CT-388vsGLP-1

CT-388 is a once-weekly subcutaneous dual GLP-1/GIP receptor agonist, mechanistically similar to tirzepatide but with a distinct molecular structure designed for differentiated pharmacology. Activation of both receptors produces complementary metabolic effects: GLP-1 receptor agonism centrally suppresses appetite through hypothalamic and brainstem signalling, slows gastric emptying, and stimulates glucose-dependent insulin secretion from pancreatic beta cells, while GIP receptor agonism enhances beta-cell insulin response, modulates lipid handling in adipose tissue, and amplifies the central anorectic effect of GLP-1 through distinct hypothalamic neuronal circuits.

The molecule was engineered with a balanced potency profile across the two receptors and incorporates fatty acid acylation that enables strong albumin binding, extending half-life to approximately one week. This pharmacokinetic profile supports once-weekly subcutaneous dosing with stable plasma exposure across the dosing interval, which is associated with better gastrointestinal tolerability than less stable formulations that produce sharp peaks and troughs.

In the Phase 2 obesity trial of 469 participants, CT-388 produced up to 22.5% placebo-adjusted body weight reduction at 48 weeks at the highest dose. The weight-loss curve had not yet plateaued at the end of the trial, suggesting further reductions might be achievable with longer dosing. Roche acquired Carmot Therapeutics in late 2024 specifically to obtain CT-388, positioning it as their lead anti-obesity asset competing directly against tirzepatide and the next-generation Lilly and Novo Nordisk pipeline.

GLP-1 (glucagon-like peptide 1) is the native incretin hormone produced by enteroendocrine L-cells in the distal small intestine and colon in response to nutrient ingestion. It is the endogenous molecule that all GLP-1 receptor agonist drugs (semaglutide, liraglutide, etc.) are designed to mimic. Understanding native GLP-1 is essential to understanding the entire drug class built upon its biology.

Upon release, GLP-1 binds to GLP-1 receptors (GLP-1R) — G protein-coupled receptors expressed on pancreatic beta cells, the GI tract, the heart, the kidneys, and critically, the brain. In the pancreas, GLP-1R activation stimulates adenylyl cyclase, raising intracellular cAMP levels, which potentiates glucose-stimulated insulin secretion. This glucose-dependence is a key safety feature — GLP-1 only promotes insulin release when blood sugar is elevated, minimizing hypoglycemia risk. Simultaneously, GLP-1 suppresses glucagon secretion from alpha cells, further reducing hepatic glucose output.

In the brain, GLP-1 receptors in the hypothalamus (arcuate nucleus, paraventricular nucleus) and brainstem (area postrema, nucleus tractus solitarius) mediate appetite suppression and satiety. GLP-1 also activates vagal afferents to slow gastric emptying, prolonging nutrient absorption and post-meal satiety. The critical limitation of native GLP-1 is its extremely rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), which cleaves the first two amino acids within 1-2 minutes, rendering it inactive. This ultra-short half-life is why pharmaceutical GLP-1 analogues require structural modifications (albumin binding, DPP-4 resistance) to achieve clinically useful durations of action.