A Phase II clinical trial that was suspended last week took atragic turn over the long weekend when two patients died afterrequiring liver transplants -- possibly as a result of adversereactions to the experimental chronic hepatitis B drugfialuridine (FIAU).
Of the 18 other patients enrolled in the trial, one is in stablebut critical condition at the University of Virginia MedicalCenter in Charlottesville awaiting a possible liver transplant,eight are hospitalized and undergoing observation, and nine areat home.
FIAU, a nucleoside analog licensed by Eli Lilly and Co. fromOclassen Pharmaceuticals Inc. in August 1992, was being testedas a treatment for chronic hepatitis B at three centers: 15patients had enrolled at the National Institutes of Health (NIH)in Bethesda, Md., three at the University of Texas, Galveston,and two at the New England Medical Center in Boston.
Lilly spokesman Ed West said that the company is now focusingon providing Itop-flight medical careJ to trial participants andon analyzing data from the current trial, as well as from earlierstudies, for clues as to what might have gone wrong.
Both deaths and all of the serious adverse reactions occurred inpatients who had received FIAU for 67 to 90 days. Phase Iclinical trials were shorter, lasting from four to six weeks.
Investigators and company officials expressed shock andsorrow that a drug that had shown such promise could turn outto be potentially harmful to patients. IThis is a tragedy foreveryone involved,J said Glenn Oclassen, chairman of privatelyheld Oclassen Pharmaceuticals of San Rafael, Calif. Oclassen hasnot been involved in the Phase II trial since licensing thecompound to Lilly.
None of the 20 Phase II trial patients had received the drugsince June 26, the day the trial was halted after the firstserious adverse reactions were observed. According to NIHspokeswoman Elizabeth Singer, NIH investigators believed thatthe toxic effects seen in patients would decrease immediatelyafter drug administration was halted. But one of the trialfatalities, an unidentified Virginia man, died on Monday, ninedays after the last dose, while the second patient died Tuesdaymorning.
Singer said four of the patients under observation at the NIHcurrently have signs of liver toxicities, but their condition isstable at this point. IThe situation changes every six hours orso,J she said. IEverything known to science and medicine wastried in order to save these patients," she added."Unfortunately, in two of the cases, it was not enough.J
Singer said there were no adverse effects during a Phase I trialin 24 HIV-positive chronic hepatitis B patients completed lastyear. But West confirmed that there was at least one death inthe Phase I study, although it was Inot such that we coulddefine the role of FIAU in that death.J
Phase I results from a FIAU trial were reported at the 32ndInterscience Conference on Antimicrobial Agents andChemotherapy (ICAAC) last October in Anaheim, Calif. Adverseevents noted at the meeting included elevated liver enzymelevels (which can be a signal of liver damage) in up to 50percent of patients at different dosages.
According to Patricia Padgett Lea, an analyst at VectorSecurities International in Deerfield Park, Ill., who covers Lilly,it is Idifficult to know when you should become alarmedJ whenmonitoring liver enzyme levels in patients with chronic liverdisease. IIt takes a while before you can see a pattern form,Jshe said. ILilly pulled the drug the minute they spotted aproblem.J
T. D. Hooton, an investigator at the University of Washington,Seattle, who has participated in trials of FIAU, agreed thatthere were no Iprospectively strikingJ adverse reactions in thePhase I data. IItLs possible that when we go back andscrutinize, weLll find something that might have been flagged.JBut he said such a search could only take place with the benefitof hindsight.
LillyLs West said that the fate of FIAU has not yet been decidedat the Indianapolis-based pharmaceutical giant. He said thecompany will consider the fact that the drug showedeffectiveness in addressing a large, unmet medical needworldwide as its researchers study the current situation.
II seriously doubt that our people would consideradministering the drug to any human at any time in the nearfuture because we just donLt know what happened here,J saidNIH's Singer.
-- Lisa Piercey Business Editor
(c) 1997 American Health Consultants. All rights reserved.