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Setmelanotide Offers Significant, Long-Lasting Weight Loss
Setmelanotide can lead to significant weight loss that lasts for at least 3 years, according to results presented at the latest French Pediatric Society conference. The treatment is effective for adults and children alike.
Setmelanotide is the culmination of two decades of research involving the identification of genes involved in early-onset obesity and the characterization of the melanocortin 4 receptor. It became available via early access in 2021.
Currently limited to use in treating obesity linked to a biallelic POMC/PCSK1 or LEPR deficiency, setmelanotide is being tested with respect to other mutations responsible for severe obesity, raising hopes that it will soon be indicated for use in a larger number of patients.
Fewer than 1% of patients who suffer from severe obesity have monogenic forms of obesity. In recent years, the hope for a targeted treatment for patients with these monogenic forms has become a reality.
Although only a small number of patients currently meet the criteria for setmelanotide treatment (namely, those with obesity linked to a biallelic POMC)/PCSK1 enzyme or LEPR deficiency and patients with Bardet-Biedl syndrome), there is a real hope that patients with other forms of severe obesity will be able to benefit from this product, including those with heterozygous (not just homozygous) monoallelic variants, who account for more than 10% of patients with severe early-onset obesity.
Restoring Satiety Signaling
“Setmelanotide is a melanocortin 4 receptor agonist,” said Béatrice Dubern, MD, PhD, pediatrician at Trousseau Hospital in Paris and member of the French medical research institute (INSERM)/Sorbonne University team on nutrition and obesity. “Its mode of action rests on activation of the leptin-melanocortin signaling pathway in the hypothalamus, which regulates hunger, satiety, energy expenditure, and, therefore, body weight. Rare genetic variants in the leptin-melanocortin pathway are associated with polyphagia and severe early-onset obesity. It is believed that more than 60 genes involved in this leptin-melanocortin pathway are currently associated with obesity.”
In July 2021, the European Medicines Agency approved setmelanotide for daily use via subcutaneous administration.
Weight Loss Maintained
In phase 3 studies, setmelanotide (melanocortin 4 receptor agonist) demonstrated its effectiveness in reducing weight and hunger for patients with obesity caused by a POMC/PCSK1 or LEPR deficiency.
Twenty-four patients aged 6 years and older showed a significant response to setmelanotide after 1 year of treatment and were included in the extension study. “Significant response” was defined as a reduction in body weight ≥10% after 52 weeks for patients aged 18 years and older or a reduction in body mass index (BMI) z-score ≥0.3 after 52 weeks for patients younger than 18 years.
Among all patients, the mean variation (standard deviation) in BMI was −24.8% (8.2%, n = 24), −21% (13%, n = 23), and −24% (17.9%, n = 15) at 12, 24, and 36 months, respectively.
For patients aged ≥18 years (n = 11), the mean variation (standard deviation) in weight was −25.1% (7.7%, n = 11), −22.9% (12.5%, n = 11), and −24.4% (13.2%, n = 8) at 12, 24, and 36 months, respectively.
For children and adolescents (patients aged <18 years, n = 13), the mean reduction (standard deviation) in BMI z-score was −1.31 ([0.66], n = 13), −1.10 ([0.79], n = 11), and −1.01 (1.22], n = 4) at 12, 24, and 36 months, respectively.
For patients younger than 18 years, the mean variation in BMI z-score was −1.01 SD after three years on setmelanotide (standard deviation, 1.22 [n = 4]). The mean BMI z-score was +2.42 SD (standard deviation, 1.22 [n = 4]) after 3 years of treatment with setmelanotide.
In sum, the patients who achieved a reduction in body weight of at least 10% or ≥0.3 mean variation in BMI z-score after 1 year experienced long-lasting, clinically significant benefit after 3 years. The finding supports the long-term use of setmelanotide for this group.
“We feared that setmelanotide’s effectiveness would decrease over time, but after 3 years, this had not happened, and we are hopeful that this sustained efficacy will be long lasting. The first two patients who took the drug in 2016 have not noticed any loss of efficacy as it stands,” said Dubern.
This is all the more encouraging. In the study presented at the 2023 pediatric conference, setmelanotide’s safety profile was reassuring, and it was consistent with previous studies. Side effects reported in ≥15% of patients include injection site reactions, skin hyperpigmentation, nausea, diarrhea, mood disturbances, abdominal pain, vomiting, gastroenteritis, and spontaneous erection.
In addition to the lack of control group, Dubern acknowledged one other constraint of this study. “Only the patients who responded to treatment with setmelanotide during early-phase trials (85.7%) were enrolled.”
Dubern summarized the clinical implications. “In patients with early-onset obesity, starting before 5 years of age, doctors should really be considering the possibility that genetics might be involved in such cases. For confirmation and to seek expert opinion, specialist obesity clinics can be found throughout France. Additionally, the INSERM NutriOmics research team headed by Prof Karine Clément, MD, PhD, Sorbonne University, in conjunction with Prof Christine Poitou, MD, PhD, has developed a diagnostic tool [called] ObsGen for practitioners faced with patients with potentially genetic causes of obesity. We can answer any questions they have about the likelihood of a particular patient having a genetic form of obesity and guide their next steps. Treating patients with genetic obesity early on helps limit the condition worsening during adolescence, prevents related complications, and can reduce the stigmatization and suffering experienced by these people. It’s a huge issue. A clinical trial with setmelanotide is currently being carried out in children over 2 years of age.”
Hypothalamic Obesity
During the pediatric conference, another speaker presented the results of a phase 2 study that evaluated the efficacy and tolerability of setmelanotide as a new treatment for hypothalamic obesity. Lesions in the hypothalamus can alter melanocortin 4 receptor pathway signaling and thus lead to hypothalamic obesity. Eighteen patients aged 6 to 40 years with a BMI ≥95th percentile (for patients aged 6 to 18 years) or ≥ 35 kg/m2 (for adults aged ≥18 years) and hypothalamic obesity (craniopharyngioma or other benign brain tumors, surgical removal, and/or chemotherapy) were enrolled. A significant proportion of patients achieved a reduction of ≥5% of their BMI (n = 16, 88.9%, CI 90%, 69% to 89%, P < .0001), and 72.2% achieved a reduction of ≥ 10% by week 16. The mean change in BMI was −14.9% (9.6%, n = 17). These early results may justify further studies of setmelanotide in treating hypothalamic obesity.
This article was translated from the Medscape French Edition.
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