75-LB: CT-388, a Novel Once-Weekly Dual GLP-1 and GIP Receptor Modulator, Is Safe, Well-Tolerated, and Produces More than 8% Weight Loss in Four Weeks in Overweight and Obese Adults

Abstract

GLP-1 and GIP can deliver complementary pharmacology when combined. CT-388 is a biased dual GLP-1 and GIP receptor modulator that exhibits no to minimal β-arrestin coupling at either receptor, designed for once-weekly subcutaneous dosing. A Phase 1, randomized, placebo-controlled, double-blind study was conducted where single ascending doses (0.5-7.5 mg) and multiple ascending doses (MAD; doses 5-12 mg via titration in 3 cohorts) for 4 weeks were administered to overweight/obese adults. Primary objective was to investigate safety and tolerability of CT-388. Total of 64 participants (men/women: 28/36; median age/BMI: 34 years/33 kg/m2) received at least 1 dose of CT-388 or placebo. PK profile was investigated over a wide dose range (0.5-12 mg) and supports once-weekly administration. Percent change in body weight from baseline at Day 29 was dose responsive and significantly greater in CT-388 treated participants versus placebo (p <0.0001) across the 3 MAD cohorts with Least Square Mean difference [95% CI] of -4.8% [-6.3, -3.3], -6.4% [-7.8, -5.0], and -8.5% [-10.4, -6.7]. Mean percent decrease from baseline at Day 23 in fasting glucose (↓8-10%), insulin (↓20-26%), HOMA-IR (↓26-33%), AUC0-120min glucose (↓26-28%) and AUC0-120min insulin (↓33-58%) during oGTT were seen in cohorts dosed up to 12 mg CT-388, suggestive of improved insulin sensitivity. Over the 4-week treatment period, CT-388 was generally well tolerated with no treatment-related discontinuations. The most frequent side effects reported were gastrointestinal (decreased appetite, nausea, vomiting, diarrhea), which were mostly mild in severity. In summary, CT-388 delivers clinically meaningful weight loss and metabolic control with a favorable tolerability profile. These data warrant further clinical evaluation of CT-388, possibly with minimal to no titration, for the treatment of obesity, T2DM, and other weight-related comorbidities. Disclosure M. Chakravarthy: Employee; Carmot Therapeutics, Inc. F. A. Argüelles-Tello: Research Support; Carmot Therapeutics, Inc. A. A. Sun: None. M. Elliott: Employee; Carmot Therapeutics, Inc. L. Acosta: None. J. E. Rankin: None. S. K. Hansen: Board Member; Carmot Therapeutics, Inc.