By Randall Osborne
Genentech Inc. is moving ahead with its own Phase III trial to broaden the label of its recombinant tissue plasminogen activator (tPA) Alteplase for stroke, after a key study by marketing partner Boehringer Ingelheim GmbH failed to show statistically significant clinical benefit in preliminary findings.
"We're more than halfway enrolled [in the U.S. study]," said David Stump, vice president of clinical research for South San Francisco-based Genentech.
Alteplase, marketed as Activase in the U.S., is meant to be administered within three hours of the onset of acute ischemic stroke. A serine protease enzyme, it breaks up clots and restores blood flow. The drug was first approved in the late 1980s for treatment of acute heart attack.
The 800-patient overseas Phase III trial by Ingelheim, Germany-based Boehringer, called the European Cooperative Acute Stroke Study II (ECASS II), was designed to measure the drug's effect in patients presenting for treatment as long as six hours from the onset of symptoms.
Although the ECASS II showed lower overall mortality compared with earlier stroke trials, patients measured in the primary endpoint — minimal functional deficit or no deficit — did not reach statistical significance compared with placebo.
The safety profile for Alteplase was "comparable to the placebo," Stump told BioWorld Today. "It doesn't seem to change that much after three hours. The big question is where is the benefit?"
As in earlier trials, the Alteplase group showed increased frequency of severe intracranial hemorrhages — a risk that apparently goes with using the drug, Stump said.
"What you're looking at is net clinical benefit in these patients," he added, emphasizing the data from ECASS II "shouldn't dissuade anyone from what's now established" for treating stroke patients up to three hours from developing symptoms.
"We've treated something near 10,000 patients in the last two years," Stump said.
Genentech's U.S. trial is studying Activase in patients presenting three to five hours into their symptoms. Data "won't be [available] this year, for sure," he said. "It will be well into next year, or the year after."
Data from the first ECASS trial were used to support South San Francisco-based Genentech's new drug application for Activase with the FDA. (See BioWorld Today, June 7, 1996, p. 1.)
Activase was approved for stroke in June 1996, and for myocardial infarction in November 1987. In 1990, it was approved for pulmonary embolism. (See BioWorld Today, June 19, 1996, p. 1.)
Rights to another tPA, Retavase, belong to Malvern, Pa.-based Centocor, Inc., against which Genentech has filed a patent lawsuit. (See BioWorld Today, March 19, 1998, p. 1.)
More details about the ECASS II trial results are expected to be disclosed in September at the Third Congress of the European Federation of Neurological Societies in Seville, Spain.
Genentech's stock (NYSE:GNE) closed Friday at $67.50, down $0.437. *