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Executive Summary

ASTRA's FOSCAVIR (FOSCARNET) NDA FILED SEPT. 20 AS FIRST-LINE cytomegalovirus (CMV) retinitis therapy in AIDS patients. The company announced the filing at a Sept. 21 press conference in Washington, D.C. The NDA includes five U.S. studies in 400 patients and data from 1,200 patients in European clinical trials. Astra said that it is discussing a Treatment IND for foscarnet with FDA. The firm, however, has not officially filed a Treatment IND application. Approximately 250 AIDS CMV retinitis patients have received foscarnet on a compassionate use basis. Results of one pivotal trial were reported by the former chief of immunology at the National Eye Institute, Alan Palestine, MD, currently associate professor of ophthamology at Georgetown University. Twenty-four patients with non-sight threatening CMV retinitis, who had not received previous treatment with an anti-CMV drug, were randomized to an immediate treatment group (13) and a delayed treatment group (11). The major clinical endpoint was progression to CMV, which was defined as a 750 micron increase in size of the retinal lesion. All patients in the first study received an induction therapy of 60 mg/kg I.V. foscarnet three times daily for three weeks, followed by a maintenance dose of 90 mg/kg/day, given by two-hour infusion until the progression endpoint was reached. In the delayed arm, the mean time to progression was three weeks compared to 10 weeks for the group that received immediate treatment, a statistically significant difference. Seven of the 13 patients in the immediate treatment group were being treated concomitantly with AZT. Three patients in that group required discontinuation of AZT therapy because of low white cell counts. In the delayed treatment arm, only one patient needed to stop AZT therapy before receiving foscarnet. "In my opinion, foscavir does appear to be able to be used with AZT in most patients," Palestine observed. Syntex' Cytovene (ganciclovir), the only approved treatment for CMV retinitis, generally cannot be taken concomitantly with AZT due to neutropenic side effects. The major side effects from foscarnet therapy were a decrease in renal function in about 12% of the patients, and prominent changes in electrolytes, including calcium, magnesium and phosphate in about half of the patients. A few patients also had low neutrophil counts. All adverse reactions occurred with greater frequency in the immediate treatment group. Results from the second pivotal study in 38 subjects, conducted by Myles Lippe, MD, of the Davies Medical Center in San Francisco, were presented by Astra Associate Clinical Research Director Sarah Martin-Munley, MD. Subjects in this trial included patients who had become resistant to ganciclovir or had been discontinued from ganciclovir therapy due to toxicity. After receiving the induction dose of 60 mg/kg three times daily, patients were randomized to maintenance doses of 60 mg/kg/day or 120 mg/kg/day. Median time to progression in the higher maintenance dose group was 15 weeks compared with eight weeks for the lower dose group, a statistically significant difference. All patients developed negative serum CMV cultures during therapy. Again, decreased renal function, in 25% of patients, was the most common and significant side effect. Martin -Munley noted, however, that when patients are removed from foscarnet therapy for a few days, renal function returns to normal. Three other trials, whose results were not statistically significant, confirmed that the maintenance dose of 120 mg/kg/day is the most effective maintenance dose of foscarnet, Martin-Munley said. While "most patients who initially responded to Foscavir did relapse on the maintenance regimen at some point," Palestine observed, there is no evidence that patients become intolerant or resistant to the drug. FDA has estimated that about 40% of the AIDS CMV retinitis patients may be unable to tolerate ganciclovir treatment. About 20% of the 140,000 patients currently diagnosed with AIDS are expected to develop CMV retinitis. Approved in June 1989, gancilovir's NDA took two-and-one-half years to clear FDA, mainly because the application relied heavily on compassionate use data ("The Pink Sheet" July 3, 1989, p. 4). In the one controlled trial, the median time to progression for ganciclovir treated patients was 10 weeks. The median time to progression ranged from seven to 20 weeks among patients treated on a compassionate use basis. Upon approval of Cytovene, Syntex agreed to conduct five Phase IV studies, including a comparison study with foscarnet. Astra has studies underway in Houston and San Francisco which will generate additional efficacy data for the foscarnet NDA, the company's VP-Medical Affairs Nigel Rulewski said. In addition, foscarnet is being studied in combination with Bristol-Myers Squibb's ddI (dideoxyinosine), in comparative studies against ganciclovir and for the treatment of acyclovir-resistant herpes.

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