A report by the Health Research Group (HRG) issued last weekquestioned whether the National Institutes of Health shouldhave begun its trials of fialuridine (FIAU), given toxicity resultsof an Eli Lilly & Co. study in healthy volunteers.
HRG also alleges that Lilly failed to immediately report thehospitalization of one of these volunteers to either NIH or FDA.
Lilly began a Phase I study of FIAU in 16 healthy volunteersjust before NIH launched a study in patients with hepatitis B onMarch 24. HRG said that "one of these normal volunteers(subject 1203) showed a more than 3.5-fold increase in (liverenzyme) AST and a 7.2-fold increase in (liver enzyme) ALTafter just two 5-mg doses of FIAU, and was hospitalized forfour weeks because of this.
"Another normal volunteer (subject 508) had a 2.8-foldincrease in AST and a 4.7-fold rise in ALT after just one dose ofFIAU."
HRG, a branch of Ralph Nader's consumer watch dog groupPublic Citizen, said in its report that "the severe liverabnormalities in subject 1203 were first noted on March 17thand again on March 25th, one week before and one day afterthe commencement at NIH of the ill-fated trial on March 24th,which has killed five people to date."
HRG Director Sidney Wolfe said he found the Lilly data inappendix 5 of FDA's task force report on FIAU, which wasreleased last month. The report notes that subject 1203"discontinued the study due to changes in liver function tests,"which improved after the subject was hospitalized for fourweeks.
FDA spokeswoman June Wyman said the task force concludedthat animal and clinical studies conducted prior to the NIH trial"were not predictive of what would happen in the NIH study."
HRG disagreed, stating that "there is no question that Eli Lillyshould have stopped the NIH trail by the end of March or inthe first days of April." Lilly halted the trial on June 26 after10 of 18 patients in the trial showed severe adverse sideeffects to the drug. At the end of August, patients began dying.
HRG also cited animal hepatoxicity data, which the group saidshould have called into question the decision to proceed withhuman trials.
Responding to HRG's report, Lilly representative Suzanne Smallsaid the trial Lilly initiated in March was a bioequivalencestudy comparing the tablet formulation of FIAU with the liquidformulation. She said one patient experienced "a mild increasein liver enzymes" and was withdrawn from the study.
Small said the "mild elevation in liver enzymes" did notwarrant an immediate report to FDA. FDA requires that serious,unexpected and causally related adverse reactions be reportedwithin 10 days. If they are not in this category, adverse eventsare reported in an annual report to the agency.
Eleven years ago, Lilly (NYSE:LLY) of Indianapolis wassanctioned by FDA for failing to report adverse reactions to thenon-steroidal anti-inflammatory drug Oraflex. Soon after itsapproval in the U.S. in 1982, the drug was pulled from themarket after it was linked to the death of several patients fromliver and kidney toxicities.
Wyman said FDA's task force is evaluating whetherinvestigators and Lilly complied with FDA reportingregulations. The task force's report concluded that researchersfailed to note FIAU's toxicity in part because the drug's effectson the liver mimicked those of hepatitis B (see BioWorld, Nov.17).
The task force recommended increased requirements forreporting adverse events and more stringent rules to requireinvestigators to issue toxicities reported by patients in drugtrials that are drug-related.
GENETIC DIFFERENCES IN LONG-TERM HIV SURVIVORS
By David C. HolzmanWashington Editor
WASHINGTON -- Long-term survivors infected with HIV maybe genetically different from those whose disease progressesmore normally, and triple-drug therapy with nucleosideanalogs loses effectiveness because the virus quickly mutatesand becomes resistant, researchers reported Friday.
The data were presented at a workshop sponsored by theInstitute of Medicine titled "Toward an Understanding of theCorrelates of Protective Immunity to HIV Infection."
Long-term survivors were about twice as likely to have certaingenes in HLA class 2 alleles as those with full-blown AIDS,Susan Buchbinder of the AIDS Office at the San FranciscoDepartment of Public Health reported.
The class 2 gene products are present on antigen-presentingcells involved in activation of CD4 positive cells, saidBuchbinder.
The big question, she said, is whether the long-term survivorsare a distinct group or the tail of a random distribution. Shesaid her results suggested the former, and "I hope this will leadto exploring mechanisms."
But during a question session, David Baltimore of RockefellerUniversity argued that Buchbinder's results offered no hint of aplateau in the graph of disease onset.
Buchbinder's study involved a cohort of 6,704 men who hadvisited a sexually transmitted disease clinic and who have beenstudied by the Centers for Disease Control and the SanFrancisco Department of Public Health since 1982.
Long-term survivors were defined as those who hadmaintained CD4 counts above 500 for more than a decade.Their CD4 counts declined much more slowly than those ofpeople with AIDS -- 0.8 per year vs. 80.5 per year, on average.
Following Buchbinder, George Shaw of the University ofAlabama, Birmingham, presented evidence showing that HIVcan very quickly develop resistance to therapies using severalconventional compounds concurrently.
Nineteen men received AZT and ddC, or AZT and ddI, plusnevarapine, together. In each case, CD4 counts rosedramatically (from around 106 to 170 in one man, for example)but then quickly fell back to baseline. As CD4 count rose andfell, the virus population fell and then rose, said Shaw. Theoccurrence of mutation correlated with bottoming out in thevirus populations and topping out of CD4 count.
The mutations were changes in amino acid positions 181 and188 of the reverse transcriptase gene, which are known toconfer drug resistance.
By the 18th week of drug therapy, all patient viral populationshad become drug resistant, but in 10 of the patients, thechange had taken place within a week.
Furthermore, "genetic resistance was detectable after a five-week drug holiday," said Shaw.
"So the genotype, the phenotype, and all the virologic markersall correlate," he concluded.
CENTOCOR OFFERS TO BUY BACK TOCOR II
By Jennifer Van BruntSenior Editor
Centocor Inc. has made a tender offer to acquire all 2.25 millionoutstanding units of its financing vehicle Tocor II.
Under the proposal announced on Friday, Centocor will offer$40 per Tocor II unit (NASDAQ:TOCRZ), payable in shares ofCentocor common stock (NASDAQ:CNTO). This puts a value onthe purchase of $90 million -- the exact amount that was raisedwhen Centocor spun off Tocor II in January 1992 to fund itsresearch programs in small peptide molecules in five targetareas, including inflammation and autoimmune disease.
The number of shares of Centocor stock to be issued per unitwill not be less than 2.73 or greater than 3.20 (and will becalculated based on the average closing price of the stock for30 trading days preceding the fifth trading day prior to theoffer's expiration.) Thus, Centocor could be shelling out as muchas $6.56 per share or $14.75 million cash (based on a closingstock price of $12.25 on Friday) to make up the difference, aswell as the shares themselves.
By acquiring Tocor II, Centocor gets access to the products thatare targeted at the same disease indications that Centocor itselfhas singled out for monoclonal antibody-based drugdevelopment efforts.
Each unit of Tocor II consists of one share of Tocor II commonstock, one callable warrant to purchase a share of Centocorcommon stock (exercisable at $49.75 per share) and one seriesT warrant to purchase a share of Centocor common stock(exercisable at $64.50 per share). These securities trade as aunit until Dec. 31. Centocor had the option to purchase all theTocor II shares at $58 per share in 1993, $76 per share in1994 and $106 per share in 1995.
Even though Centocor's $40 offer is less than the 1993 optionprice, it's significantly more than the $22 value (average) thatthe market has placed on Tocor II units since the beginning ofNovember. "The $40 offer places a more than acceptablepremium" on the securities, said Wole Fayemi, a biotechnologyanalyst who follows Centocor for Hambrecht & Quist. "This isclearly a good deal for Tocor II shareholders." That sentimentwas reflected in Friday's market activity on the units, in whichshares jumped by $13.25 each to close at $36.25.
And since the built-in purchase price was only going up overthe next several years, now is also the best time for Centocor tohave made its tender offer, Fayemi told BioWorld. As well,Tocor II's R&D programs are well-adva nced, with a peptide-based adhesion antagonist lead compound already identifiedand ready to go into the clinic in late 1994, Fayemi said.
Centocor of Malvern, Pa., is filing a registration statement withthe Securities and Exchange Commission for the shares of itscommon stock to be offered in exchange for the Tocor II units.The offer will be outstanding for 20 business days once theregistration statement becomes effective. On Friday, Tocor II'sboard of directors unanimously recommended that holders ofTocor II stock accept the offer.
-- Brenda Sandburg News Editor
(c) 1997 American Health Consultants. All rights reserved.