Efpeglenatide

A once-weekly GLP-1 receptor agonist made of a single-residue-modified exendin-4 peptide chemically conjugated to a human IgG4 Fc fragment, developed by Hanmi, licensed to and returned by Sanofi, and approved in South Korea for obesity in October 2026 with no US program.

Also referenced as: HM11260C, LAPS-Exendin 4, SAR439977, Eppe

Also appears in: Metabolic

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What is Efpeglenatide?

Efpeglenatide is an Fc-conjugated peptide: a 39-residue analog of exendin-4 (the Gila monster venom peptide marketed as exenatide) carrying a single amino-acid modification, joined through a 3.4 kDa polyethylene glycol linker to the Fc fragment of human immunoglobulin G4. The peptide half of the molecule is what binds the GLP-1 receptor; the Fc half is there to borrow the long circulating life of an antibody, which turns a peptide that native exenatide clears in hours into one injected once a week. Hanmi Pharmaceutical built it on its LAPSCOVERY platform under the code HM11260C (earlier LAPS-Exendin 4; Sanofi’s code was SAR439977), and because the Fc fragment is chemically coupled rather than genetically fused, it is a different kind of construct from dulaglutide, even though both are described loosely as “GLP-1 Fc” drugs.

It attracts attention for two reasons that pull in opposite directions. It is one of the few GLP-1 receptor agonists with a positive cardiovascular outcomes trial (AMPLITUDE-O, run by Sanofi under a 2015 license), and it is also a drug its global partner handed back in 2020 before any filing. Hanmi then redirected it to obesity in South Korea, where the Ministry of Food and Drug Safety approved it on October 7, 2026 as the country’s first domestically developed GLP-1 weight-management drug. There is no US marketing application and no US-directed trial, and as a conjugate of a synthetic peptide with a recombinant Fc fragment rather than a bare synthetic peptide, it does not appear to have any meaningful presence in research-peptide catalogs.

How it works

• GLP-1 receptor agonism. The active portion is a single amino acid-modified exendin analog conjugated via a 3.4 kDa mini-PEG linker to a human IgG4 Fc region; the Fc conjugation extends the duration of action and is thought to contribute to the molecule’s low immunogenicity (Hompesch et al., BMJ Open Diabetes Research and Care, 2021;9(1):e002208). Phase 2 pharmacokinetic studies in type 2 diabetes measured a geometric mean half-life of 135 to 180 hours, a time to peak concentration of 72 to 144 hours after a single dose, and peak-to-trough ratios of only 1.3 to 1.4 with once-weekly injection (Yoon et al., Diabetes, Obesity and Metabolism, 2020;22(8):1292–1301). That is a flatter exposure profile than exenatide’s 2.4-hour half-life provides.
• Incretin effects. In an exploratory phase 1b study in people with type 2 diabetes, 6 mg weekly efpeglenatide was non-inferior to liraglutide 1.8 mg daily in delaying gastric emptying at peak drug concentration, as measured by acetaminophen absorption, and both efpeglenatide regimens showed comparable or more favorable glucometabolic effects and improved beta-cell function on mixed-meal and graded glucose-infusion testing (Hompesch et al., BMJ Open Diabetes Research and Care, 2021). In the 12-week EXCEED 203 dose-ranging trial, nausea and vomiting rates were consistent with the GLP-1 class and subsided after the first two weeks, and no neutralizing antibodies were detected (Rosenstock et al., Diabetes Care, 2019;42(9):1733–1741).
• Weight reduction in people without diabetes. In the 20-week BALANCE 205 phase 2 trial (NCT02075281), 297 adults with a BMI of 30 or more, or 27 or more with a comorbidity, were randomized to four efpeglenatide regimens or placebo alongside a hypocaloric diet; every regimen reduced weight significantly versus placebo, with placebo-adjusted losses between 6.3 and 7.2 kg (Pratley et al., Diabetes, Obesity and Metabolism, 2019;21(11):2429–2439).
• Cardiovascular and kidney outcomes. AMPLITUDE-O reduced major adverse cardiovascular events by 27% and a composite kidney outcome by 32% relative to placebo in high-risk type 2 diabetes (Gerstein et al., New England Journal of Medicine, 2021;385(10):896–907). A follow-on analysis found the benefit was graded by dose: 6 mg weekly cut MACE by 35% (hazard ratio 0.65) while 4 mg produced a non-significant 18% reduction (hazard ratio 0.82), with a significant trend across all primary and secondary outcomes (Gerstein et al., Circulation, 2023;147(13):1004–1013).

Research status

Phase 2 (Hanmi, 2010–2015). Hanmi ran the early program itself, across sites in North America, Europe and Korea. Two phase 2 pharmacokinetic and dose-finding trials established dose-proportional exposure and glycemic lowering with weekly 1 to 4 mg and monthly 8 to 16 mg regimens (Yoon et al., Diabetes, Obesity and Metabolism, 2020). EXCEED 203 (NCT02057172), a 12-week placebo-controlled dose-ranging study in 254 participants referenced to open-label liraglutide, found that every weekly dose of 1 mg or more lowered HbA1c significantly versus placebo, with 4 mg non-inferior to liraglutide 1.8 mg (Rosenstock et al., Diabetes Care, 2019). A once-monthly phase 2 trial (NCT02081118) in 209 metformin-treated patients lowered HbA1c by a placebo-corrected 0.71 percentage points over 16 weeks, but the authors noted that glucose effects and gastrointestinal events fluctuated between peak and trough concentrations (Del Prato et al., Diabetes, Obesity and Metabolism, 2020;22(7):1176–1186); the monthly regimen was not carried forward. BALANCE 205 reported discontinuation for adverse events in 5 to 19% of efpeglenatide-treated participants depending on regimen.

The Sanofi years and the AMPLITUDE program (2015–2020). Sanofi licensed efpeglenatide on November 5, 2015, together with a weekly insulin and a weekly GLP-1/insulin combination from Hanmi; the insulin and combination rights went back to Hanmi in December 2016, and efpeglenatide stayed with Sanofi. Five phase 3 AMPLITUDE trials started between December 2017 and August 2019, AMPLITUDE-M under Hanmi’s sponsorship and the other four under Sanofi’s. AMPLITUDE-M (NCT03353350) randomized 406 adults inadequately controlled on diet and exercise alone to efpeglenatide 2, 4, or 6 mg weekly or placebo: at week 30, HbA1c fell from 8.1% to 6.9, 6.6, and 6.4% respectively, each dose superior to placebo (placebo-adjusted −0.5, −0.8, and −1.0 points), with gastrointestinal events the most common adverse reactions (Frias et al., Diabetes Care, 2022;45(7):1592–1600). In May 2020, Sanofi notified Hanmi that it was returning the rights, citing a strategic exit from diabetes and cardiovascular research, and the return took effect later that year. AMPLITUDE-D (versus dulaglutide, NCT03684642), AMPLITUDE-L (added to basal insulin, NCT03713684), and AMPLITUDE-S (added to metformin with or without a sulfonylurea, NCT03770728) were all terminated early for funding reasons; in the truncated data, efpeglenatide was non-inferior to dulaglutide 1.5 mg on HbA1c at week 56, with weight reductions of roughly 3 kg across arms, and showed numerically greater glycemic and weight effects than placebo in the other two trials (Aroda et al., Diabetes, Obesity and Metabolism, 2023;25(8):2084–2095).

AMPLITUDE-O (NCT03496298). The outcomes trial randomized 4,076 adults with type 2 diabetes and either prior cardiovascular disease or chronic kidney disease plus another risk factor, at 344 sites in 28 countries, to efpeglenatide 4 mg, 6 mg, or placebo weekly. The sponsor’s exit ended the trial before it reached its planned event count; after a median 1.81 years of follow-up, MACE had occurred in 7.0% of efpeglenatide recipients versus 9.2% on placebo (hazard ratio 0.73; 95% CI 0.58–0.92; P<0.001 for non-inferiority, P=0.007 for superiority), and the composite kidney outcome in 13.0 versus 18.4% (hazard ratio 0.68) (Gerstein et al., New England Journal of Medicine, 2021). This was the first cardiovascular benefit demonstrated for an exendin-based GLP-1 receptor agonist, after exenatide’s own EXSCEL had been neutral and lixisenatide’s ELIXA neutral as well. Exploratory analyses found the effect independent of concomitant SGLT2 inhibitor use (Lam et al., Circulation, 2022;145(8):565–574) and of baseline kidney function (Gerstein et al., Diabetes, Obesity and Metabolism, 2024;26(4):1216–1223). No regulatory submission anywhere followed from these data.

Korean phase 3 in obesity (2024–2026). Hanmi’s NCT06174779 (HM-EXC-301) randomized 448 Korean adults aged 19 or older without diabetes (BMI 30 or more, or 27 to under 30 with a weight-related condition) to weekly efpeglenatide or placebo, with co-primary endpoints of percent weight change and the proportion losing at least 5% at week 40 and secondary follow-up to 64 weeks. The trial began January 3, 2024, reached primary completion on August 14, 2025, and completed on March 13, 2026. Hanmi’s topline disclosure in October 2025 reported a mean weight change of −9.75% at week 40 versus roughly −1% on placebo, with about 79% versus 14% losing at least 5%. Figures cited at approval were somewhat lower (a 9.02% versus 0.89% mean change and 75.1% versus 13.5% responders); the basis for the difference was not stated, and the 64-week results have not been disclosed. The most frequent adverse events in the efpeglenatide arm were diarrhea (17.6%), nausea (16.6%), dyspepsia (15.6%), constipation (14.6%), and vomiting (11.6%). As of November 2026, the primary results have not appeared in a peer-reviewed journal; the only publications from this program are a pooled population pharmacokinetic model (Choi et al., Frontiers in Pharmacology, 2025;16:1715585) and an exposure-driven model of nausea and vomiting tolerance (Seo et al., Frontiers in Pharmacology, 2026;17:1846164). Mean weight loss of about 9% at 40 weeks in a population with a mean BMI near 32 is well below the 15 to 21% reported in the semaglutide and tirzepatide obesity trials, though the populations, durations, and designs differ.

Regional approval and what remains active. Hanmi filed with the Ministry of Food and Drug Safety on December 17, 2025, and approval came on October 7, 2026 for chronic weight management, alongside diet and exercise, in adults with obesity or overweight who do not have diabetes. The one ongoing trial is HM-GLOW-301 (NCT07379333), a planned 118-participant Korean phase 3 in type 2 diabetes inadequately controlled on metformin plus dapagliflozin, whose investigational-trial approval came on January 21, 2026 and which started April 13, 2026, with HbA1c at 36 weeks as the primary endpoint and completion expected in January 2028. No US investigational trial has enrolled since the AMPLITUDE program closed in early 2021, and no application has been submitted to the FDA or the European Medicines Agency.

Common dosage forms

• Eppe auto-injector. Single-dose prefilled auto-injector pens in strengths spanning 2 mg to 10 mg, the presentation approved in South Korea.
• Clinical-trial pens. Prefilled pens at 2, 4, and 6 mg used in the AMPLITUDE phase 3 program, and presentations of 8, 12, and 16 mg from the phase 2 program; none of these was ever marketed.

Key considerations

• Regulatory status. The Research Market status reflects that efpeglenatide has no US approval and no US-directed development program. Its only marketing authorization is South Korea’s, granted October 7, 2026 for chronic weight management, and the last US-sited trial closed in 2021.
• Evidence versus indication. AMPLITUDE-O’s cardiovascular and kidney benefits were shown in type 2 diabetes at 4 and 6 mg weekly over a median 1.8 years, in a trial the sponsor stopped short of its planned event count. The Korean obesity approval rests on a 448-participant trial whose primary results remain unpublished and whose 64-week data have not been disclosed; the cardiovascular data do not transfer to people without diabetes at the 10 mg maintenance strength, which was never studied in an outcomes trial.
• Truncated program. Three of five phase 3 diabetes trials were terminated early for funding when Sanofi withdrew, and their published results are from incomplete datasets. Weight loss in the diabetes trials was modest (roughly 3 kg over 56 weeks), and the Korean obesity result of about 9% at 40 weeks sits well below the newer incretin drugs.
• Class-typical safety profile. Diarrhea, nausea, dyspepsia, constipation, and vomiting each affected 12 to 18% of participants in the Korean phase 3, and 5 to 19% of BALANCE 205 participants stopped treatment for adverse events. Phase 2 and phase 3 reports found low immunogenicity and no neutralizing antibodies, a point of difference from unconjugated exenatide; the Korean label’s warnings have not been published in English, and the GLP-1 class warnings (pancreatitis, gallbladder disease, thyroid C-cell findings in rodents) have not been confirmed for this product.
• Naming confusions. Efpeglenatide is not exenatide, though it is built from it, and the Korean brand name appears in English as Eppe. HM11260C, LAPS-Exendin 4, and Sanofi’s SAR439977 are the same molecule at different stages of development. It is distinct from dulaglutide (a GLP-1 analog genetically fused to IgG4 Fc) and from Chinese Fc-fusion GLP-1 agonists such as efsubaglutide alfa, despite the shared “Fc” shorthand.