GAITHERSBURG, Md. _ An FDA advisory committeerecommended Friday that the agency grant accelerated approval toindinovir, a potent _ and sought after _ anti-HIV, protease inhibitormade by Merck & Co. Inc., of Whitehouse Station, N.J.
Moments later, FDA Commissioner David Kessler vowed that theagency would approve indinovir, to be sold as Crixivan, by the timeMerck is ready to for the drug's formal launch, which is expected thisspring.
Ferdinand Massari, Merck's director of clinical research, said,"What's most dramatic is the speed with which the agency hasreviewed the applications both of Abbott's ritonavir and Merck'sindinovir. The agency has broken all records."
Kessler said FDA officials left for Brazil Friday to complete therequired inspections of Merck's foreign plants, one of the last stepsneeded for formal approval. The agency already has inspectedMerck's domestic plants, he said.
FDA approval would permit "tens of thousands" of HIV infectedpeople to obtain a drug that dramatically reduces viral activity andbuttress their failing immunity. Over the next several months, Merckplans to complete clinical endpoint trials to confirm that lab evidenceof antiviral activity can be borne out in widespread use.
Jeffrey Chodakewitz, of Merck, told the committee that more than2,000 patients had been treated with the drug since clinical trialsbegan in 1993. Two surrogate marker studies, involving more than500 patients taking indinovir alone, and with such nucleoside analogsas zidovudine, could reliably reduce viral RNA activity and increaseCD4 cell counts in many patients for at least 24 weeks.
"More than 90 percent of three-drug patients achieved andmaintained this reduction through 24 weeks," Chodakewitz said.
In some patients, viral activity declined for more than 48 weeks witha sustained increase in CD4 levels of 100 cells, he said.
When indinovir was given with zidovudine, the pair severelyimpaired HIV's ability to mutate into hardier, more resistant strains.Just four of 22 patients developed resistant strains of virus on thetwo-drug regimen, compared with nine of 21 among patients takingindinovir alone.
A Dramatic, Durable Effect
Thomas Quinn, a committee member and professor of medicine atJohns Hopkins University, in Baltimore, said the "data clearly showsthat indinovir has a dramatic _ and clearly durable _ effect inlowering viral RNA, with some patients having reductions down toundetectable levels.
"On that basis" he said, "I can vote yes."
Six members voted in favor of approval; three abstained, arguing thatthe drug should be approved only for late-stage patients, since thecompany's studies enrolled mainly HIV positive people with CD4cell counts of 500 or below.
Chodakewitz said that the drug was well tolerated when given aloneor in combination with other drugs. "There were no significant druginteractions," he said, whether patients were also taking other anti-retroviral drugs or antimicrobials commonly taken by AIDS patients,including Fluconazole, clarithromycin, trimethoprim-sulfamethoxazole or isoniazid.
Twelve patients died during the course of the studies, but only oneappeared to be related to antiviral medication. As it happened, thatpatient was in a control group, taking zidovudine, not indinovir,Chodakewitz said. About 10 percent of patients developed highbilirubin levels, but none showed any signs of liver toxicity. Fifty-five of the 2,000 patients developed flank pain and hematuria typicalof nephrolithiasis, although only half of them had stones or gravel.
Linda Distlerath, Merck's executive director of public affairs, saidthat the approval has come six months before the company expectedit would _ and so it will take several months for the company to gearup to satisfy the desperate clamor for the drug. Merck is building twofactories to produce indinovir; one in Elkton, Va., and another inFlint River, Ga.
She said Merck also is concerned that if the drug is made too broadlyavailable before the company can step up production, some peoplemay be unable to continue therapy, which may leave them infectedwith resistant virus. "We want to make sure that anyone who startstherapy will be able to get refills," she said. Distlerath declined to sayhow much the drug would cost.
A Lost Opportunity
About 1,400 people currently take the drug under a compassionateuse program. They were selected by lottery from 12,000 people whosubmitted their names. Merck has not followed up on these patientsto track their response to the drug, a failure that Laurence Freedman,acting chief of biometry at the National Institutes of Health,characterized as a "disappointing loss of opportunity."
"A lottery is nothing more than a form of randomization," he said."The company had names and addresses and could have followed upon these patients even through death certificates. That would havebeen guaranteed an interesting study performed at minimal expense.
Given the drug's effectiveness, and the low incidence of side effects,several committee members and people who spoke during a period ofpublic comment, objected to a planned confirmatory study, calledprotocol 320, that would randomize dozens of patients into a groupgiven nucleoside analogs, possibly condemning them to more rapiddecline than they might experience taking indinovir.
Douglas Mayers, head of HIV drugs and gene therapy at the WalterReed Army Institute of Research, in Washington, agreed that such astudy presented ethical problems. "To run long-term endpointstudies, you have to suspect both arms are equally effective," Mayerssaid, adding that he also was troubled by the prospect that such astudy might be carried out in third-world country where people can'tget access to any drug.
"Based on the data we've seen it's obvious that 320 is not ethical,"said Kiyoshi Kuromiya, director of the Critical Path AIDS Project inPhiladelphia, another nonvoting consultant to the community.
Massari of Merck, said the debate really hinges on whetherresearchers are willing to accept surrogate markers as sufficient proofof a drug's safety and effectiveness. "If you don't you need clinicalendpoints," he said, which can only be obtained by testing the drug inpatients. n
-- Steve Sternberg Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.