(Alteplase, Activase®) for Acute Ischemic Stroke

NINDS Contributions to Approved Therapies NINDS invests in and conducts research across the spectrum of neuroscience and neurology research, from basic studies on fundamental biological mechanisms, to clinical trials to test new treatments in patients. Here, we describe the path leading to the development and approval of one therapy for a neurological disorder, and we highlight contributions enabled by NINDS and NIH support.

Tissue Plasminogen Activator (Alteplase, Activase®) for Acute Ischemic Stroke

Overview A stroke occurs when the blood supply to first treatment for acute ischemic stroke unprecedented speed. These efforts revolu- brain tissue is blocked by a blood clot to receive Food and Drug Administration tionized stroke care, and the success of tPA (ischemic stroke), or when a blood vessel (FDA) approval. Known by the generic set the stage for further progress in stroke in the brain ruptures (hemorrhagic name alteplase and marketed as Activase® research. stroke), causing brain cells to die and (Genentech), tPA works by dissolving resulting in functional impairments. blood clots that block blood flow to Stroke is a leading cause of death and the brain. When administered quickly disability both globally and in the U.S., after stroke onset, tPA helps to restore where approximately 800,000 people blood flow to brain regions affected by experience a stroke each year. a stroke, thereby limiting the risk of lasting damage. Although stroke remains a critical health issue, better management of cardio- NINDS played a major role in the develop- vascular risk factors, greater awareness of ment of tPA—from funding early studies symptoms, and prompt medical attention that provided a rationale for its use, to are helping to prevent strokes and leading pivotal clinical trials that support- improve outcomes. Accordingly, the death ed the treatment’s FDA approval in 1996. rate from stroke in the U.S. fell 77% Most notably, NINDS scientists recognized between 1969 and 2013. Another major the importance of urgent treatment for advance was the clot-dissolving medicine acute stroke and pioneered protocols for tPA (tissue plasminogen activator), the assessing and treating patients with

Learn more at: https://www.ninds.nih.gov/About-NINDS/Impact/NINDS-Contributions-Approved-Therapies tPA (Alteplase, Activase®) for Acute Ischemic Stroke Development Timeline Clot-retrieval devices are shown to be more effective than tPA alone for strokes involving clots in large arteries. 2015

Postmarketing studies show benefits of tPA treatment in commu- nity hospital settings when rapid treatment protocols are followed. 1998- 2001

1996 FDA approves tPA for the treatment of acute ©Biogen ischemic stroke.

NINDS launches Know Stroke public education campaign. 1995 Pivotal Phase III trial demonstrates the safety and efficacy of tPA for acute ischemic stroke.

• Pilot clinical trials test tPA in stroke patients, including the first studies to 1985- develop organized stroke teams and protocols for treatment within 3 hours of 1992 symptom onset. • Several studies report the efficacy of tPA in animal models of stroke with im- proved outcomes and low risk of hemorrhage when treatment is delivered early. 1987 FDA approves tPA for Small and then large-scale clinical trials 1983- treatment of acute myocardial test tPA in heart attack patients. 1988 infarction, or heart attack.

1977- Belgian researchers isolate tPA from a melanoma cell line in large 1981 quantities and show that it can dissolve blood clots in animal models.

1947 Danish researchers describe enzyme that will become known as tissue plasminogen Academic and industry researchers express activator (tPA). recombinant tPA, enabling purification in amounts sufficient for commercial use.