Mutation of the MC4 Receptor Gene

MC4 deficiency due to heterozygous mutations in the MC4 gene is the most common genetic cause of obesity. RM-493 may restore MC4 function by increasing activity in the one normal copy of the MC4 gene. A 2005 epidemiological study performed in Europe reported a prevalence of 1%-2% of genetic defects in the MC4 gene in the obese population with a body mass index, or BMI, of greater than 30 kg/m2, and studies performed in both Europe and the United States, in 2000 and 2003, respectively, reported a prevalence of up to 4% of these genetic defects in more severely obese populations with a BMI of greater than 35 kg/m2. These prevalence rates suggest that there are approximately one million people in the United States with obesity caused by a mutation of the MC4 gene. These patients have a higher risk than the general population for early onset obesity and severe obesity and their complications such as diabetes. Furthermore, MC4 deficiency may offset the beneficial effects of diet and exercise for sustained weight loss, limiting treatment options for these individuals.

Prader Willi Syndrome (PWS)

PWS, another form of genetic MC4 deficiency, is an orphan disease with a prevalence ranging from approximately one in 8,000 to one in 25,000 patients in the United States. PWS patients exhibit intellectual disability and delayed growth. A hallmark of the disease is severe hyperphagia, which leads to severe obesity and other complications.

For PWS patients, obesity is the greatest threat to their health, and these patients often die at a young age from obesity-related complications. Hyperphagia has a significant negative impact on the patients’ quality of life as well as causes obesity and a range of associated co-morbidities. Normal satiety, or the feeling of fullness after eating, does not exist in a person with PWS. The physiological drive to eat is so powerful and overwhelming that most PWS patients will go to great lengths to eat large quantities of food, even if it is spoiled, indigestible, or unpalatable to others.

Hyperphagia impairs the PWS patients’ ability to live independently, requiring costly and constant supervision to prevent overeating. Without supervision, PWS patients are likely to die prematurely as a result of choking, stomach rupture, or tissue necrosis, or from complications caused by morbid obesity, such as right heart failure and respiratory failure. While a small number of PWS patients are cared for in costly group homes, the majority of PWS patients are cared for in their homes, and their families undertake substantial effort to create physical barriers to eating. These efforts result in extremely stressful environments as caregivers often place locks and alarms on cabinets and refrigerators that contain food to impede PWS patients’ efforts to obtain food at all times. The typical annual cost of treating a PWS patient is approximately $100,000, excluding the often significant costs of drug therapies related to other medical and psychological conditions, and the costs of any lost time from work experienced by their families due to responsibilities related to the care of a PWS patient.

Currently, there is no approved treatment for PWS, and most research to date has targeted the treatment of specific symptoms. For many individuals affected by the disorder, the elimination of some of the most difficult aspects of the syndrome, such as hyperphagia and obesity, would represent a significant improvement in quality of life and provide the potential opportunity for patients to live independently.