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WARNER-LAMBERT’s COGNEX WILL REQUIRE WEEKLY BLOOD MONITORING AT OUTSET OF TREATMENT; ALZHEIMER THERAPY APPROVED SEPT. 9 WILL COST $3.05/DAY DIRECT PRICE

Executive Summary

Alzheimer's patients treated with Warner-Lambert's Cognex are directed to undergo weekly blood monitoring for "at least the first 18 weeks" following initiation of therapy, approved labeling states. Warner-Lambert's Cognex (tacrine) was approved Sept. 9 by FDA for the treatment of patients with "mild to moderate dementia of the Alzheimer's type." Cognex is the first drug approved specifically to treat symptoms of Alzheimer's, which, FDA estimates, affects 4 mil. people in the U.S. and results in the deaths of 100,000 people annually. After the first 18 weeks of therapy, if patients remain on the drug through that period, monitoring may be decreased to once every three months. Weekly blood monitoring should be resumed, however, for a "minimum of six weeks on each occasion that the dose of tacrine is increased," labeling notes. The requirement for weekly blood monitoring in the first four- and-one-half months of therapy with Cognex and its attendant costs results from the potential for elevated alanine aminotransferase (ALT) enzyme levels in the liver that were found to occur during clinical trials of the drug. In patients with mildly elevated ALTs, data show that Cognex therapy can be continued at a lower dose or stopped and then resumed at a lower dose. "Clinically evident signs and symptoms of liver injury are rare" if tacrine therapy is promptly stopped when increased ALT levels are detected, labeling states, adding, however, that it is impossible to rule out chronic sequelae due to the current lack of long-term use data. In patients continuing to show "modest" ALT elevations (greater than two times upper limit of normal), labeling states that continued monitoring may be indicated. The initial dose of Cognex is 40 mg/day (10 mg q.i.d.), which should be maintained for a minimum of six weeks with the weekly blood monitoring. Labeling cautions: "It is important that the dose not be increased during this period because of the potential for delayed onset of transaminase elevations." Following six weeks of treatment at 40 mg/day, the dose of Cognex should be increased to 80 mg/day (20 mg q.i.d.). If patients continue to tolerate treatment and no evidence of elevated ALTs occurs, patients should be titrated to 120 mg/day and 160 mg/day (at q.i.d intervals) at six-weeks intervals, labeling states. In clinical trials, Cognex showed a small but clinically meaningful benefit for some Alzheimer's patients. The trial results showed a wide range of patient responses due to a number of factors, including the failure of many patients to stay on the drug during the clinical trials period and the variability of analyses used to measure cognitive and behavioral functions. Labeling states that Cognex is an "effective" treatment for Alzheimer's. Rather than quantifying the efficacy of Cognex, the clinical pharmacology section instead provides the full trial results of 970-26 (a 12-week study) and 970-61 (a 30-week study) and explains the study endpoints. Data on Cognex presented to FDA's Peripheral & Central Nervous System Drugs Advisory Committee at its third and last meeting on Cognex March 18 showed that about 20% of patients completing clinical trials had a four-point improvement on the Alzheimer's Disease Assessment Scale/Cognitive Subscale (ADAS-COG) ("The Pink Sheet" March 22, p. 7). The primary efficacy study (970-61), which enrolled 663 patients for 30 weeks of treatment of as high as 160 mg/day of Cognex, also looked at the Clinician Interview-Based Impression of Change (CIBIC) measurement scale. The study found that 42% of 62 evaluable patients in the highest dosage group, 160 mg per day, were improved. The other pivotal trial on which the approval was based was a 12-week, double-blind, parallel group study (970-26) of 468 patients at doses up to 80 mg/day. The clinical pharmacology section of labeling makes clear that tacrine is not a cure for Alzheimer's and cannot arrest the dementia that is manifested in the disease. Tacrine "presumably acts by elevating acetylcholine released by the still intact cholinergic neurons. If this theoretical mechanism of action is correct," labeling states, "tacrine's effects may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that tacrine alters the course of the underlying dementing process." Labeling highlights the fact that while the clinical trials "clearly documented tacrine's effectiveness," the results of the longer-term trial varied due to tolerance of the drug and the length of time patients stayed on the drug. The clinical results, labeling states, "are based on only a fraction of the patients initially randomized to tacrine, those who could tolerate tacrine and remain on treatment uninterrupted for the full 30 weeks. In considering the expected outcome in a group of patients newly started on tacrine," labeling states, "account must be taken both of the likelihood of staying on therapy and the responses in patients who do so." At the March 18 meeting, Parke-Davis VP-Clinical Development Mark Pierce, MD, estimated that 60% to 75% of patients taking Cognex would still be on the drug in six months. In the clinical trials, the drop-out rate approached 70% but the company blamed that on the rigidity of the clinical trial design with regard to handling elevated liver enzymes. Based on results of the company's Treatment IND, which has been in place since February 1992, and rechallenges of patients taken off drug due to elevated liver enzymes, Pierce predicted that "real world" conditions would result in a higher percentage of patients staying on the drug. Committee member Ira Shoulson, MD, University of Rochester, reasoned that the number of patients who benefit from the drug would be smaller than the number of those who can tolerate Cognex. He calculated that 12% of patients would show the same four-point improvement in the ADAS-COG as were reported in 20% of patients in clinical trials. He also estimated that 60% of patients would remain on the drug. Elevated ALTs were the most common cause for withdrawal from the clinical trials (8% of all Cognex treated patients, or 212 of 456 patients withdrawn). Side effects in addition to the potential for elevated ALTs most commonly cited as reasons for withdrawing from the trials were nausea and/or vomiting (1.5%), agitation (.9%), rash and anorexia (.7% apiece) and confusion (.5%). The most common adverse events associated with use of the drug were elevated ALTs, nausea and/or vomiting, diarrhea, dyspepsia, myalgia, anorexia and ataxia, with all but ALTs and ataxia appearing to be dose-dependent, labeling notes. Cognex received FDA approval eight months after Warner-Lambert filed its last major data submission for the drug and seven months after the third advisory committee review that resulted in a unanimous recommendation for the drug's approval by FDA. Cognex has been "approvable" at FDA since May 10. Two previous advisory committee reviews of Cognex in March and July of 1991 resulted in a recommendation against approval and a recommendation for further data. FDA received data from 970-61 in mid-February of this year. The Cognex NDA (20-070) that was approved Sept. 9 originally was filed June 1, 1990. FDA classified the drug as a "1P," meaning a new molecular entity receiving priority review by the agency. The history of tacrine goes back to 1986, when William Summers, MD, a California physician, reported significant clinical improvements in Alzheimer's patients taking the drug (then called THA). The Summers study, which FDA subsequently determined to be flawed, led the National Institute of Aging, FDA and Warner- Lambert together to create a protocol for studying the drug. It was the data from that protocol that was turned down by the advisory committee at its March 1991 meeting. Warner-Lambert said Sept. 9 that shipping for Cognex will begin by the end of September and the drug should be "widely available" by mid-October. The company expects to send out 200,000 "stat-grams" to physicians alerting them to the launch. Availability of Cognex supplies will apparently not be affected by the consent decree signed by Warner-Lambert Aug. 16. The consent decree, which dealt with widespread manufacturing problems uncovered at Warner-Lambert's mainland U.S. and Puerto Rico facilities, allows the company to continue manufacturing medically necessary drugs, Cognex, and other investigational drugs, such as the epilepsy treatment Neurontin (gabapentin), while the company undergoes certification of its laboratory and manufacturing processes ("The Pink Sheet" Aug. 23, p. 10). Cognex will be $3.05/day direct price regardless of the dosage strength. Assuming an average 15%-30% mark-up, daily costs for patients taking Cognex would be $3.50-$3.97 and annual costs between $1,280 and $1,447, excluding the costs of doctor visits and blood monitoring. The $3.05/day is about the same as that charged by Warner-Lambert under the Treatment IND. Warner-Lambert has an existing patient assistance program in place for its drug therapies and administered the COPING program to Cognex Treatment IND patients requiring financial assistance. The program is now being made easier to enroll in. Cognex will be available in capsules of 10 mg, 20 mg, 30 mg and 40 mg. Warner-Lambert is working with Alza to develop a once- daily dosage form and a transdermal delivery system. Pharmaceutical Sector President Joseph Smith told the New York Society of Securities Analysts April 21 that Cognex will be promoted by Warner-Lambert's entire sales organization, except for the sales force devoted to female health ("The Pink Sheet" April 26, p. 9). The 2,000 doctors who participated in the Treatment IND and those who took part in the controlled studies will be used as teachers on the use of the drug. For caregivers, Warner-Lambert intends to produce a "user friendly" patient kit for caregivers about the drug and its effects that includes a diary to track patients' progress. Physicians will distribute the kit. The company also will provide a caregiver manual with information about caring for Alzheimer's patients and coping mechanisms for caregivers. In the clinical pharmacokinetics section, labeling points out that there appears to be "no clinically relevant influence of age" on tacrine's clearance; that women have an average tacrine plasma concentration 50% higher than men; that the effect of race on tacrine clearance has not been studied; and that in smokers, mean plasma concentrations of tacrine are "approximately one-third" of that in nonsmokers. Thomas Ferguson Associates will handle professional journal advertising for Cognex. Warner-Lambert said it has no plans at this time for direct-to-consumer ads. FDA's approval letter for Cognex cautions Warner-Lambert against advertising or promotional labeling that could be considered "false, misleading or lacking fair balance." The letter says these conditions would occur if: "the presentation of the evidence supporting the conclusion that tacrine is effective contains the results of only those analyses described in the approved labeling...that are most favorable to tacrine or places disproportionate emphasis on the results of selected analyses so as to misrepresent the intent or approved product labeling; "the effects of tacrine are represented in terms of the numbers of months that would ordinarily have to elapse to produce a mean decrement in ADAS[-COG] scores numerically equivalent to the mean difference between tacrine and placebo observed in controlled trials. This representation of tacrine's effects," FDA notes, "was proposed in a draft version of labeling ...and was rejected because it was found misleading." Finally, FDA said it will consider Cognex ads or promotions false or misleading "if there is an implication" that the use of tacrine "will lead to economic savings or behavioral improvements that have been been established and/or are speculative." The agency pointed out that it is making note of these issues "because our review of promotional materials provided in your June 23, August 13, 25 and 30 and September 2, 1993 submissions...leads us to conclude that your campaign will be misleading if so implemented."

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