Setmelanotide Promising in Obesity Caused by Rare Genetic Disorders

Marlene Busko

November 11, 2019

LAS VEGAS — The investigational drug setmelanotide was associated with a "clinically meaningful" effect on weight loss and hunger in two small trials in patients with obesity caused by two types of rare genetic mutations, researchers reported here at Obesity Week 2019.

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist designed to target the central melanocortin pathway involved in hunger regulation, is being developed by Rhythm Pharmaceuticals to treat patients with obesity as a result of pro-opiomelanocortin (POMC) or leptin receptor (LEPR) deficiencies. The trials were sponsored by Rhythm Pharmaceuticals.

Individuals with these gene deficiencies have a normal weight at birth but develop persistent severe obesity within months because of insatiable hunger (hyperphagia).   

Peter Kühnen, MD, of Charité University, Berlin, Germany, lead investigator in the POMC deficiency obesity phase 3 trial reported that eight of 10 participants lost 10% or more of their initial weight after 1 year of therapy, thus meeting the trial's primary efficacy endpoint.

And Erica van den Akker, MD, PhD, lead investigator of the phase 3 LEPR deficiency obesity study, told delegates that five of 11 patients in that trial met the same primary efficacy endpoint.

The drug also met its secondary efficacy endpoints and was generally well tolerated.

"Even though the syndromes, the mutations that were presented in the trials today are rare," it may turn out that similar pathways could be implicated in at least 10% of all obesity cases, said Lee M. Kaplan, MD, PhD, session chair and president of the American Society of Metabolic and Bariatric Surgery, speaking to Medscape Medical News.

"You are talking about the possibility that you have an entry into a mechanistic approach to treating obesity that right now is focused on these extreme cases, but may be actually quite contributory, to a lesser extent but more than other drugs, to the less rare genetic obesities," suggested Kaplan, who is a scientific consultant for Rhythm Pharmaceuticals.

Rare Form of Obesity, No Current Therapy

Kühnen told Medscape Medical News that there are no effective approved therapies for patients with either of these genetic disorders.

“Despite significant effort to control their weight and appetite, such as supportive care or lifestyle interventions, patients [with these gene defects] often regain weight after any short-term period of weight loss," Kühnen noted in a statement issued by Rhythm Pharmaceuticals.

And such patients are not likely to respond to bariatric surgery because the signaling pathways in the brain related to hunger and appetite would still be affected even after surgery, he explained.

The trial in the POMC-deficient patients showed that although responses varied, setmelanotide "has a profound impact" on weight loss in some cases, he noted.  

"This is the starting point," according to Kühnen. The next steps are "to test other patients with a genetic defect in this cascade, and then let's see who will benefit from it."

In the same statement, van den Akker, of Erasmus MC-Sophia Children's Hospital University in Rotterdam, the Netherlands, noted that in the LEPR deficiency obesity trial, "two patients experienced roughly 15% weight loss, while two other patients showed greater than 20% weight loss," which is "unprecedented" in this patient population.

She added that the findings "strongly suggest 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."

To Medscape Medical News, she elaborated that, since only case reports or case series have been reported in the medical literature, clinicians may think this genetic deficiency is "very rare, one in a million."

But a study published last week by van den Akker and others in the Netherlands suggests that the true prevalence could be around 1000 patients in Europe alone. Cases may be being missed because genetic testing is not always performed, she explained.

Promising Results in 21 Patients

The phase 3 trial in POMC-deficient patients tested setmelanotide in 10 patients: four adults (aged 19 to 30) and six children and adolescents (aged 11 to 18).

After a year of treatment at a therapeutic dose, the adults had a 22% decrease in mean body mass index (BMI), from 43.9 to 34.6 kg/m2 (P = .056).

And the six children and adolescents had a 49% decrease in BMI z-scores from 3.35 to 1.73 (P = .007).  

The phase 3 trial of the LEPR-deficient patients tested the therapy in eight adults (aged 19 to 37) and three children and adolescents (aged 11 to 18).

They had a mean BMI of 48.2 kg/m2 and a mean weight of 133 kg, and a "most hunger" score of 7.1 (on a scale of 0 to 10, where 10 indicated they had experienced extreme hunger at some point the previous day).

After about a year of therapy, the adults had a 10.6% decrease in mean BMI, from 51.2 to 45.8 kg/m2 (P = .01).

And the children and adolescents had a 13.3% decrease in BMI z-scores, from 3.52 to 3.03 (P = .12).

In both studies, when the therapy was stopped during a 4-week withdrawal period mid-trial, patients' weight and perception of hunger scores rapidly increased and then fell again when the study drug was resumed.

Setmelanotide was well tolerated in both trials, with no reported drug-related adverse cardiovascular events or significant changes in blood pressure or heart rate.

In the LEPR deficiency obesity trial, one participant discontinued therapy because of mild, treatment-related hypereosinophilia and one participant died of a cause not related to study drug.

NDA Submission by Next Year

Rhythm is also evaluating setmelanotide in patients with Bardet-Biedl syndrome and Alström syndrome.

The company expects to submit a new drug application to the US Food and Drug Administration for POMC deficiency obesity and LEPR deficiency obesity by the end of 2019 or early 2020.

Obesity Week 2019. Presented November 4, 2019.

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