The study, “Effect of Setmelanotide, an MC4R Agonist, on Obesity in Bardet-Biedl Syndrome,” was published in the journal Diabetes, Obesity and Metabolism.
BBS has been associated with mutations in more than 24 genes. The rare genetic disorder is characterized by early onset obesity and uncontrollable hunger, called hyperphagia. Additional complications include eyesight degeneration, cognitive problems, kidney abnormalities, and polydactyly, or having extra fingers or toes.
Although the mechanism behind obesity in BBS is not fully understood, researchers think it is linked to the malfunction of the hypothalamus, a region in the brain that produces key hormones for the regulation of appetite.
The activation of the melanocortin-4 receptor or MC4R, a pathway responsible for regulating energy balance and body weight, is defective in BBS, studies in mice have found. Specifically, research shows defects in the tightly organized movement of a protein called leptin receptor, or LEPR, in the nerve cells of the hypothalamus, which are known as hypothalamic proopiomelanocortin (POMC) neurons.
Setmelanotide, by Rhythm Pharmaceuticals, is a small peptide that binds and activates MC4R. The therapy has been granted breakthrough therapy designation in the U.S., by the Food and Drug Administration (FDA), to treat obesity linked to MC4R pathway mutations. In the EU, the Committee for Orphan Medicinal Products, an arm of the European Medicines Agency, has granted setmelanotide orphan medicine status to treat BBS.
The ongoing Phase 2/3 trial (NCT03013543) is evaluating setmelanotide in people with severe obesity and hyperphagia. Besides BBS patients, the study also includes people with other conditions related to the MCR4 pathway — POMC deficiency, LEPR deficiency, Alström syndrome, SRC1 deficiency, SH2B1 deficiency, MC4R deficiency, and Smith-Magenis syndrome.
The medication is given once daily via under-the-skin (subcutaneous) injection. The goal is to assess whether activation of the MC4R pathway via setmelanotide could reduce hunger and lessen obesity.
Earlier data have shown that both BBS and Alström syndrome patients experienced a significant decrease in hunger and weight loss.
In total, 10 people with BBS (average age 22.5 years) were recruited. Nine had genetic confirmation of BBS, while the remaining participant had a clinical diagnosis.
At the start of the trial, the group’s mean body mass index (BMI, a measure of body fat) was 44.8 kilograms (kg)/m2, and mean weight was 128.1 Kg, nearly 282 pounds.
Hunger was evaluated by caregivers using a food problem diary (FPD) and a significant event questionnaire (SEQ). At the study’s start, or baseline, the hunger score had a mean value of eight for most hunger, six for average hunger and five for morning hunger.
While adolescents received setmelanotide at a dose of 0.5 mg/day, adults were given 1 mg/day of the therapy. Dose increments of 0.5 mg were given every two weeks up to a maximum of 3 mg.
Eight participants completed the first three months of treatment, and took part in the extension phase. In all, seven patients completed the whole treatment duration of one year.
After three months, the participants experienced a significant mean reduction of 5.5% in body weight. After six months, the reduction was 11.3% and by one-year, it was 16.3%.
A similar result was obtained for BMI, which decreased by a mean of 5.5% after three months, 11.1% by month six and 16.2% after one year. Significant reductions in hunger scores also were observed. These included most, average, and morning hunger.
Body fat mass and total body mass also decreased with treatment — after one year, body fat mass dropped by 24% and total body mass by 15.8%. At six and 12 months, participants also achieved a significant reduction in waist circumference.
Blood pressure levels did not change significantly, unlike with prior (first-generation) MC4R activators, the results showed.
Blood (lipid) fat levels showed a slight but not significant decrease. No meaningful differences were seen in glucose levels either.
In general, setmelanotide was well-tolerated. However, all participants reported injection site reactions and 80% experienced hyperpigmentation of the skin.
“Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports,” the investigators wrote. “The results of this study suggest that setmelanotide may be a useful pharmacotherapy for treatment of obesity and hyperphagia in individuals with BBS.”
The efficacy and safety of setmelanotide in individuals with BBS and Alström syndrome, with moderate-to-severe obesity, is being evaluated in an ongoing Phase 3 study (NCT03746522). In turn, two other Phase 3 studies have shown weight loss after treatment in patients with POMC (NCT02896192) and LEPR (NCT03287960) deficiency.
An application seeking approval of setmelanotide is now under priority review by the FDA as a potential treatment for POMC and LEPR deficiency. A decision is expected by Nov.27.
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