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WARNER-LAMBERT COGNEX LABELING MAY NOT REQUIRE WEEKLY BLOOD MONITORING, FIRM SAYS; COMPANY EXPECTS ALZHEIMER’s TREATMENT TO ENTER MARKET BY JUNE

Executive Summary

Warner-Lambert's Cognex labeling may not require patients taking the Alzheimer's disease treatment to undergo weekly monitoring for elevated liver transaminase levels, Parke-Davis Research Chairman Ronald Cresswell, reported at an April 21 meeting of the New York Society of Securities Analysts. Asked by analysts what requirements for monitoring of liver enzyme levels are expected in final labeling for Cognex (tacrine), Cresswell said: "I think the view in the agency is that, in all likliehood, there will be something in the labeling that is perhaps a little bit less demanding than the very conservative view we took in the clinical trials." During the trials, the firm required weekly monitoring of patient liver enzyme levels. A consulting group of hepatologists has reviewed the Cognex safety data and concluded that the monitoring requirement "may not need to be as onerous as it was during the trial," Cresswell observed. He added that "we did submit a draft document [to FDA] suggesting a different schedule." During the March 18 meeting of FDA's Peripheral & CNS Drugs Advisory Committee at which Cognex was recommended for approval, committee member Ira Shoulson, MD, University of Rochester, pointed out that the inconvenience to Alzheimer's patients and their caregivers of weekly monitoring was "not a trivial issue" ("The Pink Sheet" March 22, 1993, p. 9). He thought the issue of the frequency of monitoring required "more information." The cost of weekly blood monitoring and of the drug itself dampened the enthusiasm of several committee members recommending Cognex for approval. Labeling discussions are underway between Warner-Lambert and FDA, Cresswell said, and "the approval letter is likely to be with us no later than the first week in May. Our target is for Cognex to be on the market in June." He predicted that "the labeling discussions will not be difficult." Additional dosage forms of tacrine are being developed by Parke-Davis in collaboration with Alza, Warner-Lambert Chairman Melvin Goodes disclosed. The agreement with Alza covers development of a once-daily oral dosage form and a transdermal delivery system for tacrine. The current formulation of the drug is given up to four times daily at the highest dosage levels. Cognex is protected until the year 2006 by a patent covering the use of tacrine for the treatment of Alzheimer's Disease and other dementias, licensed in 1990 from William Summers, MD. Similar to statements by Parke-Davis at the March 18 advisory committee meeting, Cresswell's estimate is that "something like 40% of the total population...for one reason or another will not choose to stay with the drug." However, he predicted that liver enzyme elevations will not be the primary reason for patients to discontinue Cognex therapy. "Probably...somewhere around 20%, maybe 25% of the people at the very high doses are not going to like the cholinergic effects [diarrhea, nausea and vomiting, and rash] and I think the liver enzymes are going to come in at substantially less than that, closer to 12% or 15%," the research exec predicted. After summarizing the two pivotal efficacy studies for Cognex, Cresswell asked, "What does this mean for the patient? I am not sure." He said that "there may be a portion of that population which is, in fact, too far gone to benefit from the drug." However, he added that "I honestly believe that this drug is appropriate for most of the Alzheimer's population." He also emphasized that "the data is so striking at 160 [mg, the highest dose tested], that every attempt should be made to get the patient up to the highest dose." "It is clear that we have not seen the most efficacious dose" of Cognex, Cresswell said. Warner-Lambert is planning to conduct further studies of the drug using doses higher than 160 mg. In addition, the firm will investigate tacrine use for the treatment of AIDS dementia, Parkinson's disease, amyotrophic lateral sclerosis and "possibly" tardive dyskinesia. Cresswell said that among patients on Warner-Lambert's Treatment IND, reports of "dramatic responses" to Cognex "are running at about a 12% rate." Physicians participating in the Treatment IND are asked to check a box on the reporting form "to say whether or not they have seen a dramatic effect," Cresswell explained. Warner-Lambert has followed up some of the "dramatic effect" reports with interviews of physicians and caregivers, he said, concluding: "The responses are there, you take them for what they are...they are anecdotal...I think they are supportive of the things we saw in the controlled clinical studies." At the March 18 advisory committee meeting, committee member Shoulson estimated that, including dropouts due to side effects, Cognex would eventually be effective in approximately 12% of the patients who try it. His calculation was based on the assumption that 60% of patients trying Cognex would tolerate the drug, and that 20% of these patients would show a "clinically significant" improvement on the Alzheimer's Disease Assessment Scale/Cognitive Subscale. Analysts asked Cresswell whether neurologists may become impatient with Cognex and publicly declare it ineffective. He responded that "you are going to see a situation where there are a number of people who cannot take the drug and there are a number of people who don't get benefit from the drug," but "if, in fact, the neurologists believe that they are seeing nothing at all, I will be very surprised." Warner-Lambert Pharmaceutical Sector President Joseph Smith responded to the same question, saying that "the reaction of the Treatment IND physicians was completely [the] opposite of what you suggested." He said that "we have a lot of happy physicians and a lot of happy caregivers." Smith also previewed Warner-Lambert's promotional plans for Cognex. He said: "We will fully utilize the [2,000] physicians from the Treatment IND...who have a lot of hands-on experience, along with the physicians who were part of the double- blind studies." He said the participating doctors "will be listed as teachers to get groups of physicians to learn how to use the drug." Warner-Lambert will also "get out as much educational material as we can." The firm met recently with the Alzheimer's Association "so they can get out educational materials to their chapters." The drug will be promoted by "our whole sales organization," except for the sales force dedicated to female health, Smith added. Parke-Davis has formed a "distinct neurological sales force," de Vink said, which will promote Cognex and Neurontin for epilepsy. The sales force will build on "our traditional relationship with neurologists through Dilantin," de Vink said. Neurontin (gabapentin) was recommended for approval as an add-on therapy for epilepsy by FDA's Peripheral & CNS Drugs Advisory Committee in December ("The Pink Sheet" Dec. 21, 1992, p. 7). De Vink said he expects Neurontin to reach annual worldwide sales of $100 mil.
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