By Lisa Seachrist
WASHINGTON — Positive results from two clinical trials of Centocor Inc.'s anti-platelet treatment, ReoPro, could position the drug as a standard of care in balloon angioplasty and stenting procedures, and offer a proof of concept for its use in combinations with clot busters.
The Malvern, Pa.-based company presented early results from two studies: the Phase III Epilog-Stent trial and the Phase II TIMI 14 study. The latter combines ReoPro with a half dose of Genentech Inc.'s clot buster, Activase, against Activase alone. The findings were presented at the annual American College of Cardiology conference, in Atlanta.
In the Epilog-Stent study, Centocor showed that using ReoPro in conjunction with stent placement reduced the number of deaths, heart attacks and urgent revascularization procedures by 51 percent compared with standard therapy.
"I think the evidence is there to say that ReoPro should be the standard of care for coronary interventions in the late 1990s," said Harlan Weisman, vice president of clinical research at Centocor. "Whether it gains commercial ground, we have to wait and see."
ReoPro is a monoclonal antibody that inhibits platelet aggregation and prevents formation of blood clots. The drug won FDA approval in December 1994 and generated $254 million in sales last year.
In November 1997, Centocor got a label expansion for ReoPro allowing the drug to be marketed to prevent cardiac ischemic complications in a broad range of patients undergoing percutaneous coronary intervention in addition to use in high-risk angioplasty patients.
The Epilog-Stent trial serves as confirmation of the decision to expand the indication. The double-blind, placebo controlled trial involved 2,399 patients at 63 sites. The study contained three treatment arms: placebo, which consisted of standard stent placement, aspirin and weight-adjusted heparin doses; ReoPro plus stent placement, aspirin treatment and weight-adjusted heparin; and ReoPro in conjunction with standard balloon angioplasty, aspirin and weight-adjusted heparin treatment.
Adjunct Therapy Cut Composite Events In Half
The company presented results of the study measuring the composite endpoint of deaths, heart attacks and urgent revascularization procedures occurring in the 30 days following treatment. ReoPro as an adjunct to stent placement decreased the composite events by 51 percent compared with placebo treatment. ReoPro in conjunction with angioplasty decreased the number of composite events by 36 percent compared with placebo.
"Biologically you would expect a synergistic effect between stent placement and ReoPro treatment and this trial demonstrated that quite convincingly," Weisman said. "For many people, stents aren't an option for their type of blockage, and what these result show is that ReoPro and angioplasty approach the benefit found with ReoPro and stents. That was surprising."
Weisman noted bleeding was similar among all groups in the trial. The company is expected to present long-term data from the trial later this year.
In addition to confirming ReoPro's place in percutaneous coronary intervention, the company presented preliminary data indicating ReoPro may one day have a role to play in urgent coronary intervention scenarios.
The TIMI 14 trial examined whether ReoPro in conjunction with Genentech's Activase (tPA) could open more blocked coronary arteries and in less time than Activase alone.
South San Francisco-based Genentech's clot bluster revolutionized urgent care for people suffering heart attacks. However, Weisman said the drug takes 90 minutes to take effect and only restores blood flow to the heart in 70 percent of patients. Overall, approximately 55 percent of people receiving Activase will have normal blood flow to the heart.
"TPA solves the fibrin and fibrinogen components of a blood clot," Weisman said. "But basic biology tells us there is a significant contribution from platelets. ReoPro takes platelets out of the equation."
ReoPro With Thrombolytics Effective
The TIMI 14 trial found that ReoPro given with a half dose of Activase restored normal blood flow to the heart in 80 percent of patients at 90 minutes, compared with 58 percent of patients who received a full dose of Activase. At 60 minutes, 75 percent of ReoPro treated patients had normal blood flow, compared with 44 percent of patients treated with Activase.
"ReoPro in conjunction with thrombolytics appears to open more blockages and restore normal blood flow faster than thrombolytics alone," Weisman said.
The company intends to explore this use of ReoPro more thoroughly using Retavase, the second generation clot bluster acquired in February from Boehringer Mannheim GmbH, of Mannheim, Germany, for $335 million. Centocor actually bought Retavase from Hoffmann-La Roche Ltd., of Basel, Switzerland, whose takeover of Boehringer Mannheim was completed earlier this year.
Currently, ReoPro and Retavase are in a Phase II trial to determine the appropriate dose of the thrombolytic before embarking on a Phase III mortality study of 15,000 to 25,000 patients at the end of this year or beginning of next.
"The Epilog-Stent trial should convince any cardiologists that are still on the fence that ReoPro is the standard of care," said Eric Schmidt, an analyst with UBS Securities, in New York. "And the TIMI 14 data provide an intriguing kind of proof of principle for using ReoPro with thrombolytics. We would expect Retavase to work as well."
Centocor could have trouble combining ReoPro and Retavase, however. Genentech filed a patent infringement lawsuit against the company March 19, after Centocor obtained rights to market the drug.
Centocor estimated ReoPro will produce $320 million to $350 million in sales this year. Schmidt noted it is likely that the company will achieve the upper end of that prediction.
Centocor's stock (NASDAQ:CNTO) closed Tuesday at $44.625 per share, down $1.3125. *