Dual Activation of MC3R and MC4R Drives Weight Loss and Reduces Food Intake in Obese Primates

Introductory Paragraph The melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists prompted the investigation of whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation is key to unlocking the melanocortin system for the treatment of general obesity. To test this hypothesis, we designed and synthesized novel peptides to probe the distinct and combined roles of MC3R and MC4R in nonhuman primates (NHPs). We show that selectively agonizing MC3R modulates food intake in a state-dependent manner. Moreover, co-agonism of MC3R and MC4R results in more substantial metabolic effects than selective MC4R agonism, highlighting both a non-redundant and a cooperative role of MC3R. To leverage these discoveries, we developed 710GO, an orally-available MC3R/MC4R dual agonist peptide that induces significant weight loss in diet-induced obese (DIO) NHPs. Oral 710GO treatment demonstrates limited weight rebound, has additive effects in combination with GLP-1s, and exhibits a clean safety profile. These results reestablish the melanocortin system, specifically concerted MC3R/MC4R agonism, as a viable mechanism for next-generation obesity therapeutics. Competing Interest Statement DLM is a consultant, chief medical officer, stockholder, and has received grant funding from Endevica Bio Inc. DLM has served as a consultant for Alkermes Inc. and Pfizer Inc. RP is the chief executive officer, stockholder, and chair of the board for Endevica Bio Inc. JLS, ACI, EZ, KJK, TLB, BS, CRP, BHR, BAB, and JYD are employees and stockholders in Endevica Bio Inc. Footnotes ↵* Co-primary authors Selective compounds in the main text were mislabeled on page 4 and have been corrected. Figure 4B updated to show non-normalized weight rebound. This change was made to allow for ease of comparison with other weight loss compounds.