Rhythm Pharmaceuticals, based in Boston, MA, is a biopharmaceutical company focusing on the development of therapies to treat rare genetic diseases that cause obesity. Until now, there have not been any pharmacologic therapies that treat such conditions.
Results from two phase III studies were recently announced by Rhythm. The first study evaluated LEPR (leptin receptor deficiency). The second study evaluated POMC (proopiomelanocortin deficiency). The Lancet Diabetes & Endocrinology published both studies.
Results showed that eight of the ten participants with POMC deficiency obesity and five of the eleven LEPR deficiency obesity participants had about a ten percent weight loss at the one year mark.
About Setmelanotide, The Drug That Is Making It Happen
The Phase III studies evaluated an anti-obesity targeted therapy called setmelanotide. It is a melanocortin-4 receptor (MC4R) agonist.
The MC4R deficiency represents the most common type of monogenic obesity. It is a severe and rare obesity beginning early in life, exhibiting endocrine disorders and unusual appetite behavior.
A critical biological pathway which includes MC4R, regulates caloric intake, hunger, and energy output. The performance of the MC4R pathway may be affected by abnormalities in genes causing an increased appetite (hyperphagia) and the early onset of severe obesity.
Typically, patients with MC4R deficiency present significant obesity, increases in body mass and bone mineral density, abnormal linear growth, hyperphagia in infancy, and hyperinsulinaemia, which is a condition involving excess levels of insulin in the blood.
About POMC and LEPR
The severe obesity caused by the POMC deficiency starts early in life. People with POMC generally present low levels of the ACTH hormone. The other commonality is pale skin and red hair.
Infants who have the disease generally have a normal weight at birth but are excessively hungry. This causes hyperphagia. The babies are significantly obese by their first birthday. They may remain obese for their entire life.
Note that it has not been determined whether or not affected individuals are vulnerable to diabetes or cardiovascular disease.
As for the LEPR gene, its function is to provide instructions for creating the leptin receptor, a protein that aids the body in regulating weight.
But the leptin receptor loses its ability to function if there are changes in the LEPR gene. If that situation occurs, the leptin cannot attach to the receptor and the brain will not receive the “full” signal.
Rhythm and the FDA
Rhythm’s New Drug Application for setmelanotide was accepted by the FDA in early 2020 for the treatment of LEPR and POMC deficiency obesities. The FDA also granted Breakthrough Therapy to the drug, which allows for expediting its development and review.
Both the EMA and FDA granted setmelanotide Orphan Drug designations for LEPR and POMC deficiency obesities. The Orphan Drug designations award certain benefits to the companies in connection with the drug they are developing.
Looking Forward
Dr. Murray Steward, CMO of Rhythm, emphasized the significance of following through on genetic testing for variants that affect MC4R activation leading to severe obesity.
