Efpeglenatide

What is Efpeglenatide?

Efpeglenatide (HM11260C; Korean brand name 에페, written Eppe or Epe in English-language press) is a once-weekly GLP-1 receptor agonist from Hanmi Pharmaceutical of South Korea. Unlike semaglutide or liraglutide, which are modified versions of human GLP-1, efpeglenatide is built on exendin-4, the Gila-monster peptide behind exenatide. A single-amino-acid-modified exendin-4 is joined through a small 3.4-kDa polyethylene glycol linker to the Fc fragment of a human IgG4 antibody, using Hanmi's LAPSCOVERY platform. The Fc fragment makes the molecule large and slowly cleared, giving a half-life of roughly 6 to 7.5 days (135 to 180 hours). The drug has an unusual history. Sanofi licensed it in November 2015 and ran a global Phase 3 program in type 2 diabetes. Its cardiovascular outcome trial, AMPLITUDE-O (4,076 people with type 2 diabetes and cardiovascular or kidney disease), found that weekly efpeglenatide cut major adverse cardiovascular events by 27% (hazard ratio 0.73) and a kidney composite by 32% versus placebo over a median 1.8 years, published in the New England Journal of Medicine in 2021. Sanofi nonetheless told Hanmi in May 2020 that it would return the rights and confirmed the decision that September; three other Phase 3 trials were stopped early for funding reasons, not safety or efficacy. Hanmi then repositioned the drug for obesity in Korea, and on 7 October 2026 the Ministry of Food and Drug Safety (MFDS) approved it as EPPE (에페오토인젝터주) in autoinjector strengths of 2, 4, 6, 8 and 10 mg — Korea's 45th domestically developed new drug and the first GLP-1 obesity medicine developed by a Korean company. The approved indication is chronic weight management, as an adjunct to a reduced-calorie diet and increased physical activity, in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 and <30 kg/m²) with at least one weight-related comorbidity — in both cases specifically in people who do not have diabetes. Prescribing began at selected Korean institutions around 29 October 2026. The registrational data come from a Phase 3 trial in 448 Korean adults with obesity and no diabetes. In the label's full analysis set (298 on drug, 148 on placebo), the least-squares mean weight change at the week-40 primary endpoint was -9.02% versus -0.89% on placebo, a treatment difference of -8.13 percentage points (95% CI -9.43 to -6.82), and 75.05% versus 13.53% lost at least 5% of body weight. Hanmi's earlier press topline quoted -9.75% versus -0.95% and 79.4% versus 14.5%; the label figures are the registrational ones. Approval is Korea-only — there is no US or European filing.

What Efpeglenatide Is Investigated For

Efpeglenatide is unusual among unapproved GLP-1 drugs in having a completed, positive cardiovascular outcome trial, but that evidence comes from type 2 diabetes at doses of 4 to 6 mg weekly. AMPLITUDE-O showed a 27% reduction in major adverse cardiovascular events and a 32% reduction in a kidney composite, with a clear dose response (6 mg did better than 4 mg). The obesity case rests on Hanmi's Korean Phase 3 in 448 adults without diabetes, which supported the October 2026 MFDS approval: a least-squares mean weight change of -9.02% at 40 weeks versus -0.89% on placebo (difference -8.13 points, 95% CI -9.43 to -6.82), with 75.05% versus 13.53% losing at least 5%, and relatively low GI side-effect rates (nausea 16.6% vs 5.4%). That weight loss is well below what semaglutide 2.4 mg and tirzepatide produce in their pivotal trials — though the Korean trial also enrolled a lighter population, mean BMI about 32 kg/m² against roughly 38 in the imported-drug trials, which flatters neither comparison. The trial has still not been published in a peer-reviewed journal; the MFDS label is currently the only primary source for its results. Earlier Sanofi trials established glycemic efficacy: in AMPLITUDE-M, HbA1c fell 0.5 to 1.0 percentage points more than placebo at 30 weeks, and in AMPLITUDE-D efpeglenatide was non-inferior to dulaglutide 1.5 mg. Hanmi is now running a Korean Phase 3 in type 2 diabetes (add-on to metformin and dapagliflozin), aiming for a diabetes indication around 2028. The honest framing: a modest weight-loss drug with unusually strong outcome data in diabetes, likely to compete in Korea on access and supply rather than on peak efficacy.

History & Discovery

Efpeglenatide came out of Hanmi Pharmaceutical's LAPSCOVERY program, which links peptides to an antibody Fc fragment to stretch their duration of action. Early names included LAPS-Exendin and LAPS-exendin-4. The first healthy-volunteer study began in 2010 (NCT01093729), and Phase 2 trials from 2011 to 2014 tested weekly, every-two-weeks and even once-monthly dosing in type 2 diabetes and obesity. In November 2015 Hanmi licensed the drug to Sanofi as a diabetes treatment. Sanofi's AMPLITUDE Phase 3 program enrolled about 6,000 patients across roughly 300 centers in 30 countries. In May 2020 Sanofi told Hanmi it would return the rights, and it confirmed the decision in September 2020. Three AMPLITUDE trials were cut short for funding reasons, but the cardiovascular outcome trial AMPLITUDE-O was reported in the New England Journal of Medicine in 2021, showing a 27% reduction in major adverse cardiovascular events. Hanmi then pivoted the drug to obesity in Korea. The MFDS approved a Phase 3 trial in October 2023, the first participant was enrolled in January 2024, and the week-40 primary endpoint was met (topline announced 27 October 2025). The MFDS designated efpeglenatide for GIFT fast-track review on 27 November 2025, and Hanmi filed for approval on 17 December 2025. The MFDS approved EPPE on 7 October 2026, Korea's 45th domestically developed new drug and the first Korean-developed GLP-1 for obesity; Hanmi began shipping on 22 October and prescribing started at selected institutions around 29 October. A Korean Phase 3 in type 2 diabetes (NCT07379333, HM-GLOW-301), testing the drug on top of metformin and dapagliflozin, was cleared on 21 January 2026 and began enrolling in April. Hanmi also signed a supply agreement with Laboratorios Sanfer for Mexico. Efpeglenatide is the first product of Hanmi's H.O.P. (Hanmi Obesity Pipeline) project, which also includes HM17321, a urocortin-2 analog licensed to Genentech.

How It Works

Efpeglenatide copies the action of GLP-1, a gut hormone that signals fullness, slows stomach emptying and helps the pancreas release insulin when blood sugar is high. It is based on exendin-4, a GLP-1-like peptide from Gila monster saliva, and is attached to a piece of an antibody so the body clears it slowly. One shot lasts about a week.

Efpeglenatide is a GLP-1 receptor agonist made by linking a single-amino-acid-modified exendin-4 to the Fc region of human immunoglobulin G4 through a 3.4-kDa mini-polyethylene glycol linker (Hanmi's LAPSCOVERY, or long-acting peptide/protein discovery, platform). Exendin-4 is naturally resistant to DPP-4, the enzyme that destroys human GLP-1 within minutes, and the Fc conjugation slows clearance. In type 2 diabetes studies, peak levels came 72 to 144 hours after a single dose and 48 to 120 hours on repeated dosing, half-life was 135 to 180 hours, and the peak-to-trough ratio was only 1.3 to 1.4 with weekly dosing (5.9 to 12.9 with monthly dosing), which is why weekly dosing became the standard. A pooled population-pharmacokinetic analysis across obesity and diabetes studies found roughly dose-proportional exposure and no need for routine dose adjustment by body weight. Downstream effects are those of the GLP-1 class: glucose-dependent insulin secretion, glucagon suppression, slower gastric emptying and reduced appetite via brainstem and hypothalamic circuits. In a Phase 1b study, 6 mg weekly slowed gastric emptying about as much as liraglutide 1.8 mg daily. Hanmi's in-vitro work, cited in its clinical papers, reports faster dissociation from the GLP-1 receptor and less receptor internalization than other GLP-1 drugs; that is a company hypothesis for tolerability, not a demonstrated clinical difference. The cardiovascular benefit in AMPLITUDE-O was dose-dependent: the 6 mg dose reduced major adverse cardiovascular events by 35% (hazard ratio 0.65) while 4 mg gave a non-significant 18% reduction. A 2026 mediation analysis found that changes in LDL cholesterol and urinary albumin, not weight loss, statistically explained about 30% of the effect, leaving most of it unexplained by measured variables.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Efpeglenatide:

• 01Peer-reviewed publication of the Korean obesity Phase 3. The drug reached a national market before its pivotal trial reached a journal, so the MFDS label is the only primary source for the registrational numbers, and the shape of the 40-to-64-week curve behind the label's statement that weight loss 'tended to be maintained' is not public.
• 02Whether the cardiovascular and kidney benefits seen in type 2 diabetes at 4 to 6 mg extend to people with obesity but no diabetes.
• 03Efficacy and tolerability of the obesity dose outside Korea.
• 04Whether Hanmi's proposed receptor-kinetics advantage translates into better tolerability than semaglutide at matched weight loss; no head-to-head trial exists.
• 05Most of AMPLITUDE-O's cardiovascular benefit is not explained by the measured risk factors; the mechanism is unresolved.
• 06Long-term body-composition data (fat vs lean mass) with the 10 mg obesity dose.
• 07The clinical meaning of the antibody response. Anti-drug antibodies appeared in 17.5% of treated patients and neutralising antibodies in 3.0% — a consequence of the Fc-conjugate design that fatty-acid GLP-1 drugs largely avoid. No effect on pharmacokinetics or efficacy was detected over 64 weeks, but longer exposure is uncharacterised.
• 08Whether the cardiovascular benefit survives the dose gap. AMPLITUDE-O tested 4 and 6 mg weekly in people with diabetes; the approved obesity dose is 10 mg weekly in people without it, so the outcome data and the marketed dose do not overlap.

Forms & Administration

Once-weekly subcutaneous injection. The Korean filing was for an auto-injector, and Hanmi has said it is developing prefilled-syringe and multi-dose pen formats. Earlier trials also tested every-two-weeks (6 and 8 mg) and once-monthly (8 to 16 mg) schedules, but weekly dosing was carried forward. Following Korean approval it is supplied as the EPPE autoinjector in 2, 4, 6, 8 and 10 mg strengths; outside South Korea it remains unavailable through any legitimate channel.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

Efpeglenatide is approved only in South Korea. The dosing above reflects the Korean label and published trial protocols; it is not prescribing guidance, and outside Korea there is no approved product.

Timeline of Effects

Monitoring & Measurement

Common Questions

Who Efpeglenatide Is NOT For

Drug & Supplement Interactions

Efpeglenatide slows gastric emptying (6 mg weekly matched liraglutide 1.8 mg daily in a Phase 1b study), so it can change how quickly oral medicines are absorbed; drugs with a narrow therapeutic range need monitoring. With insulin or sulfonylureas, hypoglycemia risk rises: level 2 hypoglycemia occurred in up to 10% of participants across treatment groups (placebo included) in AMPLITUDE-L, on basal insulin, and in up to 4% in AMPLITUDE-S, on metformin with or without a sulfonylurea. SGLT2 inhibitors combine well: in AMPLITUDE-O, cardiovascular and kidney benefits and adverse events did not differ by baseline SGLT2 inhibitor use, and Hanmi's new diabetes Phase 3 adds efpeglenatide to metformin plus dapagliflozin. It should not be combined with other GLP-1 receptor agonists, and the Korean label does not recommend combining it with other weight-management products. Because the drug raises heart rate by a mean 6.8 beats/min, caution is reasonable alongside other agents that do the same.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions