TRIUMPH-1: Phase 3 Pivotal Obesity Trial of Retatrutide

Study Overview

TRIUMPH-1 is the pivotal Phase 3 clinical trial evaluating retatrutide for the treatment of obesity in adults. It is the largest and most important trial in the retatrutide development program and will generate the definitive efficacy and safety data required for regulatory submissions to the FDA and other global health authorities. The trial is part of the TRIUMPH program (Triple Receptor Agonist Intervention Utilizing Metabolic Pathways in Health), Eli Lilly’s Phase 3 development initiative for retatrutide.

Trial Design

Study Type

TRIUMPH-1 is expected to be a randomized, double-blind, placebo-controlled, multicenter, international trial. Based on standard Phase 3 obesity trial design and FDA regulatory requirements, the trial is expected to include:

• Randomization to retatrutide (at one or more dose levels) versus placebo
• Double-blinding to minimize bias in endpoint assessment
• Multicenter, multinational enrollment to ensure a diverse and generalizable study population
• Treatment duration of at least 68-72 weeks, consistent with current regulatory expectations for obesity drug trials

Participant Population

Based on Phase 2 inclusion criteria and regulatory guidance:

• Adults with obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) with at least one weight-related comorbidity
• Expected enrollment of several thousand participants
• Broader demographic and geographic diversity than Phase 2

Dose Selection

The specific doses evaluated in TRIUMPH-1 have not been fully disclosed, but they are expected to be informed by the Phase 2 dose-response data. The 8 mg and 12 mg doses, which demonstrated the greatest efficacy in Phase 2, are the most likely candidates for Phase 3 evaluation, potentially alongside a lower dose. Dose escalation protocols similar to those used in Phase 2 are expected to be employed.

Endpoints

Expected primary endpoints:

• Percent change in body weight from baseline at the primary assessment timepoint
• Proportion of participants achieving at least 5% weight loss from baseline

Expected secondary endpoints:

• Proportion achieving ≥10%, ≥15%, ≥20% weight loss thresholds
• Changes in waist circumference
• Changes in cardiometabolic parameters (blood pressure, lipids, fasting glucose)
• Patient-reported outcomes (quality of life, physical function)
• Safety and tolerability

What We Know

From Phase 2

TRIUMPH-1 builds directly on the Phase 2 obesity trial results, which demonstrated:

• Up to 24.2% mean weight loss at 48 weeks
• 100% of participants achieving ≥5% weight loss at the highest dose
• Dramatic liver fat reduction
• Favorable cardiometabolic improvements
• Manageable GI tolerability profile with dose escalation

Expected Improvements Over Phase 2

Phase 3 trials typically include design refinements based on Phase 2 learnings:

• Optimized dose-escalation protocols may improve tolerability
• Longer treatment duration (likely 68-72 weeks) may demonstrate greater maximum weight loss
• Larger sample size provides greater statistical power and safety characterization
• More diverse patient population improves generalizability

Significance

TRIUMPH-1 will determine whether the exceptional Phase 2 weight loss results are reproducible in a larger, more diverse population and with longer treatment duration. The trial will also generate the comprehensive safety database required for regulatory approval, including assessment of less common adverse events that could not be detected in the smaller Phase 2 study.

The results of TRIUMPH-1, along with TRIUMPH-2 and potentially other TRIUMPH studies, will form the core of Eli Lilly’s regulatory submission package for retatrutide’s obesity indication.

Timeline

While specific timelines are subject to enrollment progress and other factors:

• Enrollment: Ongoing (estimated 2024-2025)
• Treatment period: 68-72 weeks estimated
• Primary results: Expected 2025-2026
• Regulatory submission: Could follow within 6-12 months of positive results

Key Questions TRIUMPH-1 Will Address

1. Reproducibility: Does the ~22-24% weight loss observed in Phase 2 replicate in a Phase 3 population?
2. Maximum effect: What is the weight loss magnitude with longer treatment duration?
3. Safety at scale: Are there any uncommon adverse events that emerge with a larger safety database?
4. Diversity: Are the effects consistent across different demographic subgroups?
5. Quality of life: Do patients experience meaningful improvements in functional outcomes and well-being?