Posted on Nov 05, 2020, 5 p.m.
A report published in The Lancet Diabetes & Endocrinology suggests that an investigational MC4 agonist called setmelanotide cuts body weight and hunger in genetically driven obesity, the trial success raises questions about broader applications.
According to Karine Clément, MD, of the Assistance Publique Hôpitaux de Paris in France and colleagues, two phase III clinical trial setmelanotide was associated with significant weight loss and hunger reduction in patients with rare genetic forms of early-onset obesity. Findings show that in those with proopiomelanocortin deficiency obesity 80% lost at least 10% of their body weight in one year, with a mean weight loss of -25.6%; and self-reported hunger scores dropped by 27%.
The team also reported that 45% of the patients with leptin receptor deficiency lost at least 10% of their body weight, with a mean weight loss of -12.5% in this group and hunger scores were decreased by 44%.
"In these two multicentre, phase III trials, the MC4R agonist setmelanotide was associated with significant weight loss and reduction in hunger scores in individuals with POMC or LEPR deficiency obesity after approximately 1 year of treatment," Clément and colleagues wrote. "To our knowledge, these trials represent the largest trials of participants with POMC or LEPR deficiency obesity treated with a pharmacological agent and confirm the efficacy and safety of setmelanotide. The results were consistent with early reports in two phase II trials in five participants."
"Taken together, setmelanotide seems most promising for patients with POMC deficiency," wrote Donna Ryan, MD, of the Pennington Biomedical Research Center in Baton Rouge, Louisiana in an accompanying editorial. "The results do not seem as encouraging for all patients with LEPR deficiency, but prescribing a trial of setmelanotide would still be a worthy approach in the face of no alternative treatments for this severe disease." Although the results are promising Ryan believes that it is not likely that setmelanotide could be used in a broader range of patients.
According to the team in those with POMC-deficient obesity the production of the endogenous MC4R ligands is impaired, and setmelanotide is an MC4R agonist therefore it is theoretically able to completely restore signalling at MC4R. In contrast, leptin is upstream of POMC and the receptor is expressed on agouti-related peptide positive neurons as well as POMC positive neurons, therefore setmelanotide might only partially restore this signalling pathway.
"The obvious question," Ryan said, "is whether setmelanotide could have a broader indication for weight management." Previous research suggests this is at least a possibility, she noted.
During studies involving a primate model of diet-induced obesity, setmelanotide promoted persistent weight loss of -13.5% over an 8 weeks period without increasing heart rate or blood pressure which was a concern with earlier MC4R agonists.
During a phase 1 study involving humans, those with obesity and either wild type MCR4 or loss of function mutation that were treated with setmelanotide infusions over a period of 28 days both groups lost weight similarly as compared with placebo. While there were no increases in heart rate or blood pressure, the most frequent side effect was hyperpigmentation which could make the drug undesirable from the perspective of a patient.
"Will patients accept tanning if weight loss is robust?" Ryan asked. "This question can only be answered through the expensive and time-consuming drug development process requiring large patient numbers. For setmelanotide, regulatory approval will probably come only for patients with proven genetic defects in the leptin–melanocortin pathway."
An effective drug for such patients may increase genetic screening for those with a history of severe early-onset obesity. "Thus, the impact of setmelanotide in the obesity clinic is likely to mean a renewed appreciation for the biological underpinnings of obesity and an increase in genetic screening to identify a subset of patients that can benefit from the drug," Ryan said.
The open-label phase III trials included 10 patients with POMC-deficient obesity with a mean age of 15 in one trial and 11 patients with LEPR-deficient obesity with a mean age of 24 in the other. The mean BMI was higher than 40 in both groups at baseline and participants in both trials received setmelanotide injections once a day at a starting dose of 1.0mg for adults and 0.5mg for pediatrics patients.
Doses were up-titrated every 2 weeks by 0.5mg until reaching an individualized therapeutic dose which was defined as weight loss of 2-3kg/week for adults or 1-2kg/week for pediatric patients, up to a maximum dose of 3.0mg for a therapeutic dose up to 48 weeks. An 11 point Likert type scale was used to measure hunger scores. According to the team, setmelanotide was well tolerated in all patients and there were no safety concerns observed.
The trial was noted to be limited by the small sample sizes which were due to the rarity of the genetic conditions as well as the lack of randomization and limited statistical power. “Overall, the efficacy and safety profile of setmelanotide supports its potential long-term use as a treatment for early-onset severe obesity and hyperphagia caused by POMC or LEPR deficiency," the team wrote. "Further evaluation of setmelanotide is warranted in other disorders resulting from variants in the central melanocortin pathway that cause impaired MC4R activation."
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