Investigational Dual GLP-1/GIP Agonist CT-388 Demonstrates 22.5% Placebo-Adjusted Weight Loss in Phase 2 Obesity Trial

Roche has announced positive topline results from CT388-103, a phase 2 dose-finding trial evaluating CT-388, an investigational dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, for obesity treatment.

The 48-week, randomized, double-blind, placebo-controlled study enrolled 469 adults with obesity or overweight with at least one weight-related comorbidity and evaluated multiple dose escalation regimens up to 24 mg administered subcutaneously once weekly.

The trial met its primary endpoint, demonstrating a placebo-adjusted mean weight loss of 22.5% using the efficacy estimand and 18.3% using the treatment-regimen estimand (P < .001) at week 48. At the highest dose (24 mg), 95.7% of participants achieved at least 5% weight loss, 87% achieved at least 10% weight loss, 47.8% achieved at least 20% weight loss, and 26.1% achieved at least 30% weight loss. Notably, participants had not reached a weight loss plateau by week 48, suggesting the potential for further reductions with extended treatment duration. Among participants with prediabetes at baseline who received CT-388 24 mg, 73% normalized their blood glucose levels at week 48, compared with 7.5% in the placebo group.

The safety profile appeared consistent with the incretin class, with predominantly mild-to-moderate gastrointestinal adverse events. Treatment discontinuation due to adverse events occurred in 5.9% of CT-388 arms versus 1.3% of the placebo arm. Complete trial results will be presented at an upcoming medical congress, Roche indicated.

“We are pleased to see such meaningful weight loss in people treated with CT-388,” Levi Garraway, MD, PhD, Chief Medical Officer and Head of Global Product Development, Roche, said in a press release. “The robust weight loss combined with a well-tolerated safety profile reinforces our confidence in the clinical development programme as we advance to Phase III trials.”

The development of dual and multi-receptor agonists represents a significant evolution beyond single GLP-1 receptor agonists in obesity pharmacotherapy. The first GLP-1 receptor agonist, exenatide, received FDA approval in 2005 for type 2 diabetes.² Subsequent development led to high-dose formulations approved specifically for obesity, including liraglutide 3.0 mg (Saxenda) and semaglutide 2.4 mg (Wegovy), which demonstrated placebo-adjusted weight losses of approximately 5% and 12%, respectively, in pivotal trials.^3,4

Tirzepatide, the first dual GIP/GLP-1 receptor agonist approved by the FDA, marked a paradigm shift in obesity treatment. In the SURMOUNT-1 trial, tirzepatide demonstrated dose-dependent weight reductions of 16.0%, 21.4%, and 22.5% (efficacy estimand) at doses of 5 mg, 10 mg, and 15 mg, respectively, at 72 weeks.⁵ The medication received FDA approval for type 2 diabetes in May 2022 (Mounjaro) and for chronic weight management in November 2023 (Zepbound).^6,7 More recently, the SURMOUNT-5 trial demonstrated superiority of tirzepatide over semaglutide in head-to-head comparison.⁸

CT-388's reported 22.5% placebo-adjusted weight loss at 48 weeks appears comparable to tirzepatide's performance, though direct cross-trial comparisons should be interpreted cautiously given differences in study populations, duration, and methodology. The biased signaling approach employed by CT-388, which minimizes β-arrestin recruitment to reduce receptor internalization and desensitization, represents a novel mechanistic refinement intended to prolong pharmacological activity.¹

References:

1. Roche announces positive Phase II results for its dual GLP-1/GIP receptor agonist CT-388 in people living with obesity. Roche. January 26, 2026. Accessed January 29, 2026. https://www.roche.com/media/releases/med-cor-2026-01-27
2. FDA approves new treatment for type 2 diabetes. U.S. Food and Drug Administration. April 28, 2005. Accessed January 29, 2026. https://www.fda.gov/
3. Pi-Sunyer X, Astrup A, Fujioka K, et al; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/NEJMoa1411892
4. Wilding JPH, Batterham RL, Calanna S, et al; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
5. Jastreboff AM, Aronne LJ, Ahmad NN, et al; SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
6. Syed YY. Tirzepatide: first approval. Drugs. 2022;82(11):1213-1220. doi:10.1007/s40265-022-01746-8
7. FDA approves new drug treatment for chronic weight management, first since 2014. U.S. Food and Drug Administration. June 4, 2021. Accessed January 29, 2026.
8. Aronne LJ, Bade Horn D, le Roux CW, et al; SURMOUNT-5 Trial Investigators. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;393(1):11-22. doi:10.1056/NEJMoa241639