Setmelanotide Lowers BMI and Hunger in Acquired Hypothalamic Obesity

Key Takeaways

• At 52 weeks, BMI changed more favorably with setmelanotide than with placebo in acquired hypothalamic obesity.
• Hunger scores also improved more with setmelanotide over 52 weeks.
• Adverse events were common, serious adverse events were more frequent with setmelanotide, and expanded FDA and EMA indications were also noted.

In acquired hypothalamic obesity, setmelanotide was associated with a 16.5% least-squares mean BMI reduction at 52 weeks, while placebo was associated with a 3.3% increase. Hunger scores also moved in a more favorable direction over the same period. The population included children and adults with obesity after hypothalamic tumor, lesion, or injury. These findings came from the randomized phase III TRANSCEND trial in acquired hypothalamic obesity.

The TRANSCEND phase III trial enrolled patients aged 4 years or older with acquired hypothalamic obesity. Eligibility required BMI at or above the 95th percentile for age and sex in younger participants, or at least 30 in adults, plus a history of hypothalamic tumor, lesion, or injury. Patients were randomly assigned 2:1 to setmelanotide 1.5 to 3.0 mg or placebo, given subcutaneously once daily for 52 weeks after dose escalation. The trial enrolled 120 patients, including 81 assigned to setmelanotide and 39 to placebo, and the primary endpoint was mean percent change in BMI over 52 weeks. The mean age was 19.9 years, with a range of 4 to 66 years, and the cohort consisted primarily of patients with craniopharyngioma. Published in The New England Journal of Medicine, the study addressed severe hypothalamic obesity that can develop after treatment for tumors involving the hypothalamus.

Over 52 weeks, least-squares mean BMI change was –16.5% with setmelanotide and 3.3% with placebo. The corresponding 95% confidence intervals were –19.3 to –13.8 and –0.6 to 7.2, respectively, with P < .001. Weekly average maximal daily hunger scores changed by a least-squares mean of –2.73 with setmelanotide and –1.45 with placebo. The 95% confidence intervals were –3.28 to –2.18 and –2.23 to –0.67, respectively, with P = .009. Baseline BMI values were 41.2 ± 9.7 in adults and 3.61 ± 1.66 in younger patients. Both BMI and hunger changed more favorably with setmelanotide during the 52-week study period.

All patients in the setmelanotide arm had an adverse event, compared with 90% in the placebo group. Serious adverse events occurred in 28% and 8%, respectively. Common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache.