Drug Targeting Blood-Brain Barrier 'Hopeful' in Stroke

May 26, 2016

BARCELONA — A possible new treatment for acute ischemic stroke targeting the blood-brain barrier has shown promising results in an early randomized clinical trial.

The drug, imatinib, is a tyrosine kinase inhibitor already available for the treatment of certain cancers.

Initial results in stroke were presented at the recent European Stroke Organisation Conference (ESOC) 2016 by Nils Wahlgren, MD, Karolinska Institute, Stockholm, Sweden.

"We believe our results open up an opportunity for a novel third treatment for acute ischemic stroke to complement thrombolysis and thrombectomy," he concluded.

Professor Wahlgren explained that in experimental models, imatinib has preserved the integrity of the blood-brain barrier, which opens up during ischemic stroke, allowing an influx of inflammatory cells into the brain, and contributes to edema, hemorrhagic transformation, and increased mortality. This effect can be made worse by the use of tissue plasminogen activator (tPA).

"This preliminary randomized study suggested that imatinib is safe and generally well tolerated in ischemic stroke patients treated with IV [intravenous] tPA. The high dose increased neurological scores, and there was a suggestion of improved functional independence and reduced risk of hemorrhagic transformation," Professor Wahlgren stated.

"The effect may be mediated by restoring the integrity of the blood-brain barrier, which can lead to reduced edema and subsequent inflammatory responses," he added.

Commenting for Medscape Medical News, president of the European Stroke Organisation, Valeria Caso, MD, University of Perugia, Italy, said the study was very hopeful.

"These are excellent results in this initial early study. We need to now see what happens in larger trials.

"We have been trying to find agents that improve the efficiency of thrombolysis for many years," she added. "Many neuroprotective drugs have been tried without success, but this agent acts differently — targeting the blood-brain barrier — so it is something novel and it really does look like it could be a light at the end of the tunnel."

I-STROKE

The current study — known as I-STROKE — was conducted to clarify whether imatinib is safe and tolerable in an acute ischemic stroke population and whether there is any indication of reduced hemorrhage and edema and improved neurologic function.

The study involved 60 patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 7 or greater who received tPA within 4.5 hours of symptom onset. They were randomly assigned to one of three doses of imatinib (15 patients each to 400 mg, 600 mg, or 800 mg daily) or no additional treatment (controls) within 1 hour of completion of reperfusion therapy.

Results showed no serious treatment-related adverse events but a few mild reversible effects, such as itching, skin reactions, and nausea and vomiting.

In terms of efficacy, there were 28 hemorrhagic transformations in the study, with no overall difference between the imatinib patients and controls. "However, interestingly there were no transformations at all in the high-dose imatinib group, who were treated within 5 hours of symptom onset," Professor Wahlgren reported.

In terms of neurologic outcomes, there was an improvement in NIHSS scores (from baseline to 90 days) in the control group and then a dose-related stepwise further improvement in imatinib-treated patients, with the highest dose showing the best effect and a significant benefit shown over the control group.

Table. I-STROKE: Results

Endpoint Imatinib 400 mg Imatinib 600 mg Imatinib 800 mg
Improvement in NIHSS scores vs control 2 points 3 points 5 points
P value .259 .106 .012

 

Professor Wahlgren noted that on average there was an improvement of 0.6 NIHSS points per 100 mg of imatinib received (P = .020).

At all individual time points apart from baseline and 2 hours there was significant improvement of NIHSS score in the high dose group compared with controls, which reached a maximum of 6 points at day 7, he added.

There was also a suggestion of an effect on functional independence (modified Rankin Scale score, 0 - 2) with a 17% increase in patients achieving this outcome in the high-dose imatinib group vs controls (78% vs 61%), but this did not reach statistical significance because of the small numbers of patients involved, he said.

A larger confirmatory study is now planned.

The current study was supported by Vinnova (the Swedish agency for innovation) and the Karolinska Institute.

European Stroke Organisation Conference (ESOC) 2016. Presented May 12, 2016.

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