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TOPLINE:

Setmelanotide treatment over a 16-week period leads to a consistent decrease in both bodyweight and hunger among patients with hypothalamic obesity, according to the results of the first known study investigating the use of this targeted treatment in this indication.

METHODOLOGY:

• No approved treatments currently exist for hypothalamic obesity, a condition resulting from hypothalamic damage, characterized by rapid and severe weight gain, and sometimes presenting as insatiable hunger.
• This phase 2, open-label study conducted at five centers in the United States investigated the melanocortin-4 receptor agonist setmelanotide as a targeted treatment of hypothalamic obesity in patients with obesity and a history of hypothalamic injury or a diagnosis of a nonmalignant tumor affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation.
• Patients were administered age-dependent setmelanotide dose titration for the first 4 weeks, followed by 3.0 mg of subcutaneous setmelanotide daily for 12 weeks, with the total treatment duration being 16 weeks.
• The primary endpoint was the proportion of patients who achieved ≥ 5% reduction in body mass index (BMI) after 16 weeks, compared with a historic control rate of < 5% reduction in BMI in patients with hypothalamic obesity.

TAKEAWAY:

• Investigators enrolled 18 participants with hypothalamic obesity (mean age, 15 years; 61% men; 78% White; mean BMI, 38) between June 2021 and January 2022 who received at least one dose of setmelanotide.
• After 16 weeks, 16 (89%) patients achieved ≥ 5% reduction in BMI from baseline (P < .0001), with 92% of the patients aged < 18 years and 80% of the patients aged ≥ 18 years meeting the primary endpoint.
• The mean percent change in the BMI, bodyweight, and waist circumference of all 18 patients was −15%, −13%, and −10%, respectively.
• The maximal daily hunger score reduced by 2.9 points at week 16 for patients ≥ 12 years.
• Setmelanotide was generally well-tolerated, with the most common adverse events being nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhea (22%).

IN PRACTICE:

In assessing the findings of their trial, the authors concluded, "The consistent efficacy across all adherent patients suggests that impaired melanocortin signaling might contribute to the underlying pathophysiology of hypothalamic obesity."

SOURCE:

The study conducted by Christian L. Roth, MD, Seattle Children's Research Institute, Seattle, Washington, was published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

The study was limited in size, non-controlled, and potentially influenced by patient heterogeneity. Instances of hyperpigmentation may have been underreported. Participants received no guidance on diet or exercise regimens, and no adjustments to these regimens were recorded.

DISCLOSURES:

The study was supported by Rhythm Pharmaceuticals. Three authors declared being employees of Rhythm Pharmaceuticals. Some authors reported receiving compensation, research support, and payments, and others reported having ties with many sources, including the funding agency.