Setmelanotide (RM-493): A First-in-Class MC4 Agonist
A new drug class for the treatment of rare genetic disorders of obesity

Setmelanotide is a potent, first-in-class MC4 agonist in development for the treatment of obesity caused by genetic deficiencies in the MC4 pathway, a key pathway in humans that regulates energy expenditure, homeostasis, and appetite. MC4's critical role in weight regulation was validated with the discovery that a mutation of the MC4 receptor gene results in early-onset and severe obesity, as do other genetic defects in the MC4 pathway. The first generation of MC4 agonists were small molecules that failed primarily due to safety issues, particularly increases in blood pressure. In contrast, setmelanotide is a peptide that retains the specificity and functionality of the naturally occurring hormone that activates MC4 and has not been shown to adversely affect blood pressure in our Phase 1 and Phase 2 clinical trials.

Development Stage:
We have initiated two Phase 2 clinical trials in rare genetic disorders of obesity associated with defects in the MC4 signaling pathway. The first Phase 2a clinical trial will evaluate the safety and efficacy of setmelanotide on weight and eating behaviors in patients with Prader-Willi syndrome (PWS), a rare genetic disorder that causes life-threatening obesity. Recent scientific evidence implicates defects in the MC4 signaling pathway as the root cause of the weight and appetite abnormalities in PWS.

The second Phase 2a clinical trial will evaluate the safety and efficacy of setmelanotide on weight and appetite in POMC-null patients. POMC-null obesity is a very rare, life-threatening genetic disorder. These patients lack the POMC gene and have severe, early-onset obesity and extreme hunger. As in Prader-Willi syndrome, scientific evidence links these signs and symptoms in POMC-null patients to a genetic defect in the MC4 pathway. We intend to use the results of our Phase 2a clinical trials of setmelanotide in these indications potentially as the foundation for planning pivotal registration clinical trials. It is our intention to work with the FDA on a focused clinical program for each indication.

Before initiating these trials, we have treated approximately 200 patients with setmelanotide. These trials included a Phase 1b proof-of-concept clinical trial with setmelanotide in obese patients, and one cohort of patients with mutations in one of the MC4 receptor genes. These clinical trials demonstrated promising weight loss with good tolerability.