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Rhythm Pharmaceuticals Reports Positive Results from Phase 2 Clinical Trial of Setmelanotide in Hypothalamic Obesity

July 12, 2022

Rhythm Pharmaceuticals reported positive interim results from a phase 2 clinical trial evaluating setmelanotide, the company’s MC4R agonist, for the treatment of severe obesity and hyperphagia in people living with hypothalamic obesity.

Photo: David Meeker, chair, president, and CEO of Rhythm

Based on the encouraging results, the company intends to proceed to phase 3 clinical development following consultation with regulatory agencies.

Hypothalamic obesity is a rare, acquired form of extreme obesity that occurs following damage to the hypothalamic region of the brain, which is responsible for controlling physiological functions such as hunger and weight regulation. It most frequently follows the growth or surgical removal of craniopharyngioma, astrocytoma or other rare brain tumors. Patients experience rapid weight gain, a reduction in energy expenditure an increase in hunger in the first six to 12 months following tumor resection, and ultimately develop severe obesity. In addition, people living with hypothalamic obesity may also experience delayed puberty and infertility, decreased physical activity, excessive daytime sleepiness, attention hyperactivity disorder, seizures, and psychiatric conditions.

Setmelanotide is a melanocortin-4 receptor (MC4R) agonist. The MC4R is part of the key biological pathway that regulates hunger, caloric intake, and energy expenditure. Variants in genes may impair the function of the MC4R pathway, potentially leading to decreased energy expenditure, hyperphagia and early-onset, severe obesity. Rhythm is developing setmelanotide as a targeted therapy to potentially restore the function of an impaired MC4R pathway and, in so doing, potentially increase energy expenditure, reduce hunger and weight in patients with rare genetic diseases of obesity.

In the EU and Great Britain, setmelanotide is marketed as Imcivree and is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. IMCIVREE should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology.

“Therapeutic options are very limited for patients with hypothalamic obesity, which is the result of damage to the medial hypothalamic region of the brain where MC4R pathway signaling is impaired due to certain tumors and their treatment. Surgical intervention, radiation treatment, or even the growth and position of the tumor itself can leave patients with aggressive, rapid, and debilitating weight gain,” said M. Jennifer Abuzzahab, McNeely Pediatric Diabetes Center and Endocrine Clinic, Children’s Minnesota and an investigator on the phase 2 trial. “I believe these interim results for setmelanotide represent a major milestone for the hypothalamic obesity community. In this 16-week trial, patients receiving setmelanotide achieved a remarkable reduction in body weight, suggesting this precision therapy has the potential to transform the care of this rare, acquired obesity.”

The Phase 2 clinical trial is a multi-center, open-label, proof-of-concept study that enrolled 18 patients with hypothalamic obesity who are between 6 and 28 years old. The trial consisted of 16 weeks of treatment with setmelanotide administered once daily by subcutaneous injection, including an initial period of dose titration. The primary endpoint is the percentage of patients who achieve more than 5 percent reduction in BMI from baseline after 16 weeks of treatment compared to a historic control of less than 5 percent in this population.

Of the 18 patients enrolled in this Phase 2 study, three discontinued due to adverse events, each of whom had achieved a reduction in BMI of more than 5 percent at the time they discontinued, and one patient was discontinued due to documented non-compliance to therapy. In total, 14 of 18 patients enrolled in this study remained on setmelanotide therapy as of July 11, 2022. Rhythm plans to present the full data from the 18 patients enrolled in this Phase 2 clinical trial at an upcoming medical meeting in the fall of 2022.

As of the data cutoff date of May 6, 2022, 11 patients were evaluable for assessment, including nine patients who completed 16 weeks of treatment and two patients who discontinued early due to treatment-related adverse events. Data highlights from an interim analysis of the full analysis set include a 17.2 percent mean percentage change in BMI. -15.8 percent mean change in body weight from baseline weight of 107.1 kg or -35.1 lb. mean weight loss from baseline.

Data highlights from an interim analysis of completers include a -19.5 mean percent change in BMI, a -17.8 mean percent change in body weight from baseline weight of 107.8 kg or 236.1 lb., a -17.8 kg or -37.7 lb. mean weight loss from baseline.

Setmelanotide also achieved a meaningful reduction in hunger scores. The mean change in hunger score for patients older than 12 years old who completed 16 weeks on therapy was -2.7 on a scale of 1-10, with 10 being most hungry.

Consistent with prior clinical experience in other rare MC4R pathway diseases, setmelanotide was observed to be generally well tolerated. The most frequently reported treatment-emergent adverse events included nausea, vomiting, COVID-19, diarrhea, injection site reaction and abdominal pain.

“We are highly encouraged by these initial results, which reinforce the importance of the MC4R pathway in regulating hunger, caloric intake, energy expenditure and ultimately body weight, as well as the potential role of setmelanotide in the management of diseases where this pathway is impaired,” said David Meeker, chair, president, and CEO of Rhythm. “We look forward to engaging with regulatory agencies to finalize our phase 3 development plans in the months ahead, as we aim to expand our reach and make setmelanotide available to the approximately 5,000 to 10,000 people living with hypothalamic obesity in the United States.”

Author: Rare Daily Staff

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