A disastrous Phase II clinical trial of the experimental hepatitisB drug fialuridine (FIAU) claimed another victim on Fridaywhen a 52-year-old man died before he was able to receive aliver transplant. He was the third person to succumb from asyndrome that investigators believe is linked to mitochondrialdysfunction caused by FIAU (see chart below).

William Stevenson, director of liver transplantation at theUniversity of Virginia, where four of the FIAU patients havebeen transferred, said that a liver was available for the ailingpatient but that he was too ill to receive it.

IOnce these patients begin to deteriorate, nothing seems to slowit down,J said Stevenson. He noted that the patient who diedFriday was Iawake and alertJ when he first arrived at thehospital early last week and was still able to talk and respondto questions on Thursday. But within 12 hours, his lactatelevels began rising precipitously and he slipped into a coma.Stevenson said the patient was on Imaximal supportJ and itwas impossible to transport him or to perform a livertransplant.

According to National Institutes of Health (NIH) researcher JayHoofnagel, one of the principal investigators of the Phase IItrial, the deadly syndrome suffered by the FIAU patients whodied has at its root liver dysfunction.

IFundamentally, the failure of liver mitochondrial function isleading to death,J he said. Mitochondria are the subcellularengines of life, responsible for the highly efficient process ofaerobic metabolism that provides the bodyLs basic source ofenergy. When mitochondria fail, the body switches to a far lessefficient method of energy production, anaerobic metabolism.One of the toxic byproducts of anaerobic metabolism is lacticacid, and too much lactic acid triggers lactic acidosis.

Although people can develop lactic acidosis from a shock to thesystem, such as severe oxygen deprivation or even simply fromoverexercising, it usually reverses when the underlyingcondition reverses. But the form of lactic acidosis seen in theFIAU trial is a relatively rare and incompletely understoodcondition.

Hoofnagel said that once the sickest FIAU patients progressedto Iintractable lactic acidosis,J even a liver transplant wasnLtable to save them. Though lactic acidosis is usually mild,Hoofnagel said that in the FIAU patients Iit may become thedriving force behind the syndrome.J He emphasized thatresearchers still donLt have a firm medical explanation for theunexpected and tragic consequences of the trial.

IThese patients (who died) flipped into lactic acidosis soquickly, so suddenly,J Hoofnagel marveled. IThis is a new kindof toxicity.J

Stevenson said it appears that FIAU may be affecting Ieverycell in the body of these patientsJ and that it may take fromone to three months for it to clear completely out of theirsystems. Two FIAU patients remain at the University ofVirginia: a 37-year-old woman who received a liver transplanton July 9 and was doing Ivery much betterJ on Friday,according to Stevenson; and a 63-year-old man who is stillawaiting the appropriate donor organ for his liver transplant.

The woman received a liver from a young (20-year-old) donorbefore she progressed to severe lactic acidosis, facts thatHoofnagel and Stevenson believe may be central to her stablecondition. Stevenson said that the Iperfect function and healthJof the donated liver may have allowed it to better survive thetoxins that were still circulating in the patientLs system. Inaddition, transplanting early in the process was crucial. IILmconvinced itLs a matter of timing,J said Stevenson.

The 63-year-old man remains at significant risk for the lacticacidosis syndrome to begin because, Stevenson said, Ihe is notimproving, which means in this context that heLs gettingworse.J

Another FIAU patient, who was transferred from the NIH toEmory University, which is equipped with transplant facilities,has not yet been listed as needing a transplant. Four other NIHtrial patients are under close observation at the NIH ClinicalCenter.

Hoofnagel said that any further development of anti-viraldrugs using the same mechanism of action as FIAU, anucleoside analog that intervenes at the level of DNA to killvirus-infected cells, will require unprecedented new levels oftoxicity testing. He said techniques such as electron microscopyand sophisticated new assays must be further developed torigorously assess the impact of such a drug on mitochondrialfunction.

IWe need to keep exploring. There are always risks, buteverything was done that could have been done,J saidStevenson. IDrugs that interfere at the level of DNA conversion-- that attempt to change genetic material -- are working closerto the origin of life than drugs of the past. When we develop adrug that can kill a virus very specifically, we will haveentered a new age of medicine.J

TRIAL'S ADVERSE EVENTS

March 1993: A clinical trial under National Institutes of Health(NIH) clinical trial protocol No. 93-DK-0031, IA Six MonthCourse of FIAU for Chronic Hepatitis B,J is initiated on the basisof promising four-week pilot studies and animal studies.

June 26: NIH investigators halt a Phase II FIAU clinical trial of15 people after 10 patients who had received the drug for 67to 90 days suffer severe symptoms, including kidney and liverdysfunction.

Eli Lilly and Co. notifies the FDA of adverse reactions and haltsthe trial at all other clinical sites.

June 30: Lilly formally suspends the trial, citing Iseriousadverse events.J Three of the patients are transferred tohospitals with transplant facilities to receive liver transplants.Of the seven remaining patients admitted to the NIH ClinicalCenter for monitoring, four show signs of liver toxicities.

July 4: Two of the three transplant candidates receive livertransplants.

July 5: One of the two transplant patients dies.

July 6: The second transplant patient dies.

July 9: The third transplant candidate receives a livertransplant. (She was reported in IcriticalJ condition as ofFriday, but doctors said she was improving.)

July 11: The fourth patient is transferred to receive a livertransplant.

July 12: The fifth patient is transferred to receive a livertransplant.

July 16: The patient transferred on July 12 dies beforereceiving a liver transplant.

Final Status:

Of the 10 patients who had severe adverse reactions, threedied; two immediately after receiving a liver transplant andone before a transplant was attempted. One patient received aliver transplant and was still alive on Friday, and one wasawaiting a liver transplant and was reported in criticalcondition. A sixth patient was transferred to a transplant-equipped hospital. Four patients remain at the NIH ClinicalCenter and were being monitored closely as of Friday.

None of the five patients who received the drug for the shorterperiod experienced any quantitatively measurable adverseevents as of Friday.

-- Lisa Piercey Business Editor

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