CT-388vsLiraglutide

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.

Liraglutide is a GLP-1 receptor agonist with 97% amino acid homology to native human GLP-1(7-37), modified by a single amino acid substitution (Lys34Arg) and attachment of a C16 palmitoyl fatty acid chain to Lys26 via a glutamic acid spacer. This acylation is the key pharmacological modification — the C16 fatty acid chain non-covalently binds to serum albumin after injection, creating an albumin-bound depot that is slowly released, extending the half-life from 1-2 minutes (native GLP-1) to approximately 13 hours. The acylation also confers resistance to DPP-4 enzymatic degradation.

Liraglutide activates the GLP-1 receptor (GLP-1R), a Gs-coupled GPCR expressed in pancreatic beta cells, the hypothalamus, the gastrointestinal tract, and the cardiovascular system. In pancreatic beta cells, GLP-1R activation increases intracellular cAMP, which enhances glucose-stimulated insulin secretion (GSIS) through PKA and Epac2 (exchange protein activated by cAMP) signaling. Crucially, this insulin secretion is glucose-dependent — it only occurs when blood glucose is elevated, which greatly reduces the risk of hypoglycemia compared to insulin or sulfonylureas. GLP-1R activation also suppresses glucagon secretion from alpha cells (reducing hepatic glucose output), promotes beta cell proliferation, and inhibits beta cell apoptosis.

The weight loss mechanism operates primarily through hypothalamic GLP-1R activation. GLP-1 receptors in the arcuate nucleus and paraventricular nucleus reduce appetite by activating POMC/CART (anorexigenic) neurons and inhibiting NPY/AgRP (orexigenic) neurons. This produces a sustained reduction in hunger and food intake. In the GI tract, GLP-1R activation delays gastric emptying, prolonging postprandial satiety and slowing the rate of nutrient absorption. The combined effects on appetite reduction and gastric emptying produce clinically meaningful weight loss — approximately 5-8% of body weight in clinical trials at the 3.0 mg daily dose (Saxenda). The LEADER cardiovascular outcomes trial demonstrated that liraglutide also reduces major adverse cardiovascular events, likely through anti-inflammatory, anti-atherogenic, and cardioprotective effects of GLP-1R activation in vascular endothelium and cardiomyocytes.