New Treatment for Ischemic Stroke on the Horizon

Caroline Cassels

November 14, 2006

November 14, 2006 — The launch of a clinical trial is raising hope that there will soon be a new treatment for ischemic stroke that will widen the window of opportunity for treatment and possibly reduce the hemorrhagic risk associated with tissue plasminogen activator (tPA), currently the only FDA-approved medication for stroke.

Researchers at the University of Rochester Medical Center in New York announced $3.4 million in funding from the National Heart, Lung, and Blood Institute to conduct a safety trial of activated protein C (APC) ( Xigris, Eli Lilly and Co ).

APC is already approved for use in sepsis, where it has shown to be safe. Berislav Zlokovic, MD, PhD, who has conducted all of the preclinical stroke research on the drug, said APC's anti-inflammatory and apoptotic properties suggest it may be effective in reducing initial and subsequent brain damage caused by ischemic stroke.

"While the overall benefits of tPA outweigh its drawbacks, it must be administered within a very small 3-hour window, which prevents many patients from receiving it. APC may offer us the opportunity to double that time, possibly up to 8 hours, maybe longer, so that more patients can receive it," Dr. Zlokovic told Medscape.

Reduced Risk of Bleeding

Over the next 5 years, 78 patients at 5 US centers will be enrolled in the study.
Individuals will receive the drug within 6 hours of stroke symptom onset. Half of the dose will be administered as a bolus and the other half will be administered by IV infusion over 1 hour. The study will also include a 3-month follow-up period.

While the primary aim of this research is to test the drug's safety profile in stroke patients, Dr. Zlokovic said investigators would also look at outcome measures.

A recent paper published in the November issue of Nature Medicine by Dr. Zlokovic and his team found that the drug blocks the prohemorrhagic pathway activated by tPA.

"Right now we are studying late applications in animal models [of APC] at 24 hours and possibly beyond. We still don't have a full set of data, but the results look encouraging," he said.

Despite the fact that more than 100 agents have been tested in the treatment of ischemic stroke, none, with the exception of tPA, has proven effective.

Most Recent Failure

The most recent failure was the investigational drug NXY-059 ( Cerovive, AstraZeneca). In late October, AstraZeneca announced it would not pursue further development of the agent after results of a phase 3 trial showed no significant reduction in stroke-related disability with treatment vs placebo.

Dr. Zlokovic said he is hopeful that APC will turn out to be a viable treatment alternative to tPA. In addition to the current investigational agent, he and his team are working on the development of newer, safer, APC molecules through their company, ZZ Biotech, that do not have the anticoagulant properties of the current drug.

"We know that not every stroke patient is the same. We think molecules such as recombinant APC are good, but there might be better molecules that can be genetically engineered so they are deprived of certain properties, including their anticoagulant effect.

"The first-generation drug may work in some individuals, but because stroke patients are such a heterogeneous group, I don't envisage that the same treatment will work for everyone equally. That's why we are developingsecond-and third-generation agents."

Nat Med . 2006;12:1278-1286.

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