51成人动漫

Setmelanotide, an investigational melanocortin 4 receptor (MC4R) agonist, was associated with significant weight loss and hunger reduction in patients with rare genetic forms of early-onset obesity, according to two phase III clinical trials.

In patients with pro-opiomelanocortin (POMC) deficiency obesity, 80% of individuals lost at least 10% of body weight at 1 year. Mean weight loss was -25.6% (SD 9.9, 90% CI −28.8 to −22.0, P<0.0001). In addition, self-reported hunger scores dropped by 27%, said researchers led by Karine Clément, MD, of the Assistance Publique Hôpitaux de Paris in France.

Writing online in , Clément and colleagues also reported that 45% of patients with leptin receptor (LEPR) deficiency obesity lost at least 10% of body weight. Mean weight loss in this group was -12.5% (SD 8.9, 90% CI −16.1 to −8.8, P<0.0001) and hunger scores were reduced 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."

In an accompanying , Donna Ryan, MD, of the Pennington Biomedical Research Center in Baton Rouge, Louisiana, said the results were promising. She added that it was possible, though not likely, that setmelanotide could be used in a broader range of patients.

"Taken together, setmelanotide seems most promising for patients with POMC deficiency," Ryan wrote. "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."

Clément and colleagues discussed the possible reasons for the differing results in the two trials. In individuals with POMC-deficient obesity, production of the endogenous MC4R ligands is impaired, they explained. Setmelanotide, an MC4R agonist, is therefore theoretically able to completely restore signaling at MC4R. Leptin, by contrast, 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 signaling pathway, they noted.

"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.

In a of diet-induced obesity, setmelanotide produced persistent weight loss (–13.5%) over 8 weeks. Importantly, it did not increase heart rate or blood pressure, which has been a concern with earlier MC4R agonists, Ryan said.

In a in humans, individuals with obesity and either wild-type MCR4 or loss-of-function mutations were treated with setmelanotide infusions over 28 days. Both groups lost weight similarly in comparison with placebo. There were no increases in heart rate or blood pressure in this study, Ryan noted, but the most frequent side-effect of setmelanotide was hyperpigmentation, and this could make the drug undesirable from a patient perspective.

"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."

However, having an effective drug for these patients will likely drive clinicians to increase genetic testing for patients 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 by Clément's group included (mean age 18) in one trial and (mean age 24) in the other. Mean body-mass index (BMI) was higher than 40 in both groups at baseline. Patients in both trials received setmelanotide injections once daily at a starting dose of 1.0 mg for adults (18 or older) and 0.5 mg for pediatric patients.

Doses were up-titrated every 2 weeks by 0.5 mg until reaching an individualized therapeutic dose, defined as weight loss of 2–3 kg per week for adults or 1–2 kg per week for pediatric patients, up to a maximum dose of 3.0 mg. Patients received the therapeutic dose for up to 48 weeks. Hunger scores were measured by an 11-point Likert-type scale. Setmelanotide was well tolerated in all individuals, and no new safety concerns were observed, the researchers said.

Limitations of the trials, they noted, included small sample sizes due to the rarity of the genetic conditions as well as 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," they said. "Further evaluation of setmelanotide is warranted in other disorders resulting from variants in the central melanocortin pathway that cause impaired MC4R activation."

Comment