Phase 1 First-in-Human Study of Retatrutide (LY3437943)

Study Overview

The Phase 1 first-in-human study of retatrutide (LY3437943) was the initial clinical evaluation of this novel triple GIP/GLP-1/glucagon receptor agonist. The study was designed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of retatrutide, providing the foundational human clinical data required to advance the molecule into efficacy-focused Phase 2 trials.

Study Design

The trial employed a randomized, double-blind, placebo-controlled design with two main components:

Single Ascending Dose (SAD) Cohorts

Small groups of participants received a single subcutaneous injection of retatrutide at escalating dose levels, starting from microgram quantities predicted from preclinical allometric scaling. Each dose level was evaluated for safety before the next higher dose was administered to a new cohort. Blood samples were collected at frequent intervals to characterize the single-dose pharmacokinetic profile.

Multiple Ascending Dose (MAD) Cohorts

Following the SAD phase, additional cohorts received multiple weekly subcutaneous injections at escalating dose levels over several weeks. The MAD phase was critical for characterizing steady-state pharmacokinetics, assessing the accumulation profile, and evaluating the safety and tolerability of repeated dosing.

Participants

The study enrolled approximately 72 participants across SAD and MAD cohorts. The SAD cohorts included primarily healthy adult volunteers, while the MAD cohorts included both healthy volunteers and adults with type 2 diabetes. The inclusion of diabetic participants in the MAD phase allowed early assessment of glycemic pharmacodynamic effects.

Key Findings

Safety and Tolerability

Retatrutide was generally well tolerated across the dose range evaluated. The most commonly reported adverse events were gastrointestinal in nature:

• Nausea: The most frequent adverse event, occurring in a dose-dependent manner and generally mild to moderate in severity
• Vomiting: Occurred less frequently than nausea, typically in conjunction with nausea episodes
• Diarrhea: Observed at moderate frequency, predominantly mild
• Decreased appetite: Reported as an adverse event but consistent with the intended pharmacological effect

No serious adverse events related to the study drug were reported. No dose-limiting toxicities were identified within the dose range tested, allowing full exploration of the planned dose escalation.

Pharmacokinetic Profile

The Phase 1 PK data established several critical parameters:

• Terminal elimination half-life: Approximately 6 days, consistent with the albumin-binding design of the molecule and supporting once-weekly administration
• Time to peak concentration (Tmax): Approximately 24-72 hours after subcutaneous injection
• Dose proportionality: Drug exposure (AUC and Cmax) increased proportionally with dose across the tested range, indicating linear pharmacokinetics
• Accumulation: Modest accumulation (approximately 2-3 fold) with weekly dosing, reaching steady state after approximately 4-5 weeks
• Low PK variability: Intersubject variability in drug exposure was within acceptable limits for a peptide therapeutic

Early Pharmacodynamic Signals

Although the Phase 1 study was not designed or powered to demonstrate efficacy, preliminary pharmacodynamic effects were observed:

• Glucose lowering: Participants with type 2 diabetes in the MAD cohorts showed dose-dependent reductions in fasting and postprandial blood glucose, providing early proof that the triple agonist mechanism was biologically active in humans
• Weight reduction: Modest but consistent body weight reductions were observed during the multiple-dose treatment period, even with the relatively short treatment durations and subtherapeutic early dose levels
• Appetite effects: Participant-reported reductions in hunger and food intake were noted, consistent with GLP-1R and GIPR central appetite suppression

Impact on Development Program

The Phase 1 results were highly informative for the design of the Phase 2 program:

• Dose range selection: The safety and PK data supported testing doses ranging from 0.5 mg to 12 mg in Phase 2 trials
• Dosing frequency: The approximately 6-day half-life confirmed that once-weekly subcutaneous administration was appropriate
• Dose escalation strategy: The observation that GI adverse events were dose-dependent and could be mitigated with gradual dose escalation informed the use of escalating-dose regimens in Phase 2
• Proof of concept: The early pharmacodynamic signals provided confidence that the triple agonist mechanism was translating from preclinical models to human biology

Publication

The Phase 1 clinical data were published as part of a comprehensive translational paper by Coskun et al. (2022) in Cell Metabolism, which integrated preclinical discovery, molecular pharmacology, and Phase 1 clinical results into a single publication describing the full translational arc from bench to bedside.

Limitations

As a Phase 1 study, the trial had inherent limitations:

• Small sample size (approximately 72 total participants)
• Short treatment duration, particularly in the SAD cohorts
• Limited diversity in the study population
• Not designed to assess efficacy endpoints
• PK characterization at lower dose levels may not fully predict behavior at therapeutic doses

These limitations are expected for first-in-human studies and were addressed by the larger and longer Phase 2 trials that followed.