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Executive Summary

Warner-Lambert's Alzheimer's drug Cognex (tacrine) will be studied in up to 3,000 patients at higher doses under a Treatment IND protocol approved by FDA on Dec. 2. The trial is expected to begin in February 1992, FDA announced in a Dec. 2 "Talk Paper." Tacrine is the first Alzheimer's drug to be awarded Treatment IND status. A second Treatment IND from Hoechst-Roussel is pending for its aminoacridine experimental Alzheimer's drug Mentane (velnacrine). Previously, Hoechst has said it was considering the Treatment IND route in July at the time of the second Cognex advisory committee. Hoechst, however, apparently delayed that application when Cognex had a difficult session with the advisory committee. A Treatment IND application ripens in 30 days; if FDA does not object, the application is approved. The decision on the Mentane application should come before 1992. Hoechst also is in "continuing" discussions with FDA on an NDA submission for Mentane, the company said Dec. 3. Hoechst said in October that it hoped to submit an NDA application by the end of this year for the Alzheimer's drug ("The Pink Sheet" Oct. 21, In Brief). The Cognex Treatment IND protocol is a dose-escalation study that provides for a beginning daily dose of 40 mg for six consecutive weeks. Patients showing no evidence of liver toxicity (elevated alanine aminotransferase, or ALT, enzymes) at the 40 mg/day dose will move to an 80 mg/day dose for another six weeks. For those patients who still show no liver toxicity, the daily dose will then be increased to 120 mg/day for six additional weeks. FDA said the protocol may "eventually include a 160 mg daily dose." The agency also noted that "there will be thorough patient monitoring and recordkeeping" to gather safety data on the 120 and 160 mg daily dosing regimens, which have not been tested extensively in Warner-Lambert's clinical trial program. Warner-Lambert will pick the investigation sites and the physicians conducting the trials. The company said Dec. 3 that it will continue to "work closely" with FDA to finalize the protocol. The company has not decided whether it will operate the program on a cost-recovery basis. The company had planned to charge for Cognex under the much larger Treatment IND protocol that was reviewed and rejected by FDA's Peripheral & Central Nervous System Drugs Advisory Committee at its second Cognex review meeting on July 15 ("The Pink Sheet" July 22, p. 6). That protocol envisioned up to 50,000 patients receiving Cognex at a cost to wholesalers of $ 3 per day, or about $ 4 a day for consumers. Warner-Lambert's original NDA filing for Cognex, reviewed and rejected by an FDA advisory committee in March 1991, included data on 40 mg, 80 mg and 120 mg doses. Warner-Lambert has been seeking expanded access for Cognex since the March advisory committee defeat as a means of answering unresolved efficacy questions about the drug. At the second FDA advisory committee meeting in July, where the company's first proposed Treatment IND protocol was rejected, the committee recommended that approval of a Treatment IND for Cognex should be conditioned on further efficacy trials getting under way. Simultaneous with the filing of its Treatment IND, Warner- Lambert announced in late October that it had begun enrolling patients in a 500-person, longer duration, higher-dose, double- blind, placebo-controlled efficacy trial that will study daily doses of Cognex as high as 160 mg. That study, which will be conducted at 33 U.S. clinical trial sites, is expected to be completed in "early 1993," Warner-Lambert said. At the July advisory committee meeting, committee members were concerned that a large Treatment IND program for Cognex could get in the way of further clinical trials. One committee consultant, Paul Meier, PhD, University of Chicago, said that the two simultaneous types of trials could create a situation analogous to the Bristol-Myers Squibb's Videx (ddI) trials. Commenting on the decision to approve the Treatment IND, Commissioner Kessler stated in the FDA "Talk Paper" that the new Cognex protocol was approved "based on evidence that the drug produced a small improvement in mental function in some patients taking the drug during controlled clinical trials and evidence that larger doses might have a greater effect." Although he acknowledged "that tacrine had some favorable benefits," Kessler pointed out that "the effects were small and of uncertain real benefit, and there is still concern about possible liver toxicity." He cautioned that "there is still a great deal to learn about tacrine." Kessler reiterated his concerns during a Dec. 3 appearance on the television news show "CBS This Morning." In addition to Hoechst's velnacrine, which is Cognex' closest challenger in the race to widen clinical use, there are at least six other companies with Alzheimer's drug studies underway: Forest Labs estimates that Synapton (physostigmine) will complete Phase III clinical trials toward the end of the first half of 1992. Forest says its interim analyses of the drug have shown no liver toxicities. Among the measurements of efficacy being used by the firm are the ADAS-COG (Alzheimer's Disease Assessment Scale) and the CGIC (Clinical Global Impression of Change) scale. Merck's heptylphysostigmine, licensed from the Italian firm Mediolanum in June 1990, is moving into larger scale clinical trials, the company reported in November. DuPont Merck is enrolling patients in a Phase III trial of the DuPont drug linopirine (newly tradenamed Aviva) that will eventually include 750 people with Alzheimer's ("The Pink Sheet" July 15, T&G-14). The study will be conducted at more than 50 centers in the U.S. and Canada. Sigma-Tau's acetyl-L-carnitine (Alcar) is currently in Phase III trials involving 400 patients at 27 U.S. centers. Enrollment in the one-year oral-dose delivery trial was completed in October. Hoffmann-La Roche has gained worldwide registration and marketing rights to Alcar, the two companies announced Nov. 11. The Janssen Research Foundation is sponsoring Phase II/III clinical trials of the calcium blocker sabeluzole for the treatment of Alzheimer's symptoms. The Alzheimer's Association reports that the 48-week study is being conducted at 16 U.S. centers and will enroll approximately 300 patients. The Miles calcium blocker nimodipine (Nimotop) is also being studied for primary degenerative dementia. A recent PMA tabulation of drugs in research puts the product in Phase III trials. In July 1990, the company said first results could be expected in about 18 months, indicating that the first reports could be emerging soon. The anti-Parkinson's drug Eldepryl (selegiline), marketed by Somerset, the 50/50 joint venture of Mylan and Bolar, is also being studied for Alzheimer's. Eldepryl is copromoted for Parkinson's by Sandoz under a September 1990 agreement.

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