Setmelanotide brings new hope for acquired hypothalamic obesity

Acquired hypothalamic obesity (AHO) is a rare and particularly challenging form of obesity to treat effectively. AHO develops when the hunger/fullness center in the hypothalamus of the brain is damaged by a tumour, surgery, radiation, trauma, or inflammation. Over 70% of people with AHO have hyperphagia, which is an abnormally increased drive to eat, characterized by heightened and prolonged hunger, longer time/larger amounts of food to reach fullness, shorter duration of feeling full after eating, severe preoccupation with food, abnormal food-seeking behaviors (eg eating food others left behind, stealing food, eating food from the trash), and distress when food is unavailable. Not only does hyperphagia lead to obesity, but feeling this degree and intensity of hunger impairs quality of life. Resting energy burn (expenditure) may also be reduced in some people with damage to the hypothalamus, which can contribute to weight gain as well.

Medications used for more common forms of obesity, including GLP1-based medicines, and bariatric surgery may help some people with AHO, but results have been variable. As blogged previously, setmelanotide (trade name Imcivree) is an MC4R agonist that is already approved in Canada for certain rare genetic forms of obesity. The MC4R pathway is a key pathway that is thought to be damaged in acquired hypothalamic obesity (AHO), leading to hyperphagia, so it makes sense to evaluate whether setmelanotide could be of benefit to reduce weight and hunger/hyperphagia in this condition.

The TRANSCEND study, recently published in the New England Journal of Medicine, enrolled 120 people age 4-66 years, and randomly assigned them to receive setmelanotide or placebo once daily. At 52 weeks, average BMI decreased by 16.5% with setmelanotide, compared with a 3.3% increase with placebo. Importantly, hunger scores and hyperphagia improved with setmelanotide more so than with placebo. The most frequent side effects with setmelanotide were skin darkening (56%), nausea (51%), vomiting (40%), and headache (38%); most of these were mild to moderate in severity. Darkening of pre-existing moles can occur because the medication can activate receptors involved in melanin production; skin and moles should be monitored on treatment. As people with AHO often have multiple pituitary hormone deficiencies, nausea/vomiting can be more serious and complicated to manage (an endocrinologist needs to be involved in care).

Setmelanotide is now approved for treatment of obesity and control of hunger in people with AHO age 4 and up in the USA and in Europe based primarily on these data, and is currently under review by Canadian regulatory authorities.

BOTTOM LINE: The TRANSCEND study demonstrates an important benefit of setmelanotide to help people with acquired hypothalamic obesity (AHO) reduce weight, hunger, and hyperphagia, and improve quality of life. Setmelanotide appears to address an important part of the underlying biology of AHO, and represents a genuinely exciting advance for people living with AHO and their families.

UPDATE SEP 22, 2026: Setmelanotide is now approved in Canada for weight management in patients 4 years and older with acquired hypothalamic obesity!

Disclaimer: I receive honoraria as a consultant from the makers of setmelanotide (Rhythm Pharmaceuticals).

Subscribe to my blog (upper right) and follow me on X @drsuepedersen !

Share this blog post using your favorite social media link below!