Efinopegdutide
MK-6024, HM12525A, JNJ-64565111, LAPS-GLP/GCG
Efinopegdutide is an investigational once-weekly dual agonist at the GLP-1 and glucagon receptors, developed principally for metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Its distinguishing result is a randomised head-to-head trial against semaglutide in which it reduced liver fat substantially more. It is not approved anywhere and has not entered phase 3.
Mechanism
Efinopegdutide is a co-agonist at the GLP-1 and glucagon receptors, built as a peptide-Fc conjugate rather than a fatty-acylated peptide. The active peptide is linked through a non-peptidyl polyethylene glycol spacer to an immunoglobulin G4 Fc fragment. Binding of that Fc fragment to the neonatal Fc receptor diverts the molecule from lysosomal degradation and returns it to circulation, and the total mass keeps it above the renal filtration threshold. The pharmacokinetic behaviour therefore resembles a monoclonal antibody more than a peptide, supporting weekly dosing.
Pharmacologically, the GLP-1 arm supplies appetite suppression, glucose-dependent insulin secretion and delayed gastric emptying, while the glucagon arm acts directly on the hepatocyte to increase fatty acid oxidation, suppress de novo lipogenesis and raise energy expenditure. The therapeutic hypothesis being tested is specifically hepatic: that glucagon receptor agonism reduces liver triglyceride content by a mechanism independent of, and additive to, the weight loss produced by GLP-1 receptor agonism. The phase 2a comparison against semaglutide was designed to test exactly this, and its results are consistent with the hypothesis, since the liver fat difference was large and statistically robust while the difference in weight loss was not statistically significant.
What the research shows
The defining published study is a 24-week randomised, active-comparator phase 2a trial in 145 adults with steatotic liver disease and at least 10% liver fat by magnetic resonance imaging proton density fat fraction; 33.1% had type 2 diabetes. Participants received efinopegdutide 10 mg weekly (n=72) or semaglutide 1 mg weekly (n=73), each titrated over eight weeks. Least-squares mean relative liver fat content fell 72.7% (90% CI 66.8-78.7) with efinopegdutide against 42.3% (90% CI 36.5-48.1) with semaglutide, p<0.001. Body weight fell 8.5% versus 7.1%, a difference that did not reach statistical significance (p=0.085). That dissociation is the key observation: the hepatic advantage was large and significant while the weight advantage was not, which supports a direct hepatic effect of glucagon receptor agonism rather than a weight-mediated one.
The important limitations are that the trial was small, ran for only 24 weeks, used an imaging surrogate rather than liver histology, and compared against semaglutide 1 mg rather than the higher doses now in wide use. Liver fat reduction is a surrogate that has not been shown to guarantee histological resolution of steatohepatitis or improvement in fibrosis. A phase 2b trial in 381 adults with biopsy-confirmed precirrhotic steatohepatitis, which included both semaglutide and placebo comparator arms, has completed, and a phase 2a study in 80 adults with compensated cirrhosis is active but not recruiting; neither had published results at the time of writing. Earlier development under the JNJ-64565111 designation produced two randomised dose-ranging phase 2 trials in obesity with and without type 2 diabetes, in which dose-dependent weight loss of 6.8% to 10.0% at 26 weeks was accompanied by significantly more nausea and vomiting than either placebo or liraglutide. Until the biopsy trial reports, the case for efinopegdutide in liver disease rests on a single surrogate-endpoint trial.
Evidence assessment
Mixed evidence
Human randomised evidence exists and includes one well-designed active-comparator phase 2a trial with a magnetic resonance imaging endpoint, but the total randomised experience is small, published follow-up has not exceeded 26 weeks, no histological endpoint has been reported in the peer-reviewed literature, and no phase 3 programme has been announced. Two further phase 2 trials have completed or closed enrolment without published results. That combination fits mixed rather than strong or limited.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease Preclinical only
Least-squares mean relative liver fat content fell 72.7% (90% CI 66.8-78.7) with efinopegdutide versus 42.3% (90% CI 36.5-48.1) with semaglutide, p<0.001. Body weight fell 8.5% versus 7.1%, which was NOT statistically significant (p=0.085). Gastrointestinal adverse events were more frequent with efinopegdutide.
A Clinical Study of Efinopegdutide in Participants With Precirrhotic Nonalcoholic Steatohepatitis (NASH) (MK-6024-013) Preclinical only
Registry status is completed; no results published as of August 2026. This is the trial that will determine whether the compound advances to phase 3.
A Clinical Study of Efinopegdutide in People With Compensated Cirrhosis Due to Steatohepatitis (MK-6024-017) Preclinical only
Registry status is active, not recruiting; no results published as of August 2026.
Efficacy and safety of glucagon-like peptide-1/glucagon receptor co-agonist JNJ-64565111 in individuals with obesity without type 2 diabetes mellitus: A randomized dose-ranging study Preclinical only
Dose-dependent weight reductions of 6.8%, 8.1% and 10.0% versus placebo at week 26, with significantly higher rates of nausea and vomiting than either placebo or liraglutide.
Safety
The published safety experience is limited to phase 2 exposure over 24 to 26 weeks. Gastrointestinal adverse effects, principally nausea, vomiting and diarrhoea, were the commonest events and occurred somewhat more often than with semaglutide in the head-to-head trial, consistent with the added glucagon receptor component and the dose-escalation schedule. In the earlier obesity dose-ranging work under the JNJ-64565111 designation, nausea and vomiting were significantly more frequent than with both placebo and liraglutide, and only 72.4% of participants completed treatment. Increases in heart rate have been reported for glucagon-containing multi-agonists generally. Glucagon receptor agonism raises theoretical concerns about hepatic glucose output and about amino acid handling, and a dedicated hepatic impairment study has been conducted precisely because the target population has liver disease. There are no data on cardiovascular outcomes, malignancy, long-term hepatic safety, or use in pregnancy. Nothing is known about immunogenicity over prolonged exposure to an Fc-conjugated construct. Material sold outside clinical trials has no assurance of identity, purity or sterility.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Investigational. Efinopegdutide has no MHRA marketing authorisation and is not available on prescription or through the NHS. Supplying or selling it as a medicine outside a clinical trial would breach the Human Medicines Regulations 2012. |
| United States | Investigational. Efinopegdutide has no FDA approval for any indication and has not entered phase 3. A phase 2b study in precirrhotic steatohepatitis has completed and a phase 2a study in compensated cirrhosis due to steatohepatitis is active but not recruiting, with results not published as of mid-2026. Lawful supply in the United States is confined to authorised clinical trials; anything sold online under this name is unapproved and unregulated. |
| WADA (sport) | Not prohibited. Efinopegdutide is not listed on the WADA Prohibited List. WADA's separate Monitoring Programme is revised annually and carries no sanctions; the list in force for the relevant year should be checked. |
Questions
It is a peptide conjugate rather than a simple peptide. A dual-agonist peptide is joined through a polyethylene glycol linker to an antibody Fc fragment, giving it antibody-like pharmacokinetics. It is manufactured biologically, not by chemical peptide synthesis.
On liver fat, yes, in one 24-week randomised trial: a 72.7% relative reduction versus 42.3%. That was against semaglutide 1 mg, and the endpoint was imaging, not liver biopsy. On body weight the difference was not statistically significant. It has not been compared on histology, on clinical liver outcomes, or against higher semaglutide doses.
The glucagon receptor arm acts directly on hepatocytes to increase fatty acid oxidation and suppress lipogenesis, independent of weight loss. The supporting evidence is that the liver fat advantage over semaglutide was large and significant while the difference in body weight reduction was not.
Not soon, if at all. No phase 3 programme has been announced. The next decision point is the biopsy readout from the completed phase 2b steatohepatitis trial, which will determine whether the developer commits to phase 3. Many compounds do not progress past this stage.