Evidence Grade C — Moderate human evidence. 63 published studies, 39 human. 0 registered clinical trials.
Medically reviewed by a licensed medical professional
This entry covers survodutide's development specifically for MASH (metabolic dysfunction-associated steatohepatitis) — a liver disease caused by fat accumulation that leads to inflammation and scarring. The same drug is listed separately for its obesity indication. The MASH programme has produced some of the strongest liver histology data of any drug in development.
Survodutide (MASH Indication) is also known by these brand and alternate names:
63 published studies: 39 human, 0 animal, 1 in-vitro, 32 reviews
Survodutide is in Phase III development for MASH (not yet approved for this indication). The Phase II MASH trial (293 patients, 48 weeks, with liver biopsies) showed MASH improvement without worsening fibrosis in up to 62% of patients, compared to 14% with placebo. Per-protocol analysis showed up to 83% MASH improvement. Liver fat reductions of 64–67% were observed.
Phase III trials for MASH are underway. The biopsy-confirmed results from Phase II are among the strongest reported for any MASH drug candidate. See compound #160 for the obesity indication.
For the MASH indication, survodutide's glucagon receptor activation directly stimulates liver fat oxidation, reduces new fat production, and promotes fat mobilisation from liver cells. The GLP-1 component contributes weight loss and anti-inflammatory effects. This dual hepatic mechanism addresses both the root cause (excess liver fat) and the inflammatory consequence of MASH.
The Phase II MASH trial (293 patients) used liver biopsies — the gold standard for assessing liver disease — and showed MASH improvement without worsening fibrosis in up to 62% of patients, with per-protocol analysis reaching 83%. Liver fat reductions of 64-67% were observed. These results earned Breakthrough Therapy Designation from the FDA. The Phase III LIVERAGE programme (approximately 1,800 patients) began in October 2024, with a separate trial for patients with liver cirrhosis. Key uncertainties include the non-linear dose response seen in Phase II (6.0 mg was less effective than 4.8 mg), the high treatment discontinuation rate, and whether the impressive Phase II results will translate to Phase III. The MASH space is increasingly competitive, with tirzepatide, retatrutide, pemvidutide, and efinopegdutide all pursuing the same indication.
Survodutide (BI 456906) is a 29-amino-acid acylated glucagon analog modified with GLP-1-active substitutions, developed by Boehringer Ingelheim with the molecule licensed from Zealand Pharma. Molecular weight 4,231.62 Da. CAS number: 2805997-46-8. EC50 values: GCGR 0.52 nM, GLP-1R 0.33 nM. This entry focuses specifically on the MASH/liver disease indication and the Phase 3 LIVERAGE program. The compound received FDA Breakthrough Therapy Designation in October 2024 for non-cirrhotic MASH with F2-F3 fibrosis.
For the MASH indication, survodutide's dual GCGR/GLP-1R agonism provides a complementary hepatic mechanism: the glucagon component directly increases hepatic lipid oxidation through cAMP-PKA-CREB signaling, reduces de novo lipogenesis via SREBP-1c downregulation, and promotes hepatic fat mobilization. The GLP-1 component provides systemic metabolic benefits including weight reduction and improved insulin sensitivity. Both pathways converge on reducing hepatic steatosis, inflammation, and fibrogenic signaling.
Phase 2 MASH trial (Sanyal et al., NEJM July 2024; NCT04771273; N=293; 48 weeks with biopsy): MASH improvement without worsening fibrosis was achieved in 47% (2.4 mg), 62% (4.8 mg), and 43% (6.0 mg) versus 14% placebo (dose-response P<0.001). Per-protocol analysis showed up to 83% MASH improvement and 75% MASH resolution. Liver fat reduction of at least 30% was observed in 57-67% of participants versus 14% placebo. Fibrosis improvement of at least 1 stage: 34-36% versus 22% placebo. Gastrointestinal events were common: nausea 66%, diarrhea 49%, vomiting 41%. Non-linear dose response was observed with the 6.0 mg dose being less effective than 4.8 mg.
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Linaclotide is marketed as Linzess (approved August 2012). It is taken as a daily oral capsule on an empty stomach, at least 30 minutes before the first meal. The recommended dose is 290 mcg for IBS-C and 72 or 145 mcg for chronic constipation. In clinical trials, approximately 34% of IBS-C patients met the composite improvement endpoint compared to 17% on placebo. Diarrhoea is the most common side effect (approximately 20%) and the leading reason for discontinuation. Linaclotide has a boxed warning against use in children under 6 years due to deaths in young mice, though no such events have been reported in humans. It competes with plecanatide (which targets the same pathway) and other IBS-C treatments.
Elamipretide (Forzinity) was approved by the FDA for Barth syndrome based on the TAZPOWER trial. The randomised crossover phase (12 patients) did not meet its primary endpoints, but the open-label extension (168 weeks) demonstrated durable improvements in walking distance and muscle strength that formed the basis for approval. Barth syndrome affects approximately 1 in 300,000–400,000 births. A larger Phase III trial in primary mitochondrial myopathy (218 patients, MMPOWER-3) did not meet its primary endpoint, and the drug was not approved for that broader indication. Elamipretide remains approved exclusively for Barth syndrome. See also SS-31 (#158) for the research compound context.
Palopegteriparatide is marketed as Yorvipath (Ascendis Pharma, approved August 2024). It is the first FDA-approved PTH replacement therapy for hypoparathyroidism, a condition that previously had no approved hormone replacement and was managed only with high doses of calcium supplements and active vitamin D — an approach that does not fully normalise calcium metabolism. In the PaTHway trial, 79% of patients achieved independence from calcium and active vitamin D supplements while maintaining normal blood calcium levels, compared to 5% on placebo. This represents a fundamental shift in managing hypoparathyroidism — from supplementation to actual hormone replacement. Patients also showed improvements in kidney function markers and bone metabolism parameters.
Evidence Reviews
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