By Lisa Seachrist

Washington Editor

WASHINGTON — Genentech Inc.'s second-generation answer to its clot buster Activase (tissue plasminogen activator—tPA) has shown promise in two large Phase II trials.

TNK-tPA, a bioengineered version of tPA, dissolved the clots that cause heart attacks just as well as Activase, but only required a single intravenous injection as compared to the 90-minute infusion of Activase to clear a blocked coronary artery.

"In practice, TNK-tPA is easier to set up and administer," said David Stump, vice president of clinical research at the South San Francisco company and Genentech Fellow. "The key will be to show that there is no difference in outcomes between TNK-tPA and Activase in Phase III trials."

Genentech is set to start that Phase III trial by the end of the third quarter. The study will pit TNK-tPA head to head against Activase in 16,500 patients in Europe and North America. The company expects accrual to take most of 1998.

The Phase II results reported this week at the European Society of Cardiology in Stockholm tested how well TNK-tPA restored coronary blood flow as compared to Activase in a total of 886 patients. The randomized study pitted a five- to 10-second intravenous injection of the second-generation clot buster against the 90 minute infusion of Activase. After 90 minutes, patients receiving TNK-tPA had 63 percent of the blood flow restored and those receiving Activase had 62.5 percent restored.

A second Phase II study in 3,325 patients, which assessed the number of intracranial hemorrhages caused by the new clot buster, showed the drug caused brain bleeds at approximately the same rate as Activase. While both clot busters employ heparin as part of the therapy, TNK-tPA appears to require less of the blood-thinning medication and the Phase III trial will employ the modified dose.

"These may be the largest Phase II trials in thrombolytics that have ever been conducted," Stump said. "And the results of these trials give us a high level of comfort going into Phase III. We have a pretty good idea about how the drug works."

TNK-tPA was engineered to be a faster-acting, more potent form of tPA. Stump noted, however, the Phase II results offered only a hint that TNK-tPA is faster acting than Activase, and the Phase III trial may provide a more complete answer.

Activase currently holds 79 percent of the thrombolytic market and netted Genentech more than $280 million in 1996. Stump told BioWorld Today that should TNK-tPA ultimately obtain approval for marketing, it is unlikely to replace Activase entirely.

"There is a ten-year record of using Activase," Stump said. "And Activase is indicated in stroke and pulmonary embolism as well as heart attack." *