CT-388vsHGH Fragment 176-191

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.

HGH Fragment 176-191 is the unmodified C-terminal segment of human growth hormone, representing exactly the last 16 amino acids of the 191-amino-acid GH molecule. Research identified this region as containing the molecular determinants responsible for GH's lipolytic activity, independent of the N-terminal domain that binds the growth hormone receptor and drives IGF-1 production and tissue growth.

The fragment activates lipolysis in white adipose tissue through interaction with beta-adrenergic signaling pathways. This triggers the cAMP/protein kinase A cascade that phosphorylates and activates hormone-sensitive lipase and perilipin proteins on the surface of lipid droplets within fat cells. The result is the breakdown of stored triglycerides into free fatty acids and glycerol, which are released into circulation for oxidation by energy-demanding tissues such as skeletal muscle and the liver.

Because the fragment lacks the binding regions for the GH receptor (located in amino acids 1-175), it does not activate the JAK2-STAT5 signaling pathway responsible for hepatic IGF-1 synthesis, somatic growth, or the insulin-antagonistic effects of full-length growth hormone. However, the shorter half-life compared to AOD-9604 (which has an additional stabilizing tyrosine residue) means more frequent dosing is required, and clinical evidence supporting its efficacy in humans remains very limited.