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Wine's anti-aging ingredient: can it spawn a new class of drugs?

How they work is unclear, but Cambridge biotech's forging ahead

By Carolyn Y. Johnson
Globe Staff / May 17, 2010

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For years, Sirtris Pharmaceuticals grabbed headlines for its scientific success in pursuit of a tantalizing goal: drugs that could fight aging itself.

The Cambridge company, built on the discovery that an ingredient found in red wine had life-lengthening effects in yeast, sparked the public imagination and became a biotech success story. In 2008, it was purchased by GlaxoSmithKline for $720 million.

But even as Sirtris and others have published results showing the promise of the ingredient, resveratrol, against diseases of aging, several groups of researchers have questioned whether the original findings that led the company to create a new class of pharmaceuticals really explain why the drugs work.

“It’s complicated right now, and it’s certainly not a clear picture,’’ said Matt Kaeberlein, an assistant professor of pathology at the University of Washington who published a 2005 study that raised questions about the initial test-tube experiment that showed how resveratrol worked.

The original idea about resveratrol is that it mimics the life-prolonging effects of a restricted-calorie diet, by activating an enzyme called SIRT1.

Sirtris crafted drugs that acted like resveratrol, but were unrelated to it and caused more potent activation of SIRT1, and has seen benefits in animal studies, most notably in mice with type 2 diabetes. Two drugs are now being tested in human clinical trials.

But understanding how the drugs work has been controversial.

In January, scientists from Pfizer published a paper in the Journal of Biological Chemistry that concluded resveratrol and several related Sirtris compounds did not directly activate SIRT1. That followed a study published in the journal Chemical Biology and Drug Design last fall, in which Amgen scientists came to a similar conclusion.

And in 2005, Kaeberlein and colleagues suggested the positive results from the initial test used to detect increased SIRT1 activity might be a consequence of the way the studies were done. They showed that resveratrol activated SIRT1 only in the presence of a particular compound with a fluorescent tag used in the experiments, opening the possibility that resveratrol might not work the way people thought.

Sirtris’s chief executive, George Vlasuk, said research soon to be published will provide strong evidence to answer critics’ questions. But the ongoing debate highlights a vexing truth about the quest for new drugs. The industry’s most tantalizing promise in recent years — that researchers could understand a disease so precisely they could custom-design drugs to fight it — has crashed up against the incredible complexity of human biology.

The mechanism of a drug — how it actually works — can remain mysterious after it is developed, tested, and even approved.

This month, for example, a study in the journal Cell Metabolism showed that metformin, a widely used drug approved by the Food and Drug Administration in 1994 to treat type 2 diabetes, works differently than widely thought.

Knowing the mechanism of a drug is important. It can help researchers optimize a compound, understand a disease, and better anticipate side effects. But that knowledge is not essential for a drug to be successful, and even as scientists question how the Sirtris drugs work, they say the doubts about the mechanism do not diminish the promising animal studies.

“The mechanism is important for scientists to work out so we understand the biology, but it doesn’t matter from a therapeutic perspective. . . . If these compounds are effective against type 2 diabetes, patients don’t care about the mechanisms,’’ Kaeberlein said.

Sirtris’s drugs have shown promising biological effects in mouse models of type 2 diabetes. The company has developed compounds designed to activate SIRT1 with greater potency than resveratrol and has shown they improve insulin sensitivity and reduce glucose levels.

One of Sirtris’s drugs is now in a clinical trial designed to test its safety and efficacy in diabetes patients and is being explored as a potential treatment for cardiovascular and inflammatory diseases. Another compound is being tested for safety. Last month, however, a trial of a proprietary formulation of resveratrol in multiple myeloma patients was suspended because of safety concerns.

Anthony Sauve, an associate professor of pharmacology at Weill Cornell Medical College who is also a member of Sirtris’s scientific advisory board, compared the initial test that demonstrated resveratrol’s effects and laid the foundation for Sirtris’s drug pipeline to a questionnaire. Even if particular questions are flawed or irrelevant on a questionnaire, it may provide tools to predict people’s behavior accurately.

“The compounds have been biologically active,’’ Sauve said.

David Sinclair, a cofounder of the company and a pathology professor at Harvard Medical School, said the questions about the original test have intensified the research. He is confident that research will reveal the initial test was telling researchers something important about how the drug works.

“Just because you don’t understand fully the way something is working in the test tube, history has taught us you shouldn’t call these things an artifact,’’ he said. “Instead, they should be seen as an invitation to understand new mechanisms of how we might understand drugs and even understand how biology works.’’

“Potentially shutting down a whole area of research just because you don’t understand it, I think, is dangerous.’’

Carolyn Y. Johnson can be reached at cjohnson@globe.com.