West Coast Editor

SAN FRANCISCO - Held just down the road from the famed wine country of Napa Valley and Sonoma County, the 26th annual JPMorgan Healthcare Conference fittingly opened with buzz about a diabetes drug candidate formulated from resveratrol, the red-wine component that has made headlines lately in life-span research.

Called SRT501, from Sirtris Pharmaceuticals Inc., the oral small molecule is one of a handful in the Sirtris pipeline that targets sirtuins, the genes that control aging. Lead compound SRT501 is a version of resveratrol with about five times the bioavailability of the native substance. The drug activates Sirt1, lowering glucose while providing sensitivity to insulin.

"As far as we can tell, [SRT501] operates by one of the few safe mechanisms that does both," said Christoph Westphal, CEO of Cambridge, Mass.-based Sirtris, which unveiled positive data Monday from a Phase Ib, 28-day trial in Type II diabetics given SRT501.

Treatment-naïve patients got once-daily doses of either 2.5 g or 5 g of SRT501, and both doses proved well tolerated and safe, with drug levels identical at days one and 28, suggesting no buildup in the systems of patients.

Researchers found neither serious adverse events nor dose-related adverse events, and SRT501 gave a statistically significant improvement in an oral glucose tolerance test on day 28 at two hours, along with a trend toward lower fasting plasma glucose levels.

"We seem to be mimicking a natural process that is safe," Westphal told BioWorld Today. The dual benefits of SRT501 copy the benefits of calorie restriction - dieting - and the compound is being tested in patients with Type II diabetes in a Phase Ib twice-daily study. A Phase IIa trial in combination with metformin is expected to yield data later this year.

Sirtris scientists, with those from Harvard University and the University of California, San Diego, described in a recent Nature paper more compounds that activate Sirt1, and Westphal said the small-molecule drugs behind SRT501 - unrelated to resveratrol - are a thousand times more potent, allowing for human doses in the "low hundreds of milligrams" rather than the "metformin[-size] doses" given of SRT501. The new compounds will enter human trials in the first half of this year. (See BioWorld Today, Nov. 29, 2007.)

Harvard's David Sinclair discovered that resveratrol works like dieting to activate Sirt1, and the substance already has found its way into over-the-counter food supplements for youth seekers, but opinions vary regarding whether such pills provide enough serum resveratrol to do the anti-aging trick.

JMP Securities, in a December research report on Sirtris, hailed preclinical results showing that SRT501 lowered glucose and insulin in a manner comparable to Januvia (sitagliptin), the DPP-4 inhibitor from Whitehouse Station, N.J.-based Merck & Co. Inc. that was approved last fall, and predicted Sirtris' approach "will translate into meaningful benefit in ongoing clinical trials." The Phase Ib data represent a step in that direction. Merck won approval last April of Janumet, which combines Januvia's active ingredient with metformin, the most popular drug for Type II diabetes in the U.S.

Januvia, though, is not an insulin sensitizer, Westphal noted. "It's a great drug, and a lot of folks think it might be a very important drug, but we think that [our compound] should be at least as good as, or potentially better than the DPP-4s, at least in terms of efficacy," he said.

The glitazone class provides the insulin-sensitizing benefit along with glucose improvements, "but they have been under significant pressure recently," he pointed out.

Glitazones include Avandia (rosiglitazone, GlaxoSmithKline plc) and Actos (pioglitazone, Takeda Pharmaceutical Co. Ltd. and Eli Lilly and Co.). In mid-November, the FDA said new warnings had been added to the existing black box on Avandia's label, alerting doctors that patients with Type II diabetes taking the drug - especially those with underlying heart disease - are at an increased risk for a heart attack.

CIBC World Markets' analyst Bret Holley wrote in a November report that data from Sirtris' Phase IIa trial with SRT501 should provide the first true proof of concept, and acknowledged that Sirtris' shares have "appreciated substantially" since its $60 million initial public offering in the spring, but found "some additional upside [likely] in the near term, driven by early data for SRT501." Holley has an $18 price target on the stock. (See BioWorld Today, May 24, 2007.)

Other biotech firms investigating Sirt1 include Cambridge, Mass.-based Elixir Pharmaceuticals Inc. and Boulder, Colo.-based Pharmion Corp., but "we're unaware of anyone who's within two to three years of us," Westphal said, adding that about a half-dozen pharma companies also have shown an interest in the field.

In August, sirtuins formed the basis of a potential $100 million joint research venture between Pharmion and Methylgene Inc., of Montreal. The companies plan to study sirtuin inhibitors as monotherapy and combination therapy for cancer. (See BioWorld Today, Aug. 21, 2007.)

"We've guided Wall Street to not expect a partnership for 2008," he said, though Sirtris has "high-level dialogue going on with several companies," as big pharma checks out the bigger picture of age-related conditions. Sirtris' work with SRT501 is the first time an orally available small molecule has been used to genetically target aging - the diseases of which are many and varied, well beyond diabetes.

"We're in a pretty fortunate position," Westphal said, citing $127 million in Sirtris' coffers as of Sept. 30. The firm's guidance for burn in full-year 2007 was $25 million to $28 million. "Based on that, you can see that we're quite well financed."

Sirtris' stock (NASDAQ:SIRT) closed Monday at $13.19, up 7 cents. The JPMorgan conference, with more than 6,000 attendees expected, continues through Thursday.