A drug born of a revolutionary approach to cancer treatment causes rapid weight loss and improved metabolic function in monkeys, scientists have found. Coming in the wake of multiple setbacks for proposed diet drugs, the early success of a peptide dubbed “adipotide” by its creators may open a new front in the war against obesity, several researchers said.
The study, published Wednesday, describes trials in which three species of primates responded to injections of the synthetic peptide by eating less, shedding belly fat and showing changes in metabolic function likely to keep at bay Type 2 diabetes — a frequent consequence of obesity.
The trick behind the therapy: killing fat cells by robbing them of the blood supply that nourishes them.
This strategy, known as angiogenesis inhibition, is the basis for more than 15 drugs used to treat cancers of the brain, colon, lungs and kidneys. The new study, reported in the journal Science Translational Medicine, is the first to test the strategy in primates as a treatment for obesity.
After four weeks of daily injections of adipotide and a four-week follow-up with no treatment — and without forced changes in diet or exercise — 10 obese female rhesus macaques lost an average of 11% of body weight and 39% of fat deposits.
Much of that loss came in the three weeks after the drug was discontinued, during which the treated macaques continued to become lighter and leaner.
Study coauthor Dr. Wadih Arap, an oncologist at the M.D. Anderson Cancer Center in Houston, who pioneered the approach with his wife, Renata Pasqualini, a cancer researcher at the center, expressed satisfaction at the treated monkeys’ weight loss and metabolic improvements. But he acknowledged that “we’re a little bit at a loss to explain” all of the effects in the two species of macaques and a small group of baboons that were tested.
He called the study a “proof of concept,” and added that “we’re not done” tinkering with the structure of the potential drug.
One key issue is safety: The drug appeared to cause some dehydration, a moderate drop in the monkeys’ phosphorus and potassium levels and small kidney lesions in some. Those effects disappeared after the drug was discontinued, but they could become a cause for concern as the drug candidate enters the phase of clinical trials in humans, which is expected to begin in the coming months.
To develop the drug further, M.D. Anderson has partnered with a Pasadena-based company, Arrowhead Research Corp. Arap and Pasqualini own stock in the company and founded the subsidiary, Ablaris Therapeutics Inc., that aims to bring the weight-loss agent to a potentially gigantic market.
Adipotide was designed to attach itself just to the blood vessels that feed the body’s fat deposits. Then it attacks them, causing them to wither and die. Apparently robbed of much of their blood supply, fat deposits respond by shedding fat cells.
Most remarkable to obesity researchers, the rapid release of fat cells into the bloodstream does not appear to result in dangerous levels of fat coursing through the body, where it could be expected to inflame blood vessels, disrupt metabolism and prompt an uptick in appetite. Instead, the fat cells are burned as fuel.
What happens next is a matter of informed speculation. The monkeys receiving a daily shot of adipotide continued to eat a wide range of foods offered to them and did not appear to suffer nausea or discomfort. But they began to consume less than they had at the outset. That, said Arap, was a surprise, since weight loss typically ramps up the appetite as the body struggles to preserve its fat supplies.
Obesity researcher Randy Seeley of the University of Cincinnati College of Medicine, who directs the Cincinnati Diabetes and Obesity Center, suggested that the body’s remaining fat deposits send messages to the brain’s appetite centers that they’re operating at capacity and can’t possibly store any more fat. The message dictates: Eat less.
“What they have tapped into is a whole layer of biology about how adipose tissue communicates with the brain and other organs about its status, and we didn’t know anything about that until they came along,” said Seeley, who was not involved in the study. He said he was until recently an ardent skeptic that this weight-loss strategy would ever work but now finds the approach “incredibly cool.”
Others caution that much more work needs to be done to better understand adipotide’s mode of action and safety before a drug based on the peptide is ready for use in patients.
“This is exciting and very interesting work,” said Yihai Cao, a microbiologist at the Karolinska Institute in Sweden who studies angiogenesis in tumors. But, he added, the researchers will need to clearly show that adipotide is reducing blood vessels that nourish fat without harming other blood vessels, as well as how appetite changes and metabolic improvements are related to that effect.
Cao also stressed that the gap between monkeys and humans is “a big jump.”
“Whether this will reach the clinic remains to be seen,” he said.
Arrowhead Research Corp. is in discussions with the Food and Drug Administration and expects to have research trials in humans underway within a few months, said Chris Anzalone, the company’s chief executive. One of the first patient populations likely to be tested are obese men with prostate cancer, who are more than twice as likely as leaner men to die of the disease, Anzalone said.
Meanwhile, Ablaris Therapeutics is working on changes that could address side effects and create a formulation that could be injected less often than daily.
Anzalone said that the drug was likely to be a short-term solution to weight loss and metabolic danger, leaving patients the difficult task of maintaining their health gains with diet and exercise afterward.
“We will see how this works in humans,” said Anzalone. “My sense is this will never be intended for long-term use. Sometime after the drug, we believe that lifestyle changes will have to take over.”