The US Food and Drug Administration approved setmelanotide (IMCIVREE, Rhythm Pharmaceuticals), as the first and only therapy indicated for acquired hypothalamic obesity, a rare condition caused by injury to or dysfunction of the hypothalamus, according to a press release from Rhythm Pharmaceuticals.
The approval applies to adults and pediatric patients aged 4 years and older to reduce excess body weight and maintain long-term weight reduction.
Acquired hypothalamic obesity (HO) most often develops following the growth or treatment of craniopharyngioma, astrocytoma, or other hypothalamic-pituitary tumors, although traumatic brain injury, stroke, and inflammatory processes are also recognized causes. Damage to the hypothalamus disrupts signaling in the melanocortin-4 receptor (MC4R) pathway, impairing energy balance regulation of energy balance and body weight and leading to rapid, sustained weight gain, often accompanied by hyperphagia or reduced energy expenditure.
The approval was based on results from the global phase 3 randomized controlled TRANSCEND trial (N = 142). Patients who received setmelanotide (n = 94) achieved a mean body mass index reduction of 15.8% from baseline at 52 weeks, compared with a 2.6% increase with placebo (n = 48), corresponding to a placebo-adjusted reduction of 18.4%. The primary endpoint of mean change in body mass index from baseline was met with statistical significance.
Setmelanotide was generally well tolerated. Adverse events reported in more than 20% of participants included skin hyperpigmentation, nausea, vomiting, and headache.
Warnings and precautions include acute adrenal insufficiency, reported as a serious adverse reaction in 5% of treated patients with secondary adrenal insufficiency and in no patients who received placebo, as well as sodium imbalance in patients with concomitant central diabetes insipidus. Hyponatremia occurred in 6% of treated patients compared with 2% of those who received placebo, and hypernatremia occurred in 5% and 4%, respectively.
Additional class-related precautions include disturbance in sexual arousal, depression and suicidal ideation, hypersensitivity reactions, and skin hyperpigmentation, including the development of new or darkening of preexisting melanocytic nevi. Setmelanotide is contraindicated in patients with a history of serious hypersensitivity to the drug or its excipients. It is not recommended during breastfeeding and should be discontinued if pregnancy occurs unless the potential benefit justifies the potential risk.
Setmelanotide is not indicated for obesity due to suspected pro-opiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency with variants classified as benign or likely benign, or for other obesity types unrelated to acquired HO, Bardet-Biedl syndrome, or confirmed genetic deficiencies in these pathways.
Setmelanotide is approved in the U.S. for adults and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome or POMC, PCSK1, or LEPR deficiency confirmed by genetic testing. In the European Union and the United Kingdom, it is authorized for the treatment of obesity and the control of hunger associated with genetically confirmed Bardet-Biedl syndrome or genetically confirmed loss-of-function biallelic POMC deficiency, including PCSK1 deficiency, or biallelic LEPR deficiency in adults and children aged 2 years and older.
The drug is available in the US immediately. Rhythm Pharmaceuticals also offers a patient support program, Rhythm InTune, to assist with education, insurance navigation, and injection training.
“Acquired HO is a severe disease that requires early and proactive management. With the availability of IMCIVREE, physicians can offer a targeted therapy,” said Ashley Shoemaker, MD, MSCI, associate professor of pediatrics and pediatric endocrinology at Vanderbilt Health.
