Forty percent of trial patients with Alzheimer's disease showed signs ofimprovement with high doses of Cognex, a drug developed by theParke-Davis division of Warner-Lambert, according to a studypublished in today's issue of the Journal of the American MedicalAssociation (JAMA).An accompanying study, however, showed that many patients onCognex were at risk of serious, but reversible, liver toxicity. "Togetherthese studies reveal the benefits, limitations and toxic effects of tacrine(the generic name of Cognex) for patients with Alzheimer's disease,"JAMA's senior editor, Margaret Winker, noted.Alzheimer's disease affects nearly 4 million Americans and is ranked,along with heart disease, cancer and stroke, as one of the four leadingcauses of deaths. It is also one of the most costly diseases - $100billion annually in the U.S., according to Parke-Davis.Morris Plains, N.J.-based Warner-Lambert's stock (NYSE:WLA) wasup 88 cents a share on Tuesday, closing at $61.50.The 30-week study on high-dose responses to tacrine was requested bythe FDA. In 1991, an FDA advisory committee recommended that thedrug not be approved, concluding that the efficacy of the drug at lowdoses had not been demonstrated, especially given the risk of livertoxicity. The drug was finally approved in September 1993 on the basisof the 30-week, high-dose study.For the new study, patients were divided into four groups. One groupreceived a placebo, a second group received a low dose of tacrine, andthe third and fourth groups were given successively higher doses, withthe fourth group eventually receiving 160 mg a day for the last 12weeks. Outcomes were measured by various clinical scales.In the end, the researchers concluded, "Patients treated with 160 mg aday of tacrine showed statistically significant and clinically observedimprovements on objective cognitive tests, clinician- and caregiver-related global evaluations, and quality of life assessments. Astatistically significant dose-response relationship and a substantiallylarger treatment effect than those reported in previous studies suggestthat higher doses of tacrine are more beneficial than lower dosespreviously studied."In addition to objective improvements in cognitive scores, patientsshowed improvements in their ability to find their way without gettinglost, ability to recall names and faces, and personal hygiene skills.The researchers noted, however, that a substantial number of patientswere unable to complete the study because of concerns over livertoxicity (28 percent). Other side effects - especially gastrointestinalproblems such as nausea, vomiting, diarrhea, anorexia, and abdominalpain - caused an additional 16 percent to drop out. At the beginningof the study, 663 patients were enrolled at 33 centers in the U.S.; only263 were able to complete it. But the authors noted there was noevidence that the large number of drop-outs influenced the results ofthe study.Since not all patients are able to tolerate the high doses, the researchersrecommended that physicians titrate, or gradually increase, the tacrinedose to the maximum that a particular patient can tolerate.The liver-toxicity study involved 2,468 men and women who hadparticipated in tacrine drug trials in Canada, France and the U.S. Allwere at least 50 years old and had mild to moderate symptoms ofAlzheimer's. Serum alanine aminotransferase (ALT) levels weremeasured as markers for potential liver damage. ALT levels exceedingthe upper limit of normal were recorded in 49 percent of patients; 25percent had ALT levels three times higher, and 2 percent had ALTlevels 20 times higher. Elevated ALT levels were more common inwomen than men. In all cases, however, ALT levels returned to normalwhen tacrine was discontinued."Nonetheless, the marked interpatient differences in susceptibilitymake it likely that tacrine could produce life-threatening hepatoxicityin some patients," the researchers concluded. "Until the highlysusceptible patients can be readily identified, the risk of severehepatoxicity should be weighed against the potential benefit of tacrinetherapy in each individual."However, in her editorial comment, Winker noted that once a patienthas responded to tacrine, the decline associated with Alzheimer'scontinues, and that if the treatment is stopped, so do the benefits.Decisions about whether to use tacrine should be made with the patient,the caregiver and the physician, she said. Winker also recommendedthat the cost of the drug ($112 a month) and of clinical monitoring(around $148 a month) be considered when making decisions about itsuse."Ultimately," she wrote, "better drugs are needed ... Until then, tacrinemay be a reasonable drug to try for selected patients." Winker notedthat there is no apparent way to identify which patients will benefitfrom tacrine.
-- Philippa Maister
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