CT-388vsMazdutide

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.

Mazdutide is a dual-receptor agonist that activates both GLP-1 and glucagon receptors, combining appetite suppression with increased energy expenditure. The GLP-1 component functions similarly to other GLP-1 agonists — binding to receptors in the hypothalamus to reduce hunger, stimulating glucose-dependent insulin secretion from pancreatic beta cells, and slowing gastric motility to prolong post-meal satiety.

The glucagon receptor component distinguishes mazdutide from pure GLP-1 agonists. Glucagon binding in the liver activates adenylyl cyclase, increasing cAMP and activating protein kinase A, which phosphorylates key enzymes in fatty acid oxidation and ketogenesis. This drives the liver to burn stored fat as fuel rather than accumulate it — a mechanism with direct therapeutic relevance for patients with metabolic-associated fatty liver disease (MAFLD). In adipose tissue, glucagon signaling promotes lipolysis and may activate thermogenic programs in brown and beige fat cells.

The engineering challenge in dual GLP-1/glucagon agonists is balancing the hyperglycemic effect of glucagon against the glucose-lowering effects of GLP-1. Mazdutide achieves this by tuning the relative receptor affinities so that GLP-1-mediated insulin secretion offsets glucagon-driven glucose production, resulting in net glycemic improvement alongside enhanced fat oxidation and energy expenditure.