PRECLINICAL PROFILE OF RGH-706, A NOVEL MCHR1 ANTAGONIST, FOR THE TREATMENT OF METABOLIC SYNDROMES SPECTRUM FROM WEIGHT MANAGEMENT TO RARE DISEASE LIKE PRADER-WILLI SYNDROME

Obesity is a worldwide health crisis affecting billions of people. High BMI accounted for 15% of the non-communicable diseases related to deaths. Obesity causes cardiovascular and metabolic diseases including MAFLD/MASH and predispose to cancer. With the advent of incretin analogues (GLP-1 agonists and GIP) the efficacy greatly improved, but the tolerance and side effect profile interfere with adherence. Fast rebound following cessation of GLP-1 treatment also indicate a need for a well-tolerated, and long-term maintenance therapy in weight management. Melanin-concentrating hormone (MCH), one of the most well-characterized neuropeptides expressed neurons in the hypothalamic hunger centre (LH) and it plays pivotal role in energy homeostasis. MCHR1 present in numerous brain regions. It provides metabolic and hedonic control of energy homeostasis. Inhibition profoundly reduce food intake and energy conservation. in vitro and extended in vivo data shown efficacy of RGH-706. The comparative manner of analysis provides point of differentiation for RGH-706. The long residence time and the delayed development of in vitro potency comes with sustained and non-habituating efficacy in DIO animal models. The effect is. Western diet-induced MAFLD/MASH model responded with remarkable improvement in steatosis, inflammatory and fibrotic status, surpassing drug candidates. In vivo efficacy of RGH-706 proved to have 10-to >1000-times over various lclinical candidates. The clear differentiation is demonstrated across species, provided the foundation to proceed into clinical development. A successful Phase II study in Prader–Willi syndrome (PWS) further verified the preclinical achievements. RGH‑706 may play a therapeutic role in supporting the transition from GLP‑1 therapy.