Cedars-Sinai stroke intervention researchers have been informed that the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, will award an $8 million grant to fund a multicenter Phase II clinical trial of an experimental drug for stroke.
The drug, 3K3A-APC, will be used in combination with recombinant tissue plasminogen activator, or rtPA - the "clot-busting" drug currently approved to treat ischemic strokes shortly after onset. In laboratory rodent studies, 3K3A-APC, used in combination with rtPA, had a protective effect on the lining of blood vessels, eliminating hemorrhaging, reducing brain damage, and improving animals' mobility after stroke. The new drug has completed a Phase I trial in 64 healthy volunteers to assess safety and dosing levels.
Ischemic strokes block arteries, depriving the brain of oxygen. The existing clot-buster, rtPA, may restore blood flow and often reverse the effects of a stroke if administered within three hours after symptoms begin. The drug, however, increases risk of internal bleeding in some patients, which can have brain-injuring and other harmful effects.
"Stroke is the fourth leading cause of death in the United States and a leading cause of disability, often leaving people to live out their lives with limited cognitive and physical skills. When patients receive rtPA within the three-hour time frame, the beneficial effects are often dramatic. But the drug is not without its limitations and potential side effects. Our objective in this and other studies is to spare more lives and livelihoods by making treatments more effective with fewer risks," said Patrick Lyden, MD, chair of Cedars-Sinai's Department of Neurology, director of the Stroke Program and the Carmen and Louis Warschaw Chair in Neurology.
The Phase II study will evaluate safety, tolerability and activity of 3K3A-APC when given after rtPA in patients who have experienced moderately severe ischemic stroke. The drug will be given intravenously as a 15-minute infusion every 12 hours for up to five treatments, and four dose levels will be evaluated. About 100 participants, ages 18 to 80, will be followed for 90 days.
APC - activated protein C - is a naturally occurring enzyme in the body that reduces inflammation, protects against cell death and acts as a blood thinner to prevent clotting. The drug 3K3A-APC is a synthesized and slightly modified protein that maintains APC's cell-protective and anti-inflammatory benefits while reducing anticlotting activity. It is designed, therefore, to protect brain cells and cerebral blood vessels while reducing the risk of treatment-related bleeding.
The clinical trial grant was awarded to Lyden, the study's principal investigator. He was also principal investigator of the Phase I trial and a major contributor to the clinical trial leading to Food and Drug Administration approval in 1996 of rtPA, still the only proven and approved drug for stroke treatment.
The award is also in conjunction with a NeuroNEXT Infrastructure Resource Access award to ZZ Biotech LLC, the company developing 3K3A-APC. Kent Pryor, PhD, the company's chief operating officer, will be the principal investigator for this aspect of the study. ZZ Biotech will also enlist the collaboration of NeuroNEXT, a research network funded by the National Institute of Neurological Disorders and Stroke.
The institute created NeuroNEXT - the Network for Excellence in Neuroscience Clinical Trials - to increase its ability to explore promising treatments by partnering with academia, private foundations and industry. With this support, the researchers will have access to the NeuroNEXT Clinical Coordinating Center at Massachusetts General Hospital and Data Coordinating Center at the University of Iowa. The University of Rochester in New York will provide a central laboratory, and about 15 NeuroNEXT centers will participate in the study.
The new drug originated in the laboratory of John Griffin, PhD, professor in the Department of Molecular and Experimental Medicine at The Scripps Research Institute, which licensed development rights to ZZ Biotech.
Berislav Zlokovic, director of the Zilkha Neurogenetic Institute and professor and chair of the Department of Physiology and Biophysics at Keck School of Medicine of the University of Southern California, and scientific founder of ZZ Biotech, will be a co-investigator of the Phase II trial.
ZZ Biotech is a company developing APC and related products for stroke and other neurological disorders. Zlokovic is the scientific founder, Pryor is the chief operating officer, Griffin is a member of the scientific advisory board and Lyden is a consultant.
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