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Once-Promising Stroke Drug Fails in Trial

Experts differ on the reasons why NXY-059 showed no effect

WEDNESDAY, Aug. 8, 2007 (HealthDay News) -- An experimental, emergency-use stroke drug that gave patients a modest but definite benefit in one trial has shown no effect at all in a new trial.

The outcome is puzzling the international team of physicians who reported the new results for the drug, called NXY-059, in the Aug. 9 issue of the New England Journal of Medicine.

Right now, "we consider that the disparity between the two studies occurred by chance," concluded the researchers.

"There is a 5 percent chance of a false-positive result in any clinical trial," noted study co-researcher Dr. Kennedy R. Lees, professor of cerebrovascular medicine at the University of Glasgow in Scotland.

He was referring to the results of a trial reported in 2005 in which NXY-059 gave more protection against stroke damage to the brain than the existing standard treatment, tissue plasminogen activator (tPA). In the earlier trial, the experimental agent was also effective when given as long as six hours after a stroke. tPA has a much smaller window of effectiveness, about three hours.

"The likelihood that our previous trial was positive simply because of the play of chance underscores the need for replication by a second pivotal trial," the journal report said.

However, another of the study's researchers said that may not happen.

When two studies produce conflicting results, the larger one is more likely to be correct, said Dr. Patrick Leyden, director of the University of California, San Diego/Veterans Administration Stroke Center. "It has a better chance of avoiding statistical flukes."

Leyden said that, because of the negative results of the second trial, "the development of the drug has been ended."

The newly reported trial included more than 3,300 people treated for ischemic stroke, in which a clot blocks a brain blood vessel.

It found no difference in end results, such as stroke-linked disability, between those patients who got NXY-059 and those who did not.

But there is another theory afloat to explain the disparity in findings -- that the version of the drug used in the second trial was somewhat different than that used in the first trial. One proponent of that theory is Dr. Peter H. Proctor, a physician with no academic affiliation, who is engaged in pharmaceutical research. He noted that some patents that he holds do give him a financial interest in the matter.

NXY-059 is a member of a chemical family whose brief designation is PBN, Proctor said. That PBNs have a strong tendency to "hydrolyze" -- react chemically with water -- is well known, he said. Proctor contends that the breakdown products of hydrolysis reactions produce the beneficial effects of NXY-059.

NXY-059 has a completely different action than tPA, which reduced brain damage by dissolving a clot that blocks a brain artery. Instead, NXY-059 protects brain cells by trapping free radicals, inflammatory cells that are generated in a blocked artery. "It is the hydrolysis products that are biologically active," Proctor said.

There could well have been less hydrolysis in the drug used in the second trial than that used in the first, he said.

AstraZeneca, the pharmaceutical company that's developing NXY-059 as a stroke treatment, obtained a patent between the two trials on a method of stabilizing the molecule by certain methods -- including preventing hydrolysis in the compound, Proctor said. Thus, it is possible that patients in the two trials received versions of the drug different enough to account for the conflicting results, he said.

When he tried to present that idea to AstraZeneca officials, "they wouldn't talk to me," Proctor said. But he acknowledged that he is in a patent battle that pits him against the drug company. Proctor said he holds patents on the medical use of hydrolysis products of PBN chemicals.

However, study co-investigator Leyden said AstraZeneca did investigate Proctor's claim. "They took the allegation very seriously, did the testing, and said they were confident there was no breakdown product involved," he said.

In the meantime, Proctor said a paper written by him, describing the proposed beneficial effects of PBN-linked hydrolysis reactions, has been accepted by the journal Stroke and will be published in that journal in September.

AstraZeneca did not respond immediately for a comment on the paper.

More information

There's more on current stroke treatments at the American Heart Association.

SOURCES: Kennedy R. Lees, M.D., professor, cerebrovascular medicine, University of Glasgow, Scotland; Peter H. Proctor, M.D., Ph.D., Houston, Texas; Patrick Leyden, M.D., director, University of California, San Diego/Veterans Administration Stroke Center; Aug. 9, 2007, New England Journal of Medicine
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