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Metreleptin aids in weight reduction among adults with obesity plus very low leptin levels
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ORLANDO, Fla. — Adults with obesity and low endogenous levels of leptin lost more weight after treatment with the leptin analogue metreleptin than with placebo, and lower leptin levels were associated with greater weight loss, according to data presented here.
“This [treatment] will be suitable only for people with very low leptin,” Murray Stewart, DM, FRCP, executive vice president and head of research and development at Novelion Therapeutics, told Endocrine Today.
Unlike past studies, in which leptin therapy was ineffective for treating obesity in general, Stewart and colleagues are exploring its use in a subset of people with obesity and leptin levels in the lowest percentile, who may have a high risk for developing diabetes and liver and kidney disease.
“Leptin controls and correlates with fat mass. If you’ve got low leptin, that will drive you to be hungry, alter your metabolism and you’ll gain weight. If you give leptin to those people, they’ll lose weight,” Stewart said. “If you look at the people in the first percentile [women with leptin level less than 5 ng/mL and men less than 2 ng/mL], it’s not just a normal variation, they’re not producing leptin at all, 1% of what you would predict. Those are the people that can change.”
Stewart and colleagues evaluated the effects of daily metreleptin (Myalept, Aegerion Pharmaceuticals/Novelion Therapeutics) 10 mg or 20 mg vs. placebo in adults with low leptin levels. In a first study, researchers analyzed pooled data from 396 participants with BMI between 23 kg/m2 and 40 kg/m2 from four studies, categorized according to leptin level (women, < 16 ng/mL, < 8 ng/mL and < 5 ng/mL; men, < 5 ng/mL, < 3 ng/mL and < 2 ng/mL). A separate phase 2, randomized, double-blind, controlled study included 267 adults with low leptin levels (women, ≤ 16 ng/mL; men, ≤ 5 ng/mL) and BMI 27.5 kg/m2 to 29.9 kg/m2 with a history of obesity-related risk factors or BMI 30 kg/m2 to 38 kg/m2. Designed as a 52-week study, the second phase was ended at 24 weeks after metreleptin developers decided not to pursue the drug for patients with uncomplicated obesity; 67% of participants completed 24 weeks, and 44% completed 12 weeks.
In the first study, at week 10, greater weight loss was observed in both metreleptin dose groups vs. placebo, with greater reductions at the higher dose. Among those who received 20 mg metreleptin, participants with lower leptin levels lost more weight. In the second study, at week 8, the 20-mg group experienced significant weight loss (P < 0.05).
In a secondary analysis of data from both studies, at week 12, 38.8% of those in the 10-mg groups and 37.5% of the 20-mg groups lost at least 5% of baseline body weight vs. 21% of the placebo groups. At week 24, 46.7% of those in the 10-mg groups and 58.3% of the 20-mg group lost at least 5% of baseline body weight vs. 38.1% of the placebo groups.
Adverse events were mild or moderately severe with injection-site reactions, headache, fatigue, gastrointestinal events and upper respiratory tract infection most common.
Stewart said he sees these studies as a preliminary step toward precision medicine, targeting therapies to subsets of patients with specific characteristics.
“The next step is [to ask], do the people with low leptin obesity differ from the people with high leptin obesity other than their leptin levels? No one’s asked that question before,” Stewart said. – by Jill Rollet
Reference:
DePaoli A, et al. 296-LB. Presented at: American Diabetes Association 78th Scientific Sessions; June 22-26, 2018; Orlando, Fla.
Disclosures: Stewart reports he is an employee and shareholder of Novelion Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.