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08-05-2024 | Hypothalamic Disease | Editor's Choice | News

Data support setmelanotide as a treatment for hypothalamic obesity

Author: Laura Cowen


medwireNews: The synthetic melanocortin-4 receptor (MC4R) agonist setmelanotide leads to clinically meaningful reductions in BMI and hunger among people with hypothalamic obesity, phase 2 study findings indicate.

Writing in The Lancet Diabetes & Metabolism, Christian Roth (Seattle Children’s Research Institute, Washington, USA) and co-authors say their data “support the use of setmelanotide for treatment of rapid excess weight gain and hyperphagia in patients with hypothalamic obesity.”

They add: “The consistent efficacy across all adherent patients suggests that impaired melanocortin signalling might contribute to the underlying pathophysiology of hypothalamic obesity.”

Roth et al explain that the MC4R pathway within the hypothalamus is involved in the regulation of hunger, food intake, and energy expenditure, which in turn affect bodyweight. Previous research has shown that setmelanotide is associated with significant reductions in bodyweight and hunger in people with obesity due to MC4R pathway diseases.

“Given that MC4R signalling is impaired following hypothalamic damage, setmelanotide might alleviate symptoms of hypothalamic obesity by activating remaining hypothalamic MC4Rs and MC4Rs in the forebrain, brain stem, spinal cord, and periphery,” they suggest.

To test this hypothesis, the investigators recruited 18 patients with obesity and a history of hypothalamic injury or a diagnosis of a nonmalignant tumor affecting the hypothalamus that had been treated with surgery, chemotherapy, or radiation.

At baseline, the participants were aged 6–40 years (mean age 15 years; 61% male; 78% White) and had a mean BMI of 38.0 kg/m2. They were given subcutaneous setmelanotide once daily at a dose titrated up to 3.0 mg for a total duration of 16 weeks.

The researchers report that, at 16 weeks, 16 (89%) participants were still on treatment, all of whom met the primary endpoint of a clinically meaningful reduction in BMI of at least 5% from baseline. The mean reduction in BMI was 15% overall.

Among the secondary endpoints, there was a reduction in BMI Z score of at least 0.2 points for 92% of the 13 patients younger than 18 years old, and a reduction in bodyweight of at least 5% for 80% of the five patients aged 18 years or older.

In addition, 11 patients aged 12 years or older experienced a clinically meaningful reduction in maximal daily hunger score of 2.9 points, on a scale of 0–10, which corresponded to a 45% decrease from the mean baseline score. Roth and team note that the reductions in hunger scores were apparent from the first week of treatment.

All patients had at least one treatment emergent adverse event (AE) during the study, typically mild or moderate nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhea (22%). The only serious adverse event, Clostridium difficile colitis, was not treatment-related, say the investigators.

Two participants discontinued treatment due to treatment-related AEs of moderate severity, one due to hyperpigmentation and one due to increased liver transaminase levels.

Fourteen participants continued treatment in a long-term extension study. All 12 who completed at least 12 months of treatment still had a BMI reduction of 5% relative to the mean index trial baseline, with an average reduction of 26%.

Roth et al note, however, that patients who reduced, interrupted, or discontinued setmelanotide treatment, either during the phase 2 trial or the long­term extension trial, had an immediate increase in BMI that decreased when the setmelanotide dose was restarted or increased.

“Given these findings, patients with a history of hypothalamic insult might require long­term administration of setmelanotide to restore energy balance and maintain benefits of controlled hunger and weight gain,” they remark.

The authors conclude that their study “supports the further investigation of setmelanotide as a novel treatment for hypothalamic obesity,” and a phase 3 trial is already underway.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet Diabetes Endocrinol 2024; doi:10.1016/ S2213-8587(24)00087-1


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