[tt] Sirtris and resveratrol trials

[Hughes, James J.]

http://www.nytimes.com/2007/07/08/business/yourmoney/08stream.html

July 8, 2007
Slipstream
An Age-Defying Quest (Red Wine Included)
By JASON PONTIN

SIRTRIS PHARMACEUTICALS wants to sell you the elixir of youth. Yet the
company's founders are neither cranks nor quacks, but include a
well-regarded Harvard scientist and a serial entrepreneur.

Imagine a pill, derived from a compound found in something as benign as
red wine, that treated the most feared and debilitating diseases of
aging: illnesses like diabetes, neurodegenerative conditions like
Alzheimer's and Parkinson's, and many forms of cancer. Imagine,
furthermore, that this pill had no injurious side effects. Imagine,
finally, that the pill's only side effect conferred what human beings
have always wanted: an increase in life span. That's what Sirtris wants
to create.

Christoph Westphal, the chief executive of Sirtris, who has an M.D. and
a Ph.D. in biology from Harvard Medical School, was previously a venture
capitalist at Polaris Ventures and was a founder of Acceleron Pharma,
Alnylam Pharmaceuticals and Momenta Pharmaceuticals, among other
companies. The last two companies, which are publicly traded, have a
combined market value of more $1.4 billion.

Sirtris was founded in the spring of 2004 by Dr. Westphal to
commercialize the research of David Sinclair, a professor of pathology
at Harvard Medical School and the director of the Glenn Laboratories for
the Biological Mechanisms of Aging. Mr. Sinclair, who at the relatively
youthful age of 37 is already renowned for his investigations into how
we grow old, discovered in 2003 that a molecular compound called
resveratrol, found in red wine and other plant products, extends the
life span of mice by as much as 24 percent and the life span of other
animals, such as flies and fish, by as much as 59 percent.

Dr. Westphal, a self-described "geek" who relaxes by reading papers in
academic journals like Nature and Science, was stunned by Mr. Sinclair's
discovery, and visited him in his lab to discuss the implications for
drug development. The two soon decided to start a company.

"I figured if there's going to be one chance that I'd take an 80 percent
pay cut to be the C.E.O. of a company rather than general partner in a
venture firm, then this was it," Dr. Westphal, 39, told me when I
visited Sirtris's offices in Cambridge, Mass. "If we're right on this
one, everyone's going to want to take these drugs and they're going to
treat many of the major diseases of Western society."

Since founding the company, Dr. Westphal and Mr. Sinclair have raised
more than $103 million in venture funding, from various investors like
Polaris Venture Partners, the Novartis Bioventures Fund and the Genzyme
Corporation. In May, Sirtris completed a successful initial public
offering, raising an additional $62 million in capital.

Thus, Sirtris now has $140 million in cash and annual expenses of only
$37 million, according to Dr. Westphal.

"We can control our destiny," he says. "We can actually go for this
crazy idea that you can target genes that control the aging process."

Mr. Sinclair believes that resveratrol works by activating a gene called
SIRT-1, which many biologists think plays a fundamental, if still
obscure, role in regulating life span in mammals. Scientists have shown
that increasing the activity of SIRT-1 in animals slows down aging and
postpones or eliminates diseases of old age.

No one really knows why SIRT-1 has the effect it does. One theory,
proposed by Leonard Guarente, Mr. Sinclair's mentor, who discovered the
sirtuin genes (as they are collectively known) and is a biology
professor at the Massachusetts Institute of Technology, is that SIRT-1
is activated by caloric restriction.

Biologists have known for 70 years that mice will live much longer when
they are fed a nutritious diet with 30 to 40 percent fewer calories than
they would normally eat. (Mr. Guarente and Mr. Sinclair think that this
could be an ancient evolutionary adaptation to scarcity and starvation.)
Resveratrol may therefore be mimicking caloric restriction without an
arduous diet that few people can maintain for very long.

"Nobody knows why we age," Mr. Sinclair explained to me. "We're working
on genes that increase fitness and defenses against diseases. The body
mounts those defenses when it's under adversity. Caloric restriction is
one of those triggers and the molecules we're developing are also one of
those triggers."

Dr. Westphal and Mr. Sinclair stress that they are not working to "cure"
aging, a condition that, so far at least, is common to all humanity and
that most physicians do not consider a disease. "Curing aging is not an
endpoint the federal drug agency would recognize," Dr. Westphal says
dryly. Instead, both men say, they are working to ameliorate the
diseases of aging.

While Mr. Sinclair has bragged that resveratrol is as "close to a
miraculous molecule as you get," much uncertainty surrounds his research
and the commercialization of his discovery faces many challenges.

Quite apart from any scientific debate about why resveratrol works and
whether it will have the same beneficial effect in humans that has been
demonstrated in animals with short life spans, no one knows if
resveratrol will be toxic when taken in therapeutic doses. Mr. Sinclair
argues that the compound is unlikely to be toxic because it is
modulating enzymes "that naturally go up and down according to diet."

In any case, he says, mice have consumed as much as 400 milligrams of
resveratrol per kilogram of body weight without ill effect. On the
contrary, the rodents became sleek, slim and powerfully athletic. (A
human would have to drink 10,000 bottles of wine a day to consume the
same quantity of resveratrol.)

But Phillip A. Sharp, a 1993 Nobel laureate in medicine and physiology
who has advised Sirtris, strongly disagrees: "Mice are not men, and even
if you treat a mouse he can't tell you if there's something wrong with
his paw," said Mr. Sharp, who is also the director of the McGovern
Institute for Brain Research at M.I.T. "Until you go into long-term
human studies, there will always be unknown risks."

SIRTRIS has begun such studies. The company has one compound, called
SRT501, an improved formulation of resveratrol that is in early clinical
trials for the treatment of diabetes. Later this year, Dr. Westphal
says, the company will also begin clinical trials with SRT501 to treat
Melas syndrome, a disorder of the cell's mitochondria, in which
sufferers age with unnatural haste.

The company is also developing other "sirtuin activators" that are
unrelated to resveratrol, and which Dr. Westphal describes as "one
thousand times" as powerful as SRT501. In theory, drugs derived from
such compounds would be more effective at lower doses. Sirtris hopes to
have its first drugs in commercial production by 2012 or 2013. While
that may seem far off, it's wonderfully fast for the biopharmaceutical
industry, where development is onerously slow, difficult and uncertain.

This speed of research and development owes much to Dr. Westphal's
energy and Mr. Sinclair's ambition.

"For as long as I can remember, I've wanted to develop drugs that combat
diseases of aging," Mr. Sinclair says. "As soon as I realized I was
mortal, I started to worry. I set a goal to see if we could make drugs
that would target the diseases of aging in my lifetime. I didn't know it
would be possible at all - and I didn't know it would happen so
quickly."

Jason Pontin is the editor in chief and publisher of Technology Review,
a magazine and Web site owned by M.I.T. E-mail:
pontin at nytimes.com