Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control in preclinical models and participants with obesity

  • Mol Metab. 2026 Jan:103:102291. doi: 10.1016/j.molmet.2025.102291.
Manu V Chakravarthy  1 ,  Ruben Rodriguez  2 ,  Anne Hergarden  2 ,  Michael A Elliott  2 ,  Juan P Frias  3 ,  Federico A Argüelles-Tello  4 ,  Edgar Tenorio  2 ,  Jonathan E Rankin  5 ,  Jingtao Wu  2 ,  Shyam Krishnan  2 ,  Daniel A Erlanson  2 ,  Raymond V Fucini  2 ,  Derek Bone  2 ,  Jeffrey S Iwig  2 ,  Luis Acosta  2 ,  Ashley Untereiner  2 ,  Asmita Pant  2 ,  Avalon Patton  2 ,  Leyla L Sanchez-Sanchez  4 ,  Jian Luo  2 ,  Alexandra Steinberg  2 ,  Damian Bialonczyk  2 ,  Stig K Hansen  2
Affiliations
  • 1. Genentech Inc., 1 DNA Way, Ste 258A, South San Francisco, CA, 94080, USA (previously Carmot Therapeutics Inc., 740 Heinz Ave, Berkeley, CA, 94710, USA. Electronic address: [email protected].
  • 2. Genentech Inc., 1 DNA Way, Ste 258A, South San Francisco, CA, 94080, USA (previously Carmot Therapeutics Inc., 740 Heinz Ave, Berkeley, CA, 94710, USA.
  • 3. Charles R Drew University of Medicine and Science, 1731 E 120th St, Los Angeles, CA, 90059, USA.
  • 4. Clinical Pharmacology Department, Avant Santé Research Center, SA de CV Nuevo León, Av Lázaro Cárdenas 500, Residencial San Agustín 1er Sector, 66260, San Pedro Garza García, Mexico.
  • 5. Syneos Health, 1030 Sync St, Morrisville, NC, 27560, USA.
PMID: 41319798 DOI: 10.1016/j.molmet.2025.102291
Abstract

Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5-7.5 mg] or 4 once-weekly doses [5-12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with Other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was -4.7% to -8.0% across CT-388 doses vs -0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes.

Keywords
Glucagon-like peptide-1; Glucose control; Glucose-dependent insulinotropic polypeptide; Obesity; Signaling bias; Weight loss.
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