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THA trials suspended, research probed.

THA trials suspended, research probed

Food and Drug Administration (FDA) investigators are looking into the quality of early research on a highly publicized experimental drug for Alzheimer's disease. Clinical trials of the drug, called tetrahydroaminoacridine or THA, were suspended late last month after some patients developed signs of liver toxicity.

Originally reported to improve memory in some Alzheimer patients, THA was considered by many to be the most promising treatment yet for the incurable disease (SN: 9/5/87, p.149). The recent suspension of tests, however, raises doubts about the drug's ultimate potential. And allegations that the original research results were embraced prematurely may temper the current movement for speedier approval of experimental drugs.

"It illustrates a problem,' says Paul Leber, head of the FDA's drug review division for neuropharmacological drugs. On the one hand, the agency is under pressure to speed the approval of drugs that show signs of effectiveness against incurable diseases. On the other hand, he says, referring to the new findings of liver toxicity, "I'm glad we had only 50 or so patients in this trial, and not 50,000.'

The federal government last month initiated the clinical trials jointly with Warner-Lambert Co. of Morris Plains, N.J., following the publication last November of research in the NEW ENGLAND JOURNAL OF MEDICINE. That research, by Arcadia, Calif., psychiatrist William K. Summers and his colleagues, found significant THA-associated memory improvement in Alzheimer patients. The new trials, which were designed in part to determine what dosage levels might be appropriate for use against Alzheimer's, were to include more than 300 patients. Fewer than 50 were treated before the trials were suspended, after liver enzymes in some patients became elevated from 6- to 20-fold--a "substantial signal' of liver toxicity, Leber says.

Liver damage is not uncommon in clinical trials of new drugs, and in many cases is reversible. Indeed, previous trials with other experimental drugs have been restarted after patients' enzyme levels returned to normal, Leber says. But those elevations were generally less severe than the levels encountered with THA, he adds, and there is some concern that the liver damage might be occurring at drug concentrations lower than those necessary to treat Alzheimer's.

The suspension of trials follows months of controversy regarding the methodology and conclusions of Summers's original research. The June 18 NEW ENGLAND JOURNAL OF MEDICINE ran five letters critical of the research and raised questions regarding his involvement in a for-profit corporation that had started offering experimental THA treatments for $12,000 per year. Summers replied in the same issue that a nonprofit entity is being incorporated to take over the business of providing such treatments.

The FDA investigation into Summers's work has reportedly been going on for several months.

Marshall Molloy, manager of media relations for Warner-Lambert, says his company has for some time been aware that "there was a level of discussion' within the FDA concerning Summers's work. Nevertheless, he says, "Given the total body of evidence, we believe that continued interest in the drug is warranted.'

Leber, too, doesn't discount the possibility that THA may progress to further trials. However, he says, nothing more will be done until the liver toxicity problems are better understood. "There's no rush,' he says. "This drug is no miracle.'
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Title Annotation:tetrahydroaminoacridine
Author:Weiss, Rick
Publication:Science News
Date:Nov 7, 1987
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