Stroke Rekindles Researchers’ Attention

by Brenda Patoine

March, 2006

Stroke research is heating up again, fanned by promising results from large-scale clinical trials for a new drug under investigation for acute stroke. The results are generating excitement in a field that has been strangely quiet in recent years, following a long series of disappointments that seemed to scare off pharmaceutical investment and put a damper on the search for therapies that might make a dent in stroke’s devastating toll. 

Stroke remains the No. 1 cause of long-term disability in the United States, and the third leading cause of death. It costs the country more than $54 billion annually in health-care expenses alone, and untold billions in lost productivity. Yet, for the vast majority of people who suffer a stroke, there is little doctors can do.

“I’ve always been surprised at how relatively underweighed the need for a stroke treatment is in the public’s eye,” says Dennis Choi, head of neuroscience research for Merck & Co. Inc. “It just hasn’t been seen as a priority for society to address aggressively.” 

A Legacy of Disappointment

In the 1990s, stroke research was on fire. Scores of so-called neuroprotective drugs, perhaps a hundred or more, were in development. Virtually every major pharmaceutical firm had a robust stroke program, and academic research centers were inundated with clinical trials testing drugs that seemed to hold promise for finally getting a handle on the problem of stroke. None made it to market.

With the exception of tissue plasminogen activator (tPA), the clot-dissolving agent approved for the treatment of acute stroke in 1996, there have been no breakthroughs in stroke care. Even tPA gets mixed reviews, and everyone agrees that it is underutilized, thanks to a tight therapeutic window of three hours, serious risks of hemorrhage, and a health-care system that does not reliably get patients the right care at the right time. Compounding the problem is the fact that many stroke sufferers, whether because of ignorance or denial, do not seek urgent care.

This bleak landscape may finally be seeing some light. In February, the results of a second large clinical trial testing the efficacy of an investigational stroke drug known generically as NXY-059 were presented at the American Heart Association’s annual stroke conference. Suddenly, stroke researchers are talking about neuroprotection again, and optimism is replacing the cynicism fueled by past failures.

Stanford’s head of neurosurgery, Gary Steinberg, says the drug’s clinical benefits are extremely encouraging: “It has the potential to open up a whole new era in stroke treatment.”

AstraZeneca, which is testing NXY-059 under license from Renovis Inc., says its proposed mechanism of action is “free radical trapping.” The idea is to neutralize the unstable molecules, released by dying neurons, that help fan a widening cascade of damage and nerve cell death after an ischemic stroke—the kind of stroke caused by a blood clot that restricts the flow of oxygen to the brain.

The fact that NXY-059 has so far survived the test of large-scale clinical trials may, however, have more to do with how the research landscape has changed than with how the drug works. After the widespread failures of the 1990s, industry and academia teamed up to figure out what went wrong and fix it. The result was the Stroke Therapy Academic Industry Roundtable, or STAIR. The group has since published a stringent set of guidelines for the development of stroke drugs.

Failure by Design?

The consensus was that a lot of the drugs that failed in the heyday of neuroprotectant development may have been good drugs, but the trials were not designed well. Outcome measures may have been too stringent to identify subtle benefits in improving a patient’s day-to-day functioning, and many trials simply were not large enough to have the statistical power necessary for drug approval. Moreover, drugs that showed promise in animal studies when given within two hours of an induced stroke were given up to 12 hours post-stroke in patients, so there was a disconnect between animal and human testing.

“We had some learning to do, and we had to go to school on how to do clinical trials and preclinical work that were complementary to one another,” says Wade Smith, the director of neurovascular care at the University of California, San Francisco. NXY-059, Smith says, is one of the few drugs to have met all of the STAIR criteria, and its success so far is an indication of how productive the effort to improve drug development has been.

Perhaps more important, Smith and Steinberg say, any success story in neuroprotection can help re-stimulate interest in stroke research, which will eventually translate to better prognoses for the 700,000 or so people who suffer a stroke each year. “We see renewed interest already,” Steinberg says.

Merck, for one, is back in the stroke game—for the third time, after two previous drugs failed in preclinical development. It has licensed a compound, ONO-2506, which was developed by Japan-based Ono Pharmaceuticals. ONO-2506 is said to block the activation of astrocytes, a type of nonneuronal glial cell in the brain. This mechanism may in turn help protect nerve cells from the cascade of toxicity following a stroke.

A North American clinical trial of the drug was discontinued in May 2005 for lack of efficacy, but Merck apparently has not given up on it yet. Choi suggested the study’s failure to demonstrate efficacy was related to trial design issues—a problem all too familiar to researchers involved in the previous round of failures.