medwireNews: Phase 2 trial results support use of the melanocortin-4 receptor agonist setmelanotide for the treatment of rapid excess weight gain and hunger in patients with hypothalamic obesity.
“The consistent efficacy across all adherent patients suggests that impaired melanocortin signalling might contribute to the underlying pathophysiology of hypothalamic obesity”, say Christian Roth (Seattle Children’s Research Institute, Washington, USA) and colleagues.
The open-label, multicentre trial involved 18 patients aged 6–40 years (mean age 15 years) with obesity and a history of hypothalamic injury in the preceding 8 months or a diagnosis of a craniopharyngioma or another non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy or radiotherapy between 6 months and 15 years previously.
Obesity was defined as a BMI in the 95th percentile for those aged 6 to 17 years or at least 35 kg/m2 for those aged 18 years or older.
The patients were predominantly male (61%) and White (78%), and all were on concomitant medications, most commonly thyroid hormones, desmopressin, and glucocorticoids, which the participants continued to take for the duration of the study.
Previous attempts to lose weight using pharmacotherapy had been made by 72% of patients, four of whom continued with treatment – naltrexone and oxytocin in three patients and methylphenidate in one patient. However, no diet or exercise guidance was provided and adjustment to these variables was not recorded, the investigators note.
Subcutaneous setmelanotide was started at a daily dose of 1.0 mg for 2 weeks in patients aged 6 to younger than 16 years, increasing to 2.0 mg for a further 2 weeks and to 3.0 mg thereafter. For patients aged 16 years and older, setmelanotide was started at a daily dose of 2.0 mg for the first 2 weeks and then increased to 3.0 mg/day.
In all, 89% of patients met the primary endpoint of at least a 5% reduction in BMI after 16 weeks of treatment. This included 92% of 13 participants younger than 18 years of age and 80% of five patients older than 18 years. The collective mean reduction in BMI was 15%.
“With setmelanotide therapy, adherent patients reversed the trajectory of weight gain and experienced a rapid and consistent decrease in BMI”, Roth et al comment in The Lancet Diabetes & Endocrinology.
Key secondary endpoints among the paediatric patients younger than 18 years included a clinically meaningful reduction of at least 0.2 points in BMI Z score at week 16, which was achieved by 92% of patients, with scores decreasing by a mean of 1.3 points from 3.9 points at baseline.
There was also a sustained reduction in hunger among the 11 children aged 12 years and older, starting after 1 week of setmelanotide treatment. Maximal daily hunger scores fell by an average of 2.9 points by week 16, which was a 45% decrease from the mean baseline score of 6.6 points.
All patients experienced at least one adverse event, the most common of which were nausea (61%), vomiting (33%) and skin hyperpigmentation (33%); all events except for one were mild or moderate in severity. Two patients discontinued setmelanotide, one due to hyperpigmentation and one due to increased liver transaminase levels.
The investigators report that 78% of patients who completed the 16-week trial opted to continue taking setmelanotide in the 12-month extension phase, “indicating patient satisfaction with the clinical benefit and tolerability of treatment.”
Although yet to be completed, the preliminary results from the extension phase suggest “sustained and increased benefit”, note the authors, with a mean 26% reduction in BMI from baseline.
Describing the findings as “encouraging”, Manuel Tena-Sempere (University of Córdoba, Spain) says in a related commentary: “Considering that weight gain is frequently intractable in patients with hypothalamic obesity, these findings hold promise for the development of effective and well tolerated treatments for the management of this complex condition.”
He adds that “conclusive demonstration of the robustness of these data,” are needed and are anticipated on the completion of an ongoing double-blind, randomised, placebo-controlled, phase 3 trial of setmelanotide in patients with hypothalamic obesity.
By Lucy Piper
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