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 online by Urva et al. in The Lancet on October 27, 2022 (print issue November 26, 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 four U.S. centers, with dulaglutide 1.5 mg as a reference arm.

Duration

12 weeks of treatment, then 4 weeks of follow-up.

Population

72 adults aged 20-70 years with type 2 diabetes for at least 3 months, HbA1c 7.0-10.5%, BMI 23-50 kg/m² and stable body weight. All participants used metformin throughout the study.

Dose Cohorts

Five ascending dose cohorts were studied:

• Cohort 1: 0.5 mg weekly for 12 weeks (9 participants on retatrutide)
• Cohort 2: 1.5 mg weekly for 12 weeks (9)
• Cohort 3: 3 mg weekly for 12 weeks (11)
• Cohort 4 (3/6 mg): 3 mg for 4 weeks, then 6 mg for 8 weeks (11)
• Cohort 5 (3/6/9/12 mg): 3 mg for 2 weeks, 6 mg for 2 weeks, 9 mg for 4 weeks, then 12 mg for 4 weeks (12)

In each cohort at least nine participants received retatrutide, three received placebo and one received dulaglutide 1.5 mg. In total 15 participants had placebo and 5 had dulaglutide.

Pharmacokinetic Results

The trial established key PK parameters:

• Half-life: Approximately 6 days, supporting once-weekly injection
• Median tmax: 12-48 hours after the dose
• Dose proportionality: Exposure (AUC and Cmax) increased approximately in proportion to dose

Efficacy Signals

Glucose and body weight were secondary outcomes. Changes at week 12, compared with placebo, in the three highest dose groups:

These differences were statistically significant. The two lowest doses did not produce significant changes. Weight loss appeared dose dependent and had not plateaued by week 12. With dulaglutide 1.5 mg, the placebo-adjusted changes were -0.6% for HbA1c and +0.08 kg for body weight.

Safety

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

• Overall: Treatment-emergent adverse events in 63% of retatrutide participants, 60% on dulaglutide 1.5 mg and 54% on placebo. Four participants (6%) stopped treatment because of an adverse event
• Most common: Diarrhea and nausea. Both were most frequent in the highest-dose group (3/6/9/12 mg, n=12), where each affected 50% and vomiting 25%; in the placebo group nausea and diarrhea each affected 13%. Most GI events were mild or moderate and resolved within about 10 days. The authors suggested a more gradual escalation could reduce them in the highest-dose group
• No pancreatitis, medullary thyroid carcinoma, or major hypoglycemia
• Heart rate: Pulse rose in the higher-dose groups. In the three highest-dose groups the increase was 2 to 13 beats per minute 24 hours after the last dose, and -1 to 10 beats per minute averaged over the final 4 weeks (dulaglutide: 2 and -4)

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. Early weight loss: Placebo-adjusted weight loss of up to about 9 kg in 12 weeks in people with type 2 diabetes

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(10366):1869-1881. doi:10.1016/S0140-6736(22)02033-5