Genentech Inc. said Wednesday it will ask the FDA toexpand the label for Activase (tPA) based on a five-yearstudy funded by the National Institutes of Health (NIH)showing the clot-dissolving drug was effective for acuteischemic stroke, a condition where little if any treatmentis available.
However, Michael Walker, director of the stroke andtrauma division of the NIH's National Institute ofNeurological Disorders and Stroke (NINDS), toldBioWorld Today it would be wrong for physicians to treatstroke with tPA the same way they use the drug for acuteheart attacks.
The Phase III trial results showed that three months aftera stroke, complete or nearly complete recovery was 30percent more likely among those treated with Activasethan placebo _ a statistically significant finding.
But the studies also showed the drug had to beadministered within three hours of onset of the ischemiaand even then intracerebral hemorrhage was a significantside effect. The dosage used also must be lower than thatfor heart attack patients.
If Activase is administered more than three hours after astroke, Walker said, bleeding in the brain increases,nullifying any clinical benefit from dissolving the bloodclot.
Walker warned against physicians stretching the use oftPA beyond guidelines used in the study.
"One of the worst things that could happen," he said, "isif people give cardiologic doses [of tPA] to strokepatients outside the treatment limits."
The NIH trial, Walker said, "demonstrates tPA obviouslyis an effective treatment for stroke." But he added beforethe drug is widely used physicians should understandclearly the study's findings, hospitals should learn to treatstroke with the same urgency as myocardial infarctionand the public should be educated to recognize the signsof stroke.
Walker noted a key aspect of the trials was discovery ofthe importance of handling ischemic stroke as anemergency, within three hours, signaling a need for morestudies and treatments.
Genentech, of South San Francisco, has FDA approval ofActivase for heart attacks and acute pulmonary embolism.Activase accounts for 75 percent of sales in the U.S.among thrombolytic agents.
Paul Laland, Genentech spokesman, said based on thefindings in the NIH study the company will file a productlicense application in 1996 to expand the label to includeacute ischemic stroke.
Results of the NIH-sponsored trials are published intoday's New England Journal of Medicine. The studies,involving 624 patients, were organized and funded by theNINDS.
Limiting treatment to within three hours was based onprevious trials indicating concerns that bleeding causedby Activase becomes more of a problem the longer ittakes to administer the drug following the stroke.
Even within three hours, 6.4 percent of those receivingActivase experienced hemorrhages within 36 hours of thetreatment compared with .6 percent in the placebo group.Differences in mortality at three months in the drug andplacebo groups were not statistically significant.
The investigators concluded the drug's benefitsoutweighed the adverse reactions. "Despite an increasedincidence of symptomatic intracerebral hemorrhage,treatment with intravenous tPA within three hours of theonset of ischemic stroke improved clinical outcome atthree months," they wrote in the journal article.
Wall Street analysts viewed the studies cautiously.Activase, which sells for more than $2,000 per dose, is 10times more expensive than its nearest market competitorand is Genentech's largest selling drug. It generatedrevenues of $281 million in 1994 and $225.5 millionthrough the first three quarters of this year.
"I would term the study mixed," said Peter Drake, ananalyst with Vector Securities International Inc., ofDeerfield, Ill. "The results were not what I expected orhoped for. The real issue is what is the risk benefit for thepatient."
As for broadening the use of Activase, Drake said thestudy "represents a step in the right direction, but I can'tsay it will have a major impact on tPA sales."
Sharon Seiler, an analyst with Oppenheimer & Co., inNew York, said the NIH study doesn't change her long-term assessment of Genentech.
"It's positive," she said, "but you could expect slowgrowth in sales in the near term."
A problem in using Activase for ischemic stroke istreating patients within three hours. The study took fiveyears, in part, because of the length of time needed toenroll stroke patients who fit the profile. In addition togetting to the emergency room within three hours, acomputed tomography scan was required before treatmentto make sure the stroke wasn't caused by bleeding.
Of the approximately 500,000 U.S. patients who sufferstrokes each year, 80 percent are caused by blood clotsand the other 20 percent result from bleeding in the brain.Stroke is the third leading cause of death in the U.S.behind heart disease and cancer.
Barry Sherman, Genentech's chief medical officer, said itis difficult to estimate how many stroke victims arrivingat emergency rooms might be eligible for Activase. Hesaid Genentech currently is conducting a study using a 5-hour window of treatment.
"We're enthusiastic about the data [from the NIH trials],"Sherman said. "The caution [among NIH investigators]stems from the fact that this is new and new in an areawhere there is not an effective therapy."
Genentech's stock (NYSE:GNE) closed Wednesday at$51.75, up 25 cents. n
-- Charles Craig
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