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CT-996 (RG6652)

Modality: GLP-1 Receptor Agonist

Disease State: Type 2 Diabetes, Overweight or Obesity

Summary

CT-996 is being investigated as an oral, once daily treatment for obesity and type 2 diabetes.¹ CT-996 is a small molecule agonist of the GLP-1 receptor and unlike the endogenous GLP-1 hormone, CT-996 is specifically designed to be a biased agonist that activates cAMP signaling with minimal-to- no beta-arrestin recruitment.^2-4

Clinical Trials

Type 2 Diabetes, Overweight or Obesity
Phase	Enrollment Status	Title
Phase II	Recruiting	A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center, Phase II Study to Evaluate the Efficacy, Safety, and Tolerability of Once-Daily RO7795081 Administered for 38 Weeks to Participants With Obesity or Overweight With at Least One Weight-Related Comorbidity	View Details
Phase II	Recruiting	A Randomized, Double-Blind, Placebo- and Open-Label Active Comparator- Controlled, Parallel-Group, Multi-Center Phase II Study to Evaluate the Efficacy, Safety, and Tolerability of Once-Daily RO7795081 Administered for 30 Weeks to Participants With Type 2 Diabetes Mellitus	View Details

Proposed Mechanism of Action

Unlike the endogenous GLP-1 hormone, CT-996 is specifically designed to be a biased agonist that activates cAMP signaling with minimal-to- no beta-arrestin recruitment.^2-4

CT-996 was purposefully designed with biased-signaling

Side by side image illustrating unbiased GLP-1RA signalling vs biased receptor modulator and the subsequent limitation of B-arrestin recruitment with retention of cAMP signaling potency^2,4

Oral, synthetic small-molecule (non-peptide) designed for once-daily administration⁷
cAMP- biased GLP-1R agonist⁶
Signal bias means minimal β-arrestin recruitment⁷
- Results in reduced GLP-1R receptor internalization

ClinicalTrials.gov. A Double-Blind, Randomized, Placebo-Controlled Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of CT-996 in Overweight/Obese Participants and in Patients With Type 2 Diabetes Mellitus [Internet; cited 2025 March]. Available from: https://clinicaltrials.gov/study/NCT05814107?cond=obesity&term=CT-996%20&checkSpell=&rank=1.
Smith, Lefkowitz, Rajagopal. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov. 2018 Apr;17(4):243-260. doi: 10.1038/nrd.2017.229.
Jones B. The therapeutic potential of GLP-1 receptor biased agonism. Br J Pharmacol. 2022 Feb;179(4):492-510. doi: 10.1111/bph.15497.
Roche. Roche Pharma Day 2024. Presented at: Roche Pharma Day 2024; September 30, 2024; London, https://assets.roche.com/f/176343/x/f513f69de2/pharma_day_20240930_final_online_v02.pdf
Rodriguez R et al. Biased GLP-1 Improves Weight Loss with Additional Benefits on Glucose Homeostasis via Biased GIP in Diabetic Rodent Models. Poster presented at the American Diabetes Association 83rd Scientific Session, 23-26 June 2023; San Diego, CA.
Luo J, et al. American Diabetes Association 84th Scientific Sessions; June 21−24, 2024; Orlando, FL. Poster 771-P Available from: https://medically.roche.com/global/en/endocrinology/ada-2024/medical-material/ADA-2024-poster-luo-efficacy-of-CT-996-pdf.html

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cAMP
cyclic adenosine monophosphate
GLP-1
Glucagon-like peptide-1
GLP-1R
glucagon-like peptide 1 receptor
GIP
Gastric inhibitory polypeptide
GIPR
glucose-dependent insulinotropic polypeptide receptor
PK
pharmacokinetic
T2DM
Type 2 Diabetes Mellitus