Acute Ischemic Stroke

Overview

AIS InsetA stroke is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. As a result, the affected area of the brain becomes inactive and eventually dies. Strokes can be classified into two major categories: acute ischemic stroke and hemorrhagic stroke. Acute ischemic strokes ("AIS") are those that are caused by interruption of the blood supply by a blood clot (ischemia), while hemorrhagic strokes result from rupture of a blood vessel or an abnormal vascular structure. About 87% of strokes are acute ischemic strokes, with the remainder classified as hemorrhagic.

At the site of blood flow blockage, there exist two major ischemic zones – the core ischemic zone, with only 10-25% blood flow, and the surrounding ischemic penumbra having partially reduced blood flow1. The core zone suffers from a severe lack of glucose and oxygen, which rapid depletes energy stores and triggers the loss of ion gradients, ultimately leading to neuronal cell apoptosis (excitotoxicity), all within minutes. The ischemic penumbra zone however may remain viable for several hours via collateral arteries that branch from the main occluded artery in the core zone. Unfortunately, penumbra zone neuronal cell death also eventually occurs due to inflammation and apoptosis, as collateral blood supply is inadequate to maintain cellular function indefinitely. Approximately 20% of persons who progress to cerebral infarction and approximately 10% of those who suffer a cerebral hemorrhage have a history of evolution of deficit over several hours to several days (and, rarely, longer). As such, next generation stroke therapies are being developed to protect the viable cells of the penumbra with anti-apoptotic, pro-angiogenesis, or immunodulation functions during the hours to a week after a stroke1,2

As time goes on, a lack of blood flow in the ischemic zone (infarct) leads to fluid buildup (edema) and swelling which creates intracranial pressure. This pressure on the brain leads to tissue compression resulting in additional ischemia. Additional events in acute ischemic stroke include vascular damage to the blood vessel lining or endothelium, loss of structural integrity of brain tissue and blood vessels, and activation of the immune system and inflammation. A stroke can lead to permanent damage with memory loss, speech problems, reading and comprehension difficulties, physical disabilities, and emotional behavioral problems being commonly observed outcomes.

Due to this devastating chain of events, the clinical priority is to remove the blood clot blockage as soon as possible after onset and re-establish normal blood flow. Currently, the only Food and Drug Administration (FDA) approved therapeutic-based treatment is tissue plasminogen activator (“tPA”), a protein involved in the breakdown of blood clots (thrombolysis) to re-establish normal blood flow (recanalization). However, tPA is only effective if administered within 3-4.5 hours of an acute ischemic stroke3, as outside this therapeutic window tPA is not only ineffective but its use leads to a greater risk of hemorrhage (bleeding in the brain). As such, it is estimated that in the U.S. only 2-5% of AIS patients are treated with tPA4. As a consequence of this limited time window, only a small percentage of stroke victims are treated with the currently available therapy; most simply receive supportive or “palliative” care. The long-term costs of stroke are substantial, with many patients requiring extended hospitalization, extended physical therapy or rehabilitation (for those patients that are capable of entering such programs), and many require long-term institutional or family care.

According to the World Heart Federation, each year approximately 15 million people worldwide suffer a stroke of which 6 million will die and 5 million will be permanently disabled5. Worldwide, stroke is the leading cause of adult disability and the second leading cause of death in developed countries6.

Each year in the US, approximately 800,000 people continue to experience a new or recurrent stroke (ischemic or hemorrhagic). Approximately 610,000 of these are first events and 185,000 are recurrent stroke events. In 2013, stroke caused ~1 of every 20 deaths in the United States. On average, every 40 seconds, someone in the United States has a stroke, and someone dies from a stroke approximately every 4 minutes. The cost including health care services, medications, and lost productivity is estimated to be approximately $34 billion USD7.

Risk factors for stroke include advanced age, hypertension (high blood pressure), previous stroke or transient ischemic attack (“TIA”), diabetes, high cholesterol, cigarette smoking, and atrial fibrillation.

Event Free Survival Functions
Kaplan-Meier Survival Curves
Kaplan-Meier graph

Stroke represents an area of tremendous unmet medical need. Lower levels of the protein tissue KLK1 in the blood and urine have also been independently associated with first-ever stroke and lower long term survival and are an independent predictor of recurrence after an initial stroke. In a 2,478 patient case-controlled clinical study of KLK1 levels in stroke patients, higher KLK1 activity is predictive of fewer stroke recurrences and longer event-free survival time. Event free survival functions were measured using Kaplan-Meier survival curves8.

Published preclinical and clinical research with a naturally occurring KLK1 protein has demonstrated reduced blood pressure, cell death, and inflammation and increased angiogenesis (creation of new blood vessels) and neurogenesis. DiaMedica believes DM199 has the potential to preserve “at risk” brain tissue by establishing better collateral circulation, decreasing inflammation, reducing apoptosis, and helping generate collateral circulation by initiating angiogenesis and vasculogenesis. 

DM199 for the Treatment of Acute Ischemic Stroke

In the People’s Republic of China, a urine-extracted version of KLK1 (“uKLK1”) is currently being used to treat AIS. The Chinese product, Urinary Kallidinogenase for Injection, is isolated from human urine and marketed by Techpool Bio-Pharma Inc. (Techpool) under the name Kailikang®. Kailikang® is prescribed to stroke patients up to 48 hours after an AIS and is given by intravenous administration.

More than 40 published clinical studies that show a beneficial effect of Kailikang® (urinary kallikrein) treatment in AIS, including a meta-analysis covering 24 clinical studies involving 2,433 patients. The review used well-established methods for meta-analysis. The authors conclude that “[human urinary KLK1] appears to ameliorate neurological deficits for patients with acute ischemic stroke and to improve long-term outcomes”.

In a double-blinded, placebo-controlled, Phase III trial of 446 patients treated with uKLK1 or placebo up to 48 hours after a stroke, significant differences were found in the European Stroke Scale and Activities of Daily Living at three weeks of treatment and at three months using the Barthel Index with uKLK1 treated vs placebo.

DM199’s synthetic KLK1 protein is being developed to treat ischemic stroke patients in China as an improved product over the urine-sourced KLK1 protein currently used there. DiaMedica also intends to seek worldwide approval for DM199 as a novel therapy for acute ischemic stroke. With the potential that effective treatment can be initiated up to 48 hours after the first sign of symptoms, DM199 may fill a large unmet need for stroke patients who cannot receive tPA, benefiting millions of people around the world who currently have limited treatment options.

 

 

  1. Ramos-Cabrer, P., Campos, F., Sobrino, T., Castillo, J. Targeting the Ischemic Penumbra. Stroke. 2011; 42: S7-S11.
  2. Sinden, JD., Muir, KW. Stem Cells in Stroke Treatment: The Promise and the Challenges. International Journal of Stroke. 2012 Jul; 7(5): 426-434.
  3. del Zoppo, G., Saver, J., Jauch, E., Adams, H. Expansion of the Time Window for Treatment of Acute Ischemic Stroke with Intravenous Tissue Plasminogen Activator. Stroke. 2009 Aug; 40(8): 2945-2948.
  4. Miller, D., Simpson, J., Silver, B. Safety of Thrombolysis in Acute Ischemic Stroke: A Review of Complications, Risk Factors, and New Technologies. Neurohospitalist. 2011 Jul; 1(3): 138-147.
  5. MacKay, J., Mensah, G. Global burden of stroke. The Atlas of Heart Disease and Stroke. 2004; 15:50-51.
  6. World Heart Federation. 2016. Stroke.
  7. Mozaffarian, D. et al. Heart Disease and Stroke Statistics – 2016 Update. 2015. American Heart Association. 2015; 132:e167-197.
  8. Zhang, Q., et al. Plasma Tissue Kallikrein Level is Negatively Associated with Incident and Recurrent Stroke: A Multicenter Case-Control Study in China. Annals of Neurology. 2011 Aug; 70(2): 265-273.