SYNERGY-Outcomes: MASLD/MASH Phase 3 Liver Outcomes Trial

Study Overview

SYNERGY-Outcomes is Eli Lilly’s dedicated Phase 3 trial program evaluating retatrutide for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) with liver fibrosis. The trial was designed based on the extraordinary liver fat reduction data from the Phase 2 obesity trial, where retatrutide demonstrated approximately 82% relative reduction in liver fat at the 12 mg dose.

Scientific Rationale

Why MASH is a Critical Target

MASH with fibrosis is a progressive liver disease that can lead to:

• Liver cirrhosis and liver failure
• Hepatocellular carcinoma (liver cancer)
• Need for liver transplantation
• Increased cardiovascular mortality

The global MASH population is estimated at 80-100 million people, with only one approved therapy (resmetirom/Rezdiffra, approved March 2024).

Retatrutide’s MASH Advantage

Retatrutide’s triple receptor agonism provides multiple complementary mechanisms for liver disease:

1. Glucagon receptor: Direct hepatic fat oxidation, suppression of de novo lipogenesis
2. GLP-1 receptor: Reduced hepatic insulin resistance, anti-inflammatory effects
3. GIP receptor: Potential anti-fibrotic signaling
4. Weight loss: Reduction in visceral adiposity and portal pressure

The Phase 2 MASLD substudy (Sanyal et al., Nature Medicine 2024) demonstrated:

• 82% relative liver fat reduction at 12 mg
• 86% of participants achieved liver fat normalization
• Far exceeding resmetirom (~30-35%) and semaglutide (~40-50%)

Study Design

Population

Approximately 4,500 adults with:

• Biopsy-confirmed MASH (NAS score ≥4)
• Liver fibrosis stage F2-F3 (significant fibrosis, but not cirrhosis)
• BMI ≥25 kg/m²

Endpoints

Co-primary endpoints (assessed by paired liver biopsies):

1. Resolution of MASH (NAS <3) without worsening of fibrosis
2. Improvement in fibrosis by at least one stage without worsening of MASH

Key secondary endpoints:

• Composite liver histology improvement
• Change in liver fat by MRI-PDFF
• Change in liver fibrosis biomarkers (ELF score, FIB-4, APRI)
• Change in body weight
• Long-term clinical liver outcomes (progression to cirrhosis, liver events)
• All-cause mortality

Duration

The biopsy-based endpoints will be assessed at approximately 72 weeks, with a longer-term outcomes component potentially extending to 3-5 years.

Competitive Landscape

Significance

If successful, SYNERGY-Outcomes could establish retatrutide as the most effective pharmacological treatment for MASH — addressing the liver disease directly while simultaneously treating the underlying obesity that drives disease progression. This would represent a “treat-the-root-cause” approach that no current MASH therapy can match.

Timeline

• Enrollment: 2024-2025
• Primary biopsy endpoint: Expected 2026-2027
• Long-term outcomes: 2028-2029