The MASH Pipeline in 2026: Two Approvals, $8 Billion in M&A, and 16 Phase 3 Trials

From Zero Approved Drugs to Two, in 14 Months

MASH — metabolic dysfunction-associated steatohepatitis, renamed from NASH in 2023 — is a liver disease affecting an estimated 5–7% of US adults (JAMA Network Open, 2023). Fat accumulates in the liver, triggering inflammation and scarring that can progress to cirrhosis. Until recently, there was no approved treatment.

That changed fast. In March 2024, the FDA granted accelerated approval to resmetirom (Rezdiffra, Madrigal) for noncirrhotic MASH with moderate to advanced fibrosis — the first-ever approved treatment (FDA). Fourteen months later, in August 2025, semaglutide 2.4 mg (Wegovy, Novo Nordisk) became the second approved treatment for the same indication, based on the ESSENCE Phase 3 trial (FDA).

Both are accelerated approvals — confirmatory trials are still required. That matters: the companies racing for a third approval are also watching whether the first two survive their confirmatory studies.

Who Is Running Phase 3 Trials Right Now

Of the 267 currently recruiting MASH trials, 16 are in Phase 3 — 11 of them pharma-primary MASH programs; the rest academic or adjacent. The competitive programs cluster into two mechanism classes racing for a next approval: FGF21 analogs (synthetic versions of a liver hormone that regulates fat metabolism) and GLP-1-based combinations (drugs built on the same biology as Ozempic and Wegovy). A third mechanism, THR-beta agonism (activating thyroid hormone receptor beta in the liver to reduce fat), is already represented by Madrigal's approved resmetirom.

Madrigal's two recruiting trials are follow-on programs for the already-approved drug — new patient populations and post-transplant settings. They are not racing for a first approval; they are extending the label of one they already have.

Why Nearly $8 Billion Went Into FGF21

FGF21 analogs reduce liver fat through a different pathway than GLP-1 drugs, which is why large pharma kept buying into the class even after semaglutide's approval — the two mechanisms could be complementary rather than simply competitive. The commercial opportunity is real: Rezdiffra generated approximately $958 million in its first full year of sales in 2025, and analyst projections for the broader MASH treatment market range from $24 billion to $34 billion by 2030, depending on how competitive the space becomes (Grand View Research; Madrigal Q4 2025 earnings).

The GLP-1 Combination Bets

Boehringer Ingelheim's survodutide adds glucagon receptor signaling on top of GLP-1, thought to provide extra liver fat reduction. Their two LIVERAGE trials are enrolling approximately 3,400 patients across noncirrhotic and cirrhotic cohorts — one of the few programs targeting cirrhotic MASH directly. Survodutide holds FDA Breakthrough Therapy Designation for the non-cirrhotic indication (Boehringer Ingelheim). Eli Lilly's SYNERGY-Outcomes is testing two drugs under one master protocol: retatrutide (a GLP-1/GIP/glucagon triple agonist) and tirzepatide (the GLP-1/GIP dual agonist behind Mounjaro).

Who Has the Most Active Trials

ClinicalTrials.gov lead sponsor counts reflect registration data, not current ownership. Akero Therapeutics and 89bio are still listed as lead sponsors on trials filed before their acquisitions closed — so Novo Nordisk's and Roche's effective footprints are larger than this table shows.

*Novo Nordisk's 5 recruiting trials reflect semaglutide programs registered before the Akero acquisition. Efruxifermin trials remain registered under "Akero Therapeutics" as lead sponsor.

What to Watch Next

• The FGF21 race is a class race, not just a company race. If one FGF21 analog reads out strong Phase 3 data, it raises the probability floor for the whole class — but it also creates immediate commercial head-to-head pressure. Expect intensity to build around 2027–2028 as SYNCHRONY, ENLIGHTEN, and ZENITH start reporting.
• Cirrhotic MASH is the open field. Both approved drugs are for noncirrhotic patients only. Boehringer's LIVERAGE-Cirrhosis and Akero/Novo's SYNCHRONY cirrhosis cohort are among the few directly targeting F4 patients. A first approval there doesn't compete against resmetirom or semaglutide for the same label.
• China-based programs are entering the picture. Innovent's mazdutide (a GLP-1/GIP dual agonist) has a Phase 3 trial currently recruiting — the GLORY-3 study — comparing it head-to-head against semaglutide. These programs are primarily enrolling in China but worth tracking as the market for MASH drugs develops globally.
• Confirmatory trial risk cuts both ways. A successful read-out validates the MASH market and likely accelerates the rest of the pipeline. A disappointing one creates an opening for drugs immediately behind — and raises questions about the $8B in acquisitions made on the assumption that accelerated approval becomes full approval.
• Phase 2 is pointing beyond FGF21 and GLP-1. Of 41 recruiting Phase 2 MASH trials, several are testing siRNA approaches (gene-silencing therapies targeting specific drivers of liver fat and fibrosis) and combination regimens pairing approved drugs with new mechanisms. None have reached Phase 3 yet, but the field clearly isn't treating the current two classes as the final answer.