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Rhythm Initiates Two Phase 2 Clinical Trials of Setmelanotide (RM-493) in Rare Genetic Disorders of Obesity Caused by MC4 Pathway Deficiencies

BOSTON, June 4, 2015 /PRNewswire/ -- Rhythm announced today the initiation of two Phase 2 clinical trials focused on evaluating the safety and effectiveness of setmelanotide (RM-493), the company's novel melanocortin 4 receptor (MC4R) agonist, for the treatment of Prader-Willi Syndrome (PWS) and POMC-null 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."

About Setmelanotide (RM-493)

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 Rhythm's Phase 1 and Phase 2 clinical trials.

About Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a rare genetic disease with a prevalence ranging from approximately one in 8,000 to one in 25,000 patients in the U.S. A hallmark of PWS is severe hyperphagia—an overriding physiological drive to eat—leading to severe obesity and other complications. Obesity is one of the greatest health threats to PWS patients, and hyperphagia impairs the ability of PWS patients to live independently, requiring costly and constant supervision to prevent overeating. Without supervision, these patients are likely to die prematurely as a result of choking, stomach rupture, or from complications caused by morbid obesity. Currently, there are no approved treatments for the obesity and hyperphagia associated with PWS.

About POMC-Null Genetic Obesity

First described as POMC deficiency syndrome, patients with POMC-null obesity have homozygous loss-of-function in the pro-opiomelanocortin (POMC) genes, which results in early-onset, severe obesity. This genetic disorder may also be associated with hormonal deficiencies, such as hypoadrenalism, and red hair and fair skin are common. POMC-null obesity is a very rare genetic disorder, and there are no approved treatments for the obesity and hyperphagia associated with this condition.

About Rhythm (

Rhythm is a biopharmaceutical company developing peptide therapeutics that address unmet needs in gastrointestinal diseases and obesity. Rhythm is developing the ghrelin peptide agonist, relamorelin (RM-131), for the treatment of diabetic gastroparesis and other gastrointestinal functional disorders; and the MC4R peptide agonist, setmelanotide (RM-493), for obesity caused by genetic deficiencies in the MC4 pathway. Rhythm investors include MPM Capital, New Enterprise Associates, Third Rock Ventures, Ipsen, and Pfizer Ventures. The company is based in Boston, Massachusetts.

Bart Henderson
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