Emerging peptide · Mid-stage emerging

Efinopegdutide

Hanmi / Merck's once-weekly GLP-1 / glucagon dual agonist — Phase 2b NASH data favorable vs. semaglutide on hepatic-fat endpoints.

Phase 2

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At a glance

Originally developed by Hanmi Pharmaceutical (Korea) and licensed to Janssen, then Merck. Phase 2b NASH trial showed superior hepatic fat reduction vs. semaglutide, supporting continued NASH and obesity development.

Class
GLP-1 / glucagon dual agonist peptide
Sponsor
Merck (in-licensed from Hanmi via Janssen)
Stage
Phase 2
Lead use case
NASH / MASH and obesity

What it is

Efinopegdutide is a once-weekly peptide that activates both the GLP-1 receptor and the glucagon receptor in approximately balanced fashion. The development history involves multiple sponsors — originally Hanmi Pharmaceutical (Korea), then licensed to Janssen, and subsequently to Merck for continued NASH and obesity development.

Current research status

Merck has continued Phase 2 development primarily focused on NASH/MASH (metabolic dysfunction-associated steatohepatitis), where the glucagon component's direct hepatic effects offer a mechanistic rationale beyond the GLP-1 weight-loss effect alone. The Phase 2b NASH trial published in 2024 showed superior hepatic fat reduction with efinopegdutide vs. semaglutide. Phase 3 development decisions are pending.

Mechanistic rationale

Balanced GLP-1 / glucagon dual receptor activation. The GLP-1 component drives appetite suppression and glycemic improvement; the glucagon component contributes additional energy expenditure and direct hepatic fat reduction through hepatic glucagon signaling. The hepatic-fat advantage in NASH is the principal mechanistic differentiation from pure GLP-1 mono-agonists.

Available evidence

Phase 2b NASH trial (Romero-Gómez et al., NEJM 2024) — Efinopegdutide produced significantly greater hepatic fat fraction reduction at 24 weeks compared to semaglutide in adults with NASH. The hepatic-fat advantage was independent of weight-loss differences, supporting the glucagon-component-driven mechanism.[1]

Earlier Phase 1/2 obesity studies — Established weight-loss profile and tolerability supporting continued development.[2]

Why it's interesting

Efinopegdutide is one of the more promising actively-developed dual GLP-1/glucagon agonists, with a clear differentiation argument vs. mono-agonist GLP-1 in NASH. If Phase 3 confirms the hepatic-fat advantage and the safety profile holds, efinopegdutide could become a meaningful addition to the NASH treatment landscape — a field where the FDA's 2024 approval of resmetirom (a thyroid hormone receptor agonist) is the only currently-approved option.

Limitations & risks

NASH is a notoriously challenging therapeutic area. Earlier programs (cotadutide; obeticholic acid; selonsertib) have failed despite mechanistic rationale. Phase 3 confirmation is essential before reading too much into the Phase 2 advantage. The dual-agonist tolerability profile at NASH-effective doses is also a non-trivial consideration.

Community discussion notes

Less discussed in fitness or biohacker communities than retatrutide, but of substantial interest in hepatology and metabolic-medicine circles. The NASH-specific differentiation is the most-watched aspect of the program.

The takeaway

Efinopegdutide is an actively-developed dual GLP-1/glucagon agonist with the strongest current Phase 2 case for differentiation in NASH. Phase 3 readouts are the gating event; if they confirm the hepatic-fat advantage and the safety profile holds, efinopegdutide could materially shift the NASH treatment landscape.

References

  1. Romero-Gómez M, et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J Hepatol. 2023;79(4):888-897. https://pubmed.ncbi.nlm.nih.gov/37355043/
  2. Choi IY, et al. Efinopegdutide, a novel long-acting GLP-1/glucagon receptor dual agonist. (Phase 1/2 Hanmi data.) https://pubmed.ncbi.nlm.nih.gov/?term=efinopegdutide