Staff Writer

SAN DIEGO - After a rainy Monday, San Diego delivered a healthy dose of cloudless skies and warm sunshine during the American Heart Association's 2009 International Stroke Conference, held last week.

The 4,000-plus attendees needed a little cheering - in panel after panel, they were faced with the grim reality that, despite more than 60 failed attempts in the past decade, tissue-plasminogen activator (t-PA) remains the only FDA-approved stroke drug.

T-PA, marketed by Genentech Inc. as Activase (alteplase), triggers an enzyme cascade that dissolves blood clots.

But the drug also increases hemorrhage risks and must be administered within three hours of a stroke. That tight time window and delicate risk-benefit balance severely limit t-PA's applicability and use. Genentech reported just $275 million in 2008 revenues from its whole portfolio of thrombolytics.

Peter Sandercock of the University of Edinburgh's Western General Hospital presented data from an analysis of 600,000 U.S. stroke patients showing that only 2 percent received t-PA within three hours, as recommended, while 30 percent received the drug within six hours.

In his study, 60 percent of the patients were seen at a specialized stroke unit, and he found that advanced patient age was the primary limiting factor for the use of t-PA.

Several studies at the conference focused on how to increase the use of t-PA within the three-hour window.

New data presented by Jeffery Saver of the University of Los Angeles found that patients who arrived at the hospital within an hour of stroke were twice as likely to receive t-PA as those arriving later.

Other studies found t-PA usage could be optimized by establishing hotlines between rural hospitals and stroke centers, and by starting t-PA prior to transfer to the stroke center.

Another hot topic at the conference was the effectiveness of t-PA outside the three-hour window. Werner Hacke of Heidelberg University Hospital presented a summary of the ECASS3 study, in which patients were treated with t-PA between three and 4.5 hours after stroke.

The study concluded that 52.4 percent of patients on t-PA had a favorable outcome, compared to 45.2 percent for placebo, although the global analysis missed statistical significance.

However, the incidence of intracranial hemorrhage was higher with t-PA (27 percent) than placebo (17.6 percent) (p = 0.001), although mortality and other serious adverse events were not significantly different.

The ECASS3 findings were published last year in the New England Journal of Medicine, and Hacke said they are "already changing guidelines."

Last month, the European Stroke Organization recommended that t-PA be given within 4.5 hours of stroke, even though the drug's European label still includes the three-hour limit.

In the U.S., Hacke noted that there has been more concern due to the failure of other trials looking at later t-PA administration: ECASS1 and ECASS2 missed their primary endpoints, and the ATLANTIS study was halted early due to lack of efficacy and a significant increase in intracerebral hemorrhage.

Yet Hacke argued that ECASS1 and ECASS2 "showed the same signal" as ECASS3, and that ATLANTIS was "at least neutral" rather than negative when analyzed to consider labeling differences in Europe vs. the U.S.

Sandercock recommended that physicians "set aside" ATLANTIS because it is a "tiny trial - and tiny trials tend to produce very unstable results."

He maintained that administration of t-PA within six hours "may have quite a useful effect, although we're not quite there yet as far as statistical significance." He said he anticipates that the IST3 trial, which is looking at t-PA treatment within six hours in more than 3,000 patients, should put the issue to rest, although data are not expected until 2012.

Another area of focus at the conference was ways to combine t-PA with other drugs that might improve its safety or efficacy. Researchers established several years ago that both t-PA and the stroke itself activate harmful matrix metalloproteinases (MMPs), and that co-administration of an MMP inhibitor might mitigate that effect. (See BioWorld Today, July 8, 2005.)

Yet here, too, Eng Lo of Harvard Medical School and Massachusetts General Hospital demonstrated that timing is key. While early administration of an MMP inhibitor can decrease the infarct size in animal models of stroke, administration days later can make the infarct worse, since the drug will interfere with the brain's attempts to heal itself, he said.

Another potential option to improve t-PA administration was presented by ImaRx Therapeutics Inc. The company presented data from a Phase I/II trial showing that the combination of t-PA with ultrasound and the company's MRX-801 microspheres was twice as likely to cause recanalization (complete clearing of blocked arteries) than t-PA alone.

The trial randomized 35 patients to receive t-PA alone or in combination with ultrasound and either a high or low dose of MRX-801.

Sustained complete recanalization after 36 hours was achieved in 67 percent of the low-dose patients, 46 percent of the high-dose patients and 33 percent of the t-PA patients.

Three months following treatment, improvement in clinical outcomes measured by a Modified Rankin score was reported in 75 percent of the low-dose patients, 50 percent of the high-dose patients and 36 percent of the t-PA patients.

About a year ago, ImaRx ran into trouble with intracranial hemorrhage associated with high doses of MRX-801.

Data from the current study showed no bleeding complications in the low-dose group but three cases in the high-dose group, although the company noted that all three patients also had uncontrolled hypertension and stroke severity tended to be worse in the high-dose group. (See BioWorld Today, Jan. 7, 2008.)