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Adipose Tissue_Appetite_and Obesity

ORF50-07 - Dual MC3R/MC4R Activation Drives Weight Loss, Limits Rebound, and Preserves Lean Mass in Obese Nonhuman Primates

Monday, June 15, 2026
2:45 PM - 3:00 PM CT
Location: Room W185ABC
Disclosure(s):
Jillian L. Seiler, PhD: Endevica Bio: Employee (any industry) (); Kalohexis: Stockholder ()

The melanocortin pathway is a compelling target for obesity therapy, but multiple prior clinical programs focused on selective melanocortin-4 receptor (MC4R) agonism have not succeeded in demonstrating safe, translational efficacy in general obesity. We tested whether combined engagement of melanocortin-3 receptor (MC3R) and MC4R better recapitulates endogenous melanocortin signaling and improves metabolic outcomes by examining both mono-agonists and combined agonists to parse individual receptor contributions in nonhuman primates (NHPs) across metabolic states and in diet-induced obesity (DIO). Ligands with distinct MC3R and MC4R selectivity profiles were evaluated to quantify effects on feeding, body weight, and body composition. In lean animals fed ad libitum, selective MC3R or MC4R agonism did not materially change 24-hour food intake. In contrast, in an overnight fast/refeeding challenge, MC3R agonism produced a larger and more persistent suppression of refeeding than selective MC4R agonism, supporting state-dependent regulation of feeding by MC3R. In DIO NHPs dosed subchronically, selective MC4R agonism reduced food intake and body weight, while selective MC3R agonism did not reduce body weight in this setting; notably, combined MC3R+MC4R agonism produced greater weight loss than MC4R agonism alone, indicating cooperative, non-redundant receptor contributions and supporting combination agonism as the most effective approach. Building on these findings, we developed 710GO, an orally available dual MC3R/MC4R agonist that reduced caloric intake and induced significant weight loss in DIO NHPs. Chronic oral dosing achieved ~11.8% weight loss versus vehicle over 15 weeks and was followed by limited weight rebound after treatment cessation, with preferential fat mass loss and relative sparing of lean mass. Given historical concerns around cardiovascular liability with melanocortin agonists, telemetry monitoring showed no changes in heart rate, blood pressure, or QTc over 24 hours at doses up to 60 mg/kg PO. Together, these data support dual MC3R/MC4R activation as a strategy to enable meaningful weight loss with favorable weight-loss quality and limited rebound in obese primates, while addressing key limitations that have historically hindered selective MC4R agonist approaches.