Rob C. Witzel for The New York Times
Seeking Clues to Obesity in Rare Hunger Disorder
By ANDREW POLLACK
JAN. 14, 2014
Lisa Tremblay still recalls in horror the time her daughter Kristin pulled a hot dog crawling with ants from the garbage at a cookout and prepared to swallow it.
Kristin has a rare genetic abnormality that gives her an incessant, uncontrollable hunger. Some people with the condition, called Prader-Willi syndrome, will eat until their stomach ruptures and they die. And, not surprisingly, many are obese.
“She’s eaten dog food. She’s eaten cat food,” said Ms. Tremblay, who lives in Nokomis, Fla. When Kristin, now 28, was a child, neighbors once called social welfare authorities, thinking Kristin was not being fed because she complained of being hungry so much.
Once an obscure and neglected disease, Prader-Willi is starting to attract more attention from scientists and pharmaceutical companies for a simple reason: It may shed some light on the much broader public health problems of overeating and obesity.
“These are remarkable human models of severe obesity,” said Dr. Steven B. Heymsfield, a professor and former executive director of the Pennington Biomedical Research Center in Baton Rouge, La.
“When we discover the underlying mechanism of these very rare disorders, they will shed light on garden-variety obesity.”
One drug being developed to help obese people lose weight has shown some preliminary signs of success in patients with Prader-Willi. The drug, beloranib, is believed to work by reducing fat synthesis and increasing fat use. In a small trial, it reduced weight and body fat and lowered the food-seeking urge, according to the drug’s developer, Zafgen.
“This is the first thing that has really been tried and been at all successful in individuals with Prader-Willi,” said Dr. Jennifer Miller, associate professor of pediatric endocrinology at the University of Florida and the lead investigator of the trial.
There are reasons to be cautious about the link between Prader-Willi and general obesity because the mechanisms behind both are not well understood and could be different.
But Prader-Willi patient advocates are actively encouraging the association
in hopes that linking the syndrome to the broader problem will attract more academic and pharmaceutical industry research on their disease. “The more interest and research there is on it, the more it helps our kids,” said Janalee Heinemann, director of research and medical affairs at the Prader-Willi Syndrome Association.
There are also reasons to be cautious about the Zafgen results. The trial involved only 17 people, and the main part of it lasted only four weeks. On some measures — including the trial’s primary one of weight reduction — the difference between the drug and a placebo was not statistically significant.
Still, Thomas E. Hughes, Zafgen’s chief executive, said the results were strong enough that the company would conduct a larger study aimed at getting beloranib approved to treat Prader-Willi.
“It gives us a way to establish the benefit of our drug in what would arguably be the toughest of patients to treat,” he said.
Another company, Ferring Pharmaceuticals, plans to begin a study of its drug carbetocin soon. The drug works in the same manner as oxytocin, sometimes called the love hormone because it promotes human bonding. A small French study suggested oxytocin might not only improve behavioral problems associated with the disease but also curb appetites.
Rhythm, a start-up company, also plans to test its experimental obesity drug, RM-493, for Prader-Willi. Arena Pharmaceuticals, which sells the weight loss drug Belviq, says Prader-Willi is an area of interest. And some academic trials are underway as well, making for what advocates say is an unusual amount of activity.
“Our biggest problem in 2014 and 2015 is making sure to have enough families to get the studies done,” said Dr. Theresa Strong, chairwoman of the scientific advisory board of the Foundation for Prader-Willi Research.
The Prader-Willi Syndrome Association knows of at least 8,000 Americans with the condition. Most patients are missing a chunk of chromosome 15. Others have two complete copies of the chromosome.
If the insatiable appetite were not enough, people with Prader-Willi also have slow metabolisms, meaning they gain weight exceedingly easily. Most also have intellectual disability and autistic behaviors.
Keeping weight in check is a constant battle for parents and caregivers.
“We lock up our refrigerator. We lock up our freezer. We lock up the pantry,” said Mark Greenberg of Denver, a consultant to a hedge fund whose 14-year-old son Zachary has Prader-Willi.
The family even locks the garbage pail in the kitchen.
Alarms sound if Zachary tries to leave the house.
Appetite is a huge problem because it makes it impossible for people to live independently or to hold a job.
Jim Kane of Baltimore, Md., said his daughter Kate, who has a high school diploma, has been fired from several jobs for taking food from other employees.
She has also been arrested for shoplifting food, he said, once at an airport for taking a couple of granola bars.
Scientists do not understand the mechanisms behind Prader-Willi, though the insatiable appetite stems from dysfunction of the hypothalamus, the part of the brain that controls hunger.
Researchers say that as with other diseases, including Alzheimer’s and high cholesterol, many things might be learned from studying the most extreme or earliest onset cases.“These mechanisms, if we were able to understand them in Prader-Willi, would shed an incredible amount of light on appetite,” said Dr. Joan Han, an endocrinologist at the National Institutes of Health who is conducting research on the syndrome and other rare eating-related disorders.
Her own research, for instance, has found low levels of a protein called brain-derived neurotrophic factor in the blood of people with Prader-Willi. Other studies have also linked lack of the protein to obesity.
But some experts say Prader-Willi patients differ from other obese people in ways like their high levels of the appetite-increasing hormone ghrelin.
“There are some distinctive characteristics of Prader-Willi syndrome that suggest it may not be a stand-in or model for all of obesity,” said Elisabeth M. Dykens, director of Vanderbilt University’s Vanderbilt Kennedy Center, which studies developmental disorders.
For Zafgen, however, Prader-Willi represents a potentially faster path to the market for a relatively limited investment. While beloranib has shown good results in early studies as a treatment for general obesity, winning approval for that use will probably require clinical trials involving thousands of patients to rule out serious side effects.
Winning approval for Prader-Willi might require testing in only dozens or hundreds of patients. And there might be more tolerance of side effects because there is a desperate need for treatments.
Also, since Prader-Willi is a rare disease, Zafgen would qualify for tax breaks and some market exclusivity under the Orphan Drug Act and could potentially charge an extremely high price for the product.
Zafgen’s beloranib works by inhibiting methionine aminopeptidase 2, an enzyme. The inhibition appears to stimulate the burning of fat and reduce its formation.
The 17 patients in Zafgen’s study were residents of a home for people with Prader-Willi in Gainesville, Fla., where diet is strictly controlled. During the study, the daily calorie intake was increased 50 percent to make it easier to see if beloranib affected weight and appetite.
Kristin Tremblay was one of the participants in the study. Her mother said she did not notice big changes when Kristin came home right after the study ended.
Oddly, however, Kristin did have trouble finishing one salad. And she had not gained weight despite the increase in calories during the study.
“I would try it again,” Ms. Tremblay said. “It certainly didn’t hurt her.”