BOSTON, November 6, 2015— Rhythm Pharmaceuticals, Inc. announced today the results from a proof-of-concept, Phase 1b clinical trial assessing the safety and efficacy of setmelanotide (RM-493), the company’s novel melanocortin-4 receptor (MC4R) agonist, in obese patients with a heterozygous genetic defect in MC4R. The trial demonstrated that after four weeks of treatment, setmelanotide reduced weight in patients with an MC4R heterozygous deficiency obesity, with good tolerability. The study results were featured in an oral presentation at the ObesityWeek 2015 conference in Los Angeles.
Setmelanotide activates MC4R, which is part of the key pathway that can independently regulate energy homeostasis and appetite. The critical role of the MC4 pathway in weight regulation was validated with the discovery that single genetic defects along this pathway result in early onset and severe obesity. An expanding set of severe obesity genetic defects are now identified that involve genes in the pathway that are either upstream of MC4R—specifically, pro-opiomelanocortin (POMC) deficiency obesity, leptin receptor deficiency obesity, and likely Prader-Willi Syndrome (PWS)—or genes that are downstream of MC4R or that affect MC4R itself.
“This early study with setmelanotide focused on MC4 pathway defects downstream of the MC4 receptor,” said Fred Fiedorek, MD, CMO of Rhythm. “While downstream defects are not our current area of focus, these findings assert a foundation for our ongoing Phase 2 setmelanotide studies in upstream MC4 pathway genetic deficiencies, which may cause more severe, life-threatening obesity.”
In this pilot study, obese (BMI≥30kg/m2) patients with a heterozygous MC4R loss-of-function mutation were enrolled in a double-blind, placebo-controlled, randomized, parallel-group study for 4 weeks. Eight patients (six active, two placebo) received placebo or RM-493 at 0.01 mg/kg/day (~ 1 mg/day) by continuous subcutaneous infusion. Key endpoints were safety, weight loss, waist circumference, and caloric intake. Setmelanotide was well tolerated over 4 weeks, with no serious adverse events or discontinuations. The most common side effects were headache and skin tanning, with the latter believed to be due to off-target activity at the related melanocortin-1 receptor. Setmelanotide demonstrated strong trends for placebo-subtracted weight loss ( 2.62 kg; p=0.088); WC ( 5.1 cm; p=0.188) and daily caloric intake ( 351 kCal/day; p= not significant), without clinically important effects on heart rate or blood pressure.
“The weight loss demonstrated in this study is promising, since these patients only have one functioning MC4R,” said Sadaf Farooqi, PhD, Wellcome Trust Senior Clinical Fellow and Professor of Metabolism and Medicine at the University of Cambridge Metabolic Research Laboratories. “We are very excited about the potential of Rhythm’s ongoing studies focused on treating more life-threatening forms of genetic obesity, in which we believe there is potential for even greater efficacy.”
“We are taking a different approach to treating rare genetic disorders of obesity, focusing on specific genetic deficiencies affecting the MC4 pathway,” said Keith Gottesdiener, CEO of Rhythm. “We believe that this approach has the potential to restore lost function in the MC4 pathway.”
About MC4 Heterozygous Deficiency Obesity
MC4 heterozygous deficiency, also known as heterozygous MC4R mutation carriers, in which one of the genes for the MC4R are not fully functional, results in a strong predisposition to early onset and severe obesity and is the most common genetic cause of obesity. There are currently no approved therapies for MC4 heterozygous deficiency obesity.
About Setmelanotide (RM-493)
Setmelanotide is a potent, first-in-class MC4R 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. The critical role of the MC4 pathway in weight regulation was validated with the discovery that single genetic defects along this pathway result in early onset and severe obesity. A Phase 2 setmelanotide trial is ongoing for the treatment of Prader-Willi syndrome (PWS), a rare genetic disorder that causes life-threatening obesity. Recent scientific evidence implicates defects in the MC4 pathway as the likely cause of the weight and appetite abnormalities in PWS. A second Phase 2 trial is ongoing for the treatment of pro-opiomelanocortin (POMC) deficiency obesity, a very rare, life-threatening genetic disorder of the MC4 pathway associated with unrelenting appetite and obesity
Rhythm is a biopharmaceutical company focused on developing peptide therapeutics for the treatment of rare genetic deficiencies that result in life threatening metabolic disorders. Rhythm’s lead peptide product candidate is setmelanotide, a first in class melanocortin 4 receptor, or MC4R, agonist for the treatment of rare genetic disorders of obesity. The company is based in Boston, Massachusetts.