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ASTRA's FOSCAVIR (FOSCARNET) FOR TREATING CYTOMEGALOVIRUS RETINITIS IN AIDS PATIENTS UNANIMOUSLY RECOMMENDED FOR APPROVAL BY FDA ADVISORY COMMITTEE

Executive Summary

Astra's Foscavir (foscarnet) for the treatment of cytomegalovirus retinitis was unanimously recommended for approval by FDA's Antiviral Drugs Advisory Committee at its June 12 meeting. Committee member John Graybill, MD, Audie Murphy Memorial Veterans Hospital, San Antonio, said: "We have evidence from two studies that show . . . very dramatic responses [especially] in the controlled study, and I would certainly argue that the drug is effective from those two studies." Astra submitted the final section of its rolling NDA for Foscavir in September 1990 ("The Pink Sheet" Sept. 24, T&G-7). The NDA contains data on over 1,600 patients worldwide. Included in the filing are five U.S. trials involving a total of 189 patients. For over a year, foscarnet has been available on a compassionate use basis to 1,000 patients, including CMV retinitis patients who are intolerant or resistant to the only approved CMV retinitis therapy, Syntex' Cytovene (ganciclovir). When FDA announced that an advisory committee was scheduled to review Foscavir, Astra offered to submit a Treatment IND application for the drug, but FDA said that it might slow down the NDA review process. Invited guest Derek Link, ACT-UP New York, asked the committee to urge FDA to approve Foscavir within two weeks after the advisory committee meeting. FDA Antiviral Drugs Division Assistant Director for Medical Affairs Dianne Murphy, MD, pointed out that "this drug is one of the first to have most of its development for use in HIV patients occur in the Antiviral Division and under subpart E [expedited review] influence." She added: "Both the company and we have much to extract in the form of lessons to be learned. One of the most important lessons that should be stressed is the need to fully develop the preclinical evaluation, if expedited development in FDA review is to be truly facilitated." FDA had requested additional preclinical toxicity studies because many of the previous studies were done for the oral and transdermal forms of the drug for herpes simplex infection. In its Foscavir data presentation, Astra focused on the results of two pivotal U.S. trials. The first study, FOS-03, presented by Alan Palestine, Georgetown University clinical associate professor of ophthalmology, evaluated the effects of immediate versus late foscarnet treatment in AIDS patients with non-sight-threatening CMV retinitis. The endpoint in the study was progression of retinitis by 750 microns, which was determined with photographs evaluated by an independent reading center. The study enrolled 24 males, none of whom were previously treated with foscarnet or ganciclovir. Patients in the immediate-treatment arm received "60 mg per kg of foscarnet three times a day for three weeks followed by 90 mg per kg maintenance dose," Palestine said. The delayed-treatment group received the same regimen. "We see a dramatically significant difference between the time to progression in the two groups, with a median time to progression of three weeks in the no treatment group versus 7.5 weeks in the treatment group," the investigator stated. Palestine noted that "every patient progresses on this drug and that's true of antiviral therapy for CMV in general . . . the goal, however is to significantly slow down progression of the disease." CMV retinitis occurs in about 15%-20% of AIDS patients, he noted. The second pivotal study was a maintenance dose comparison trial (015/915) involving 64 male patients who had no previous CMV retinitis treatment. The study presenter, Mark Jacobson, University of California at San Francisco assistant professor of medicine, noted that "about a third had previously used zidovudine (Burroughs Wellcome's Retrovir) and a little more than a quarter continued to receive zidovudine during the course of the trial." After induction therapy, the first 30 patients were assigned to a maintenance dose of foscarnet either 60 mg/kg five days a week or the same dose given seven days a week. The next set of 34 patients were randomized to either a maintenance dose of 90 mg/kg or 120 mg/kg daily. After 11 patients dropped out during the induction phase, 53 patients continued on maintenance therapy during the eight-week study. Seven patients withdrew during the latter phase due to adverse events. "You can see there is a significant difference in the time to retinitis progression between the 120 and 90 mg/kg dosing arms with median times to progression of 186 days at the higher dose and 72 days in the lower dose," Jacobson said. One of the controlled trials in Cytovene's NDA showed a median time to progression of 10 weeks. The median time to progression ranged from seven to 20 weeks among patients treated with Cytovene on a compassionate use basis. The Cytovene NDA, approved in June 1989, took two-and-one half years to clear FDA, because the filing relied mostly on compassionate use data. Committee members had a prolonged discussion over whether Foscavir should be recommended as preferable to Cytovene for treating CMV retinitis, since Cytovene generally cannot be taken concomitantly with Retrovir due to neutropenic side effects. "We certainly have no basis for deciding whether it's first-line," committee member Alvin Novick, MD, Yale University professor of biology, said. "It would be inappropriate to make a commitment in [the] label on that subject pending some kind of comparative studies of efficacy and toxicity." Astra is sponsoring a comparative study of Foscavir and Cytovene in 240 CMV retinitis patients. Douglas Jabs, MD, Johns Hopkins University, who is chairing the study, informed the committee that "recruitment for the primary portion of that study should be completed this summer." He added that it will be "at least a year" before the study results are released. In the study, patients will be randomized to one of the two drugs, induced with 60 mg/kg IV every eight hours for two weeks, and then given a 90 mg/kg daily maintenance dose. After the first relapse, patients are to be re-induced and put on a 120 mg/kg daily maintenance dose. The study will also look at survival. FDA Division of Antiviral Drugs Supervisory Medical Officer Sandra Kweder, MD, told the advisory committee: "I think we can say with the limited amount of data there is, foscarnet is associated with anemia and some myleosuppression, although these have rarely been severe enough to require discontinuation of the drug." She added: "We can also say that in some patients foscarnet may be able to be safely administered to patients concomitantly with zidovudine, but I think that may is not the same as can." Kweder noted that FDA is "very interested particularly in learning more about the safety and tolerance profile of foscarnet in combination with zidovudine." She pointed out that the toxicities seen in the studies that concerned FDA the most were: "nephrotoxicity, electrolyte and mineral abnormalities, seizures and hematologic effects." Committee members expressed concern about the incidences of adverse reactions occuring in the trials, especially seizures and renal abnormalities or failures. Several committee members recommended that post-marketing studies be conducted, including studies in patients with renal insufficiency and studies to determine the optimal maintenance regimen for Foscavir. Committee member David Feigal, MD, University of California, San Diego Medical Center, said: "I think high on my list of things to be added would be a rapid reporting mechanism for possible drug-related deaths." Committee guest Judith Feinberg, MD, Johns Hopkins University, said: "We need some data in women and minorities. And I think it's clear we need prospective studies to [look at] the toxicities and toxicity mechanism." She also suggested studies on the interaction of foscarnet with Bristol- Myers Squibb's Videx (ddI) and Roche's Hivid (ddC). Astra VP of Medical Affairs Nigel Rulewski pointed out that the company plans to conduct several post-marketing studies, including a study of foscarnet in patients with renal insufficiency and a study on "the effects of prehydration and simultaneous hydration on renal function."
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