Efpeglenatide: Mechanism, Research & UK Safety Profile
Also known as: HM11260C, SAR439977
Investigational long-acting weekly GLP-1 receptor agonist (Fc-fusion structure). Developed by Hanmi Pharmaceutical; later partnered with Sanofi. AMPLITUDE-O (NEJM 2021) reported MACE-3 benefit in adults with T2D and high CV risk or CKD. Programme status has evolved during 2021–2026. Not licensed for human therapeutic use at the time of review.
Molecular weight
Approx. 44 kDa (exendin-4-based Fc fusion)
Half-life
Approximately one week via Fc-fusion architecture (FcRn-mediated recycling and PEG linker reducing renal filtration).
Category
GLP-1 mono-agonists
Overview
Efpeglenatide is an investigational once-weekly GLP-1 receptor agonist based on an exendin-4 peptide fused to a human IgG4 Fc fragment via a polyethylene glycol (PEG) linker. The Fc-fusion architecture extends the half-life to support weekly dosing. The molecule was developed by Hanmi Pharmaceutical (South Korea) and entered a development partnership with Sanofi (as SAR439977). The AMPLITUDE-O cardiovascular outcomes trial (Gerstein HC et al., NEJM 2021) evaluated efpeglenatide in adults with type 2 diabetes who had high cardiovascular risk or chronic kidney disease, reporting a statistically significant reduction in MACE-3 (hazard ratio approximately 0.73; 95% confidence interval approximately 0.58–0.92). Despite this evidence, the efpeglenatide development programme has experienced ownership and prioritisation changes during 2021–2026. At the time of review the compound is presented as investigational with its evidence base anchored to AMPLITUDE-O; the current programme status should be confirmed via the sponsor pipeline and ClinicalTrials.gov.
Discovery & Research History
Efpeglenatide originated at Hanmi Pharmaceutical as part of their LAPSExendin (Long-Acting Peptide / Somatology ExendinFc) platform, which fuses exendin-4-based GLP-1 receptor agonists to an IgG4 Fc domain to extend half-life. The Sanofi partnership (as SAR439977) was announced in 2015. Phase 2 data in type 2 diabetes established the efficacy and tolerability profile. The AMPLITUDE-O cardiovascular outcomes trial was the pivotal evidence-generation event, reporting in the NEJM in 2021. Subsequent to AMPLITUDE-O, programme prioritisation changes and ownership transitions have meant that regulatory submissions resulting in licensed medicines have not followed at the time of review.
Mechanism of Action
Efpeglenatide is a full agonist at the GLP-1 receptor (GLP-1R). The exendin-4-derived peptide component confers DPP-4 resistance and GLP-1R binding; the Fc fusion and PEG linker extend the half-life to approximately one week via FcRn-mediated recycling and reduced renal filtration. The pharmacological mechanism mirrors the GLP-1 receptor agonist class: glucose-dependent augmentation of insulin secretion, suppression of postprandial glucagon, slowing of gastric emptying and central appetite suppression via hypothalamic and brainstem GLP-1 receptors.
Researched Effects
- MACE-3 cardiovascular benefit in adults with type 2 diabetes and high CV risk or CKD in AMPLITUDE-O (hazard ratio approximately 0.73; 95% CI approximately 0.58–0.92; NEJM 2021).
- HbA1c reduction and body-weight reduction in phase 2 and AMPLITUDE-O trial cohorts.
- Renal composite endpoint benefit observed in the AMPLITUDE-O cohort, which specifically enrolled participants with CKD.
Theoretical Research Protocols
- Dosage range
- Trial-arm doses as reported in AMPLITUDE-O and phase 2 studies are research records. This page is not a prescribing or self-administration guide. Refer to the primary trial publications for the dose arms studied.
- Frequency
- Once-weekly subcutaneous injection in trial protocols.
- Duration
- AMPLITUDE-O median follow-up approximately 1.8 years; phase 2 studies 12–26 weeks.
- Administration routes
- Subcutaneous injection (once weekly; clinical trial and research setting)
Safety Profile
Common side effects (research)
- Nausea, vomiting, diarrhoea and constipation consistent with the GLP-1 receptor agonist class.
- Injection-site reactions.
- Decreased appetite.
Rare risks
- Acute pancreatitis (class-monitored signal for all GLP-1 receptor agonists).
- Acute kidney injury risk with severe GI events and dehydration.
- Immunogenicity considerations apply to Fc-fusion proteins.
- Long-term safety requires further characterisation given programme status changes.
Contraindications
- Investigational compound — eligibility is defined by the relevant clinical trial protocol.
- Pregnancy and breastfeeding are typical trial exclusions.
- History of medullary thyroid carcinoma or MEN2 (by class analogy with other exendin-based GLP-1 RAs).
UK Regulatory Status
United Kingdom (MHRA): Investigational at the time of review. Efpeglenatide is not licensed by the MHRA for any human therapeutic indication.
European Union (EMA): Investigational. Not EMA-licensed at the time of review.
Notes: Efpeglenatide's evidence base is anchored to AMPLITUDE-O (NEJM 2021). Despite favourable cardiovascular outcome data, programme status has evolved with ownership and prioritisation changes during 2021–2026. The current pipeline status should be confirmed via the sponsor and ClinicalTrials.gov. Efpeglenatide must not be used outside an appropriately authorised research setting.
Related research resources
Key Research Studies
Gerstein HC et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes (AMPLITUDE-O). N Engl J Med 2021;385(10):896–907.
AMPLITUDE-O evaluated efpeglenatide versus placebo in 4,076 adults with T2D and high CV risk or CKD (median follow-up 1.81 years). The primary MACE-3 endpoint (CV death, non-fatal MI, non-fatal stroke) favoured efpeglenatide: hazard ratio approximately 0.73 (95% CI approximately 0.58–0.92). Renal composite outcomes also favoured the active treatment arm. Importantly, approximately 15% of participants were taking background SGLT2 inhibitors, and the CV benefit appeared present across subgroups.
Read sourceRosenstock J et al. Efpeglenatide monotherapy with weekly subcutaneous dosing in type 2 diabetes — phase 2. Lancet Diabetes Endocrinol 2019.
Phase 2 evaluation of once-weekly efpeglenatide across dose levels in adults with T2D, reporting HbA1c reduction and body-weight reduction consistent with the GLP-1 receptor agonist class profile.
Frequently Asked Questions
What is efpeglenatide?
An investigational once-weekly GLP-1 receptor agonist based on an exendin-4 peptide fused to an IgG4 Fc domain (Fc-fusion). Developed by Hanmi Pharmaceutical and later partnered with Sanofi. The AMPLITUDE-O trial (NEJM 2021) reported a statistically significant reduction in MACE-3 in adults with T2D and high CV risk or CKD.
What is efpeglenatide's regulatory status in the UK?
Efpeglenatide is investigational and is not licensed by the MHRA for any human therapeutic indication. Despite the cardiovascular outcome data from AMPLITUDE-O, the programme has experienced ownership and prioritisation changes during 2021–2026, and no MHRA marketing authorisation has followed at the time of review. Efpeglenatide must not be used outside an appropriately authorised research setting.
What did AMPLITUDE-O find?
AMPLITUDE-O (NEJM 2021, Gerstein HC et al.) was a cardiovascular outcomes trial in 4,076 adults with T2D and high CV risk or CKD. It reported that efpeglenatide reduced the primary composite endpoint of MACE-3 (CV death, non-fatal MI, non-fatal stroke) with a hazard ratio of approximately 0.73 (95% CI approximately 0.58–0.92). Renal composite outcomes also favoured efpeglenatide.
How does efpeglenatide differ from other weekly GLP-1 receptor agonists?
Like dulaglutide and once-weekly semaglutide, efpeglenatide is designed for weekly subcutaneous injection. Its distinctive structural feature is the exendin-4 peptide fused to an IgG4 Fc domain (Fc-fusion), compared with the GLP-1 analogue + IgG4 Fc approach of dulaglutide or the fatty-acid-acylated GLP-1 analogue approach of semaglutide. The programme status has evolved since AMPLITUDE-O.
Related trials
No published trials yet linked to this page. Source verification required.