Zafgen’s Mysterious Weight Loss Drug Advances Into First Trial for Obese Women

Xconomy Boston — 

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.

Tom Hughes

Tom Hughes

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 … Next Page »

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7 responses to “Zafgen’s Mysterious Weight Loss Drug Advances Into First Trial for Obese Women”

  1. Peter Brooks says:

    The first, interesting research, purchased by Zafgen for this was the results of a 2004 study by Mikhail Kolonin, in Nature Medicine 10, 625 – 632 (2004) “Reversal of obesity by targeted ablation of adipose tissue”, who pioneered an innovative and radical approach that showed quite remarkable results in animal studies.

    This didn’t work through affecting angiogenesis, but by the targeted induction of apoptosis in the vasculature of fat tissue.

  2. i’m51 yrs old with fibromygia i’ve had it long time @5’3 and 240lb ipray this drug works i know diets don’t my weight is slowly killing me i’m i’ve done alot of different diets alot of different machines some work for awhile some did’nt wok at all i still want to know why some people are thin and some are morbidly obese i was’nt an over weight child seems like it seems like something changes i did’nt gain mine until i was in my early 20’s i would like to know

  3. firm belly says:

    It will be interesting to follow the results of this clinical trial. If it produces the startling effects you are looking for, it could be a tremendous benefit to those who are morbidly obese.

  4. barryc1963 says:

    “obesity is one of the biggest market opportunities in the pharmaceutical business now. An estimated two-thirds of American adults are overweight or obese” 2/3 are overweight??? Some people are desperately trying to ADD weight. Too bad big pharma can’t come up with a “SAFE” fast metabolism pill.