Centocor has spent about $250 mil. on post-approval trials since 1995 to demonstrate the efficacy of ReoPro in combination with coronary stents and to generate outcomes data for the antiplatelet monoclonal, Centocor CEO David Holveck reported at the recent Wharton New Ventures in Health Care Conference.

After spending $300 mil. to bring ReoPro (abciximab) to market, the firm has committed another $250 mil. "to do extensive studies afterward in order to prove outcomes and to be able to get at least a demonstration of its effectiveness with stents," the CEO explained.

That post-approval investment is about equal to the last 15 months of revenues produced by the product. From Jan. 1, 1998 to March 31, 1999, ReoPro returned $264 mil. in revenues to Centocor on $466 mil. in sales to customers by Centocor's marketing partner for the product, Lilly.

The $250 mil. post-approval funding estimate is also high when compared to Centocor's total R&D spending of $214 mil. across the full range of the company's projects from January 1, 1996 to March 31, 1999. ReoPro has been in post-approval trials since 1995, which may explain the higher figure cited by Holveck.

Post-approval trials on ReoPro have focused on use in unstable angina, acute myocardial infarction, thrombotic strokes and in combination with stents in percutaneous transluminal coronary angioplasty.

The primary focus, however, has been on the use with stents. Centocor conducted the 63-center, 2,399-patient EPISTENT trial, which used ReoPro in combination with Johnson & Johnson's Palmaz-Schatz stent.

The most recent data from that study was reported in late 1998 from one-year follow-up. Patients with ischemic heart disease receiving ReoPro with stent replacement had reduced risk of death of 57% compared to patients receiving stents without ReoPro.

Co-marketer Lilly has also invested in ReoPro/stent combination studies. Lilly's Phase IV ADMIRAL study in 299 patients in France demonstrated ReoPro reduced death, recurrent MI and urgent revascularization by 46.5% at 30 days in acute MI patients undergoing primary stenting and PTCA, compared to placebo.

The size of the post-approval work on ReoPro and the focus on the use with stents is helping to fuel speculation about Centocor as a merger partner. J&J, which has seen a dramatic erosion in the position of its Cordis business because of a downturn in its stent business, could use the ReoPro combination results to create a package to reinvigorate its stent franchise.

However, with Lilly as the co-marketer, and the Lilly spin-off, Guidant, as one of the prime beneficiaries of the Cordis losses in stent market share, a J&J offer may be complicated.

Holveck has recognized the value of ReoPro as a component of more complicated, multi-product regimens. He described the extensive post-marketing program as representative of an industry trend away from strategies focused on selling single products toward "more of a clinical franchise" strategy in which companies market complete therapies.

ReoPro is not the "silver bullet," Holveck explained. "It has to be a combination of other products - fibrinolytics, heparin [and] devices," he said. Outcomes studies are needed to "get the data to prove that is the best standard. We have to start to market not products but a standard of care with a mixture of products that are already out there - some of which we don't sell but nonetheless are standards - and be able to demonstrate that with data."

Another expensive post-approval project just getting underway for Centocor is the 16,000-patient GUSTO IV-AMI study beginning this summer. The study will examine the combination of ReoPro and low-dose Retavase (reteplase) in heart attack patients. Centocor acquired the fibrinolytic from Roche in March 1998.

In addition, Phase II ReoPro studies are being conducted in thrombotic stroke, and the 4,400-patient Phase III GUSTO IV-ACS trial is looking at ReoPro for acute coronary syndrome. A substudy of GUSTO IV-ACS is enrolling patients to assess the safety of combining ReoPro with Pharmacia & Upjohn's Fragmin (dalteparin) rather than unfractionated heparin in patients with acute coronary syndrome.

Centocor announced in March that it will comarket Fragmin to cardiovascular specialists for treatment unstable angina when it is approved for the indication. The user fee goal date for the indication is in May.

ReoPro Post-Approval Trials Have Cost $250 Mil. Including J&J Stent Work

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