The payer challenge: managing a silent, widespread disease
Payers have had MASH on their radars for some time. Its chronic, progressive nature coupled with silent onset makes it a candidate for population health management akin to diabetes or cardiovascular disease. Now that treatments are arriving, this has become an immediate reality raising significant affordability issues. The key concerns of payers are:
Large budget impact:
This is likely to be significant given the high list prices of the approved drugs and large population, potentially overwhelming plans, health systems and available funds. The Insitute for Clincial and Economic Review (ICER) issued an affordability warning for REZDIFFRA, estimating $22B in annual treatment costs if all eligible U.S. patients (3.8M) were treated.[2]
Questions over the long-term impact:
Payers like to see clear data on clinical, patient relevant outcomes e.g., survival, avoidance of transplants, which for a disease such as MASH require long term measurement. Signs that this may be problem can be seen from the ICER assessment in which the committee agreed with just 8 votes to 7 that REZDIFFRA had adequate evidence of a superior health benefit to lifestyle management alone, rating the quality of evidence as of "moderate certainty". [2]
Implications for European market access
These issues signal difficulties ahead for HTA in Europe, where the authorities are likely to take a strict view on the strength of the evidence as well as the quality of long-term health economic modelling, and budget impact. This concerns raised to date suggests potential outcomes along the lines of an ASMR rating of III or IV in France and a minor additional benefit through the AMNOG in Germany.
Curiously, European countries that rely more on cost-effectiveness assessments for reimbursement such as the UK, (instead of budget impact and or additional clinical value measures), may end up approving reimbursement more easily given that ICER’s assessment met its own cost-effectiveness thresholds, despite the budget impact concerns.
Disease management dilemmas:
Payer decisions will be further complicated by uncertainties associated with managing the disease:
- Asymptomatic early stages: Many patients do not experience symptoms in the early stages of the disease, despite ongoing liver damage
- Treatment not always needed: According to a meta-analysis of the placebo arms of clinical trials in patients with MASH, 25% showed improvement on a common measure of disease activity
- Pharmacological interventions alone are not enough: As recommended by physicians and clinical guidelines, lifestyle adjustments are still needed, as well as bariatric surgery for some patients to aid with weight loss
- Variation amongst patients: How might treatment be adapted to account for fast and slow progressors, patients with broader metabolic issues, those with genetic predispositions to MASH etc?
It is clear therefore, that there are many ways in which payers could restrict access to pharmacological treatment should questions arise around the health economic evidence. In addition, payers will have to weigh up taking a more preventative, population health-oriented approach against the overall financial impact.
WEGOVY: the disruptor
The entrance of WEGOVY as a treatment option for patients with MASH, with arguably comparable clinical effectiveness and safety to REZDIFFRA, has two profound disruptions in the market:
- Price: WEGOVY’s list price is approximately a third that of REZDIFFRA’s
- Therapeutic positioning: WEGOVY addresses broader metabolic/cardiovascular health, aligning strongly with the MASH population
Both aspects lend themselves to positioning WEGOVY as a first line treatment, and potentially as a population health management intervention. This profoundly alters the market dynamics and possibly relegates REZDIFFRA and other future liver-focused drugs to second line, shrinking the addressable number of patients. With several large population indications already included in its label, it will be difficult for REZDIFFRA to compete for first line positioning and or an advantageous formulary placement, despite its first mover advantage.
Downstream, once reimbursement for WEGOVY takes hold, the entrance of any new therapy will have its price benchmarked against the GLP-1, thereby limiting the ability to charge a significant premium. Time will tell whether these factors will affect further investment in MASH as a therapeutic area.
Whilst this is a plausible payer scenario, physicians have commented that given the multifaceted nature of MASH, both drugs may serve better as complementary therapies rather than direct competitors. In this scenario WEGOVY would be focused more on MASH resolution and related metabolic effects, whilst REZDIFFRA would be used to address fibrosis. Indeed, with other mechanisms of action in the pipeline, including next generation GLP-1s, FGF21 analogues, and pan-PPAR inhibitors, combination therapies could well become the norm. Payers and manufacturers will need to model the evolving treatment pathway carefully to understand the full clinical and financial impacts of these changes.[5]
Conclusion
After years of many failed attempts, MASH patients are now beginning to get access to therapies that can address the progression of their disease. However, it’s clear we are just at the beginning of understanding the roles of these treatments in the patient journey, as well their economic consequences. To manage this, manufacturers should continue investing in evidence to support broader labels, differentiated claims and opportunities for combination therapies. They must be mindful of the significant financial impact that their therapies may have, and so should robustly demonstrate health economic benefit as well as bring innovative contracting/pricing models to the payers to enable as broad access as possible.
Contact
If you are interested in discussing any of the issues above for your company/drug development program, please contact me through my email address dniven@nivenbiopharma.com. Feel free to also visit my website at www.nivenbiopharma.com for more information. I have no conflicts of interest in the production of this article.
Sources
- Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease, Estes et al, Hepatology, 2018
- Resmetirom and Obeticholic Acid for Non-Alcoholic Steatohepatitis (NASH), Final Report, ICER, May 2023
- FDA labels for REXDIFFRA and WEGOVY, FDA (as of Sep 2025)
- Drugs.com
- Therapeutic Strategies for MASH: An Update on Drug Candidates Under Investigation in Late Phase Clinical Trials, Dinerman et al, International Journal of Translational Medicine, January 2025
