After Resmetirom: The Next Wave of MASH Therapies
A deep dive into the most promising targets and pipelines reshaping the MASH field.
A Historic Turning Point for MASH
An estimated 150 million people worldwide live with metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), a substantial proportion of whom will progress to cirrhosis or hepatocellular carcinoma. Until March 2024, this enormous patient population had virtually no approved pharmacological options.
That changed when the FDA approved Resmetirom (Rezdiffra) by Madrigal Pharmaceuticals — the first drug ever approved specifically for MASH. The milestone sent an unambiguous signal to the industry: the MASH market is officially open.
But Resmetirom is not an endpoint. It is a starting gun.
What Resmetirom Gets Right — and Where It Falls Short
Resmetirom is a thyroid hormone receptor beta (THRβ) agonist. By selectively activating hepatic THRβ, it promotes fatty acid oxidation and reduces intrahepatic triglyceride accumulation, ultimately improving liver fibrosis.
Phase III MAESTRO trial results:
- MASH histological resolution (without fibrosis worsening): 25.9% vs placebo 14.2%
- Fibrosis improvement ≥1 stage (without MASH worsening): 24.2% vs 14.2%
Statistically significant — but not transformative. Approximately three-quarters of patients did not respond. The core limitations:
- No direct intervention on the root drivers: insulin resistance and visceral obesity
- Limited efficacy in advanced fibrosis (F4)
- Narrow mechanistic coverage for a multi-factorial disease
This is precisely why the next wave matters.
The Most Promising Targets in Development
1. GLP-1 Receptor Agonists: The Frontrunner
Novo Nordisk’s semaglutide is in Phase III for MASH (ESSENCE trial). Phase II data showed a MASH resolution rate of approximately 40% — meaningfully higher than Resmetirom.
Eli Lilly’s tirzepatide (dual GLP-1/GIP agonist) produced even more striking Phase II results, with fibrosis improvement rates exceeding 50%.
Why are GLP-1 agents so effective? Because they target the disease upstream — improving insulin resistance and reducing body weight, which in turn alleviates hepatic lipotoxicity. They treat the cause, not just the consequence.
2. FGF21 Analogues: Directly Targeting Fibrosis
Akero Therapeutics’ efruxifermin (EFX) is the most closely watched non-GLP-1 candidate:
- Mechanism: FGF21 directly suppresses hepatic stellate cell activation, reducing collagen deposition
- Phase II data: fibrosis improvement rate of 39% in F2–F3 patients
- Key differentiator: demonstrated activity in advanced fibrosis (F3–F4), where GLP-1 data are weaker
- Phase III HARMONY trial is ongoing
89bio’s pegozafermin, another FGF21 analogue, is racing through Phase III in parallel.
3. Pan-PPAR Agonism
Inventiva’s lanifibranor simultaneously activates all three PPAR subtypes (α/δ/γ), targeting lipid metabolism, inflammation, and insulin sensitivity in a single molecule. The Phase III NATiV3 trial has completed enrollment; data readout is anticipated in 2025.
4. FXR Agonists: Learning from Failure
Obeticholic acid (OCA) failed twice at the FDA — once for pruritus and LDL concerns, and ultimately withdrew in 2023. Yet the FXR mechanism retains scientific merit, particularly in combination regimens. Next-generation FXR agonists (cilofexor, EDP-305) continue in development with improved selectivity profiles.
5. Combination Therapy: Where the Endgame Lies
Accumulating evidence suggests MASH is too complex for monotherapy. Early trials of GLP-1 + FGF21 and GLP-1 + THRβ combinations are underway. In five years, combination regimens may well become standard of care.
Pipeline at a Glance
| Company | Drug | Target | Stage |
|---|---|---|---|
| Novo Nordisk | Semaglutide | GLP-1 | Phase III |
| Eli Lilly | Tirzepatide | GLP-1/GIP | Phase III |
| Akero | Efruxifermin | FGF21 | Phase III |
| 89bio | Pegozafermin | FGF21 | Phase III |
| Inventiva | Lanifibranor | Pan-PPAR | Phase III |
| Madrigal | Resmetirom | THRβ | Approved |
Industry Perspective
For pharma companies: GLP-1’s strong efficacy data are actively reshaping the standard of care in MASH. Companies without a GLP-1 or GIP asset need a differentiated thesis — FGF21 is currently the most compelling non-GLP-1 path, particularly for patients with advanced fibrosis. Combination therapy will define the next competitive frontier; staking out combination patents early is critical.
For investors: The MASH market is projected to exceed $20 billion, but the winner-takes-most dynamics are already becoming apparent. Smaller companies must carve out defensible positions in specific subpopulations — advanced fibrosis patients, GLP-1 non-responders, or combination partners — to survive alongside Novo Nordisk and Eli Lilly.
Author: Cherainboow | Cantab University of Cambrige Researcher
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