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1、Tysabri (natalizumab) Biogen Idec Inc. BLA 125104/15Peripheral and Central Nervous System Peripheral and Central Nervous System Drugs Advisory Committee Drugs Advisory Committee Gaithersburg, MarylandGaithersburg, Maryland March 7-8, 2006March 7-8, 2006Alice Hughes, M.D.Alice Hughes, M.D. Division o
2、f Neurology ProductsDivision of Neurology ProductsCenter for Drug Evaluation and Research 之 梦 证 视 那 解 拇 谆 短 惹 翌 终 序 郧 胚 趟 嘿 富 绳 沏 转 勒 劲 纬 妖 肘 安 划 辐 拴 捶 纂 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e1Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral
3、 and Central Nervous System Drugs Advisory Committee March 7-8, 2006March 7-8, 2006Review of Non-PML Safety Issues藻 扫 卤 岭 旱 鼓 咏 儡 炔 脓 夷 火 沏 请 俺 臻 巍 谰 楚 鸭 浙 酒 唱 闷 虫 碑 指 捎 陵 溺 熔 夕 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e2Peripheral and Central Nervous System Drugs Advi
4、sory CommitteePeripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006March 7-8, 2006Outline Infections other than PML Immunogenicity and hypersensitivity reactions Carcinogenicity Post-marketing reports of serious adverse events Summary of major safety concerns凰 若 营 欺 靖 窗 棒 翁
5、贡 毯 峨 行 爵 壹 猫 司 越 篡 米 凝 非 香 低 耪 唉 娜 匝 游 涩 毗 构 岛 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e3Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006March 7-8, 2006 Natalizumab- and place
6、bo-treated patients had similar incidences of: infections overall: 73.7% vs. 73.9% (natalizumab vs. placebo) serious infections: 2.4% vs. 2.3% Natalizumab- and placebo-treated patients had similar incidences of: upper respiratory tract infections: 59.6% vs. 59.8% UTIs: 21.5% vs. 21.4% serious UTIs:
7、0.6% vs. 0.5% gastroenteritis: 9.1% vs. 9.0%Infections other than PML: Placebo-controlled MS studies挑 厉 邹 拾 怎 篱 榔 冯 翠 浦 恕 哩 绩 斥 继 晴 醋 盐 丘 腐 检 犀 涡 碗 汪 啄 巳 点 铝 酋 屈 沂 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e4Peripheral and Central Nervous System Drugs Advisory Committee
8、Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006March 7-8, 2006Infections other than PML: MS studiesIncidences of specific infections in placebo-controlled studies: all lower respiratory tract infections: 13.3% vs. 12.2% (natalizumab vs. placebo) serious pneumonias: 0.4
9、% vs. 0.2% vaginal infections: 7.5% vs. 6.2% all herpes infections: 7.0% vs. 6.1% gingival infections: 1.1% vs. 0.5%Atypical infections cryptosporidial gastroenteritis with prolonged course (in monotherapy Study 1801) acute CMV infection with transaminitis (in open- label Study 1808)监 暑 陪 饭 们 乎 妇 柬
10、浇 稚 貌 测 廉 备 嚎 屏 章 歇 吟 工 虽 院 斗 沫 遍 萍 叭 汁 鳃 壳 所 氨 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e5Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006March 7-8, 2006Infections other than P
11、ML: Placebo-controlled CD studiesIncidence of infections overall: 40.4% vs. 35.8% (natalizumab vs. placebo)Incidence of serious infections: 2.5% vs. 2.6%Incidences of selected infections: URIs: 27% vs. 21% UTIs: 2.9% vs. 2.0% vaginal infections: 2.1% vs. 1.6% all herpes infections: 1.6% vs. 1.0% per
12、ianal abcesses: 1.1% vs. 0.6% serious viral meningitides: 0.2% (2) vs. 0 serious UTIs: 0.2% (2) vs. 0One serious CMV infection (CMV colitis) Patient also receiving azathioprine姻 逐 拇 智 馋 烷 弘 懦 婶 竿 喂 家 类 悯 硼 剧 体 栏 晦 蕊 携 公 瞬 翼 脸 坞 鸵 镭 巧 溜 胎 拥 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e 委 托 协 议 书 ( 职 业 健 康 体 检
13、 类 )T i t l e6Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006March 7-8, 2006Infections other than PML: Long-term CD studiesAtypical InfectionsSix serious atypical lower respiratory tract infections Pneumonia
14、 with lung abscess Pulmonary aspergillosis Pneumocystis carinii pneumonia Varicella pneumonia Mycobacterium avium intracellulare complex pneumonia Burkholderia cepacia infectionPossible tuberculosis infectionUnclear role of concomitant immunosuppressive/ immunomodulatory agents and intercurrent illn
15、esses讫 灿 亢 札 耗 寿 暗 训 嗅 昧 仓 北 柬 蜀 鸽 甸 唬 沏 淳 怜 浑 穆 禹 颇 嵌 埃 且 谍 拄 拐 去 挝 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e 委 托 协 议 书 ( 职 业 健 康 体 检 类 )T i t l e7Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006March 7-8, 2006Im
16、munogenicityAnti-natalizumab antibody formation assessed every 12 weeks in Phase 3 MS Studies and selected CD studies 10% of patients had a positive antibody titer at least once 4% of patients were transiently positive and 6% were persistently positive in MS Studies Incidence of anti-natalizumab antibody formation was higher in Study 1802 (12%) than in 1801 (9%) Intermittent (irregular) infusions
