New hope in the search for a new obesity treatment

Obesity is a massive health threat across the globe and remains hard to counter, despite many thousands of diets and medications. A study published in July in the New England Journal of Medicine gives a few severely obese patients a new medical ally—and the world a narrow ray of hope. Though the study focused on just two patients, their conditions were severe, and the success of their treatment was dramatic.

As infants, the two unrelated girls were on the extreme high end of the normal weight range for 1-year-olds, but by the time they reached 17, they were almost triple the average weight for their age. They started the treatment at age 17 and 18, when they weighed, respectively, 336 and 341 pounds. The new treatment’s impact: a weight loss of 33% in 42 weeks for one and of more than 13% in 12 weeks for the other. Peter Kühnen of the Charité hospital in Berlin, the lead author of the study, said in an interview that during ongoing treatment for months after the initial period, the subjects have continued to lose weight without problematic side effects.

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The treatment addresses a rare genetic problem. “If you think of yourself at the hungriest moment of your life, that’s how these patients feel every minute of every day,” said Dr. Keith Gottesdiener, a co-author on Dr. Kühnen’s report and chief executive of Boston-based Rhythm Pharmaceuticals, which makes setmelanotide, the medication used in the study.

In the body, one path to satiety—the feeling that we are full—starts when fat cells produce the hormone leptin. In turn, leptin stimulates a gene to make the substance pro-opiomelanocortin or POMC (“pom-see”). POMC is spliced into key hormones, one of which moves through the brain to reach receptors on brain cells that send the message, “I’m full.”

In the girls and others being studied, the POMC-producing gene is defective. This malfunction thwarts the chain of messages that normally lead from the stomach to the brain. But when a patient takes setmelanotide, it stimulates the brain’s melanocortin-4 receptor directly and ends hunger. (Molecules smaller than setmelanotide—it’s of a middling size—have caused worrisome side effects when used as medications, but so far setmelanotide hasn’t had this problem.)

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