Pro-opiomelanocortin (POMC) Deficiency Obesity
Pro-opiomelanocortin (POMC) deficiency obesity is a life-threatening ultra-orphan disease, with approximately 50 patients reported to date. We estimate that actual prevalence of this disorder could be between 100 and 500 patients in the U.S. Patients with POMC deficiency have unrelenting hyperphagia that begins in infancy, and they develop severe, early-onset obesity. POMC deficiency obesity results from two different homozygous genetic defects, both upstream (which refers to the relative position of the defect earlier in the pathway) of the MC4 receptor. Currently, there is no approved treatment for the obesity and hyperphagia associated with POMC deficiency obesity.
In 2016, The New England Journal of Medicine reported results from a setmelanotide Phase 2 trial in POMC deficiency obesity that demonstrated substantial weight loss in two adult patients. We have initiated a Phase 3 registration study to evaluate the safety and efficacy of setmelanotide in patients with POMC deficiency obesity, with setmelanotide administered once daily by subcutaneous injection for 12 months.
Leptin Receptor (LepR) Deficiency Obesity
Leptin receptor (LepR) deficiency obesity is an ultra‑rare orphan disease resulting in extreme hyperphagia and severe, early-onset obesity with an estimated prevalence of 1% of subjects with severe, early-onset obesity. We estimate actual prevalence could be between 500 and 2,000 patients in the United States. Like other deficiencies upstream in the MC4 pathway,LepR deficiency results in loss of function in the MC4 pathway. Therefore, patients with this indication also manifest intense hyperphagia and severe obesity from early childhood. Currently, there is no approved treatment for the obesity and hyperphagia associated withLepR deficiency obesity.
At ObesityWeek 2016, investigators presented initial data for the first patient enrolled in a Phase 2 non-randomized, open-label clinical trial of setmelanotide for the treatment of LepR deficiency obesity. We plan to initiate a Phase 3 registration study for LepR deficiency obesity in the near future.
Bardet-Biedl syndrome (BBS) is a life-threatening, ultra-rare orphan disease with a prevalence of approximately one in one hundred thousand in North America, which we estimate has an addressable patient population of approximately 1,500 to 2,500 patients in the United States. BBS is a monogenic disorder that causes severe obesity and hyperphagia (extreme, unrelenting hunger) as well as vision loss, polydactyly, kidney abnormalities, and other signs and symptoms. For these patients, hyperphagia and obesity can have significant health consequences for which there is currently no approved treatment. Recent scientific studies identify deficiencies affecting the MC4 pathway as a potential cause of the obesity and hyperphagia associated with BBS.
Prader-Willi syndrome (PWS) is a life-threatening orphan disease with prevalence estimates ranging from approximately one in 8,000 to one in 52,000, and with at least 8,000 diagnosed patients in the United States. A hallmark of PWS is severe hyperphagia, an overriding physiological drive to eat that leads to severe obesity and other complications. For PWS patients, hyperphagia and obesity are the greatest health threats, and these patients are likely to die prematurely as a result of choking, stomach rupture, or from complications caused by morbid obesity. Currently, there is no approved treatment for the obesity and hyperphagia associated with PWS.
Recent scientific studies identify deficiencies affecting the MC4 pathway as the likely cause of the obesity and associated symptoms of PWS, such as hyperphagia, and demonstrate that an MC4R agonist can directly impact these symptoms.
We are evaluating setmelanotide for the treatment of PWS in a Phase 2 study.
Additional Rare Genetic Deficiencies in the MC4 Pathway
We are also focusing on additional upstream MC4 pathway deficiencies for which setmelanotide can function as replacement therapy and provide activation of the pathway downstream of the defect, promoting satiety and weight control. The company is currently evaluating setmelanotide for the treatment of the following genetic disorders of obesity: POMC deficiency obesity, LepR deficiency obesity, Prader-Willi syndrome, Bardet-Biedl syndrome, Alström syndrome, POMC heterozygous deficiency obesity, and POMC epigenetic disorder.