News Article
Pramlintide-Metreleptin Increases Weight Loss in Proof-of-Concept Trial
PHOENIX (EGMN) - An experimental combination of amylin and leptin analogs helped overweight and obese people lose weight while reducing food cravings in a 24-week proof-of-concept trial presented at the annual meeting of the Obesity Society.
More than half, 56%, of evaluable subjects lost at least 10% of their weight with the combination of pramlintide (Symlin) and metreleptin - and 28% of people given both drugs lost 15% or more in the small three-pronged study.
In contrast, monotherapy with either component produced more modest weight loss. The 10% benchmark was reached, respectively, by 35% and 21% of the pramlintide-only and metreleptin-only arms. Likewise, just 5% on pramlintide and 11% on metreleptin had weight loss of at least 15% of their body weight in the brief study.
"I believe there is something special about the combination," said the lead author, Dr. Steven R. Smith of the Pennington Biomedical Research Center in Baton Rouge, La.
Pramlintide is an analog of amylin, a beta-cell hormone cosecreted with insulin in response to meals. Dr. Smith noted that it has been shown to increase satiety, inducing sustained weight loss accompanied by a decrease in circulating leptin in obese people. It is approved as an adjunct treatment of diabetes for people who cannot achieve glucose control with optimal insulin therapy.
Leptin, an adipocyte-derived hormone, is believed to promote a decrease in food intake while increasing energy expenditure. Metreleptin, an analog of leptin, has been shown to promote weight loss in people deficient in leptin, but did not cause significant weight loss as a monotherapy in overweight people without a deficiency, noted Dr. Smith.
The combination trial followed preclinical studies that showed amylin agonism restored responsiveness to leptin in rats, he said. Amylin Pharmaceuticals, San Diego, sponsored the study. It markets pramlintide, has research rights to metreleptin, and is developing the combination therapy.
Of 177 people enrolled in the trial, nearly two-thirds were women. On average, they were about 39 years old with a starting weight of 92 kg and body mass index of 32 kg/m².
The protocol called for a 4-week lead-in period during which all participants went on a 40% kcal deficit diet while taking pramlintide (180 mcg twice a day for the first 2 weeks, then 360 mcg twice a day). Subjects had to lose 2%-8% of their body weight to continue in the study.
After 4 weeks, 139 subjects were randomized: 27 subjects to 5 mg of metreleptin plus placebo twice daily; 56 subjects to 360 mcg of pramlintide plus placebo twice daily, and 56 subjects to 360 mcg of pramlintide plus 5 mg of metreleptin twice daily. The metreleptin doses are "very modest," Dr. Smith said, compared with the doses used previously in unsuccessful monotherapy studies.
All patients in the second leg of the trial were encouraged to go on a 20% kcal deficit diet.
At the end of 24 weeks, 93 were evaluable: 19 on metreleptin, 38 on pramlintide, and 36 on the combination. There was significantly more weight loss since enrollment in the combination arm versus pramlintide: 12.7% vs. 8.4% of body weight. All told, 68% of each monotherapy group and 89% of the combination group lost more than 5%.
Dr. Smith was asked how much of the weight loss was a result of the lifestyle intervention and how much was a result of the drugs in the study. He said he did not know and that a new study would be needed with a different design to answer that question.
Among the other findings, patients reduced their scores on a binge eating scale by 30% with metreleptin, 24% with pramlintide, and 43% with the combination. Compared with pramlintide, the combination produced significantly less difficulty in resisting food cravings, less frequent eating in response to food cravings, and less hunger.
The most common adverse events were mild to moderate injection site reactions and nausea, with no reports of anxiety or depression. Nausea was not seen beyond 4 weeks after randomization in the combination arm, though it continued throughout the study in the pramlintide arm.
"What I think is really fascinating is if you add metreleptin to the pramlintide you don't see these nausea events further out in the study, and I don't completely understand this, but I think it is a fascinating bit of biology," Dr. Smith said.
He concluded that the results are consistent with preclinical results and suggest that "amylin agonism restores responsiveness to leptin in general obesity." The results warrant further mechanism-of-action studies and further clinical development of the combination "as part of an integrated neurohormonal approach to obesity pharmacotherapy," he said.
Dr. Smith disclosed that he had been a consultant to and advisory board member for Amylin, from which he has received research support. Other investigators included Amylin employees and shareholders.
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