WASHINGTON _ Centocor Inc. has a shot at becoming thebiotechnology industry's honorary "comeback kid" if things go welltoday and tomorrow at a meeting of the FDA's Cardiovascular andRenal Drugs Advisory Committee.But, according to some analysts, it could be a long shot.The committee will make a recommendation to the FDA on whether ornot to approve Centocor's ReoPro (formerly known as CentoRx) forthe treatment of high-risk angioplasty patients.ReoPro, which works by keeping platelets from sticking together in theblood, reduced life-threatening complications of angioplasty (surgicalrepair of a clogged artery using an inflatable catheter) by 35 percent ina Phase III trial. At the same time, the drug doubled the rate of majorbleeding episodes in patients.Skeptics have expressed doubts about the high price tag for the drug(analysts predict more than $1,000 a dose) and the bleeding side effect.The advisory committee must weigh whether or not the increasedbleeding gives ReoPro an acceptable risk-to-benefit ratio.Centocor will make its case to the FDA advisory panel on the basis of asingle Phase III trial (vs. the strategy of conducting two trials in orderto reproduce results). "It's a very large bet on their part," said Cowenand Co. analyst Carol Werther. "The company really believes in thisproduct but it's quite possible that the FDA will want more data. ThePhase III trial was not large from a cardiology standpoint." (A total of708 patients received the efficacious dose of ReoPro.)Questions about the use of the anticoagulant drug heparin in the trialcould lead the committee to recommend that FDA request more clinicaltrial data. One potential flaw in the Phase III study design was use of afixed dose of heparin, vs. a weight-adjusted dose. Centocor has arguedthat the fixed dose probably worsened the bleeding profile of ReoPro.The hypothesis that physicians could better manage bleeding episodesby using weight-adjusted doses of heparin in combination with ReoProis currently being tested by the company in a pilot study of 100patients. The pilot trial is supposed to be a "prologue" for another largePhase III study. The advisory committee may advise the FDA to waitfor those results, according to analysts.Heparin causes dose-dependent anti-thrombotic effects and bleedingcomplications similar to the ReoPro effects reported. The crux of theissue: is ReoPro really any more efficacious than a larger dose ofheparin alone? The data must conclusively differentiate between theimpact of the two drugs.As Centocor well knows, an advisory committee recommendation forapproval is only one tenuous step toward product licensure. InSeptember 1991, an advisory panel recommended that the FDAapprove the Malvern, Pa., company's lead product for sepsis, HA-1A.Seven months later, the agency ignored that advice and demandedfurther clinical testing of the drug. Subsequent trials revealed HA-1Amight actually harm some patients and development was terminated.If approved by the FDA, ReoPro will be marketed by Eli Lilly & Co.,of Indianapolis, and manufactured by Centocor. Profits will be split 50-50. "FDA approval (of ReoPro) would cap the rebound story forCentocor," PaineWebber analyst Linda Miller told BioWorld. "Theyoutlined a strategy for turning the company around and, so far, they'vesucceeded."Miller said she expects "substantial debate" at today's meeting aboutthe bleeding, the Phase III study design and the exact definition of thepatient population that stands to benefit from use of the drug.ReoPro has been one of the pillars of Centocor's rehabilitation strategyin the wake of the HA-1A debacle and the company's management hasearned high marks from analysts for its aggressive cost-cutting andlicensing strategies. Analyst Wole Fayemi, of Hambrecht & Quist Inc.,said the drug could generate as much as $20 million for Centocor in1994, if it wins final FDA approval.ReoPro is a chimeric monoclonal antibody Fab fragment directedagainst the platelet IIb/IIIa receptor, believed to be the final commonpathway for platelet aggregation (blood clotting). Results of the pivotalPhase III trial using ReoPro (known as c7E3 Fab to investigators) werepublished on April 7 in The New England Journal of Medicine(NEJM).Target Patients Had Complications, RisksThe target population for the trial was patients undergoing angioplastywho were at high risk for complications. Cowen's Werther said high-risk patients represent between 10 to 25 percent of the 400,000 to500,000 angioplasty patients in the U.S.In a prospective, double-blind trial, 2,099 patients treated at 56 centerswere randomized into three treatment groups: a bolus and infusion ofplacebo, a bolus of ReoPro and an infusion of placebo, or a bolus andinfusion of ReoPro. The primary endpoint of the study was a compositeof six related objective endpoints, including death, nonfatal myocardialinfarction, emergency percutaneous coronary angioplasty (PTCA),emergency coronary artery bypass graft surgery, stent placement andballoon-pump insertion.As compared with patients who received placebo, patients whoreceived a bolus and infusion of ReoPro had a statistically significant35 percent reduction in the rate of primary endpoint events (p value =0.008). The drug's only statistically significant benefits were inreducing nonfatal myocardial infarctions and emergency PTCAs.Results for the other four components of the composite endpoint werenot statistically significant.Major bleeding episodes (defined as episodes requiring a bloodtransfusion, among other things) occurred in 99 (14 percent) of the 708patients who received a bolus and infusion of ReoPro. In contrast, 46(7 percent) of the 696 patients who received a bolus and infusion ofplacebo experienced such episodes. The difference was statisticallysignificant with a p value of less than 0.001.A NEJM editorial accompanying the results said that the drug"undoubtedly" provided protection against thrombosis (formation ofblood clots) for high-risk angioplasty patients. But the author, LaurenceHarker from Emory University School of Medicine in Atlanta,predicted the drug would not be widely used. He cited "the associatedcosts and risk of hemorrhage; the predictable formation of neutralizingantibodies, precluding retreatment; and the inevitable development ofsafer antiplatelet therapies" as strikes against ReoPro. n
-- Lisa Piercey Washington Editor
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