Rhythm Pharmaceuticals Publishes Longer-Term Data on LEPR Deficiency Obesity Study

As Boston-based Rhythm Pharmaceuticals moves its lead obesity treatment into a second Phase III trial, the company was bolstered by the publication of longer-term data from its Phase II study of setmelanotide in Nature Medicine.

The longer-term data showed once daily subcutaneous injection of setmelanotide resulted in reductions in hyperphagia and body-weight in three patients with leptin receptor (LEPR) deficiency obesity. Setmelanotide is a first-in-classmelanocortin-4 receptor (MC4R) agonist used to treat patients with LEPR deficiency obesity, an ultra-rare orphan disease that results in hyperphagia (an abnormally increased appetite) and severe, early-onset obesity. The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation to setmelanotide.

The obesity targets the company is taking aim at are caused by genetic deficiencies in the MC4 pathway, a biological pathway in people that regulates weight by increasing energy expenditure and reducing appetite.

Rhythm’s researchers conducted a series of in vitro analyses of MC4R function in the study and the data suggests that setmelanotide's mechanism for MC4R activation may differentiate from the natural ligand and first-generation compounds, the company said. Additionally, Rhythm said the data showed setmelanotide “might overcome the presence of the naturally occurring neurotransmitter that inhibits the activation of MC4R.” Lastly, the MC4R research showed that setmelanotide may rescue specific MC4R mutations where the natural ligand cannot, Rhythm said.

The longer-term data released in the Nature Medicine publication showed that safety and tolerability of setmelanotide were consistent with previous findings and no serious adverse events were reported.

Keith Gottesdiener, chief executive officer of Rhythm, said the company was pleased with the longer-term Phase II study results, which represent “an important milestone” for its clinical development program.

“We are also encouraged by ongoing efforts to improve our understanding of the cellular and molecular mechanisms along the MC4 pathway. The fact that in vitro data suggest setmelanotide may rescue specific MC4R mutations where the natural ligand cannot might identify a subset of patients who may benefit from treatment with setmelanotide, which warrants further study,” Gottesdiener said in a statement.

Not only is Gottesdiener pleased, but so too is Pfizer, which has a significant stake in Rhythm. Last year the pharma giant acquired an additional block of shares that increased its holdings to a 5 percent stake in the company. Shares of Rhythm are up about 4 percent on the news of the longer-term data being published.

Rhythm anticipates completing enrollment in its Phase III LEPR deficiency trial by the end of 2018.

In addition to the newly initiated Phase III trial, Rhythm is also studying setmelanotide in a Phase III trial for the treatment of pro-opiomelanocortin (POMC) deficiency obesity, an ultra-rare genetic disorder associated with severe, early-onset obesity and unrelenting, abnormally increased appetite (hyperphagia).

Setmelanotide is also being studied in a Phase II trial for the treatment of obesity caused by Bardet-Biedl syndrome (BBS), a monogenic disorder that causes severe obesity and an insatiable appetite. Patients with the rare disease can also experience vision loss and kidney abnormalities.