A disastrous clinical trial of the experimental hepatitis B drugfialuridine (FIAU) claimed its fourth victim when Carlton H. LeeJr., the congressional liaison officer for the National Commissionon AIDS, died last Friday at the University of Pittsburghhospital.
In addition, a fourth FIAU trial subject had a liver transplanton Tuesday.
Lee was transferred to the hospital on July 28 from theNational Institutes of Health's (NIH) clinical center in Bethesda,Md. According to a University of Pittsburgh hospitalspokesman, the 35-year-old Lee never received a transplantbecause he was comatose within 12 hours of arrival. Thespokesman said that Lee succumbed so quickly that atransplant was impossible.
FIAU has been directly linked to the deaths of three other trialparticipants due to its effect on mitochondrial function.
According to Stephen Strauss, one of the principal investigatorsof the Phase II trial at the NIH, the drug appears to produce afatal syndrome characterized by intractable lactic acidosis. Hesaid all four patients who have died have suffered from asimilar syndrome.
In addition, a patient from an earlier pilot study of the drug,who succumbed four-and-a-half months after his last dose ofthe drug, died with an almost identical toxicity profile.
Three other patients from the NIH trial remain in criticalcondition: a 37-year-old woman and a 63-year-old man at theUniversity of Virginia and a patient at Emory University inAtlanta. The Emory patient received a liver transplant during a10-hour operation on Tuesday night and was still in theintensive care unit on Wednesday.
The 37-year-old woman had a setback late last week when shedeveloped a blood clot in an artery that feeds the liver. Doctorsfeared the clot might cause damage to the bile duct, which runsthrough the liver, and scheduled her for a second livertransplant. According to UV spokesman Tom Doran, the clotwas a complication of surgery and not related to FIAU.
The 10 patients in the NIH trial who received FIAU for 67 to 90days experienced the worst toxicities. Five other NIH patientsand five patients at two other trial sites received the drug forfewer than 30 days before the trial was halted and havereported no serious adverse events to date.
All 10 patients who developed serious toxicities had receivedthe drug at least once before in earlier studies. Researchershave said that this could point to a cumulative toxicity uniqueto FIAU.
FIAU was being developed by Eli Lilly and Co. of Indianapolisas a potential treatment for chronic hepatitis B, a disease thatafflicts roughly 350 million people worldwide and for whichthere is no adequate therapy. Lilly licensed the compound, anucleoside analog, from tiny Oclassen Pharmaceuticals Inc., abiotechnology company based in San Rafael, Calif., in August1992.
The drug had shown promise in animal models and pilotstudies as a treatment for hepatitis B and had apparentlyshown no marked toxicities.
Strauss believes the disastrous FIAU trial will have asignificant impact on how preclinical research is conducted.RThis episode will place additional scrutiny on preclinicaldevelopment,S said Strauss. RAll researchers accept the fact thatthey must take small risks to move science forward, but thistrial has dealt a major blow to our confidence in being able topredict whether harm will come to patients.S
Strauss emphasized that researchers are still poring over datafrom earlier trials in an attempt to determine if there were anywarning signs of the current toxicities. He said that only inretrospect have they been able to make any meaningfullinkages.
As for the three patients in critical condition and the threeothers being monitored, Strauss said their progress is beingmeasured day by day. RPart of the pain and frustration of thisexperience is that no one will feel comfortable about theircondition, even if theyUre feeling perfectly fine right now, untila few months have gone by,S said Strauss.
-- Lisa Piercey Business Editor
(c) 1997 American Health Consultants. All rights reserved.