Setmelanotide Significantly Decreases BMI in Patients With POMC Or LEPR Deficiency, Phase 3 Trials Show
One-year treatment with setmelanotide in two Phase 3 trials significantly decreased the body mass index (BMI) of people with POMC deficiency or LEPR deficiency, two genetic obesity disorders.
The data were presented at ObesityWeek 2019, the annual meeting of The Obesity Society, held Nov. 3-8 in Las Vegas.
Mutations in genes along the melanocortin-4 receptor (MC4R) pathway, such as POMC, LEPR and MC4R, are common causes of genetic obesity. Such mutations effectively block the MC4R pathway, which helps people know when to eat and signals when they are full.
Setmelanotide, developed by Rhythm Pharmaceuticals, binds to MC4R and is intended to restore this pathway and help regulate hunger and satiety, or feeling full.
In each trial — NCT02896192 for POMC deficiency and NCT03287960 for LEPR deficiency — 10 participants were treated with setmelanotide for 12 weeks, then with a placebo for 8 weeks. That was followed by setmelanotide for a further 32 weeks, totaling one year of treatment. Both trials were sponsored by Rhythm.
Previously reported findings revealed that both trials met their primary endpoint, or goal, with a high proportion of participants experiencing a decrease in body weight of at least 10%. More than half also showed less hyperphagia, or insatiable hunger, after one year of treatment.
Updated results, presented at the meeting, showed a significant decrease in BMI — which takes into account a person’s weight and height — from 43.9 to 34.6 kg/m2 on average, among four participants with POMC deficiency ages 19 and older. This corresponds to a nearly 22.3% reduction associated with setmelanotide treatment.
Among the six participants with POMC deficiency younger than 19, average BMI z-score — a standard measure of relative weight adjusted for the child’s age and sex — decreased significantly, from 3.35 to 1.73, corresponding to a 49.2% difference.
“Like many people living with rare genetic disorders of obesity, people with POMC deficiency obesity experience early-onset, rapid weight gain and severe, insatiable hunger, which are the two hallmarks of these disorders,” Peter Kühnen, MD, the lead investigator for this trial, said in a press release.
“By reducing the weight gain and hunger endemic to POMC deficiency obesity, setmelanotide has the potential to shift the treatment paradigm for these patients,” added Kühnen, from the Institute for Experimental Pediatric Endocrinology at Charité Universitätsmediz in Germany.
In LEPR, eight participants ages 19 and older — all with the protein deficiency — experienced an average BMI decrease from 51.2 to 45.8 kg/m2, which was a 10.6% reduction.
The change in BMI z-score for the two individuals with LEPR deficiency who were younger than 19 was not statistically significant.
The findings also showed that treatment with setmelanotide did not alter blood pressure and heart rate significantly in participants in either trial. Overall, setmelanotide was well-tolerated and did not lead to cardiovascular adverse events.
“Notably … two patients experienced roughly fifteen percent weight loss, while two other patients showed greater than twenty percent weight loss,” said Erica Van Den Akker, MD, PhD, lead investigator in LEPR trial.
“Weight loss of this magnitude is unprecedented in the natural history of this patient population, and strongly suggests that setmelanotide has the potential to restore MC4R pathway function and serve as a safe, effective therapy for patients with rare genetic disorders of obesity,” she added.
The company expects to file a new drug application with the U.S. Food and Drug Administration seeking approval of setmelanotide for these two forms of genetic obesity. That application should be submitted by the first quarter of 2020.
“Setmelanotide has demonstrated a statistically significant and clinically meaningful impact on the severe obesity and unrelenting hunger in patients living with POMC deficiency obesity or LEPR deficiency obesity,” said Murray Stewart, MD, Rhythm’s chief medical officer.
“With these supporting data, we are also demonstrating that setmelanotide may have additional therapeutic benefits, driving improvements in BMI and other parameters that are critical to overall health,” he added.
During ObesityWeek 2019, Rhythm also is presenting the results of glucose and lipid parameters, as well as genetic data from both trials.
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