The families of patients with Alzheimer's disease are praying for a drug that will reverse--or even stall--the dreadful mental deterioration associated with the disorder. While plenty of compounds are under scrutiny, the two that are furthest along in development have yet to make it over the finish line.
"There are no drugs on the market today that have been conclusively proven to be effective in treating Alzheimer's disease," M. Lynn Crismon, professor and head, clinical division, University of Texas at Austin College of Pharmacy, told attendees at last month's American Society of Consultant Pharmacists 3rd Annual Meeting and Exhibition in Orlando, Fla. Speaking at a Parke-Davis sponsored session called Horizons in Drug Therapy of Alzheimer's Disease, he noted that "at least 35 to 36 different drugs are in research and development."
Cholonergic agents: "Some have already bitten the dust, some are still being looked at, and some are getting close to marketing," he told the crowd. Most work has been done with cholinergic agents, as patients with Alzheimer's have been found to have dramatic deficits of the chemical messenger, acetylcholine. Compounds under scrutiny are aimed at enhancing the supply of the neurotransmitter. For example, Warner-Lambert Co.'s tacrine or Cognex (also known as tetrahydroaminoacridine or THA) is designed to boost ACH levels by inhibiting cholinesterase, an enzyme that splits acetylcholine into choline and acetic acid.
Tacrine is "to the best of my knowledge, the first real modern joint venture between the National Institutes of Health and a pharmaceutical company," Crismon said. Warner-Lambert was commissioned to run multicenter trials and, ultimately, to submit a New Drug Application. However, he added, "a lot of studies have been plagued with all kinds of methodological problems, so you see all kinds of mixed results; some positive, some negative. It's been extremely difficult to be able to make any conclusions about drug efficacy." (See following story.) (story omitted)
As a result, the compound has yet to be approved. In 1991, the Food & Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee recommended that the drug not be approved without further clinical study. Later that year, the FDA authorized a treatment IND program that currently allows thousands of patients access to the drug. Since then, new, more formal, research has gotten under way, including a large, 30-week, double-blind, placebo-controlled, parallel-group study due to finish up early in 1993.
The results of one of two studies originally submitted in support of the NDA were revived in the lay press after they appeared in the Oct. 29 New England Journal of Medicine (the study was carried out between 1987 and 1990). Although patients taking tacrine showed a decreased rate of decline with one objective measure of cognitive function, the clinicians assessing the patients' progress found no difference between those on tacrine and those on placebo, noted Crismon.
Promising findings: The findings were more promising in a study appearing in the Nov. 11 issue of JAMA. The 12-week research represents "the best designed tacrine study," Crismon related. Patients taking 80 mg of tacrine per day did "extremely well." Objective measurements of cognitive function showed improvement, as did the investigators' and caregivers' assessments of the patient.
"In a 12-week period," Crismon said, "researchers were able to reverse the average decline you'd usually see over a six-month period. That's a fairly dramatic finding. None of the earlier studies have been nearly this positive."
Tacrine does cause adverse reactions. "The hepatotoxicity is real; it's there," Crismon said. you see it in the studies; you will see it if the drug is approved." Other reported ADRs include nausea and vomiting, headache, diarrhea, abdominal pain, dyspepsia, and rhinitis.
Another cholinesterase inhibitor, Hoechst-Roussel Pharmaceuticals Inc. …