Washington Editor

Safety concerns have put the brakes on a stroke study of Reopro (abciximab), a drug already long marketed as an antithrombotic adjunct to percutaneous coronary intervention.

Specifically, partners Centocor Inc. and Eli Lilly and Co. halted enrollment in the Phase III trial known as AbESTT-II (Abciximab in Emergent Stroke Treatment Trial-II) after an independent safety and efficacy monitoring committee uncovered an unspecified number of deaths and cerebral hemorrhaging among study patients.

"The safety and efficacy monitoring committee observed a higher rate of deaths and intercerebral hemorrhaging," Centocor spokesman Michael Parks told BioWorld Today, adding that since the trial still blinded, it's difficult to know whether the high rate is "based on the Reopro group or the placebo group."

Nevertheless, Reopro's existing label notes that it potentially increases bleeding risks, particularly in the presence of anticoagulation agents such as heparin or other anticoagulants or thrombolytics, and cautions that such a risk should be weighed against anticipated benefits. "But there are not cautions or warnings related to death," Parks added.

Centocor, a wholly owned subsidiary of Johnson & Johnson, and Lilly said the committee would continue to evaluate Reopro's entire risk-benefit profile in the acute ischemic stroke setting before recommending whether the study should resume. Parks said such a determination would come before the end of the year. In the interim, patients already recruited to the trial will not receive any more drug, and their data also will be reviewed before the committee makes its final recommendation on AbESTT-II.

Should the partners opt against moving forward in the stroke setting, it is not likely to hurt the drug much. Bruce Cranna, an analyst with Leerink Swann in Boston who follows Johnson & Johnson, said the indication was not "regarded as being all that important for the drug." Along those lines, his firm has not modeled any revenue increases that could have come from a label expansion, given that he said an added indication in stroke "was not going to be much of a blip at all."

"I guess this would have been a mild positive if this trial had gone forward," Cranna told BioWorld Today, "and the fact that it's being halted is clearly a mild negative. But I think economically, at least from our perspective, there is no change to our expectations for J&J."

The companies stressed that they are not aware of any new data that change Reopro's product profile in approved indications, which they noted are supported by more than 14 randomized clinical trials and a decade of clinical experience. Currently, Reopro is used to prevent clotting in patients undergoing percutaneous coronary intervention, as well as in unstable angina patients not responding to conventional medical therapy when that procedure is planned within 24 hours.

Cranna said he wouldn't expect the halted trial to dampen any existing sales base for the drug. Sales figures for Reopro historically have not been disclosed, but Cranna said annual estimates on The Street range between $300 million and $350 million, and fairly static of late.

Results from previous trials have suggested that Reopro might be useful in treating stroke beyond the three-hour window in which the only currently approved therapy is used to dissolve blood clots in ischemic stroke patients, a length of time too short for most stroke patients to arrive in emergency rooms.

The multinational AbESTT-II study has been evaluating Reopro's safety and efficacy in improving neurological function and minimizing disability in acute ischemic stroke patients beyond three hours. About 150 sites have been participating in the 2-year-old trial, which planned to enroll 1,800 participants in two groups. To date, 811 have been recruited.

The primary analysis population was to include 1,200 patients randomized within four and a half hours, with planned treatment within five hours of stroke onset. A companion group of 600 patients was to have been randomized four and a half to five and a half hours after stroke onset, with planned treatment within six hours. That group also could include patients who wake up with stroke symptoms and can be randomized within two and a half hours.

In May, treatment of the small segment of patients - those awakening after having suffered a stroke - was stopped because of an increased risk of intracranial hemorrhage. Still, the safety and efficacy monitoring committee recommended continuing enrollment with remaining groups in the trial.

The drug's other risks also are noted on its label, including clinical trial results showing that Reopro patients were more likely than those on placebo to experience decreases in platelet counts, including severe thrombocytopenia. Also, its use can result in the formation of human anti-chimeric antibodies that could potentially cause allergic or hypersensitivity reactions including anaphylaxis, thrombocytopenia or diminished benefit upon re-administration. Cranna noted that since these issues are well known, Reopro's "risk-reward tradeoff" has been well understood within catheter labs.

"We've heard in the community that there already has been some sort of patient selection going on within the angioplasty space," he added. "I hate to comment on the label, but there is some sense that this could be a risky drug with patients whose profile suggests that they might be bleeders."

Reopro was developed by Centocor, of Malvern, Pa., and is manufactured at its site in Leiden, the Netherlands. Lilly, of Indianapolis, markets and distributes the product worldwide except in Japan.