Following in the footsteps of the United states and the European union, Health Canada has now approved setmelanotide for the treatment of specific rare forms of genetic obesity.


Setmelanotide (trade name Imcivree) is an MC4R agonist that has been approved for weight management in people age 6 and older with obesity due to Bardet-Biedl Syndrome (BBS), and for obesity due to genetically confirmed pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCKS1) or leptin receptor (LEPR) deficiency.  It is given once daily as a subcutaneous injection (under the skin).


Bardet-Biedl syndrome (BBS) is a rare autosomal recessive condition characterized by variable degrees of hyperphagia (insatiable hunger), early-onset severe obesity, and other features which can include polydactyly (extra fingers), retinal degeneration, intellectual disability, abnormalities of the kidneys, and other features.   Obesity is present in 70-90% of people with Bardet-Biedl syndrome.   Though the molecular mechanisms are not fully understood, impaired cilial signaling is hypothesized to cause dysfunction in the MC4R satiety (fullness) signaling pathway in the brain.  The insatiable hunger drive is distressing to people with BBS and their caregivers, and can require measures like locking up fridges and pantries and continued monitoring of the individual with food seeking behaviors that are driven by these insatiable hunger signals.   Setmelanotide works to treat obesity in people with BBS by improving the activity in the MC4R pathway and helping them achieve a sense of fullness.


In a 1 year study of people with BBS age 12 and older, 32% of participants achieved at least 10% weight reduction with setmelanotide. There was a reduction in hunger scores, reduced obessive focus on food, better control of eating, less hunger, and better health related quality of life.   The most commonly reported side effects were skin hyperpigmentation (experienced by 56% of patients) and injection site redness (50% of patients), with about a third of patients experiencing nausea.  Side effects in general were mild and infrequently led to medication withdrawal.  There were four serious events amongst two participants in the study, none of which were felt to be related to setmelanotide treatment.


Variants in POMC, PCSK1 or LEPR genes can also impair the normal MC4R satiety signaling pathway in the brain, causing extreme, insatiable hunger beginning at a young age, resulting in early onset, severe obesity.  These genetic forms of obesity are extremely rare.  Setmelonotide restores the activity in the MC4R pathway and helps these people feel a sense of fullness.


In studies of people age 6 and older, eight (80%) of participants in the POMC trial and five (45%) of people in the LEPR trial achieved at least 10% weight loss at approximately 1 year of treatment with setmelanotide.   Weight reduction in both groups was accompanied by a marked reduction in hunger scores.   The most common side effects were again injection site reaction, increased pigmentation of the skin, and nausea.  No serious adverse events occurred in these trials.


Setmelanotide should not be prescribed for people with other genetic forms of obesity.


BOTTOM LINE:  Setmelanotide is an important and effective new weight management medication for people with obesity due to Bardet-Biedl syndrome, POMC, PCSK1, or LEPR deficiency.

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


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