Rhythm begins two Phase II trials of setmelanotide in rare genetic disorders of obesity

Both conditions are rare genetic disorders of obesity associated with defects in the MC4 signaling pathway.

Phase 2 Trial in Prader-Willi Syndrome (PWS)

The first Phase 2 trial will evaluate the safety and efficacy of setmelanotide on weight and eating behaviors in patients with Prader-Willi syndrome (PWS). PWS is a rare genetic disorder that causes life-threatening obesity. Recent scientific evidence implicates defects in the MC4 pathway as the root cause of the weight and appetite abnormalities in PWS.

"The Phase 2 Prader-Willi clinical trial will assess the effect of setmelanotide as essentially ‘replacement therapy’ for the treatment of the severe obesity and hyperphagia in PWS," said Fred Fiedorek, MD, Chief Medical Officer of Rhythm. "We are taking a personalized medicine approach with setmelanotide to restore lost function that we believe is caused by a defect in the MC4 signaling pathway in patients with PWS."

The genetics of PWS are complex, involving loss of function of several genes on chromosome 15. Recent scientific evidence highlights that a defect in one of these — the MAGEL2 gene — impairs the function of POMC (pro-opiomelanocortin) neurons, which are key components of the MC4 pathway that normally promote satiety by activating downstream MC4 receptors.

Mice lacking the MAGEL2 gene have impaired POMC neurons and therefore develop many of the same symptoms exhibited by people with Prader-Willi syndrome. By bypassing the defective POMC neurons and activating the MC4 pathway below the "block," setmelanotide may reestablish weight and appetite control in PWS patients.

This Phase 2 trial is designed to evaluate the effects of setmelanotide on weight reduction and PWS-specific food-related behavior in obese patients with PWS. The randomized, double-blind, placebo-controlled study will evaluate the safety and efficacy of setmelanotide administered once daily by subcutaneous injection for up to 10 weeks of treatment. The trial will enroll approximately 36 obese adolescent and adult patients with PWS.

Phase 2 Trial in POMC-Null Obesity

A second Phase 2 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 for which there are no effective treatments. POMC-null 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.

"Patients with POMC-null mutations have severe obesity, with BMIs exceeding 40 and uncontrolled appetite beginning in childhood," said Peter Kuhnen, MD, Institute for Experimental Pediatric Endocrinology, Charite University Medicine Berlin, and investigator on the study. "Today there are no effective treatments for this rare genetic disorder, so we are very excited to be working with Rhythm on the setmelanotide clinical trial."

The POMC-null Phase 2 clinical trial will evaluate the safety and efficacy of setmelanotide administered once daily by subcutaneous injection for up to 13 weeks. This open-label trial is expected to enroll up to six obese adolescent and adult patients with POMC-null genetic defects.

"Our personalized medicine approach to restore MC4 pathway function in patients with Prader-Willi syndrome and POMC-null obesity is targeting what we believe is the direct cause of the extreme hyperphagia and obesity in these genetic diseases," said Keith Gottesdiener, MD, CEO of Rhythm.

"In previous setmelanotide clinical trials in general obesity, we have treated approximately 200 patients and have seen impressive weight loss with good tolerability. For PWS and POMC-null obesity, we believe there is the potential for even greater efficacy because setmelanotide should act to replace a missing MC4 signaling step. We are excited about these new clinical trials and the opportunity they represent for improving the lives of people with these genetic disorders."