Resmetirom’s Breakthrough in MASH Cirrhosis: A New Era for Liver Disease Treatment?

The liver disease landscape is on the cusp of a paradigm shift. Madrigal Pharmaceuticals’ Rezdiffra (resmetirom) has just delivered compelling data in a high-risk patient population: those with compensated metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis (F4c). The Phase 3 MAESTRO-NAFLD-1 trial demonstrated that resmetirom reduced liver stiffness and improved biomarkers of fibrosis, while also addressing portal hypertension—a key driver of life-threatening complications. This milestone positions Rezdiffra as a potential cornerstone therapy in a field where no approved treatments exist for cirrhotic MASH.

Clinical Data: A Step Toward Transforming Outcomes

The trial’s two-year data in 122 F4c patients revealed a mean reduction of 6.7 kPa in liver stiffness (measured via VCTE), with 51% achieving ≥25% reduction—a threshold linked to reduced progression to end-stage liver disease. Equally promising, resmetirom reduced the risk of clinically significant portal hypertension, which is associated with ascites, variceal bleeding, and hepatic encephalopathy. These endpoints are critical because patients with compensated MASH cirrhosis face a 42-fold higher risk of liver-related mortality compared to those without cirrhosis.

The safety profile remained consistent with prior trials, with a low discontinuation rate. While gallbladder-related side effects (e.g., gallstones) remain a concern, they were manageable, and the benefits for liver health appear to outweigh these risks in this high-risk population.

Regulatory Momentum: EU Approval and Beyond

Rezdiffra is already FDA-approved for noncirrhotic MASH (F2-F3), with over 17,000 U.S. patients treated since its March 2024 approval. The European Medicines Agency (EMA) is reviewing a Marketing Authorization Application (MAA) for the drug, with a CHMP opinion expected by mid-2025. If approved, Madrigal plans a country-by-country rollout starting in Germany by late 2025.

The MAESTRO-NASH OUTCOMES trial, now fully enrolled with 845 patients, will be pivotal. Its primary endpoint—the incidence of composite liver-related events (e.g., decompensation, mortality)—could solidify Rezdiffra’s role as the first therapy for compensated MASH cirrhosis, a population of ~200,000 patients in the U.S. alone. Positive results by 2027 would expand Rezdiffra’s label, unlocking a multi-billion-dollar market opportunity.

Commercial and Clinical Gold Rush

The global MASH market is projected to exceed $10 billion by 2030, driven by rising metabolic syndrome rates and aging populations. Rezdiffra’s mechanism—a liver-targeted thyroid hormone receptor β (THR-β) agonist—addresses the metabolic root of MASH, offering a non-invasive, oral treatment option.

Madrigal’s strategy of securing early approvals for noncirrhotic MASH while pursuing cirrhotic indications creates a “two-step” market capture. The FDA’s accelerated approval for F2-F3 patients, contingent on confirmatory trials, is already paying off: strong U.S. adoption suggests peak sales could exceed $2 billion annually.

Risks and Challenges

• Safety Concerns: Gallbladder issues and the risk of progression in non-responders require monitoring.
• Competitor Threats: Drugs like elafibranor (Amarin) and cigirsen (Gilead) are in late-stage trials, though resmetirom’s fibrosis and stiffness data provide a lead.
• Regulatory Delays: The EMA’s timeline could slip, delaying European sales.

Investment Thesis: A High-Reward Play with Clear Catalysts

Madrigal’s stock (MRGD) has lagged behind biotech peers since its 2024 approval, trading at a ~4x sales multiple versus peers’ 6-8x. However, the F4c data and upcoming EU approval could revalue the stock. Key catalysts include:
- Q3 2025: EMA’s CHMP opinion.
- 2027: MAESTRO-NASH OUTCOMES results.
- 2025-2026: Real-world data on Rezdiffra’s U.S. performance and patient outcomes.

With 17,000 patients already treated and a clear path to expanding its label, Rezdiffra’s clinical profile aligns with unmet needs in a growing market. The drug’s non-invasive endpoints and focus on hard outcomes (e.g., reduced mortality) could accelerate adoption, even in conservative clinical settings.

Conclusion: A Game-Changer for Liver Disease?

Resmetirom’s data in compensated MASH cirrhosis represent a breakthrough. By addressing a population with no approved therapies, it could redefine treatment standards. With 42% of NASH patients progressing to cirrhosis, Rezdiffra’s potential to slow or reverse fibrosis offers a lifeline.

The stock’s valuation discount presents an opportunity: if the EMA approves Rezdiffra in 2025 and the OUTCOMES trial succeeds, MRGD could see a 200-300% upside over the next three years. For investors willing to ride the risks of a late-stage biotech, Madrigal’s combination of clinical differentiation, regulatory clarity, and market size makes it a compelling play on one of the 21st century’s most pressing health challenges.

The liver’s clock is ticking—for patients and investors alike. Resmetirom may just strike the right chord.