A drug that kills a type of fat cell by choking off its blood supply caused significant weight loss in obese monkeys, potentially setting the stage for a new pharmaceutical approach to attacking obesity, according to a study released Wednesday.
After four weeks of treatment, obese monkeys given daily injections of the drug, called adipotide, lost an average of 11% of their body weight. They also had big reductions in waist circumference and body-mass index and, importantly, striking improvement in their ability to process insulin, researchers said. The drug had no effect on weight when given to lean monkeys.
Results of the study, performed at M.D. Anderson Cancer Center in Houston and published online by the journal Science Translational Medicine, confirmed a 2004 report from the same research team showing marked weight loss in mice treated with the agent.
But success in mice studies often fails to translate to people. Because the biology of monkeys is much closer to that of humans, scientists said the new findings offer hope the treatment could prove effective in people.
To that end, an initial human trial involving obese patients with advanced prostate cancer could begin early next year. Rights to the drug, which was developed at M.D. Anderson, have been licensed to Ablaris Therapeutics Inc., a unit of Arrowhead Research Corp., Pasadena, Calif. Plans to develop it for a broader population of obese patients will depend on finding a safe dose in the initial tests, among other things, the company said.
Obesity has emerged as a global public-health problem. In the U.S. alone, about one-third of adults are considered obese. The condition is associated with cardiovascular disease, diabetes, cancer and other ailments.
Several recent efforts to develop weight-loss drugs haven't yet succeeded. Typically, treatments aim either to suppress appetite or amp up the body's metabolism to cause burning of more calories.But the biology for those processes is especially complex and governed by the central nervous system. Several drugs have failed so far to clear regulatory hurdles, hampered especially by safety worries.
At M.D. Anderson, Renata Pasqualini and Wadih Arap, a wife-and-husband research team, and their laboratory colleagues have developed a map of the body's blood-vessel system as part of an effort to develop more effective cancer treatments.
Their work has shown that different blood-vessel cells have distinct molecular signatures that the researchers liken to ZIP codes. The researchers theorized they could deprive tumors of their blood supply by combining a lethal therapy with a molecule that homed in on the ZIP code of cells in blood vessels that feed cancerous growths.
After identifying ZIP codes they thought might work in prostate cancer, they wondered about the possibility of targeting vessels that feed white fat cells, which accumulate under the skin and around organs in the abdomen, and are associated with weight gain. White fat also secretes hormones that are known to promote the growth of prostate tumors.
The researchers' 2004 paper showing a 30% weight loss in obese mice drew skepticism. Randy J. Seeley, director of the diabetes and obesity center at the University of Cincinnati, figured destroying white fat cells would make animals—and people—sick. But his own lab eventually replicated the mouse study, using rats instead, and now he is intrigued.
"This is really new stuff," Dr. Seeley said of the latest results. "There's no way to know if this will become a therapy or not, but at least it opens up a new way to think about therapies, and we have not had a lot of those." He isn't involved with the research.
The monkeys experienced modest kidney side effects from the four weeks of treatment, but researchers said they resolved quickly when the therapy was stopped. Side effects could undermine long-term use of the drug, which would likely be necessary for treating obesity.
The new study was funded by the National Institutes of Health and various philanthropic foundations. The findings, Dr. Pasqualini said, indicate adipotide "looks like a promising lead in a situation where there is very little out there that's in the pipeline" for obesity. Dr. Pasqualini and Dr. Arap are entitled to royalties resulting from successful commercialization of the drug. Both researchers and M.D. Anderson are investors in Ablaris.
James Hulvat, head of research and development for Ablaris Therapeutics, said the decision to test the agent first in obese prostate-cancer patients partly reflects the interests of M.D. Anderson, which is funding the initial study. The company also hopes to find an early benefit for the drug in a limited group of patients.
"We'll carry the drug forward into a broader weight-loss indication if the [initial] clinical trial data support that," he said. The company is also interested in pursuing the agent as a potential treatment for type 2 diabetes, which is associated with obesity.