Boehringer Ingelheim gains approval of extended 4.5 hour time-window for Actilyse®

Boehringer IngelheimBoehringer Ingelheim announced that Actilyse® has been approved through a mutual recognition procedure for15 European countries* for thrombolytic treatment of acute ischaemic stroke up to 4.5 hours of onset of stroke symptoms and after prior exclusion of intracranial haemorrhage. This regulatory milestone was communicated by the reference member state Germany and will result in subsequent national approvals of the extended indication in the respective countries of the EU covered by the procedure. The national product informations will be amended accordingly.

Actilyse® can be used to break up a blood clot which has blocked a blood vessel. This may help blood flow through the blood vessel to return to normal and has the potential to prevent ischaemic damage to brain tissue. Alteplase needs to be given as soon as possible after the occurrence of symptoms to have highest chances of benefit. Until today, the thrombolytic is the only approved treatment option for patients who suffer from an acute ischaemic stroke.

Alteplase has already been approved for different indications and in many countries worldwide from 1987 onwards and after 1996 also for acute ischaemic stroke in a three hour time window after the onset of stroke symptoms. A pooled analysis of studies showed that patients treated with rt-PA up to 180 minutes after symptoms onset are at least 30 percent more likely to have minimal or no disability at three months compared with those patients who didn’t receive thrombolysis in placebo controlled trials.(1)

"Despite the newly approved time window, it is still of vital importance that stroke patients are hospitalized and treated without delay", said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "The earlier an intervention is given, the greater the potential benefit for the patient. On the other hand, those patients who - for various reasons - present themselves in the hospital beween three and 4.5 hours after their stroke can now benefit from Alteplase and a potentially better stroke outcome."

The approval is based on the results of the European Cooperative Acute Stroke Study (ECASS 3), the results of which were published in the New England Journal of Medicine in September 2008. 2,3 ECASS 3, a randomised, double-blind, placebo-controlled trial, demonstrated for the first time that thrombolysis with Actilyse® can increase favourable outcomes with only minimal or no disability after an acute ischaemic stroke when administered in an extended time-window from three to 4.5 hours after symptom onset. The study included 821 patients in 15 European countries who were recruited by a team of investigators led by Professor Werner Hacke of the University of Heidelberg.

Act fast - for the patient every second counts
"ECASS 3 was the most important breakthrough in acute stroke research of the last decade since thrombolysis has been established in acute ischaemic stroke as standard of care", underlined Prof. Werner Hacke, lead investigator of ECASS 3 and founding president of the European Stroke Organisation (ESO). "We appreciate that this milestone will now be reflected in the label. The approval will further strengthen the confidence in the lysis therapy with Alteplase even in the shorter time window." The guidelines of the European Stroke Organisation have been updated in 2009 already recommending Actilyse® beyond the three hour time window.(4)

The World Health Organization estimates that 5.7 million people in the world die each year from stroke. 5 Among survivors, 40% experience moderate to severe disability and 10% require institutional care.(6)

About ECASS 3
ECASS 3 was a randomised, double-blind, multicentre, placebo-controlled trial of Actilyse® in acute ischaemic stroke where thrombolysis is initiated between 3 and 4.5 hours after stroke onset. The study, sponsored by Boehringer Ingelheim, was requested by European authorities to support the licencing of Actilyse®. ECASS 3 started in July 2003 and was completed in February 2008. The patients included in the study were in line with the Actilyse® indication in the European Summary of Product Characteristics with the exception of the time window.

About Actilyse®
Stroke is a neurological emergency that can affect a specific area, or sometimes all of the brain. It can be caused by a burst blood vessel (haemorrhagic stroke) or occur when a vessel is obstructed by a blood clot (ischaemic stroke). Actilyse® (active ingredient: alteplase), is now in the majority of EU approved for use within 4.5 hours from the onset of symptoms in ischaemic stroke. It is a recombinant tissue plasminogen activator (rt-PA), a genetically engineered version of naturally occurring tissue plasminogen activator, which has the biological function of removing small clots that routinely form in the bloodstream. Actilyse® is the only drug indicated for thrombolytic treatment of patients with acute ischaemic stroke and is recommended by international treatment guidelines. Alteplase was first approved in 1987 in major countries across the globe in the indication acute myocardial infarction, followed by subsequent approvals in the indications (acute) pulmonary embolism and acute ischaemic stroke (registered indications can vary across the globe).

Actilyse® is registered in over 85 countries across the world and marketed outside North America and Japan by Boehringer Ingelheim. Alteplase is marketed under the brand name Activase® in the U.S.A. by Genentech, Inc. and in Canada by Roche Canada, where it has been used extensively for the treatment of acute ischaemic stroke since 1996 and 1999, respectively.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

* EU countries involved in the mutual recognition procedure: Germany, Sweden, Finland, Denmark, Ireland, UK, Netherlands, Belgium, Luxembourg, France, Austria, Portugal, Spain, Italy, Greece

1. Kennedy R Lees et al for the ECASS, ATLANTIS, NINDS, and EPITHET rt-PA Study Group Investigators. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375: 1695–703
2. Hacke W et al for the ECASS investigators. Thrombolysis with alteplase 3 to 4.5 h after acute ischemic stroke. N Engl J Med; 2008; 359: 1303-09
3. Patrick Lyden. Thrombolytic Therapy for Acute Stroke - Not a Moment to Lose. N Engl J Med; 2008; 359: 1393-95
4. European Stroke Organisation. ESO GC Statement on revised guidelines for intravenous thrombolysis. January 2009. Accessed 23 August 2011.
5. Cardiovascular diseases. Fact sheet N°317. June 2010. WHO.
6. National Institute of Neurological Disorders and Stroke. Stroke Rehabilitation Information. Accessed 9 June 2010