Phase 1b Multiple Ascending Dose Trial (NCT04143802)

Study Overview

The Phase 1b multiple ascending dose (MAD) trial of retatrutide was a critical early clinical study that provided the first evidence of dose-dependent efficacy in humans with type 2 diabetes. Published by Urva et al. in The Lancet in November 2022, this trial established the pharmacokinetic profile that would support once-weekly dosing and generated the safety data needed to advance into Phase 2.

Study Design

Design

Randomized, double-blind, placebo-controlled, multiple-ascending dose trial conducted at multiple U.S. centers.

Duration

12 weeks of treatment with follow-up.

Population

72 adults aged 18-70 years with type 2 diabetes (HbA1c 7.0-10.5%) treated with diet/exercise alone or with stable metformin. BMI 23-50 kg/m².

Dose Cohorts

Participants were randomized across ascending dose cohorts:

• 0.5 mg weekly
• 1.5 mg weekly
• 3.0 mg weekly (with and without escalation)
• 4.5 mg weekly (with escalation)
• 6.0 mg weekly (with escalation)
• 9.0 mg weekly (with escalation)
• 12.0 mg weekly (with escalation)

Within each cohort, participants were randomized 3:1 to retatrutide or placebo.

Pharmacokinetic Results

The trial established key PK parameters:

• Half-life: Approximately 6 days, confirming suitability for once-weekly injection
• Tmax: 12-72 hours post-injection
• Steady state: Achieved by approximately week 4-5 of weekly dosing
• Dose proportionality: Exposure increased in an approximately dose-proportional manner

Efficacy Signals

Despite the short 12-week treatment duration, robust dose-dependent efficacy was observed:

Safety

The adverse event profile was consistent with the GLP-1 receptor agonist class:

• Most common: Nausea (26%), diarrhea (21%), vomiting (13%)
• Dose escalation benefit: GI adverse events were less frequent and less severe with gradual dose escalation compared to fixed dosing
• No pancreatitis, medullary thyroid carcinoma, or major hypoglycemia
• Heart rate: Small dose-dependent increases observed (2-4 bpm)

Significance

This trial was pivotal in establishing:

1. Once-weekly feasibility: The ~6-day half-life validated weekly dosing
2. Dose escalation strategy: Gradual titration improved tolerability, informing Phase 2 design
3. Triple agonist proof-of-concept: Demonstrated that simultaneous activation of GIP, GLP-1, and glucagon receptors produced metabolic benefits without unexpected safety concerns
4. Unprecedented early weight loss: The magnitude of weight reduction at only 12 weeks exceeded what most single-agonist therapies achieve at this timepoint

Publication

Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The Lancet. 2022;400:1869-1881.