Ischemix is Stepping Out of the Shadows to Confront Cardiology’s Dirty Little Secret

1/9/08

No doctors thwart the Reaper more often than cardiologists, who routinely pull heart-attack victims back from the brink with artery-opening procedures. But their god-like powers suddenly fade after coronary arteries are unblocked. In fact, much of the harm from heart attacks occurs at that point due to “reperfusion injury,” which occurs when blood flow is restored to oxygen-starved tissues—just when things are looking up, the phenomenon unleashes gusts of cell-trashing “oxygen free radicals” and induces deadly calcium overload within cells. The inexorable heart-muscle destruction that follows can give the Grim Guy the last laugh, leading to fatal second heart attacks within days or the prolonged agony of congestive heart failure. But now Maynard, MA-based Ischemix thinks it’s found a way to block much of the damage and prevent cardiac miracles from turning into Pyrrhic victories.

Ischemix says its experimental drug CMX-2043 has consistently reduced reperfusion injury by 30 to 40 percent in extensive, placebo-controlled rodent tests. You heard it here first: If the drug shows similar efficacy in people—a big if, given that dozens of promising drugs for reperfusion injury have failed—Ischemix will be transformed from one of the Boston area’s least-known biotechs into a Big Pharma mob scene as drug makers scramble to secure rights to the new medicine.

Heart researchers have struck out for over three decades trying to develop reperfusion-injury blockers. Indeed, all the flailing on the reperfusion front threatens to lead to “therapeutic nihilism” concerning the problem, according to a sweeping 2004 report on the problem by scientists at the National Institutes of Health. Arguably, reperfusion injury is already the dirty little secret in cardiology: Animal studies indicate that it causes up to 50 percent of the tissue damage after heart attacks. Further, the controlled blood-flow interruption during cardiac procedures, such as coronary artery bypass surgery, or CABG (pronounced “cabbage”), also can trigger reperfusion injury—that’s probably why some 13 percent of the 500,000 U.S. patients who undergo CABG each year suffer major complications within 30 days of their operations.

All this adds up to the kind of blockbuster potential that’s increasingly scarce in drug research. Ischemix’s first goal with CMX-2043 is to cut post-CABG complications, including potentially fatal heart-beat irregularities—that indication alone represents a $500 million “market opportunity,” says CEO Reinier Beeuwkes. Following a successful safety trial with CMX-2043 last year, the company plans to launch a “proof of principle” efficacy trial in CABG patients later this year. But the plan is contingent on whether the company can raise the $15 million it needs to fund the trial, he adds.

You’d think venture investors would already have perfused the startup’s coffers. But so far Ischemix has funded CMX-2043′s development with a mere $14 million supplied by Beeuwkes himself and Ischemix’s medical director, Geoffrey Clark. Before taking a flyer on Ischemix, the two co-founded Braintree Laboratories, a leading maker of “gastrointestinal lavage” products ingested before colonoscopies. A former heart researcher, Beeuwkes served on Harvard’s faculty in the 1970s, then went on to become director of renal and cardiovascular pharmacology at Smith Kline and French Laboratories, now part of GlaxoSmithKline, before founding Braintree.

Ischemix has purposely kept a low profile during CMX-2043′s initial development, compiling considerable data on the drug before trying to sell the story to outside investors, explains Beeuwkes. One reason is the long history of withered hopes in the effort to develop reperfusion-injury blockers—potential investors aren’t easily convinced that substantial progress is now finally in the offing. Ischemix also has had a special reason to keep quiet while building the case for its new drug: A few years ago, its predecessor company, CereMedix, made an ill-fated foray under previous management into the hype-ridden world of anti-aging dietary supplements, or “nutraceuticals,” whose snaky aura can be the kiss of death for an aspiring biotech trying to raise money from hard-headed VCs.

CereMedix sprang from research on antioxidants discovered by biologist Victor Shashoua, who co-founded the company in 1999 while associated with McLean Hospital in Belmont, MA. Shashoua had developed a suite of compounds with antioxidant properties that raised hopes of blocking the damage by free radicals that appears to be a central part of the aging process. CereMedix’s plan of developing an anti-aging nutraceutical proved untenable, however, and in late 2005 Beeuwkes, a long-time investor in the startup, stepped in as CEO to develop some of Shashoua’s compounds as reperfusion-injury blockers. Though retired, Shashoua still holds a stake in the company, and his son, a physician, serves on its board.

Renamed Ischemix, the company set about tinkering with the antioxidants to give them a second key property besides the power to mitigate the free-radical damage of reperfusion injury: the ability to block its cell-killing calcium overload. Veteran pharmaceutical chemist Steven Kates, Ischemix’s vice president of research, led the effort, which yielded a family of promising candidates, the best of which was CMX-2043. While details of the drug’s mechanism remain murky, says Beeuwkes, in rat studies it appears to exert, as hoped, a two-pronged defense against reperfusion injury—a novelty that might finally break the logjam in efforts to minimize the injury. In the Phase 1 safety trial in humans last year, says Beeuwkes, “even at the highest dose we used, we didn’t see adverse effects” that seemed related to the drug. Further, the doses ranged up to about five times “what we think we may need to work in CABG patients, based on our animal studies.”

With the promising data in hand, the company is now trying to get on venture capitalists’ and Big Pharma’s radars. It just launched a new website, and Beeuwkes recently began presenting at biotech meetings. “If you’d asked me for an interview a year ago, I’d have said ‘No, thank you,’” he says. “But now it’s time to put on the slippers and go to the ball.”

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