Efinopegdutide
Medium EvidenceEfinopegdutide (MK-6024, formerly HM12525A and JNJ-64565111) is an investigational once-weekly subcutaneous dual agonist of the GLP-1 and glucagon receptors being developed by Merck for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) and steatotic liver disease. It is a synthetic oxyntomodulin-based peptide - a modified GLP-1/glucagon dual-agonist sequence conjugated to a human IgG4 Fc fragment through a 10 kDa polyethylene glycol linker using Hanmi Pharmaceutical's LAPSCovery half-life-extension platform, which stretches dosing to once weekly. The design pairs the GLP-1 arm (appetite suppression, glycemic control, weight loss) with a glucagon arm that raises energy expenditure and acts directly on the liver to burn hepatic fat - the feature that sets it apart from pure GLP-1 drugs. In the head-to-head Phase 2a trial in NAFLD (Journal of Hepatology, 2023), efinopegdutide 10 mg cut liver fat content by 72.7% at 24 weeks versus 42.3% for semaglutide 1 mg, with two-thirds of efinopegdutide recipients falling below the 5% liver-fat threshold that defines a normal liver. Merck holds FDA Fast Track designation for the MASH program and is running Phase 2b studies plus a dedicated trial in compensated cirrhosis due to steatohepatitis; the earlier type 2 diabetes and obesity indications were discontinued in favor of the liver focus.
What It Is
Efinopegdutide is the drug that reframed a familiar molecule around a single organ. Its parent hormone, oxyntomodulin, is a gut peptide secreted after meals that naturally activates both the GLP-1 receptor and the glucagon receptor - a built-in dual agonist that the body already uses to coordinate satiety and metabolism. Efinopegdutide is an engineered oxyntomodulin analog: a modified GLP-1/glucagon dual-agonist peptide site-specifically conjugated to the constant region of a human immunoglobulin G4 fragment via a 10 kDa PEG linker, using Hanmi Pharmaceutical's LAPSCovery technology to extend a peptide that would otherwise last minutes into a once-weekly injection. The molecule has an unusually well-traveled history. Hanmi, a South Korean company, discovered it as HM12525A and licensed it to Janssen (Johnson & Johnson) in 2015 for $105 million upfront, where it became JNJ-64565111 and was tested in obesity and type 2 diabetes. J&J returned the rights after those programs underwhelmed, and in 2020 Merck picked the compound back up - renaming it MK-6024 - and pointed it squarely at fatty liver disease rather than weight loss alone. That strategic pivot is the whole story of efinopegdutide. The reason a GLP-1/glucagon dual makes sense specifically for the liver is the glucagon receptor. GLP-1 receptor agonists like semaglutide reduce liver fat mostly indirectly, by driving weight loss and improving insulin sensitivity. Glucagon does something more direct: acting on hepatocytes, it increases fatty-acid oxidation and mitochondrial energy expenditure and suppresses de novo lipogenesis, so a well-balanced glucagon signal can strip triglyceride out of the liver faster than weight loss alone would predict. The tradeoff glucagon agonism has always carried is that unopposed glucagon raises blood sugar; pairing it with a GLP-1 arm that lowers glucose is what makes the combination usable. The pivotal evidence is a Phase 2a active-comparator trial (published in the Journal of Hepatology in 2023) that did something most early studies avoid - it went head to head against the best available GLP-1 drug rather than placebo. One hundred forty-five adults with NAFLD and MRI-confirmed liver fat were randomized to efinopegdutide 10 mg or semaglutide 1 mg, both once weekly subcutaneously, for 24 weeks. The least-squares mean relative reduction in liver fat content was 72.7% with efinopegdutide versus 42.3% with semaglutide, a statistically significant and clinically large gap, and roughly two-thirds of efinopegdutide-treated patients dropped below the 5% liver-fat content that marks a normal liver, compared with far fewer on semaglutide. Body-weight loss was similar in the two arms (about 8.5% versus 7.1%), which is the point: the extra liver-fat clearance came from the glucagon-driven hepatic mechanism, not simply from losing more weight. The cost was tolerability - efinopegdutide produced somewhat more gastrointestinal adverse events, chiefly nausea and vomiting, consistent with the class and with a dual-agonist dose that had not yet been fully optimized. Because it is a GLP-1/glucagon dual, efinopegdutide sits in the same competitive lane as pemvidutide, survodutide, cotadutide and mazdutide, and it competes on the MASH battlefield with the FGF21 analogs (efruxifermin, pegozafermin, efimosfermin) and the triple agonist efocipegtrutide. Its differentiator is the benchmark it set: a direct, published win over semaglutide on the imaging endpoint that MASH programs live and die by. As of 2026 the program is investigational and biopsy-endpoint Phase 2b/Phase 3-enabling work is the gating question - imaging liver-fat reduction is a promising surrogate, but regulators want histological resolution of steatohepatitis and improvement in fibrosis, and Merck is also running a dedicated study in compensated (F4) cirrhosis due to steatohepatitis. Efinopegdutide is not approved, is not available as a supplement or research chemical, and its long-term liver-outcome data are still being generated.
Regulatory Status
Efinopegdutide (MK-6024) is an investigational once-weekly subcutaneous peptide and is not approved by the FDA, EMA or any regulator for any indication. It is not a dietary supplement, a compounded product, or a research chemical available for self-administration, and any product marketed as 'efinopegdutide' outside a registered Merck-sponsored clinical trial should be treated as unverified and potentially counterfeit. Merck holds U.S. FDA Fast Track designation for the compound in nonalcoholic steatohepatitis (NASH/MASH), which supports more frequent regulatory interaction but does not imply approval or evidence of efficacy. The molecule originated at Hanmi Pharmaceutical (HM12525A), was licensed to Janssen (J&J) in 2015 as JNJ-64565111 and studied in type 2 diabetes and obesity before those indications were discontinued and rights returned; Merck re-licensed it in 2020 and redirected development to MASH and steatotic liver disease, including compensated cirrhosis. Identifiers: CAS 2055640-93-0, DrugBank DB15077, UNII DR6P1M58PO, ChEMBL4297576, KEGG D11607.
Why Researchers Study It
Efinopegdutide matters because it produced one of the cleanest existing demonstrations that adding a glucagon-receptor arm to a GLP-1 backbone does something to the liver that weight loss alone does not. Most early metabolic drugs are tested against placebo, which tells you a compound works but not whether it beats the standard of care. Efinopegdutide's Phase 2a instead went head to head against semaglutide - the best-selling GLP-1 drug in the world - and cut liver fat by 72.7% versus 42.3% at matched weight loss, which isolates the glucagon-driven hepatic mechanism as the source of the difference rather than a confound of greater appetite suppression. That makes it a reference experiment for the whole GLP-1/glucagon co-agonist class and a natural comparator for pemvidutide, survodutide, cotadutide and mazdutide. Second, it is a case study in oxyntomodulin-analog engineering: a naturally occurring dual-agonist gut hormone rebuilt with a protease-resistant sequence and a PEG-Fc half-life extension to convert a minutes-long signal into a weekly drug, illustrating how much of modern peptide therapeutics is half-life chemistry rather than new receptor biology. Third, its unusually mobile development history - Hanmi to Janssen to Merck, and from obesity/diabetes to liver disease - is itself instructive about how the field has come to see the glucagon arm less as a weight-loss accelerant and more as a targeted hepatic-metabolism tool. Finally, the open scientific question it embodies is whether an imaging biomarker (MRI-measured liver fat) reliably predicts the histological outcomes - resolution of steatohepatitis and improvement in fibrosis - that regulators require, which is exactly the surrogate-versus-outcome debate now central to the entire MASH field.
Proposed Mechanisms
- Engineered oxyntomodulin-based peptide that acts as a balanced dual agonist at both the GLP-1 receptor and the glucagon receptor, mimicking the endogenous gut hormone oxyntomodulin
- Conjugated to a human IgG4 Fc fragment via a ~10 kDa polyethylene glycol linker (Hanmi's LAPSCovery platform), extending an intrinsically short-lived peptide into a once-weekly subcutaneous drug through FcRn recycling and reduced renal clearance
- GLP-1 receptor arm suppresses appetite, slows gastric emptying, enhances glucose-dependent insulin secretion and drives weight loss - the same axis as semaglutide and tirzepatide's GLP-1 component
- Glucagon receptor arm acts directly on hepatocytes to increase fatty-acid oxidation, raise mitochondrial energy expenditure and suppress de novo lipogenesis, clearing intrahepatic triglyceride faster than weight loss alone would predict
- The GLP-1 arm offsets glucagon's tendency to raise blood glucose, allowing the hepatic-fat-burning glucagon effect to be used without worsening glycemic control - the core rationale of GLP-1/glucagon co-agonism for liver disease
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| Phase 2a (NCT03235050) - randomized, active-comparator-controlled, double-blind | 145 adults with NAFLD and MRI-PDFF-confirmed hepatic steatosis; efinopegdutide 10 mg versus semaglutide 1 mg, both subcutaneously once weekly for 24 weeks | Least-squares mean relative reduction in liver fat content at week 24 was 72.7% with efinopegdutide versus 42.3% with semaglutide (statistically significant); roughly two-thirds of efinopegdutide recipients fell below the 5% liver-fat threshold defining a normal liver. Body-weight loss was similar (~8.5% vs ~7.1%). More gastrointestinal adverse events (nausea, vomiting) with efinopegdutide. Published in the Journal of Hepatology, 2023 | Source |
| Phase 2b - randomized, placebo-controlled (MASH) | Adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis; once-weekly subcutaneous efinopegdutide at optimized doses over ~52 weeks | Evaluating histological endpoints (resolution of steatohepatitis without worsening of fibrosis, and fibrosis improvement without worsening of MASH) - the outcomes regulators require beyond imaging liver-fat reduction. Program supported by FDA Fast Track designation; results pending | Source |
| Phase 2 (MK-6024-017, NCT06465186) - compensated cirrhosis due to steatohepatitis | Adults with compensated (F4) cirrhosis attributable to steatohepatitis; once-weekly subcutaneous efinopegdutide versus placebo | Dedicated study extending the program into advanced fibrosis/compensated cirrhosis, the highest-risk MASH population; primary completion estimated 2026. Illustrates Merck's strategy of testing across the full steatotic-liver-disease severity spectrum | Source |
Commonly Discussed Benefits
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Safety & Cautions
- Efinopegdutide is an investigational drug that has never been approved and is available only within Merck-sponsored clinical trials - any 'efinopegdutide' or 'MK-6024' sold by a research-chemical vendor or compounding source is unverified, is not the studied product, and should not be used
- As a GLP-1/glucagon dual agonist it carries the gastrointestinal side-effect profile of the incretin class - nausea, vomiting and diarrhea were more frequent than with semaglutide in the Phase 2a trial and are dose-related
- The glucagon-receptor arm can raise blood glucose if not balanced by the GLP-1 arm; glycemic effects, heart rate, and hepatic parameters require monitoring in a trial setting, and the drug has not been characterized outside supervised studies
- The strongest human data so far are an imaging surrogate (MRI-measured liver fat) at 24 weeks, not the biopsy-confirmed resolution of steatohepatitis or fibrosis improvement that defines clinical benefit in MASH - efficacy on those endpoints is still unproven
- The type 2 diabetes and obesity indications were discontinued by a prior developer; efinopegdutide is not a weight-loss drug on the market and should not be conflated with approved GLP-1 or GLP-1/GIP therapies
Comparisons
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Citations
- [1] A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease - Journal of Hepatology, 2023 (72.7% vs 42.3% liver-fat reduction vs semaglutide) PubMed
- [2] Merck to Present Data for Efinopegdutide (MK-6024), an Investigational GLP-1/Glucagon Receptor Co-agonist, in Patients with NAFLD at EASL 2023 - Merck.com PubMed
- [3] A Clinical Study of Efinopegdutide in People With Compensated Cirrhosis Due to Steatohepatitis (MK-6024-017) - ClinicalTrials.gov NCT06465186 PubMed
- [4] Efinopegdutide - Wikipedia (identifiers, mechanism, development history) PubMed
- [5] Merck bags J&J castoff from Hanmi to expand NASH pipeline - Fierce Biotech (licensing history) PubMed
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Survodutide
Medium EvidenceA dual GLP-1/glucagon receptor agonist with FDA Breakthrough Therapy designation for MASH and Priority Review NDA filed February 2026. Phase 3 SYNCHRONIZE-1 reported 16.6% weight loss at 76 weeks; approval possible Q3 2026.
Pemvidutide
Medium EvidenceA GLP-1/glucagon dual receptor agonist with FDA Breakthrough Therapy Designation for MASH, showing strong weight loss and liver benefits in Phase 2 trials.
Cotadutide
Medium EvidenceA once-daily GLP-1/glucagon dual receptor agonist studied for MASH, obesity, and type 2 diabetes with demonstrated liver fat reduction and antifibrotic activity.
Efocipegtrutide
Medium EvidenceEfocipegtrutide (Hanmi code HM15211) is an investigational, long-acting, once-weekly GLP-1/GIP/glucagon 'triple' receptor agonist being developed primarily for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) rather than obesity alone. It is built on Hanmi's LAPSCovery platform as a chemical conjugate of a chimeric tri-agonist peptide (TA15211) fused to a human IgG4 Fc fragment, which extends its half-life via FcRn-mediated recycling and enables weekly subcutaneous dosing. By adding glucagon-receptor activation to the GLP-1/GIP dual mechanism, efocipegtrutide is designed to combine appetite suppression and glycemic control with increased energy expenditure and direct hepatic anti-steatotic, anti-inflammatory, and anti-fibrotic effects. In a Phase 1b/2a study in obese subjects with non-alcoholic fatty liver disease, 12 weeks of treatment reduced liver fat by roughly 20% to 59% (dose-dependent, MRI-PDFF) versus about 6% on placebo. It has FDA Fast Track designation for MASH and orphan-drug designations from the FDA and EMA for primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and idiopathic pulmonary fibrosis (IPF). The 52-week adaptive Phase 2 HM-TRIA-201 study (NCT04505436) in biopsy-confirmed MASH with fibrosis is the pivotal read the field is watching.
Efruxifermin
Low EvidenceEfruxifermin (development codes EFX, AKR-001; originally AMG 876) is an investigational, once-weekly, subcutaneously injected analog of the metabolic hormone fibroblast growth factor 21 (FGF21) being developed by Akero Therapeutics for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), including both pre-cirrhotic fibrosis and compensated (F4) cirrhosis. It is a bivalent Fc-FGF21 fusion protein - two engineered FGF21 sequences fused to a human immunoglobulin (IgG1) Fc domain - a design distinct from the glycoPEGylation used by its main FGF21-class rival, pegozafermin. The Fc fusion extends the very short half-life of native FGF21 to support once-weekly dosing while preserving agonism at FGF receptors (FGFR1c/2c/3c) together with the co-receptor beta-Klotho. In the 96-week Phase 2b HARMONY trial in biopsy-confirmed F2-F3 MASH, at least a one-stage improvement in fibrosis without worsening of MASH was reached by about 75% of patients on 50 mg and 46% on 28 mg versus 24% on placebo (published in The Lancet, August 2025). In the Phase 2b SYMMETRY trial in compensated MASH cirrhosis, about 39% of 50 mg patients with paired week-96 biopsies achieved reversal of cirrhosis without worsening of MASH versus 15% on placebo (published in the New England Journal of Medicine). Efruxifermin holds FDA Breakthrough Therapy designation and has advanced into the Phase 3 SYNCHRONY program (SYNCHRONY Histology in F2-F3 MASH, SYNCHRONY Outcomes in F4 compensated cirrhosis, and SYNCHRONY Real-World in non-invasively diagnosed MASH/MASLD, whose double-blind portion completed enrollment with safety results expected in 2026).