Obesity can be caused by mutations in the leptin receptor (LEPR) gene, causing extreme hunger that starts within the first months of life and leads to obesity during early childhood. A trial in three individuals who carry different LEPR gene mutations has now shown that a peptide drug called setmelanotide, which activates the melanocortin 4 receptor (MC4R) signaling pathway, can help to curb constant hunger and so allow patients to lose weight.

Data from the clinical study, headed by a team at the Institute for Experimental Pediatric Endocrinology of the Charité–Universitätsmedizin Berlin, suggest that if larger-scale trials can confirm efficacy and safety, the treatment may help weight loss and appetite control in patients with other defects in the MC4R pathway. “It is possible that other groups of patients with dysfunctions affecting the same signaling pathway might be suitable candidates for this treatment,” comments Peter Kühnen, M.D., whose team had previously shown that treatment with setmelanotide can play a central role in controlling energy metabolism and body weight.

The international research team, including INSERM scientists at Sorbonne Université in France, and collaborating researchers in the U.K., Germany, and the U.S., report on the study in Nature Medicine, in a paper entitled “MC4R Agonism Promotes Durable Weight Loss in Patients with Leptin Receptor Deficiency.”

The hormone leptin (also known as the “satiety,” or “starvation,” hormone) is produced in fat cells and plays a key role in energy regulation and homeostasis. Circulating leptin levels provide a measure of the body’s energy reserves, which acts as a signal to the brain to adjust appetite and food intake. Leptin usually binds to the LEPR and triggers biochemical steps that lead to production of melanocyte-stimulating hormone (MSH), which binds to MC4R, activating the body’s satiety signal. When LEPR is defective, this signaling pathway is inhibited, and so the sensation of hunger isn't curbed.

MSH is derived from proopiomelanocortin (POMC), mutations in the gene for which lead to early-onset obesity, severe hyperphagia, and deficiencies in adrenocortocotropic hormone (ACTH), and sometimes red hair. The leptin and leptin receptor gene products work upstream of MC4R, and mutations in these also result in uncontrolled hunger, and early-onset severe obesity.

Studies with first-generation drugs designed to activate MC4R demonstrated only limited efficacy, and also caused adverse side effects. Setmelanotide is a second-generation MC4R agonist that has previously been shown to curb uncontrolled hunger, and lead to dramatic weight loss in individuals with POMC deficiency, without the side effects or adverse cardiovascular adverse events demonstrated by earlier MC4R agonists, the researchers explain.

Give these previous results with setmelanotide, the team had reasoned that impaired activation of POMC neurons that results from LEPR gene mutations, and hence defects in LEPR signaling, might also contribute to a lack of MSH signaling, and so treatment using an MC4R agonist might be of therapeutic value for these patients as well. Their previous studies in LEPR-deficient mice had demonstrated that setmelanotide therapy reduced appetite, suggesting that the animals most likely exhibited a MSH deficiency due to lack of LEPR.

Setmelanotide is in development by Rhythm Pharmaceuticals for treating rare genetic orders of obesity. For their investigator-initiated clinical study the Institute for Experimental Pediatric Endocrinology team recruited three obese individuals, aged 14 years, 22 years, and 23 years, who carried mutations in both copies of the LEPR gene. Each participant was treated with an adjusted dose of setmelanotide for up to 61 weeks. In each case, the treatment was well tolerated, and led to significant reductions in hunger, and associated weight loss, averaging 11 kg during the first 13 weeks of treatment. One subject's hair color also changed from red to brown. “These subjects with LEPR deficiency experienced profound and long-lasting reductions of body weight for the first time in their lives, as even a previous attempt to reduce weight through bariatric surgery had failed (in subject 1),” the researchers report.

Interestingly, one of the subjects temporarily stopped treatment, and a second was unintentionally underdosing for a period of the trial. In parallel with their halted or low-dose therapy, both subjects reported increases in hunger and demonstrated significant weight gain until their setmelanotide treatments were restarted or dose-corrected. “The severe weight regain and marked recurrence of hunger evident following treatment withdrawal in subject 2 and the effects of misdosing in subject 3 strongly support the consistent results of setmelanotide treatment when used optimally,” the authors write.

“These subjects with LEPR deficiency experienced profound and long-lasting reductions of body weight for the first time in their lives, as even a previous attempt to reduce weight through bariatric surgery had failed (in subject 1).…These clinical data support the notion that treatment with setmelanotide results in a reduction of hyperphagia and body weight without occurrence of severe side effects and extends the therapeutic effects observed in individuals with POMC deficiency to subjects with LEPR defects.”

Further analyses by Dr. Kühnen’s team also suggested how the molecular mechanisms underpinning setmelanotide therapy may work, and help to explain why setmelanotide is tolerated better than previous candidates. “We also wanted to determine why the peptide used was so effective and why, in contrast to other preparations with a similar mode of action, it did not produce any severe side effects,” he notes. “We were able to demonstrate that this treatment leads to the activation of a specific and important signaling pathway, whose significance had previously been underestimated.”

“Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T-cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants,” the team explains.“In summary, we demonstrate that setmelanotide treatment was well tolerated and led to substantial amelioration of hunger and profound weight reduction in individuals with LEPR deficiency. Our observations open new avenues for treatment of individuals with LEPR deficiency and additional patient populations with genetic deficiencies (LEP, POMC, PCSK1, MAGEL2, CPE) leading to impaired functioning of the MC4R pathway.”



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