When administered soon after the onset of acute ischemic stroke, current approved treatments for the condition can dramatically improve patient outcomes. However, not all patients are cured, and approved treatments also carry risks, including cerebral hemorrhage or bleeding into the brain.

Now, a novel second-generation variant of a naturally occurring human protein – known as 3K3A-APC – is poised to change that. The National Institute of Neurological Disorders and Stroke (NINDS), part of the U.S. National Institutes of Health (NIH), has awarded a $4 million grant (UG3 NS119199) as the first portion of what is anticipated to be a $30 million award over six years to the Keck School of Medicine of USC to conduct a pivotal Phase 3 clinical trial of the experimental drug. The trial will gauge the efficacy of 3K3A-APC as a cerebroprotectant, a drug that hastens or augments recovery when combined with two standard treatments for acute ischemic stroke. The drug will also be tested as a treatment aimed at minimizing brain bleeds. The remainder of the grant will be funded in subsequent allotments pending review of milestones.

In Phase 2 clinical trials led by USC Neurologist Patrick Lyden, MD, 3K3A-APC reduced the incidence of brain hemorrhage due to stroke treatment by nearly 20%, a positive indicator of 3K3A-APC's potential for success. Researchers at the Keck School of Medicine are collaborating with private company ZZ Biotech, maker of the drug.

Perhaps as many as 80% of patients have brain bleeding after stroke without even knowing it. Our Phase 2 trial, called RHAPSODY, indicated 3K3A-APC may be highly effective when given together with tissue plasminogen activator (tPA) or intra-arterial therapy (IAT), the only proven stroke treatments in use today. This could make a game-changing difference in stroke patient recovery."

Dr. Patrick Lyden, study principal investigator

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Dr. Lyden, professor of physiology and neuroscience at the Zilkha Neurogenetic Institute and professor in the Department of Neurology at the Keck School of Medicine, was one of the original developers of the first treatment for stroke, the clot-buster drug tPA.

The benefits of tPA for stroke are well known -; according to NINDS, 8 out of 18 stroke patients who receive the treatment as part of a strict protocol will recover by three months after the event without significant disability. Yet, for a variety of reasons (such as tPA's role in the activation of plasmin, an enzyme that helps break down blood clots), the treatment can trigger intracranial hemorrhage.

Similarly, patients who receive IAT are also subject to higher levels of bleeding in the brain. Factors influencing the likelihood of intracranial hemorrhage as a result of IAT include disruption of the blood-brain barrier and direct vessel damage from wire and microcatheter manipulations during endovascular procedures.

Drug treatments such as 3K3A-APC had already been shown to help stabilize or protect the blood-brain barrier in preclinical animal models, thereby reducing hemorrhage associated with both ischemic stroke and thrombolytic treatment of ischemic stroke. Dr. Lyden and his team launched RHAPSODY to take their work into the clinical realm, testing the drug's effectiveness in human stroke patients. Findings from the study – published by Dr. Lyden and his colleagues in the Annals of Neurology in 2019 – confirmed the neuro and vasculoprotective properties of 3K3A-APC, yielding a drop in intracranial hemorrhage among acute ischemic stroke patients from 86.5% to 67.4%.

"The NINDS decision to provide grant funding for the Phase 3 clinical trial of 3K3A-APC further validates our RHAPSODY Phase 2 results, which established a strong link between treatment with our novel drug and reduced bleeding," commented Kent Pryor, ZZ Biotech's chief executive officer. "We are excited by the prospects of our lead clinical program, and we look forward to the continued collaboration with Dr. Lyden and his team as we progress the development of 3K3A-APC and the launch of the RHAPSODY-2 pivotal Phase 3 trial."

Berislav Zlokovic, MD, PhD, director of the Zilkha Neurogenetic Institute and professor and chair of the Department of Physiology & Neuroscience at the Keck School of Medicine, co-discovered the neuroprotective, vasculoprotective and anti-inflammatory activities of APC in the central nervous system.

"I am pleased 3K3A-APC continues to show promise as a potential frontline treatment for stroke, which is a leading cause of death for Americans and affects 795,000 of us every year," he says. "With RHAPSODY-2, I am hopeful we continue to confirm the drug's benefits."