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Executive Summary

Miles' KoGENate recombinant Factor VIII blood clotting agent was unanimously recommended for licensure by FDA's Blood Products Advisory Committee Dec. 12. The committee agreed that Miles had demonstrated KoGenate's safety and efficacy for both the treatment and prophylaxis of hemophilia A in patients who had been treated previously with other blood products and in previously untreated patients. Miles and its subsidiary Cutter Biological presented data on 155 patients from a multi-arm trial begun in May 1988 in 30 medical centers in North America, Europe and Japan. Miles reported that 58 U.S. and European hemophiliacs on self-administered "home treatment" regimens showed a response rate of 92.3% in a total of 5,892 infusions. Thirty-one hemophiliacs receiving KoGENate following major hemorrhages requiring hospitalization or for prophylaxis during surgery showed "satisfactory hemostasis in all cases." Miles submitted the KoGENate PLA in May 1989. With little hesitation the committee accepted use of the Miles product in patients previously treated with blood products. There was greater debate, however, about the use of KoGENate in previously untreated patients (PUPs). Miles presented data on 72 PUPs from a trial which began in January 1989. Data indicate that the development of inhibitors to KoGENate, which bind to the blood clotting factor and may cause it to become partially or totally ineffective, occurred much more often in PUPs. Cutter Biological Director of Clinical Research Richard Schwartz, MD, reported that 12 of 72 PUPs studied by Miles developed inhibitors to KoGENate. He added that 11 of these 12 continue to have their hemophilia successfully controlled by the agent, and that in three of the subjects the inhibitors have subsequently "melted away." The development of inhibitors by PUPs was even more pronounced,however, in severely hemophilic patients (defined as having 2% or less of normal endogenous Factor VIII). Summarizing the data presented by Miles, FDA's William Fricke, MD, chief of the Laboratory of Hemostasis and Thrombosis in the Division of Hematology, called the level of inhibitors produced in PUPs "problematic." He noted that 44 of the 72 PUPs studied by Miles were severely hemophilic, and that all 12 incidences of inhibition occurred in this subgroup, making the overall rate of inhibition in severely affected PUPs about 37%. Fricke suggested the possibility that patients treated with blood products do not develop an immune response to KoGENate as often as PUPs because their immune systems are compromised either from years of exposure to blood clotting agents or because they additionally are HIV positive. Forty percent of the American patients in Miles' home treatment protocol were HIV positive. Miles, FDA, and the committee agreed that a problem in the assessment of the Miles data is the lack of adequate studies on inhibitors developed to plasma-derived Factor VIII with which to compare inhibition of the recombinant product. Cutter's Schwartz pointed out that the only historical studies available did not monitor the level of inhibitors as often as did Miles or by standards as exacting, leading to a lower overall incidence of recorded inhibitory responses. FDA's Fricke concurred but observed that the earlier studies probably only missed occurences of low-titer inhibition. Breaking down Miles' data to show the incidence of high-titer inhibitors in severely hemophilic PUPs, Fricke reported an occurence rate of 18% -- more than twice that shown in plasma-derived agents. He agreed, however, that "it is not clear what accounts for the discrepancy." In the end, Fricke said: "The decision is going to have to be made by us, and by the hemophiliac treater, and by the patient, as to whether they're willing to take the risk to develop that inhibitor." The committee unanimously agreed that Miles had demonstrated the safety and efficacy of KoGENate. FDA then further asked whether studies of previously untreated patients should continue before the product's licensure or could they be continued post- licensure. The committee concurred with the recommendation of committee Chairman Merlin Sayers, MD/PhD, Puget Sound Blood Center, that Miles' studies in PUPs continue "independently of when licensure takes place." The committee further advised that Miles should conduct studies in neonates and early hemophiliacs. The committee also was asked by FDA whether other studies should be done. Committee consultant Raphael Shulman, MD, National Institute of Diabetes, Digestive and Kidney Diseases, suggested "that all products in the treatment of hemophilia should be studied with regard to immunogenicity just as the recombinant product will be studied." He proposed to gather data on plasma- derived Factor VIII that could be compared to that on recombinant Factor VIII. Shulman had expressed concern that earlier studies of Factor VIII inhibition served as a poor basis for comparison to Miles' studies. FDA's Fricke noted that FDA could request industry to participate in such a study but added that the data "will be a long time coming." Members of the committee also expressed interest in seeing the results of an ongoing Miles study looking at GAL, a glycoprotein sometimes found in KoGENate. Miles reported uncertainty as to how the substance appeared in the cloned KoGENate molecule, since it does not occur in humans or in the other higher primates. The company proposed that GAL might come from hamsters, where the cloned genes are implanted during formulation of Factor VIII. The company showed data, however, indicating that the additional glycoprotein molecule on the large KoGENate molecule had no significant clinical effect. Committee member Chantal Harrison, MD, University of Texas, suggested the long-term monitoring of patients being treated with KoGENate in order to study the effects of GAL.

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