Zafgen arrived on the Boston biotech scene about 18 months ago with blue-chip venture backing, a highly regarded scientist as CEO, and an audacious idea. The Cambridge, MA-based company was developing a powerful new weight loss drug made to work unlike any other treatment in development, by cutting off the blood supply to fat tissue.
One year later, results are in. The idea was wrong.
“That was the theory,” says CEO Tom Hughes. “It doesn’t appear to be the case.”
As it turns out, though, that’s not the end of the story. Allow me to begin at the beginning.
Zafgen first emerged in public in September 2008. That’s when Hughes joined the company after a stint as global head of cardiovascular and metabolism research at the Novartis Institutes for Biomedical Research in Cambridge. Third Rock Ventures and Atlas Ventures provided the initial backing. The idea was to build on research at Children’s Hospital Boston that found drugs which are made to block formation of blood vessels—a successful cancer-fighting strategy—might also help shrink fat tissue. It was a provocative finding from mouse experiments, partly because nobody had really tried it before. Many other drugs in development for obesity work on receptors in the brain, trying to coax the body to think it’s full and stop eating.
VCs listened with some interest because obesity is one of the biggest market opportunities in the pharmaceutical business now. An estimated two-thirds of American adults are overweight or obese, according to the Centers for Disease Control and Prevention.
One of the key things Zafgen learned over the past year, based on detailed animal experiments, was that its drug didn’t work through the mechanisms it intended. The company conducted experiments on its lead candidate and found at the tiny doses it intended to use, “we have absolutely no effect on angiogenesis,” the scientific term for formation of new blood vessels.
Neverthless, Zafgen’s scientists had some good reasons to still press forward. They didn’t really know why it was working, but that didn’t change the fact they saw profound weight loss and fat tissue shrinkage in mice and rats. The effect was strong enough that Zafgen envisioned developing the first drug powerful enough to compete with bariatric surgery.
So how might Zafgen’s molecule produce this magnitude of weight loss? Hughes says a couple of theories have emerged based on studies by the company’s collaborators, and some external research published in the past year. One idea is that in obese people, cells in their fat tissue lose their ability to release fat acids into the bloodstream, where they can be burned up as energy. Another is that ketone bodies—certain byproducts of fatty acids that get burned up as energy—get suppressed when obese people have high amounts of insulin circulating in the blood. This makes it more difficult for the body to burn energy from fat, and more likely to store it away in fat tissue, he says.
So while Zafgen’s drug, given at low doses, had no effect on blood vessels, it did show an ability to “unlock” the fat tissue so it can release fatty acids, Hughes says. The company found its drug is also stimulating production of more ketone bodies, so that when fat is released, it can be burned up efficiently as energy. That’s the new concept, anyway.
It’s more than an academic curiosity, as Zafgen is putting this notion to the test in its first clinical trial. The plan is to study ZGN-433 in about 40 obese women at a single site in Australia. The drug, an angiogenesis inhibitor, failed to shrink tumors in a cancer trial, but the compound had the unexpected side benefit of helping patients lose weight. Based on the animal studies the company has run to better understand the weight loss effect, Zafgen plans to try doses 100 to 500-fold lower than were envisioned when the molecule was a cancer treatment.
Hughes won’t say exactly what biological target on cells this drug is being aimed at, or which drug company used to own it. But this trial has been set up to give Zafgen a clear answer on whether the treatment—and the new weight loss concept—has a future.
The main goal, with any early-stage trial, is to see the drug is safe, well-tolerated, and properly absorbed into the body, Hughes says. These women are considered not just overweight, but significantly obese, with body-mass indexes of between 35 and 45. That means a person who is 5-foot-8 would have to weigh at least 230 pounds to enroll. They will be randomly assigned to get twice-weekly injections of the Zafgen treatment over a six-week period, or a placebo injection, according to this posting on clinicaltrials.gov.
Zafgen will be measuring how much weight these people lose in the trial, and taking important molecular measurements to see if the drug is hitting the intended target, and whether that correlates with its new theory of how the drug works. Data from the trial should be available by the second half of 2010, Hughes says.
The outcome will have to be startling for Zafgen to go forward. It’s not likely to be a drug for the masses who want to drop a few pounds. If effective, it will likely be a competitor for bariatric surgery. “It’s strong medicine for serious obesity,” Hughes says.
More specifically, Zafgen will need to show about an additional 20 percentage points of body weight loss beyond what patients get from a placebo, in a “reasonable” amount of time, Hughes says. That translates to about 70 to 100 pounds of weight loss for most obese people in about a nine-month period, he says. That’s far greater weight loss than has been seen from any of the experimental pills that are near the end of clinical development, from high-profile obesity drug developers like Arena Pharmaceuticals, Orexigen Therapeutics, and Vivus.
If Zafgen can reach its lofty goal later this year, it will be in position to raise more capital, or strike a partnership, Hughes says. If not, then it might be time for the company to throw in the towel.
“If the molecule works the way we think it does based on animal studies, we’re in good shape. If it isn’t, then maybe we shouldn’t be doing it,” Hughes says.
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