Metabolic & Endocrine · Clinical trials
MASH / NASH (Metabolic Steatohepatitis) Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About mash / nash (metabolic steatohepatitis) — and why its trials are hard
Metabolic dysfunction-associated steatohepatitis (MASH, formerly nonalcoholic steatohepatitis, NASH) is the progressive, inflammatory form of fatty liver disease, marked by hepatic steatosis, lobular inflammation, hepatocyte ballooning, and fibrosis that can advance to cirrhosis and hepatocellular carcinoma. Tightly linked to obesity, type 2 diabetes, and metabolic syndrome, it is a leading and rising cause of liver transplantation. For years there was no approved pharmacotherapy, and the field accumulated a notable failure graveyard: obeticholic acid (REGENERATE) was twice rejected by the FDA over a benefit-risk concern; elafibranor (RESOLVE-IT), selonsertib (STELLAR), and cenicriviroc (AURORA) all missed their pivotal histologic endpoints. The breakthrough came in March 2024 when resmetirom (Rezdiffra), a liver-directed thyroid hormone receptor-beta agonist, became the first FDA-approved MASH therapy, based on MAESTRO-NASH meeting both co-primary histologic endpoints. Management still centers on weight loss and cardiometabolic risk control, with incretin-based agents (semaglutide, tirzepatide) showing strong resolution signals in trials, positioning MASH as a rapidly evolving therapeutic area built on dual histologic outcomes.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Resmetirom (Rezdiffra) | 2024 | First approved therapy for noncirrhotic MASH with moderate-to-advanced (F2-F3) fibrosis, with diet and exercise | MAESTRO-NASH Phase 3 (NCT03900429; NEJM 2024) | Co-primary: NASH resolution without worsening fibrosis, and >=1-stage fibrosis improvement without worsening NAS, at week 52 | NASH resolution ~26-30% and fibrosis improvement ~24-26% versus ~10-14% placebo (both co-primary endpoints met) |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in mash / nash (metabolic steatohepatitis) development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Obeticholic acid — REGENERATE Phase 3 (FXR agonist) | Met fibrosis-improvement endpoint on interim analysis but twice rejected by the FDA (2020 CRL; second complete response letter June 2023) | Unfavorable benefit-risk balance: modest histologic benefit against pruritus, dyslipidemia (LDL rise), and gallbladder/hepatic safety concerns |
| Elafibranor — RESOLVE-IT Phase 3 (PPAR-alpha/delta agonist) | Failed to meet primary endpoint of NASH resolution without worsening fibrosis; program discontinued in NASH | Insufficient histologic efficacy; response rates not significantly better than placebo (elafibranor later approved in PBC instead) |
| Selonsertib — STELLAR-3 / STELLAR-4 Phase 3 (ASK1 inhibitor) | Failed to meet primary fibrosis-improvement endpoint in bridging fibrosis and cirrhosis | No antifibrotic benefit versus placebo; targeting a single stress-kinase pathway proved inadequate |
| Cenicriviroc — AURORA Phase 3 (CCR2/CCR5 antagonist) | Terminated after interim analysis showed lack of efficacy on fibrosis improvement | Anti-inflammatory/antifibrotic mechanism did not translate into histologic benefit |
Choosing the right endpoint
Primary endpoints that matter in mash / nash (metabolic steatohepatitis) trials
- NASH/MASH resolution without worsening of fibrosis — Histologic co-primary reflecting reversal of steatohepatitis (ballooning + inflammation)
- Fibrosis improvement (>=1 stage) without worsening of steatohepatitis — Histologic co-primary capturing the prognostically critical fibrosis component
- NAFLD Activity Score (NAS) components — Semiquantitative scoring of steatosis, ballooning, and inflammation on biopsy
- Noninvasive markers (MRI-PDFF, liver stiffness, ALT) — Supportive/secondary measures reducing reliance on serial biopsy
How iNGENū runs mash / nash (metabolic steatohepatitis) trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
Request a fixed-milestone proposal and a tailored endpoint & feasibility summary for this indication.
Frequently asked questions
MASH / NASH (Metabolic Steatohepatitis) clinical trials — FAQs
What changed with resmetirom's approval?
Why did obeticholic acid fail to gain approval?
Do lifestyle changes and diabetes drugs still matter?
Ready to discuss your mash / nash (metabolic steatohepatitis) trial?
Talk to our physician-led team about an FDA-ready, cost-efficient trial design.
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