Survodutide Phase 2 NASH Trial Analysis
Metabolic dysfunction-associated steatohepatitis (MASH) -- formerly called NASH -- affects an estimated 5% of adults worldwide, and until very recently, there was exactly one FDA-approved drug for it.
Metabolic dysfunction-associated steatohepatitis (MASH) -- formerly called NASH -- affects an estimated 5% of adults worldwide, and until very recently, there was exactly one FDA-approved drug for it. That changed when the Phase 2 trial of survodutide, a glucagon/GLP-1 receptor dual agonist, produced results striking enough to land in the New England Journal of Medicine and earn FDA Breakthrough Therapy designation within months.
The 48-week trial (NCT04771273) tested survodutide in 293 adults with biopsy-confirmed MASH and liver fibrosis. The headline numbers: up to 62% of participants achieved MASH resolution without worsening fibrosis, compared to 14% on placebo. Liver fat dropped by as much as 62%. And the drug simultaneously produced meaningful weight loss.
But the story is more nuanced than those top-line figures suggest. Here is a detailed breakdown of the trial design, efficacy data, safety signals, and what it all means for MASH treatment going forward.
Table of Contents
- What Is Survodutide?
- Why Dual GLP-1/Glucagon Agonism Matters for MASH
- Trial Design: NCT04771273
- Primary Endpoint: MASH Resolution
- Secondary Endpoints: Liver Fat and Fibrosis
- Weight Loss in the MASH Cohort
- Safety and Tolerability
- How Survodutide Compares to Semaglutide and Tirzepatide
- The Dose-Response Puzzle
- Phase 3: The LIVERAGE Program
- The Bottom Line
- References
What Is Survodutide?
Survodutide (also known as BI 456906) is an investigational peptide co-developed by Boehringer Ingelheim and Zealand Pharma. It belongs to an emerging class of drugs called dual receptor agonists -- peptides engineered to activate two metabolic receptors simultaneously.
Specifically, survodutide targets both the glucagon receptor (GCGR) and the GLP-1 receptor (GLP-1R). The molecule is derived from native glucagon, with modifications that add GLP-1 receptor activity and a C18 fatty diacid side chain that extends its half-life enough for once-weekly dosing.
This dual mechanism sets survodutide apart from semaglutide (GLP-1 only) and tirzepatide (GLP-1 + GIP). The glucagon component is the key differentiator -- and may be the reason the MASH data looks the way it does.
Why Dual GLP-1/Glucagon Agonism Matters for MASH
GLP-1 receptor agonists have shown clear benefits in MASH trials, primarily through weight loss, improved insulin sensitivity, and reduced de novo lipogenesis. But the liver itself does not express GLP-1 receptors at high levels. Most of the hepatic benefit from GLP-1 drugs appears to be indirect -- a downstream effect of losing fat mass and improving metabolic health system-wide.
Glucagon receptor activation is a different story. The liver is packed with glucagon receptors. When those receptors are activated, the liver ramps up fatty acid oxidation and energy expenditure while suppressing fat accumulation. In preclinical models, glucagon receptor agonism directly reduced hepatic steatosis, lowered ALT levels (a marker of liver cell damage), and increased circulating FGF21 -- a hormone linked to metabolic improvement.
The hypothesis behind survodutide: combining GLP-1's systemic metabolic benefits (appetite suppression, weight loss, glucose control) with glucagon's direct liver effects (fat oxidation, reduced steatosis) should produce better outcomes in MASH than either receptor alone.
The Phase 2 data suggests that hypothesis was right.
Trial Design: NCT04771273
The trial, published by Sanyal AJ, Bedossa P, Fraessdorf M, et al. in the New England Journal of Medicine on June 7, 2024, was a randomized, double-blind, placebo-controlled study funded by Boehringer Ingelheim.
Key Parameters:
| Parameter | Details |
|---|---|
| Population | Adults with biopsy-confirmed MASH, fibrosis stages F1-F3 |
| Sample size | 293 participants (received at least one dose) |
| Randomization | 1:1:1:1 to survodutide 2.4 mg, 4.8 mg, 6.0 mg, or placebo |
| Administration | Once-weekly subcutaneous injection |
| Duration | 48 weeks total |
| Phases | 24-week dose-escalation + 24-week maintenance |
| Primary endpoint | Histologic improvement in MASH with no worsening of fibrosis |
| Key secondary endpoints | Liver fat reduction of 30% or more; fibrosis improvement by at least one stage |
| Registry | NCT04771273 |
Two design details matter. First, this trial required liver biopsies at baseline and at 48 weeks -- the gold standard for assessing MASH, but invasive and painful, which limits enrollment. Second, the dose-escalation phase lasted a full 24 weeks, with participants ramping up gradually before entering the maintenance period. This extended titration may explain some of the tolerability findings.
Primary Endpoint: MASH Resolution
The primary endpoint was histologic improvement in MASH without worsening of fibrosis, assessed by liver biopsy at week 48.
MASH Resolution Without Worsening of Fibrosis (Biopsy-Confirmed):
| Group | Response Rate | P-value vs. Placebo |
|---|---|---|
| Survodutide 2.4 mg | 47% | < 0.001 |
| Survodutide 4.8 mg | 62% | < 0.001 |
| Survodutide 6.0 mg | 43% | < 0.001 |
| Placebo | 14% | -- |
All three survodutide doses cleared the primary endpoint with statistical significance. The 4.8 mg dose performed best, with nearly two-thirds of participants achieving MASH resolution.
Boehringer Ingelheim also reported a separate analysis population showing that 83% of survodutide-treated participants achieved statistically significant histological improvement in MASH, compared to 18.2% on placebo (response difference: 64.8%, p < 0.0001). This larger figure reflects a different analysis method (the efficacy estimand, which accounts for treatment discontinuations differently) and a broader definition of "improvement."
Both numbers are real. The 47-62% range reflects the more conservative intention-to-treat analysis; the 83% figure reflects what happened among participants who stayed on treatment as planned. Neither is wrong -- they answer slightly different questions.
Secondary Endpoints: Liver Fat and Fibrosis
Liver Fat Reduction
A decrease in liver fat content of at least 30% -- measured by MRI-proton density fat fraction -- was a key secondary endpoint.
Participants Achieving 30% or Greater Liver Fat Reduction:
| Group | Response Rate |
|---|---|
| Survodutide 2.4 mg | 63% |
| Survodutide 4.8 mg | 67% |
| Survodutide 6.0 mg | 57% |
| Placebo | 14% |
The mean percentage change in liver fat from baseline at 48 weeks was -62.0% in the 6.0 mg group versus -5.7% on placebo. An interim analysis at week 28 showed even more dramatic numbers, with up to 90.9% of survodutide-treated participants achieving the 30% liver fat reduction threshold.
These liver fat numbers are among the highest reported in any MASH trial to date.
Fibrosis Improvement
Improvement in fibrosis by at least one stage without worsening of MASH was the other key secondary endpoint.
Fibrosis Improvement by at Least One Stage:
| Group | Response Rate |
|---|---|
| Survodutide 2.4 mg | 34% |
| Survodutide 4.8 mg | 36% |
| Survodutide 6.0 mg | 34% |
| Placebo | 22% |
The fibrosis numbers are more modest than the MASH resolution data. The absolute difference over placebo was 12-14 percentage points across the three dose groups -- statistically significant, but not as dramatic as the MASH resolution or liver fat endpoints.
However, a sub-analysis focusing specifically on participants with moderate to advanced fibrosis (stages F2 and F3) told a stronger story: up to 64.5% achieved fibrosis improvement without worsening of MASH, versus 25.9% on placebo (response difference: 38.6%, p = 0.0005). This suggests survodutide may have more pronounced fibrosis effects in patients with more advanced disease -- exactly the population with the greatest unmet need.
Weight Loss in the MASH Cohort
While the MASH trial was not designed primarily to measure weight loss, survodutide produced substantial body weight reductions. Exact weight loss figures from the MASH trial by dose group have not been fully broken out in publications, but the data is consistent with what was observed in the separate Phase 2 obesity trial.
In that obesity trial (published in The Lancet), 386 participants with BMI over 27 received survodutide or placebo for 46 weeks. Mean body weight reductions were:
- 0.6 mg: -6.2%
- 2.4 mg: -12.5%
- 3.6 mg: -13.2%
- 4.8 mg: -14.9%
- Placebo: -2.8%
Participants who reached and maintained the 4.8 mg dose lost a mean of 18.7% of body weight. Approximately 40% of those on the two highest doses lost 20% or more.
Weight loss matters for MASH because it is one of the primary drivers of hepatic improvement. Mediation analyses from the semaglutide MASH trial showed that roughly 70-83% of improvements in steatosis, ballooning, and MASH resolution were attributable to weight loss -- but only about 25% of fibrosis benefit was weight-related. The implication: survodutide's glucagon receptor activity may contribute to liver health through mechanisms beyond simply shedding pounds.
Safety and Tolerability
The safety profile followed the pattern typical of incretin-based therapies, though the rates were notably higher than what is seen with GLP-1-only drugs.
Adverse Events (Survodutide vs. Placebo):
| Adverse Event | Survodutide (pooled) | Placebo |
|---|---|---|
| Nausea | 66% | 23% |
| Diarrhea | 49% | 23% |
| Vomiting | 41% | 4% |
| Serious adverse events | 8% | 7% |
Those GI rates are high. For comparison, semaglutide 2.4 mg in the ESSENCE trial produced nausea in roughly 40-45% of participants. The addition of glucagon receptor agonism appears to increase GI side effects, particularly nausea and vomiting.
The serious adverse event rate, however, was nearly identical between survodutide (8%) and placebo (7%), which is reassuring. No new safety signals emerged that would raise concerns beyond the expected GI tolerability issues.
One thing to watch in Phase 3: whether the extended dose-escalation protocol (24 weeks in this trial) adequately manages the GI burden, or whether real-world tolerability will be lower than these controlled trial conditions suggest.
How Survodutide Compares to Semaglutide and Tirzepatide
No head-to-head trials exist between these three drugs in MASH. Cross-trial comparisons are inherently imperfect -- different patient populations, trial durations, biopsy timing, and analysis methods all muddy the picture. With that caveat stated clearly, here is what the numbers look like side by side.
Cross-Trial Comparison: Phase 2 MASH Results
| Metric | Survodutide | Semaglutide | Tirzepatide |
|---|---|---|---|
| Receptor targets | GLP-1 + Glucagon | GLP-1 only | GLP-1 + GIP |
| Trial phase (MASH) | Phase 2 | Phase 2 (Phase 3 completed) | Phase 2 |
| Trial duration | 48 weeks | 72 weeks (Phase 2) | 52 weeks |
| Fibrosis stages | F1-F3 | F1-F3 (Phase 2); F2-F3 (Phase 3) | F2-F3 |
| MASH resolution (best dose) | 62% (4.8 mg) | 59% (0.4 mg daily, Phase 2) | 62% (15 mg) |
| MASH resolution (efficacy estimand) | 83% | 62.9% (Phase 3, 2.4 mg weekly) | 73.3% (15 mg) |
| Fibrosis improvement (best dose) | 36% (4.8 mg) | 43% (Phase 2, 0.4 mg) | 55% (5 mg) |
| Liver fat reduction | Up to -62% | Not primary endpoint | Not reported |
| Weight loss (approx.) | ~15-19% | ~10-13% | ~11-16% |
A network meta-analysis published in Hepatology in 2025, covering 29 randomized controlled trials with 9,324 participants, ranked survodutide second overall for MASH resolution (SUCRA score: 90.87%), behind only pegozafermin (91.75%) and ahead of tirzepatide (84.70%).
Several patterns emerge from these comparisons:
-
MASH resolution: All three drugs produce high rates. Survodutide and tirzepatide appear roughly comparable at their best doses; semaglutide's Phase 2 numbers were strong but its Phase 3 data (62.9%) came from a different population (F2-F3 only).
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Fibrosis: Tirzepatide showed numerically higher fibrosis improvement rates in SYNERGY-NASH, but it enrolled only F2-F3 patients (more room for improvement). Semaglutide's Phase 3 ESSENCE trial showed 36.8% fibrosis improvement. Survodutide's 34-36% came from a broader F1-F3 population.
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Liver fat: Survodutide's 62% mean reduction stands out, likely reflecting glucagon receptor-driven hepatic fat oxidation.
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Tolerability: Survodutide's GI side effect rates (66% nausea, 41% vomiting) are noticeably higher than either competitor. This could become a competitive disadvantage if it translates to higher discontinuation rates in Phase 3.
The Dose-Response Puzzle
One unexpected finding: the dose-response curve was not linear. The 4.8 mg dose outperformed both the lower 2.4 mg dose and the higher 6.0 mg dose on the primary endpoint (62% vs. 47% vs. 43%).
This inverted U-shaped response is unusual but not inexplicable. At the highest dose, more participants may have experienced GI side effects severe enough to reduce compliance or cause discontinuation, effectively lowering the observed efficacy. Alternatively, there may be a pharmacological ceiling where additional glucagon receptor activation no longer translates to better histological outcomes.
This dose-response pattern influenced the Phase 3 program design. The LIVERAGE trials are testing doses informed by this Phase 2 finding, and the extended escalation schedules aim to improve tolerability at higher doses.
Phase 3: The LIVERAGE Program
Based on the Phase 2 results and the FDA's Breakthrough Therapy designation (granted in October 2024), Boehringer Ingelheim launched two Phase 3 trials:
LIVERAGE (NCT06632444): Enrolling approximately 1,800 adults with MASH and stage F2-F3 fibrosis. The primary endpoints for Part 1 (52 weeks) are the proportion of patients achieving MASH resolution without worsening fibrosis and at least one-stage fibrosis improvement without worsening MASH. Part 2 extends to 7 years, measuring time to first liver-related event or all-cause mortality.
LIVERAGE-Cirrhosis (NCT06632457): Enrolling approximately 1,590 adults with compensated MASH cirrhosis (stage F4). The primary endpoint is time to first occurrence of all-cause mortality or liver-related events over 4.5 years.
Together, these trials cover the full spectrum of advanced MASH -- from moderate fibrosis through compensated cirrhosis. Results from Part 1 of LIVERAGE are expected in the first half of 2027, with potential FDA approval projected for late 2027 or 2028.
Survodutide also holds FDA Fast Track designation (granted 2021), EMA PRIME designation, and China NMPA Breakthrough status. Separately, five Phase 3 obesity trials (the SYNCHRONIZE program) are underway, with data expected in H1 2026.
The Bottom Line
The Phase 2 data for survodutide in MASH is strong. A 48-week trial in 293 participants with biopsy-confirmed disease showed MASH resolution rates of 43-62% (vs. 14% placebo), liver fat reductions of up to 62%, and fibrosis improvement in about a third of participants. The drug's dual glucagon/GLP-1 mechanism appears to deliver on the theoretical promise of direct hepatic fat reduction layered on top of systemic metabolic improvement.
Three things temper the enthusiasm. The GI side effect rates are high -- two-thirds of participants experienced nausea, and 41% had vomiting. The non-linear dose response raises questions about optimal dosing. And this is still Phase 2 data with a relatively small sample size; the real test comes with the LIVERAGE trials.
Still, survodutide represents a genuinely different approach to MASH. Unlike semaglutide (GLP-1 only, FDA-approved for MASH in 2025) and tirzepatide (GLP-1 + GIP), survodutide's glucagon receptor component gives it a direct line to the liver. If the Phase 3 data confirms what Phase 2 suggests, it could become a particularly compelling option for patients whose primary disease burden is hepatic rather than metabolic.
For now, survodutide is not available outside of clinical trials. Patients interested in MASH treatment should discuss currently approved options -- resmetirom (Rezdiffra) and semaglutide (Wegovy, approved for MASH in August 2025) -- with their healthcare provider.
References
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Sanyal AJ, Bedossa P, Fraessdorf M, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. New England Journal of Medicine. 2024;391(4):311-319. doi:10.1056/NEJMoa2401755. PubMed
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Boehringer Ingelheim. Survodutide Phase II trial shows 83% of adults treated achieved groundbreaking results in liver disease due to MASH. Press release, February 26, 2024. GlobeNewsWire
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Boehringer Ingelheim. Survodutide shows breakthrough improvement in liver fibrosis with no worsening of MASH in 64.5% of patients with F2 and F3 fibrosis. Press release, June 7, 2024. GlobeNewsWire
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ClinicalTrials.gov. A Study to Test Safety and Efficacy of BI 456906 in Adults With NASH. NCT04771273
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Jastreboff AM, Kaplan LM, Frias JP, et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. The Lancet. 2024;402(10403):696-708. PubMed
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Loomba R, Abdelmalek MF, Armstrong MJ, et al. Semaglutide 2.4 mg once a week in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterology & Hepatology. 2023;8(6):511-522. PubMed
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Newsome PN, Buchholtz K, Cusi K, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. New England Journal of Medicine. 2021;384(12):1113-1124. PubMed
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Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. New England Journal of Medicine. 2024;391(4):299-310. PubMed
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Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis (ESSENCE). New England Journal of Medicine. 2025. PubMed
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FDA Grants Survodutide Breakthrough Therapy Designation for Treatment of Adults With MASH. Pharmacy Times. October 2024. Source
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Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis: a network meta-analysis. Hepatology. 2025. Source
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Thomas B, et al. The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection. Diabetes, Obesity and Metabolism. 2024. Source