SYNERGY Program

SYNERGY Program

SYNERGY is Eli Lilly’s Phase 3 clinical development program for retatrutide in metabolic dysfunction-associated steatohepatitis (MASH), the more severe form of metabolic dysfunction-associated steatotic liver disease (MASLD). It is distinct from the TRIUMPH (obesity) and TRANSCEND (type 2 diabetes) programs and uses different primary endpoints suited to liver disease — including histological resolution of steatohepatitis and improvement in fibrosis.

The program includes:

• SYNERGY: histology-anchored Phase 3 trial of retatrutide in MASH with paired liver biopsy endpoints (resolution of MASH without worsening of fibrosis, and/or improvement in fibrosis stage without worsening of MASH).
• SYNERGY-Outcomes: ~4,500-patient liver outcomes trial evaluating major adverse liver outcomes (MALO) as a long-term event-driven endpoint.
• MACELD: companion liver-specific Phase 3 trial.

The rationale for retatrutide in MASH rests on the glucagon receptor component of its triple-agonist mechanism, which directly drives hepatic fatty acid oxidation. Phase 2 data showed approximately 82% relative liver fat reduction at the highest dose, the strongest pharmacological liver fat effect reported to date. The Phase 3 readout will determine whether that mechanistic effect translates into histological MASH resolution.