Pemvidutide: Dual Agonist for NASH Profile
The liver disease formerly known as NASH -- now called MASH (metabolic dysfunction-associated steatohepatitis) -- affects roughly 350 million people worldwide. Most treatments target the liver directly.
The liver disease formerly known as NASH -- now called MASH (metabolic dysfunction-associated steatohepatitis) -- affects roughly 350 million people worldwide. Most treatments target the liver directly. Pemvidutide takes a different route: it combines GLP-1 receptor activation with glucagon receptor agonism to attack liver fat from the metabolic side. Developed by Altimmune under the code name ALT-801, pemvidutide earned FDA Breakthrough Therapy Designation for MASH in January 2026 and is headed toward Phase 3 trials later this year.
What makes pemvidutide unusual among dual agonists is its balanced 1:1 potency at both receptors -- and a molecular design that may eliminate the dose-titration period required by most GLP-1-based drugs. In clinical trials, it has produced some of the highest MASH resolution rates seen to date, with an unusually clean tolerability profile.
Table of Contents
- Quick Facts
- What Is Pemvidutide?
- Development History
- How Pemvidutide Works: Mechanisms of Action
- Clinical Research
- Administration and Dosing
- Safety Profile and Side Effects
- Legal and Regulatory Status
- Frequently Asked Questions
- The Bottom Line
Quick Facts
| Property | Detail |
|---|---|
| Generic Name | Pemvidutide |
| Former Code Name | ALT-801 |
| Developer | Altimmune, Inc. (Gaithersburg, Maryland) |
| Drug Class | GLP-1/glucagon dual receptor agonist |
| Receptor Activity | Balanced 1:1 GLP-1R/GCGR agonism |
| Structure | 29 amino acid peptide with 18-carbon diacid alkyl chain (EuPort domain) |
| Route | Subcutaneous injection, once weekly |
| Primary Indications | MASH (formerly NASH), obesity, alcohol use disorder (AUD), alcohol-associated liver disease (ALD) |
| Clinical Stage | Phase 2b completed (MASH); Phase 3 planned for 2026 |
| Key Trial | IMPACT (NCT05989711) -- Phase 2b in MASH |
| FDA Designations | Breakthrough Therapy (MASH), Fast Track (MASH and AUD) |
What Is Pemvidutide?
The pemvidutide peptide is an investigational compound that activates two receptors simultaneously: the glucagon-like peptide-1 (GLP-1) receptor and the glucagon receptor. This dual action gives it a two-pronged metabolic approach -- appetite suppression and weight loss through GLP-1, paired with direct liver fat reduction through glucagon signaling.
Most people know GLP-1 drugs from the weight-loss headlines around semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound). Those drugs focus on GLP-1 alone or GLP-1 combined with GIP. Pemvidutide belongs to a different branch of the incretin family tree: the GLP-1/glucagon dual agonists, which also includes survodutide from Boehringer Ingelheim.
The "1:1 balanced" part matters. While survodutide leans toward GLP-1 activity, pemvidutide activates both receptors with equal potency. In preclinical studies, balanced agonism produced greater body weight loss and better metabolic regulation compared to biased dual agonists (Journal of Hepatology, 2024).
Structurally, pemvidutide is a 29 amino acid peptide. An 18-carbon diacid alkyl chain attaches to the backbone through what Altimmune calls the EuPort domain -- a glycosidic linkage that binds albumin in the blood, extending the half-life long enough for once-weekly dosing. This side chain also slows entry into the bloodstream, reducing peak drug concentrations. That may explain why pemvidutide does not require the gradual dose escalation that most GLP-1 therapies need to manage gastrointestinal side effects (Altimmune).
Development History
2020-2021: Altimmune, originally focused on intranasal vaccines, shifted toward metabolic disease. Pemvidutide (then ALT-801) entered preclinical testing, showing reductions in liver fat, inflammation, and fibrosis in animal models.
2022: A Phase 1 trial in overweight/obese volunteers showed that at 1.8 mg, 100% of subjects lost at least 5% body weight and 55% lost 10% or more -- without diet or exercise modifications.
2022-2023: A Phase 1b study (NCT05006885) in MASLD patients showed roughly 55% of subjects at 1.8 mg reached normal liver fat levels within 12 weeks, with up to 68.5% relative liver fat reduction.
November 2023: The MOMENTUM Phase 2 trial reported 15.6% mean weight loss at 2.4 mg over 48 weeks, with 78.1% of weight loss from fat.
November 2025: The IMPACT Phase 2b trial results were published in The Lancet and presented at AASLD's The Liver Meeting.
December 2025: 48-week IMPACT data confirmed sustained improvements in fibrosis markers and liver fat.
January 2026: FDA granted Breakthrough Therapy Designation for pemvidutide in MASH.
2026 (planned): Phase 3 registrational trial in MASH; VELOCITY Phase 3 obesity program (HCPLive).
How Pemvidutide Works: Mechanisms of Action
GLP-1 Receptor Pathway
The GLP-1 receptor is the same target activated by semaglutide, liraglutide, exenatide, and dulaglutide. Pemvidutide's GLP-1R activation triggers appetite suppression through the hypothalamus and brainstem, delays gastric emptying, improves insulin sensitivity, and reduces caloric intake. These effects are well established across the GLP-1 class.
Glucagon Receptor Pathway
This is where pemvidutide diverges from pure GLP-1 agonists and GLP-1/GIP drugs like tirzepatide. Glucagon has direct, potent effects on the liver:
- Hepatic fatty acid oxidation. Glucagon tells liver cells to burn stored fat for energy, directly reducing the fat accumulation that defines MASH.
- Inhibition of lipogenesis. It slows the liver's production of new fat from carbohydrates.
- Increased energy expenditure. Glucagon receptor activation ramps up thermogenesis, contributing to weight loss beyond appetite reduction alone.
- Anti-inflammatory and anti-fibrotic effects. Preclinical data suggest glucagon signaling reduces liver inflammation and may slow or reverse fibrosis (Altimmune, AASLD 2023).
Why Dual Agonism Matters for MASH
GLP-1 alone treats liver fat indirectly through weight loss. Glucagon receptor activation reduces liver fat through direct hepatic mechanisms. The combination may explain why pemvidutide achieves dramatic liver fat reductions (up to 68.5% in early trials) with relatively modest weight loss compared to pure GLP-1 or GLP-1/GIP drugs (Journal of Hepatology, 2024).
Unlike retatrutide (a triple GLP-1/GIP/glucagon agonist) and CagriSema (semaglutide plus an amylin analog), pemvidutide is specifically optimized for the GLP-1/glucagon axis without GIP activation -- a focused design that may make it particularly suited to liver disease.
Clinical Research
IMPACT Phase 2b Trial (MASH)
The IMPACT trial (NCT05989711) enrolled 212 patients with biopsy-confirmed MASH and fibrosis stages F2-F3 across 83 sites in the U.S. and Australia. Patients received once-weekly pemvidutide at 1.2 mg, 1.8 mg, or placebo (The Lancet, 2025).
24-week results:
| Endpoint | 1.2 mg | 1.8 mg | Placebo |
|---|---|---|---|
| MASH resolution (no worsening fibrosis) | 59.1% (p<0.0001) | 52.1% (p<0.0001) | 19.1% |
| Fibrosis improvement (no worsening MASH) | 31.8% (NS) | 34.5% (NS) | 25.9% |
| Liver fat normalization (below 5%) | 31% | 44% | 4% |
| Weight loss | -4.8% | -5.8% | -0.5% |
The MASH resolution rates were among the strongest in any MASH trial. The fibrosis endpoint did not reach statistical significance at 24 weeks, but AI-based analysis showed 30.6% of patients on 1.8 mg achieved 60% or greater fibrosis reduction vs. 8.2% placebo (p<0.001) (Altimmune, AASLD 2025).
48-week results showed continued improvement in fibrosis markers. The proportion achieving both a 0.5+ ELF reduction and 30% liver stiffness reduction: 27.8% (1.2 mg) and 32.4% (1.8 mg) vs. 3.2% placebo (both p<0.001). Liver fat reduction reached 45.2% (1.2 mg) and 54.7% (1.8 mg) vs. 8.2% placebo (Altimmune, Dec 2025).
MOMENTUM Phase 2 Trial (Obesity)
The MOMENTUM trial enrolled 391 subjects with obesity or overweight with comorbidities. Over 48 weeks, mean weight loss reached 10.3% (1.2 mg), 11.2% (1.8 mg), and 15.6% (2.4 mg) vs. 2.2% placebo. At the 2.4 mg dose, weight loss was still linear at trial's end, and 48% of subjects had their BMI drop below the obesity threshold (ADA, 2024).
MRI body composition analysis showed 78.1% of weight loss was fat mass, with only 21.9% from lean mass. Most incretin drugs lose 25-40% of weight as lean tissue, making pemvidutide's lean mass preservation a standout feature.
Lipid improvements were substantial: up to 55.8% triglyceride reduction, 20.0% total cholesterol reduction, and 21.8% LDL reduction in subjects with elevated baselines.
Alcohol-Related Trials
- RECLAIM (Phase 2, AUD): Evaluating pemvidutide in ~100 adults with alcohol use disorder. Enrollment completed ahead of schedule in November 2025; results expected in 2026.
- RESTORE (Phase 2, ALD): A 48-week study in ~100 patients with alcohol-associated liver disease, initiated July 2025.
Administration and Dosing
Pemvidutide is administered as a once-weekly subcutaneous injection at 1.2 mg, 1.8 mg, or 2.4 mg (the 2.4 mg dose has only been tested in obesity, not MASH).
The standout feature: no titration period. Most GLP-1-based drugs -- semaglutide, tirzepatide, survodutide -- require weeks to months of gradual dose increases to manage GI side effects. Survodutide needs a 24-week escalation period. In pemvidutide's trials, patients started at full dose from day one. Altimmune credits the EuPort domain for smoothing out drug concentration peaks, reducing the nausea-inducing spikes that make titration necessary in other drugs.
The planned Phase 3 MASH trial will evaluate multiple doses over 52 weeks. The VELOCITY obesity program will test all three doses over 60 weeks across roughly 5,000 subjects.
Pemvidutide is not approved for any indication. No commercial dosing guidelines exist.
Safety Profile and Side Effects
Gastrointestinal Effects
Like all GLP-1-based therapies, GI side effects are the most common: nausea (about 33% of treated subjects, mostly mild to moderate), vomiting, and occasional diarrhea or constipation. These are consistent across the GLP-1 class, from first-generation drugs like exenatide to oral agents like orforglipron.
What stands out is how rarely these events led to dropout. In the IMPACT MASH trial, treatment-related discontinuation was 0% (1.2 mg) and 1.2% (1.8 mg) vs. 2.4% for placebo. Dr. Mazen Noureddin, the trial's lead investigator, called this "one of the lowest rates of AE-related drug discontinuations observed in any MASH clinical trial to date" (HCPLive).
MOMENTUM obesity trial discontinuation rates were higher at upper doses (15-16% at 1.8 and 2.4 mg), concentrated in the first 16 weeks.
Serious Adverse Events
Across all trials: no treatment-related serious adverse events in the IMPACT MASH trial; one drug-related SAE (vomiting) among 391 subjects in the MOMENTUM trial; no severe or serious events in the Phase 1b MASLD study.
Cardiac and Metabolic Safety
No major adverse cardiac events in any trial. No clinically meaningful heart rate increases. Blood pressure improved at all dose levels. No changes in fasting glucose or HbA1c. LDL cholesterol went down rather than up -- addressing the theoretical concern that glucagon receptor agonism might raise lipids. The GLP-1 arm appears to offset that risk (Altimmune, MOMENTUM).
Limitations
Phase 2 trials enrolled hundreds of patients, not thousands. Rare adverse events would not appear at these sample sizes. Long-term safety beyond 48 weeks is unknown. The Phase 3 program will provide a clearer picture.
Legal and Regulatory Status
Pemvidutide holds three FDA designations: Breakthrough Therapy Designation for MASH (January 2026), Fast Track for MASH, and Fast Track for AUD. The Breakthrough designation -- based on IMPACT 24-week data -- brings accelerated review pathways, rolling submission options, and intensive FDA guidance (Altimmune).
As of early 2026, only one drug is FDA-approved for MASH: resmetirom (Rezdiffra), a thyroid hormone receptor-beta agonist approved in March 2024. Resmetirom works through a different mechanism (oral, THR-beta activation) and produced MASH resolution rates of 26-30% in trials. Pemvidutide's 52-59% rates compare favorably in cross-trial analysis, though head-to-head studies have not been done.
Pemvidutide's closest competitor among dual agonists is survodutide, which targets the same two receptors with GLP-1-biased activity. Key differences:
| Feature | Pemvidutide | Survodutide |
|---|---|---|
| Receptor balance | 1:1 GLP-1/glucagon | GLP-1-biased |
| Dose titration | Not required | 24-week escalation |
| MASH resolution (Phase 2) | 52-59% | 43-62% |
| GI tolerability | 0-1.2% discontinuation | 66% nausea rate |
| Phase 3 status | Planned 2026 | Ongoing |
Altimmune plans to start a registrational Phase 3 MASH trial in 2026, using biopsy-based endpoints over 52 weeks and incorporating AIM-MASH AI Assist, the first FDA-qualified AI pathology tool for MASH trials. The company is also seeking European regulatory advice and has designed the VELOCITY Phase 3 obesity program (~5,000 subjects across four trials).
Pemvidutide is not approved for any indication anywhere. It cannot be legally prescribed, sold, or marketed.
Frequently Asked Questions
How is pemvidutide different from semaglutide or tirzepatide?
Semaglutide is a pure GLP-1 agonist. Tirzepatide combines GLP-1 with GIP. Pemvidutide combines GLP-1 with glucagon. The practical difference: semaglutide and tirzepatide reduce liver fat mainly through systemic weight loss, while pemvidutide's glucagon component acts directly on the liver. Pemvidutide produces less total weight loss than tirzepatide, but its MASH-specific results are strong.
What is MASH, and how is it different from NASH?
Same disease, new name. In June 2023, the hepatology community renamed NASH to MASH to better reflect its metabolic origins and remove the "alcoholic" terminology. Older publications and trial names still use NASH.
Does pemvidutide require dose titration?
No. In all clinical trials to date, patients started at full dose from day one. Altimmune credits the EuPort domain's ability to smooth out drug concentration peaks. This could be a practical advantage over drugs like survodutide (24-week titration) or tirzepatide (multi-month escalation).
What were the main IMPACT trial results?
At 24 weeks: 52-59% of patients achieved MASH resolution (vs. 19% placebo), with liver fat normalizing in up to 44% of treated patients. At 48 weeks: fibrosis markers continued to improve, with 32.4% of patients on 1.8 mg achieving meaningful dual reductions in ELF and liver stiffness vs. 3.2% placebo. Results were published in The Lancet.
How does pemvidutide compare to resmetirom?
Resmetirom (Rezdiffra) is oral and works through thyroid hormone receptor activation. Pemvidutide is injectable and works through GLP-1/glucagon. Pemvidutide's MASH resolution rates appear higher in cross-trial comparisons, but they target different disease mechanisms and could be complementary. No combination studies exist yet.
When might pemvidutide be approved?
Phase 3 MASH trials begin in 2026, running 52 weeks. With Breakthrough Therapy Designation and potential rolling review, the earliest realistic commercial launch would be 2028-2029. The obesity program follows a separate path.
Is pemvidutide available for purchase?
No. It is an investigational drug available only through clinical trials. It is not approved, prescribed, or sold anywhere in the world.
The Bottom Line
Pemvidutide represents the GLP-1/glucagon branch of the incretin revolution -- the branch specifically designed for the liver. While semaglutide and tirzepatide generate headlines for weight loss, and orforglipron makes news as the first oral GLP-1, pemvidutide is building one of the stronger cases in the MASH pipeline.
The data so far: 52-59% MASH resolution without worsening fibrosis. Up to 68.5% liver fat reduction. Less than 2% treatment-related discontinuation in the MASH trial. No titration required. Strong lean mass preservation. Breakthrough Therapy Designation from the FDA.
But this remains Phase 2 data from 212 MASH patients. The fibrosis endpoint wasn't met at 24 weeks. No head-to-head trials have been run against resmetirom, survodutide, or semaglutide. MASH drug development has seen plenty of promising Phase 2 candidates fail at the Phase 3 stage.
Phase 3 will answer the open questions. For the 350 million people worldwide living with MASH -- most with no treatment options beyond resmetirom and lifestyle changes -- those answers matter.
This article is for educational and informational purposes only. It is not medical advice. Pemvidutide is an investigational drug not approved for any indication. Consult a qualified healthcare provider before making any treatment decisions. PeptideJournal.org has no financial relationships with Altimmune or any pharmaceutical company.
References and Sources
- Altimmune. "Pemvidutide." altimmune.com/pemvidutide/
- Noureddin M, et al. "Safety and efficacy of weekly pemvidutide versus placebo for MASH (IMPACT): 24-week results." The Lancet (2025). thelancet.com
- Altimmune. "Pemvidutide Achieved Key Measures of Success at 48 Weeks in IMPACT." Dec 2025. ir.altimmune.com
- Altimmune. "FDA Breakthrough Therapy Designation for Pemvidutide in MASH." Jan 2026. ir.altimmune.com
- Altimmune. "MOMENTUM 48-Week Phase 2 Obesity Trial Results." Nov 2023. ir.altimmune.com
- Sanyal AJ, et al. "Effect of pemvidutide on MASLD." Journal of Hepatology (2024). journal-of-hepatology.eu
- Harrison SA, et al. "24 weeks of pemvidutide in MASLD." PMC (2025). pmc.ncbi.nlm.nih.gov
- Altimmune. "MOMENTUM Phase 2 Data at ADA 84th Scientific Sessions." June 2024. ir.altimmune.com
- ClinicalTrials.gov. IMPACT: NCT05989711. MOMENTUM: NCT05295875.
- Altimmune. "RECLAIM Phase 2 Enrollment Completed." Nov 2025. ir.altimmune.com
- "Pemvidutide Progresses to Phase 3 Trial." HCPLive. hcplive.com
- Altimmune. "Phase 1 Clinical Trial of ALT-801 Results." ir.altimmune.com