Anti-aging drugs (cont.)
The large, unfathomable risks most biotech startups face make investors' due-diligence process seem like shining a penlight into Carlsbad Caverns. Thus, venture capitalists often look to the stature and track record of the people involved as the best indicator of potential. Says Sirtris board member and co-founder Richard pops, CEO of Alkermes, a biotech concern in Cambridge: "pedigree is everything" in early-stage biotech.
Westphal couldn't agree more. An avid reader of the scientific literature, he had become intrigued by research on sirtuins during his days as a venture capitalist. After Sinclair's high-profile discovery in 2003 that resveratrol extended the life span of yeast, Westphal phoned the Harvard scientist to talk about his findings' commercial potential. The research was highly intriguing, Westphal says, but Sinclair the man was equally important to him. One Sinclair forte instantly stood out: The scientist, a native of Australia with a natural flair for public speaking, has a rare knack for conveying the excitement of the grand quest to nonscientists. "Sirtris has been successful largely because we were able to raise a lot of money and get momentum early on," he says. "That's partly because David [Sinclair] is fantastic at selling the story."
The two didn't hit it off at first. Westphal, then working at Polaris Venture partners in Waltham, Mass., "came to my office in a somewhat arrogant manner," recalls Sinclair. "He said, 'Tell me more about these molecules you've found.' I told him that first he had to sign a nondisclosure agreement" to keep nonpublic details about Sinclair's work under wraps. "He said, 'I never sign those.' so I told him maybe I can't talk anymore about this. And he said, 'David, if I walk out of this office, I'm not coming back. So I suggest you tell me as much as you can.' "
After that tense beginning, says Sinclair, the conversation turned out to be "like a wonderful game of chess. I wound up telling him more than I normally would have. It soon became apparent that he's one of the smartest people I ever met. But it took me months to realize that he's also a nice guy."
Asked about the episode, Westphal says, "as a venture capitalist, you're in a world where everything is about money. That can really corrupt interactions with people."
Since combining forces with Sinclair, Westphal has organized what is arguably the most pedigree-rich scientific advisory board in biotech, including MIT's Sharp; Robert Langer, one of medicine's most prolific inventors, also of MIT; Harvard gene-cloning pioneer Thomas Maniatis; and Thomas Salzmann, formerly executive vice president of Merck's (Charts) research arm. The group now numbers 27, among them many of the world's leading experts on sirtuins.
Westphal also assembled an impressive list of directors - they include Alkermes's Pops; Aldrich, the Boston hedge fund manager and biotech veteran; and Paul Schimmel, a prominent scientist at the Scripps Research Institute in La Jolla, Calif., who has co-founded half a- dozen biotech concerns. Westphal's right arm at Sirtris is chief operating officer Garen Bohlin, 59, formerly a senior executive at the genetics institute, a biotech now owned by Wyeth.
The Sirtris team wasted very little time reaching its first milestone, which was to develop "high throughput" screening tests that enabled it to quickly analyze nearly 500,000 compounds for resveratrol- like activity. The rapid-fire winnowing led to several potent molecules that promise to replicate resveratrol's health benefits at doses hundreds of times smaller than are required with the natural substance. These two standard steps in drug development often take several years; Sirtris completed them in a little over a year.
Meanwhile, hoping to get an early indication of efficacy against disease, the company formulated a resveratrol-based drug, dubbed 501, to begin the tests in diabetic patients. Westphal cautions that the drug is likely to be a product for only a few indications - Sirtris's more potent medicines will probably have much broader applications. Still, in animal tests, 501's proprietary formulation gets more than ten times as much resveratrol into the bloodstream as do dietary supplements containing equal amounts of it, says the company.
The 501 trial's results should be available this year - if Sirtris decides to disclose them. So far the drug has shown only mild side effects. The main one has been occasional nausea among people taking it on an empty stomach. One reason for that could be that the orally administered liquid drug tastes awful; Sirtris hopes a new cherry-flavored version will go down easier.
Of all the decisions Westphal has made - reject the hype but not too much; which medicine flavors are least nauseating - the biggest may prove to be simply speed. Sirtris's rapid push into clinical trials, the costliest stage of drug development, is likely to force it to raise more money soon. One option: license drug rights to big pharma concerns. But those who reach into pharma's deep pockets tend to get entangled in its bureaucratic strings. Major decisions on developing a drug, for instance, must go through layers of managers.
Further, if Sirtris licenses rights to its drugs, it might hand over compounds to a pharma partner before their full value has been assessed and factored into the deal - the possibility that the drugs could treat many diseases of aging is still too tentative to put a pricetag on. Despite the controversy over how resveratrol works, there's no telling how many diseases it can treat. And resveratrol's ability to boost mitochondria, those cellular power plants, indicates Sirtris's medicines will be highly versatile. In fact, the list of disorders thought to involve malfunctioning mitochondria includes adult-onset diabetes, heart disease, stroke, cancer, and Alzheimer's and Parkinson's diseases-all diseases of aging.
"If I had $500 million today," says Westphal, "I'd be tempted to take our drugs into the clinic against two or three devastating neurological conditions and other metabolic diseases besides diabetes. That would be incredibly risky. But sometimes I think, 'This is the kind of company that could gather enormous resources' " based on its extraordinary promise. "It would be a real shame if we didn't go for it and try to address these huge medical problems."
At some point Sirtris will probably go public, raising the money Westphal would need to pursue this vision. In fact, the excitement about resveratrol may well allow Sirtris to make an initial public offering at an earlier stage of development than is feasible for most biotechs. Westphal declines to comment on that. When asked about it, though, he suddenly reverts to vortex-avoidance mode: "part of my job is to calm people down," he says. "You have to remember, most things in biotech don't work."
Sobering words - especially for us hopeful resveratrol watchers of a certain age. But here's an antidote: pour a glass of pinot noir, and while imbibing, step back and regard the big picture. Humanity has dreamed for millennia of medicines that extend life span. Sirtris may not fulfill the dream. But the company's very existence shows that the quest for compounds that slow aging has been transformed from sorcery into the fairly routine process of pharmaceutical development. Thus, the dream is likely to be realized within, at most, a few decades. The question now is when, not if.