Two more clinical trial patients treated with an experimentalhepatitis B drug are now awaiting liver transplants after theirconditions worsened over the weekend.
Two patients died last week after receiving liver transplants,and a third received a transplant last Friday and remains incritical but stable condition. To date, a total of five trialparticipants have required liver transplants after experiencingsevere adverse reactions that researchers believe are directlyrelated to the nucleoside analog compound fialuridine (FIAU).
According to Allan Weinstein, vice president of Lilly ResearchLaboratories, a group of experts met in Virginia last weekendto discuss what medical strategies could be used to save theremaining patients. Jay Hoofnagle, one of the principal NationalInstitutes of Health (NIH) investigators and himself an expertin the field, convened the meeting. U.S. researchers andphysicians and one researcher from overseas attended.
Weinstein said one of the strategies suggested at the meetingwas that transplants be performed earlier, before patientsprogressed to multiple system failure, a syndrome which hascharacterized the worst FIAU reactions. Because FIAU maydamage mitochondria, the energy factories of cells, and becauseall 10 of the ill patients had been treated with FIAU in anearlier trial, many experts have concluded that the drug has acumulative toxicity -- what Weinstein called a Idevastating andunseen phenomenon.J
In addition, Weinstein said that the half-life of FIAU (theamount of time it remains in the bloodstream) is significantlylonger than had been thought. Previous studies put the half-lifeat an hour and a half, but now Iwe just donLt know how long itis,J he said.
FIAU was licensed by Eli Lilly and Co. from OclassenPharmaceuticals Inc. of San Rafael, Calif., last August. The drugshowed promise in combating chronic hepatitis B in Phase Itrials when it was administered over four weeks. A Phase IItrial was under way at the National Institutes of Health, as wellas at two other U.S. hospitals, when it was suspended June 26due to serious adverse side effects in 10 of the NIH patientswho received FIAU for 67 to 90 days. The Phase II trial wastesting the efficacy of longer-term dosing.
Of the 10 hospitalized NIH patients, three have been sent homewithout symptoms; two others with signs of liver toxicities arebeing treated.
A Phase I trial in 24 HIV-infected hepatitis B victims showedthat roughly 50 percent of the patients had transient rises inliver enzymes (often a sign of liver damage). In another PhaseI FIAU trial (in non-HIV patients), a 60-year-old man died ofliver failure four months after his last dose of the drug. At thetime, the death was classified as unrelated. Weinstein saidthere were some similarities between the recent deaths but nodirect linkage has yet been established.
Weinstein said that while researchers may eventually discoverthe mechanism of action causing the adverse reactions, theproduct may never be commercially viable.
The informed consent form for the Phase II trial did notmention the Phase I trial death, although NIH officials said thetrial participants were told about it in private counselingsessions.
The FDA initiated a formal investigation of the FIAUinvestigational new drug (IND) application and the clinicaltrials last week.
-- Lisa Piercey Business Editor
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