Madrigal Doubles Down on MASH, Licensing Pfizer Drug for Combo Therapy

CONSHOHOCKEN, PA – January 09, 2026 – Madrigal Pharmaceuticals, the company that brought the first approved therapy for metabolic dysfunction-associated steatohepatitis (MASH) to market, has made a significant move to solidify its leadership, licensing a promising Phase 2 drug from Pfizer in a deal that signals a strategic pivot towards combination therapies for the complex liver disease.

The agreement gives Madrigal exclusive global rights to ervogastat, an oral DGAT-2 inhibitor, for an upfront payment of $50 million. The company plans to develop it in combination with its blockbuster drug, Rezdiffra® (resmetirom), aiming to create a more powerful, multi-pronged attack on a disease that affects millions and has long frustrated drug developers. This move not only expands Madrigal's pipeline but also sets the stage for what many experts believe is the future of MASH treatment.

A New Era of Combination Therapy

With Rezdiffra established as the foundational, first-in-class treatment for MASH with moderate to advanced fibrosis, Madrigal is now looking to build upon its success. The acquisition of ervogastat is the first major step in this strategy, positioning Rezdiffra as the anchor of future multi-drug regimens.

"As the next wave of innovation moves toward combination therapies, Rezdiffra’s strong profile as a liver-directed, well-tolerated, once-daily oral therapy positions it as the ideal foundation," said Bill Sibold, Chief Executive Officer of Madrigal, in the company's announcement.

MASH is a multifactorial disease driven by a complex interplay of metabolic dysfunction, fat accumulation, inflammation, and scarring (fibrosis) in the liver. This complexity has made it a notoriously difficult target for single-agent therapies. While Rezdiffra's approval was a landmark achievement, industry analysts and clinical experts widely agree that combination treatments targeting different pathogenic pathways will likely be necessary to achieve more profound and durable responses for a broader range of patients. Madrigal's acquisition places it at the forefront of this next-generation approach.

The scientific rationale for combining the two drugs is compelling. Professor Quentin Anstee, a lead investigator on a prior ervogastat study, noted that the drugs act on "distinct yet complementary pathways that drive liver fat accumulation," creating the potential for "additive antisteatotic and antifibrotic efficacy."

The Science Behind the Synergy

The potential power of the Rezdiffra-ervogastat combination lies in their different, yet complementary, mechanisms of action. Rezdiffra is a thyroid hormone receptor-β (THR-β) agonist, which essentially ramps up the liver's metabolic engine. It increases the ability of liver cells to break down fat through a process called mitochondrial biogenesis, helping to clear the excess fat that characterizes MASH.

Ervogastat, a diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, works on the other side of the equation. It blocks the final and critical step in the liver's production of triglycerides, the main type of fat stored in the body. By inhibiting this enzyme, ervogastat directly reduces the amount of new fat being synthesized and stored in the liver, which in turn is expected to decrease the lipotoxicity and inflammation that drive fibrosis.

In a previously published Phase 2 study, ervogastat demonstrated impressive efficacy on its own. A significant 61% of patients treated with the drug achieved at least a 50% reduction in liver fat as measured by MRI-PDFF, a key imaging biomarker. This level of fat reduction, as Professor Anstee highlighted, "has been predictive of longer-term fibrosis improvement for other mechanisms, including Rezdiffra."

However, the path for ervogastat has not been without complexities. In a prior trial known as MIRNA, Pfizer studied ervogastat in combination with another experimental drug, clesacostat. While that combination showed some positive effects, it was also associated with an increase in blood triglycerides and a decrease in "good" HDL cholesterol in some patients. Pfizer ultimately discontinued development of that specific combination in late 2025. Madrigal is betting that combining ervogastat with Rezdiffra, which has a different metabolic effect, will not only prove more effective but will also yield a more favorable overall safety and metabolic profile.

Strategic Pipeline Shuffle and Financials

The deal is a classic example of strategic realignment in the pharmaceutical industry. For Pfizer, out-licensing ervogastat is consistent with its recent efforts to streamline its R&D portfolio, divest non-core assets, and focus resources on high-growth areas like oncology. The deal allows Pfizer to offload development costs and risk while retaining a financial stake in ervogastat's future success through potential milestone payments and royalties.

For Madrigal, the acquisition is a calculated investment to cement its dominance in the MASH market, which is projected to grow into a multi-billion dollar industry within the next decade. The $50 million upfront payment, which will be expensed in the fourth quarter of 2025, represents a manageable investment for a company whose Rezdiffra sales are projected to top $1 billion in 2025. The agreement also includes rights to two other early-stage MASH assets, giving Madrigal further options to build out its liver disease pipeline.

This proactive pipeline expansion is seen by analysts as a crucial move to defend against a wave of competitors, including potent GLP-1 agonists like Wegovy, which recently gained a label expansion for MASH. By pioneering a proprietary combination therapy, Madrigal could create a higher barrier to entry and offer a more specialized, liver-focused treatment than systemic metabolic drugs.

Navigating the Path Forward

Madrigal's immediate plans for 2026 include conducting a drug-to-drug interaction study to assess the safety and pharmacokinetics of using Rezdiffra and ervogastat together. Following that, the company will consult with the U.S. Food and Drug Administration (FDA) to finalize the design of a pivotal Phase 2 combination trial.

Navigating the regulatory pathway will be a critical challenge. The FDA will require robust data demonstrating that the combination provides a clinical benefit superior to Rezdiffra alone, without introducing unacceptable safety risks. This is particularly important given Rezdiffra's accelerated approval status, which is contingent on the successful completion of ongoing confirmatory outcomes trials.

Furthermore, the evolving treatment landscape presents a practical hurdle. With an approved therapy in Rezdiffra and the effective off-label use of GLP-1 agonists for MASH, recruiting patients for new clinical trials has become more challenging. Madrigal will need to design a compelling trial that can attract participants and clearly demonstrate the value proposition of its new combination regimen in a market that is no longer a blank slate. The company is set to provide more details on its strategy at the upcoming J.P. Morgan Healthcare Conference, where investors and competitors alike will be watching closely.