Monday, December 10, 2007

Resolvyx Pharmaceuticals: Fish-Oil Mystery Solved, Blockbuster Drugs to Follow?

David Stipp 11/30/07

If you haven’t considered eating more fish or taking fish-oil pills by now, you’re probably very young, just in from Mars, or both. The case for the health benefits of omega-3 fatty acids, the compounds of interest in fish oil, rests on thousands of studies over the past two decades, and the list of ills they may ward off or ameliorate includes heart attacks, stroke, diabetes, macular degeneration, rheumatoid arthritis, Alzheimer’s disease, various cancers, osteoporosis—basically every major disease of aging, as well as psoriasis, asthma and others. But there’s a deep mystery here: Why is omega-3 linked to so many different benefits? You could spend weeks immersed in the fish-oil literature trying to answer that. But it would be easier to ask the brain trust at Resolvyx Pharmaceuticals, a two-year-old startup in Bedford, MA. The company not only offers a compelling explanation but is also poised to capitalize on it to develop drugs as versatile as fish oil itself.

Here’s the big idea: One of the main things that goes wrong as we age is the fraying of our inner controls on inflammation, the heated immune reaction, accompanied by pain and swelling, that’s triggered by invading germs or other insults. That allows pockets of low-level inflammation to linger—picture smoldering coal-seam fires across your inner landscape. Just about every degenerative disease of aging, from atherosclerosis to Alzheimer’s, has been found to centrally involve insidious inflammation. Chronic inflammation also does much of the damage in autoimmune diseases, such as rheumatoid arthritis. Thus, if you wanted to come up with a do-all miracle drug, you probably couldn’t do better than to develop a potent anti-inflammatory that could be safely taken for long periods. And if you were smart, you’d probably start, like Resolvyx’s founding scientists, by investigating the safest anti-inflammatory around, fish oil.

Omega-3 fatty acids’ anti-inflammatory effect isn’t new. But the molecular details of the effect—and the ability to explain fish oil’s remarkable diversity of likely benefits—have only come into focus over the past few years. The progress stems largely from the work of Resolvyx cofounder Charles Serhan, an anesthesia professor at Harvard Medical School. Serhan is known for groundbreaking research on natural anti-inflammatory lipids. Since 2000 his group at Boston’s Brigham & Women’s Hospital has elucidated how omega-3 fatty acids are processed in the body to give rise to sets of potent lipids, dubbed resolvins and protectins, that affect the process of inflammation.

One of Serhan’s seminal ideas is that after inflammation has done its thing, it doesn’t just passively fade as its triggering molecules dissipate. Instead, it is actively curtailed during a “resolution phase” by chemical messengers that pacify angry immune cells and halt production of inflammatory signals. Serhan’s research suggests the resolvins are among the most important of these naturally-occurring resolvers of inflammation, hence the name—mere nanograms of them can quell inflammation. The protectins play similar roles, apparently springing forth to help to resolve inflammation in asthma and other diseases, as well as preventing death of stressed, potentially suicidal nerve cells during inflammatory flares caused by strokes and other brain hits.

With the discovery of key lipids that resolve inflammation, says Serhan, “we’ve figured out an old problem that first came up in the 1920s: Why are essential fatty acids essential?” (When discovered in 1923, omega-3 fatty acids were classed as essential because, like vitamins, they were found to be critical for normal growth, and the body can’t make them from scratch—they or their immediate precursors must come from food.) Indeed, adds Resolvyx executive vice president James Nichols, without the lipid peace-makers, “you’d accumulate inflammation over time” as one insult after another triggered unresolved flare-ups.

In 2002, Serhan joined forces with Per Gjorstrup, a native of Sweden who had long worked in the drug industry and was most recently at Biogen, to form Resolvyx. The startup’s goal seemed, literally, a natural: turn the body’s own inflammation regulators into drugs to halt run-amok inflammation. But it took three years to win over venture capitalists,says Gjorstrup, now Resolvyx’s chief scientific officer. They had two main reservations: Natural resolvins and protectins act locally and typically exist only minutes before getting chewed up by enzymes, hence it seemed unlikely that drugs based on them would last long enough in the body to work. And the lipids’ chemical complexity—chains of 20-plus carbon atoms festooned with side groups—suggested it would cost too much to synthesize them in large quantities.

Eventually, Resolvyx advisor Nicos Petasis, a University of Southern California chemist, helped finesse the synthesis issue. Meanwhile, Serhan’s group and Resolvyx scientists demonstrated that the compounds have surprisingly long half-lives when administered as drugs, and that they show efficacy in animals with various inflammatory illnesses. In December 2005, CHL Medical Partners, Atlas Venture, and Flagship Ventures launched Resolvyx with a $17 million first-round financing. A year ago, Resolvyx’s pace quickened when it hired biopharma veteran (Sepracor, GlaxoSmithKline, Abbott) Paul Rubin as CEO.

Now the company faces an enviable problem: an embarrassment of riches when it comes to possible indications for its medicines. “We have an opportunity to campaign our drugs across a really broad range of conditions,” says Nichols—everything from killers such as heart disease to skin inflammation. But its limited resources necessitate a careful choice. Seeking to ward off heart attacks, for example, would require lengthy clinical trials beyond its means. Instead, the startup plans to try oral doses of a resolvin called RvE1 as a treatment for rheumatoid arthritis, inflammatory bowel diseases, and asthma. It’s also plans early trials with resolvins for diseases such as dry eye, a debilitating condition centrally involving inflammation. Nichols adds that the ability to monitor blood levels of inflammatory “markers” in patients on Resolvyx’s drugs should enable it to quickly establish “proof of concept” in early-stage clinical tests, paving the way to raise the large sums needed for bigger trials.

Resolvyx’s drugs promise to be exceptionally safe—an important plus at a time when one high-flying drug after another has crashed due to unexpected toxicity. Existing anti-inflammatories can precipitate gastric bleeding, immune suppression, and other fallout. In contrast, hefty doses of fish oil have been chronically ingested by millions with minimal adverse effects. (Remember the cod liver oil moms used to foist on grimacing kids?) Omega-3’s natural derivatives could be similarly benign. Serhan explains that the derivatives seem to grease many wheels in cells to normalize an out-of-whack process rather than hitting one or two molecular targets very hard, as do most drugs, inviting side effects.

Still, couldn’t the benefits of Resolvyx’s drugs be attained by simply popping fish-oil pills? Probably not, says Nichols. The hot-selling supplements may be good for lowering disease risks in general population, he adds. But to douse the leaping immune flames underlying diseases such as rheumatoid arthritis—and achieve maximal benefits in clinical tests—will probably necessitate the kind of stronger, precision-manufactured medicine Resolvyx is developing. Besides, many if not most patients would likely balk at chronically gulping fistfuls of omega-3 pills. The resulting fishy burps alone could prove fatal—to their social lives.