Sir2 Roads Diverged: Elixir Co-founder Joins Rival Sirtris

11/19/07Follow @wroush

The MIT biologist who co-founded Elixir Pharmaceuticals in 1999 in a bid to turn his research on a gene called Sir2 into drugs that might extend lifespans has defected to Elixir’s primary rival, Sirtris Pharmaceuticals (NASDAQ: SIRT). Both companies are developing drugs against aging-related diseases such as cancer and diabetes, and both are based in Cambridge.

Leonard “Lenny” Guarente, a professor in MIT’s department of biology since 1982, is frequently mentioned as a possible future Nobelist for his discovery that lifespan in mice, yeast, worms, and other organisms is regulated by the activity of Sir2—the more active the gene is, the longer the animal lives. But Sirtris, co-founded by Harvard pathologist David Sinclair in 2004, is now the dominant company doing research on potential drug compounds that enhance the activity of Sir2-like genes in humans. Today Sirtris announced that Guarente—who left Elixir in the fall of 2006—has joined the company as co-chair of its scientific advisory board.

Guarente said in a statement that he was “delighted” to join the SAB at Sirtris, which raised $60 million in an initial public offering in May. Guarente lauded Sirtris for being “highly focused” on developing therapies that target sirtuins, the class of enzymes encoded by Sir2.

That focus has been notably waning at Elixir, which hopes to raise $86 million in its own upcoming IPO. Elixir asserts in its IPO registration statement that its researchers “mine the pathways involved in the regulation of aging discovered by our founders”—but the company’s main commercial hopes rest on Glinsuna and Metgluna, diabetes drugs that it has licensed from a Japanese manufacturer and aims to market in the United States, pending FDA approval. In its 179-page IPO registration statement filed with the SEC, the company does not detail its research on drugs aimed at affecting the activity of sirtuins until page 69—and then, it’s in reference to drugs that block Sir2, rather than enhancing it. (The company believes that blocking sirtuins may help in the treatment of cancer.)

Guarente declined to renew his consulting contract with Elixir after it expired last fall. He has had a long and well-reported courtship with Sirtris, and his appointment to the Sirtis advisory board—which also includes such MIT luminaries as Robert Langer and Philip Sharp—would presumably have come sooner if not for a one-year noncompete agreement with Elixir, which has now run out.

“Guarente and Sirtris are both focused on developing drugs to treat diseases of aging by targeting the sirtuins, genes that control the aging process,” Sirtris CEO Christoph Westphal told Xconomy last night. “Guarente is a leader in academic aging research, and Sirtris is the leading sirtuin company, so this is a natural fit for both of us.”

Yet it’s a fit that wouldn’t have seemed natural just a couple of years ago. Sinclair, a protégé of Guarente’s at MIT in the late 1990s, declined an offer to join Guarente at Elixir. Instead, he and Westphal, then a partner at Polaris Venture Partners, went on to found Sirtris after Sinclair’s own discovery that resveratrol, a chemical found in red wine, mimics the lifespan-extending effects of very-low-calorie diets in mice, flies, and fish—seemingly by activating SIRT-1, one of seven Sir2-like genes in humans. Around the same time, Sinclair and Guarente had a well-publicized falling out over the genetic mechanisms by which caloric restriction leads to longer lifespan in yeast cells.

The former competitors have now patched up their differences. In fact, in October Sirtris obtained an exclusive license to commercialize work in Guarente’s lab on the cholesterol-regulating effects of SIRT-1, and Guarente is co-author with Westphal and Sirtris corporate development director Michelle Dipp on a Trends in Biochemical Sciences review paper on the therapeutic applications of sirtuins, published this month. Guarante’s appointment to the Sirtris advisory board “should be a huge sign to the public that David and Lenny are working together,” says Dipp. “Which is really nice to see, because they are really the leaders in the sirtuin field.”

Sirtris is conducting a Phase II clinical trial in India of a proprietary formulation of resveratrol that may help patients with type 2 diabetes control their glucose levels, and Westphal says that the company will soon publish results on a new compound that is 1000 times as potent as resveratrol when it comes to activating SIRT-1. Elixir, meanwhile, is pursuing research on an entirely different class of biological molecules involved in aging and aging-related diseases: ghrelins, which stimulate the release of growth hormones and increase appetite. The company hopes that compounds that block ghrelins might turn out to be treatments for diabetes and obesity.

Elixir’s IPO filing never mentiones Guarente by name, but the company is clearly aware that his ongoing work could lead to competing treatments for diabetes. In the obligatory section on the risk factors facing the company, Elixir states: “While certain of our founders have continued to assist us in various roles, including as scientific consultants, we no longer have an active relationship with several of our other founders. Although bound by confidentiality obligations relating to their work at Elixir, we do not have rights to any of their future discoveries and none of our founders is prohibited from competing against us.”

Wade Roush is a contributing editor at Xconomy. Follow @wroush

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  • Hank Stram

    Resveratrol has been recommended by Dr. Oz, as the single best supplement to take.
    According to Wikipedia, Consumer Lab, an independent dietary
    supplement and over the counter products evaluation organization,
    published a report on 13 November 2007 on the popular resveratrol
    supplements. The organization reported that there exists a wide range
    in quality, dose, and price among the 13 resveratrol products
    evaluated. The actual amount of resveratrol contained in the
    different brands range from 2.2mg for Revatrol, which claimed to have
    400mg of “Red Wine Grape Complex”, to 500mg for Biotivia Transmax,
    which is consistent with the amount claimed on the product’s label.
    Prices per 100mg of resveratrol ranged from less than $.30 for
    products made by Biotivia.com, jarrow, and country life, to a high of
    $45.27 for the Revatrol brand. None of the products tested were found
    to have significant levels of heavy metals or other contaminants.

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