Congruence Therapeutics  announced that the first participant has been dosed in its Phase 1/1b clinical trial evaluating CGX-926, an oral small-molecule MC4R corrector being developed for the treatment of genetic obesity caused by mutations in the melanocortin-4 receptor (MC4R).

The first-in-human Phase 1/1b study is designed to evaluate the safety, tolerability, and pharmacokinetics of CGX-926, while also exploring preliminary efficacy in individuals with MC4R-deficient obesity. Mutations in the MC4R gene represent the most common form of genetic obesity and lead to early-onset obesity and hyperphagia (i.e., increased drive to eat).

In the brain, MC4R is a key part of the leptin–melanocortin pathway, a central regulator of appetite and metabolic homeostasis. Genetic studies have extensively validated MC4R, a G protein-coupled receptor (GPCR), as a key driver of disease. It is estimated that between 70,000 to 100,000 individuals in the United States carry pathogenic MC4R variants leading to early onset obesity.

CGX-926 is an oral small-molecule corrector designed to bind and stabilize mutant MC4R, thereby restoring receptor folding, trafficking to the cell surface, and downstream signaling. Preclinical data presented at ObesityWeek in November 2025 demonstrated that CGX-926 dose-dependently reduced body weight and food consumption in a proprietary genetic mouse model of MC4R deficiency. In these studies, CGX-926 also induced weight loss while preserving lean muscle mass.

MC4R agonists, such as setmelanotide, have demonstrated clinical benefit in patients with ligand deficiencies driven by upstream mutations, including in POMC, LEPR and others. However, these therapies do not directly address defects in the MC4R receptor itself and are not indicated for use in patients with MC4R mutations.

Dr. Sadaf Farooqi, Professor of Metabolism and Medicine at the University of Cambridge, UK is serving as the Principal Investigator for the Phase 1b trial in participants with MC4R mutations.  Dr. Farooqi is a world-leading clinician scientist specializing in the genetic causes of obesity and has served as Principal Investigator on a number of other related trials, including those of setmelanotide. She commented that: "after more than two decades of research on MC4R, I am delighted to be testing this new treatment in people with MC4R deficiency, with Congruence Therapeutics.  Given the prevalence of this condition, and the lack of targeted therapy, this development offers real hope for people with this condition who suffer from persistent hunger and obesity from childhood."

"Dosing the first participant in this study marks an important milestone for our CGX-926 program and highlights the ability of our Revenir™ platform to generate development-ready therapies targeting genetically validated drivers of disease," said Michael D. Harvey, Ph.D., Chief Development Officer of Congruence Therapeutics.

Congruence has engaged Quotient Sciences to execute the trial, leveraging their Translational Pharmaceutics^® platform to evaluate the safety and pharmacokinetics of CGX-926 while also enabling an early assessment of efficacy in participants with MC4R-deficient obesity at the University of Cambridge.

Congruence Therapeutics expects data to emerge from the Phase 1/1b program in the first half of 2027.