BETHESDA, Md. _ The FDA's Cardiovascular and Renal DrugsAdvisory Committee voted unanimously on Friday to recommendapproval of the thrombolytic agent reteplase for management of acutemyocardial infarction (AMI) in adults _ including the dissolution ofblood clots obstructing coronary arteries, reduction of the incidenceof congestive heart failure, improvement in ventricular function post-AMI and reduction of mortality associated with AMI.

Reteplase was developed by Boehringer Mannheim Corp., aGaithersburg, Md.-based division of the Boehringer MannheimGroup, which is part of Bermuda-based Corange Ltd. Therecombinant plasminogen activator, if ultimately approved by theFDA, will compete directly with Genentech Inc.'s tissue plasminogenactivator (tPA, marketed as Activase in the U.S. and alteplase inEurope) and with streptokinase, which is marketed by Astra AB andKabi Pharmacia AB of Sweden.

If licensed, reteplase will be the first new thrombolytic agentapproved solely on the basis of comparative clinical trials rather thanthe standard placebo-controlled trials. That's because, with effectiveagents such as tPA and streptokinase available, it's no longer ethicalto administer placebos to heart attack patients. As a result,Boehringer Mannheim conducted two open-label Phase III trialscomparing reteplase to tPA and one larger double-blinded Phase IIIstudy comparing reteplase to streptokinase.

The two reteplase vs. tPA studies are known as RAPID I and RAPIDII (Reteplase and Alteplase Patency Investigation During MyocardialInfarction) and enrolled 606 and 324 patients, respectively. Thesetrials used arterial patency at 90 minutes as the primary endpoint.RAPID I demonstrated that reteplase caused a statistically significantincrease in the number of patients who achieved complete patency ascompared to tPA and RAPID II reinforced that finding.

Although it's an important measure of a drug's performance, patencyalone is no longer considered adequate for approval of thrombolytics_ mortality is the gold standard. Thus, Boehringer Mannheimconducted the INJECT study (International Joint EfficacyComparison of Thrombolytics) with the primary endpoint ofmortality. However, for this 6,010-patient trial conducted entirely inEurope at 208 centers, the company chose to compare reteplase withstreptokinase, not tPA as in the RAPID trials. Company officialsclaim that's because streptokinase is the thrombolytic of choice inEurope (as opposed to the U.S. where tPA captures 75 percent of themarket).

INJECT compared mortality rates between patients treated withstreptokinase and reteplase. At 35 days, the reteplase group had an 9percent mortality rate vs. a 9.5 percent rate in the streptokinasegroup. The difference of about one-half a percentage point was notsignificant. However, because INJECT was a comparative trial, thefinding met the criteria for approval as set out by the FDA.

Reteplase did significantly reduce congestive heart failure, aprospectively defined secondary endpoint of the INJECT trial, ascompared to streptokinase, but it also caused a statistically significantincrease in the rate of hemorrhagic strokes. The FDA's analysis ofthe INJECT data basically concurred with the sponsor's presentationof the data, a fact which smoothed the way for the committee torecommend approval.

Committee Debates Comparative Trial Issues

Comparative trials can be difficult to design and interpret becausethey seek to establish equivalence rather than superiority _ the aim ofmost placebo-controlled trials (i.e., the experimental drug is betterthan sugar water). Alastair Wood, a professor of medicine andpharmacology at Vanderbilt University, in Nashville, Tenn., and anFDA panel member, noted that statistical analyses deemed critical inplacebo-controlled trials are "turned on their head" when applied toequivalence trials. The results can be confusing and the committeespent much of Friday afternoon discussing that fact.

For example, the INJECT study was designed to prove the followinghypothesis: reteplase retains at least 50 percent of the mortalitybenefit of streptokinase. That doesn't sound like a stunning clinicalvictory to most people. In fact, according to the estimate of one FDAreviewer, the data suggest that reteplase retains about 65 percent ofthe efficacy of streptokinase.

Such a finding represents a marketing challenge perhaps bestexpressed by Wood. "If I put two cups of medicine in front of mysick Mother and tell her, `This one is at least 50 percent as good asthis one,' which one do you think she'll choose?" The 50 percentthreshold was actually set by the FDA itself, not BoehringerMannheim, but some panel members criticized it as too low. Wood,for example, argued that new thrombolytic agents should have toprove that they retain at least 75 percent of the efficacy ofcomparative agents.

But, for complex statistical reasons, a higher comparative efficacythreshold would dictate that clinical trials be four or five times aslarge as the 6,000-patient INJECT study, already huge by ordinaryproduct license application standards. Gregory Fulton, director ofmarketing at Boehringer Mannheim told BioWorld Today that hedoes not view the complex statistical issues involved in equivalencetrials an obstacle to effective marketing. "If the FDA follows thecommittee's recommendation, reteplase will have been deemed safeand effective enough to be approved. After that, we will applysignificant internal resources to appropriately promote the drug andtackle our competition directly," he said.

Although he would not disclose what his company plans to charge forreteplase, Fulton said that "the price point could be a significantfactor" in marketing the drug. Genentech's tPA at about $2,200 perdose is 10 times more expensive than streptokinase. Fulton did pointout that Boehringer Mannheim is funding GUSTO III (GlobalUtilization Strategy for Thrombolysis of Occluded Arteries), a15,000-patient trial that will compare reteplase and tPA directly interms of mortality. Those results, due in 1997, could either help orhurt reteplase's ability to penetrate the increasingly competitivethrombolytic marketplace. n

-- Lisa Piercey Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.