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2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 Abatacept

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2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 Abatacept 2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 abatacept Table of Contents 1 背景及び概観................................................................................................................................. 4 1.1 アバタセプト製剤開発の概要..................................................................................................... 4 1.2 生体試料分析法............................................................................................................................. 4 1.2.1 ヒト血清中アバタセプトの定量................................................................................................. 5 1.2.2 ヒト血清中の抗薬物抗体の検出................................................................................................. 6 1.2.3 ヒト血清中アバタセプト中和抗体の検出................................................................................. 6 2 個々の試験結果の要約................................................................................................................. 7 3 全試験を通しての結果の比較と解析......................................................................................... 7 1 2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 abatacept List of in-text Tables Table 1.2-1: 生体試料測定法.......................................................................................................... 5 Table 1.2.1-1: 生体試料中薬物濃度分析法の分析性能.................................................................. 6 2 2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 abatacept 用語及び略号一覧 略号 英語 日本語 ADA Anti-drug antibody 抗薬物抗体 BMS Bristol-Myers Squibb ブリストル・マイヤーズ スクイブ社 DMARDs Disease-modifying antirheumatic drugs 疾患修飾性抗リウマチ薬 ECL Electrochemiluminescence 電気化学発光 ELISA Enzyme-linked immunosorbent assay 酵素免疫吸着測定法 JIA Juvenile idiopathic arthritis 若年性特発性関節炎 MSD MesoScale discovery メソスケールディスカバリー MTX Methotrexate メトトレキサート NAb Neutralizing Antibody 中和抗体 PK Pharmacokinetics 薬物動態 RA Rheumatoid Arthritis 関節リウマチ 3 2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 abatacept 1 背景及び概観 本邦において、アバタセプトは点滴静注用製剤（以下、本剤）及び皮下注製剤として、関節リウマ チ（以下、RA）［既存治療で効果不十分な場合に限る］の治療薬として承認されており、単独療法 又は疾患修飾性抗リウマチ薬（DMARDs）との併用療法として使用可能である。また、本剤は米国、 EU をはじめ、各国で若年性特発性関節炎（以下、JIA）の治療薬として承認されている。米国では、 中等度から重度の多関節型 JIA 患者における症状及び徴候の緩和を適応として承認されており、単 独療法又はメトトレキサート（以下、MTX）との併用療法が可能である。 本概要は、JIA を適応とした本剤の国内製造販売承認申請を目的として、少なくとも 1 剤の生物学 的製剤又は MTX に対して効果不十分又は不耐容の多関節に活動性を有する日本人 JIA 患者を対象と した国内第 3 相試験［IM101-365 試験、（以下、365 試験）］【モジュール 5.3.5.2-1】及び日本人以 外の患者を対象とした海外第 3 相試験［IM101-033 試験（以下、033 試験）］【モジュール 5.3.5.1-1】の 2 試験の結果に基づいて作成した。 1.1 アバタセプト製剤開発の概要 365 試験で使用した製剤は、本邦において RA の治療薬として承認されている点滴静注用市販製剤と 同一である。本剤の開発の概要は初回申請時に提出済みである【「オレンシア点滴静注用 250mg」 承認申請 CTD（以下、点滴静注用 CTD）モジュール 2.7.1、1 章】。本申請の評価資料である 033 試 験及び 365 試験では、それぞれ生物学的同等性が確認されているアバタセプトのプロセス E 及び F の点滴静注用製剤【点滴静注用 CTD モジュール 2.7.1、2.2 項】を体重に基づく用量で投与した。本 邦では、無菌で発熱性物質を含まない単回使用の 250 mg/バイアル凍結乾燥製剤（プロセス F）及び 調製用の専用シリンジが別途供給されている。 1.2 生体試料分析法 JIA を対象としたアバタセプトの開発プログラムにおいて、ヒト血清中のアバタセプト濃度の定量 並びに抗薬物抗体（以下、ADA）及び中和抗体（以下、NAb）活性の検出にはバリデーションされ た生体試料分析法を用いた。バリデーションで得られた分析データは、これらの分析法が十分な真 度及び精度を有するとともに、選択性及び特異性に優れた分析法であることを示した。また、実試 料とともに分析した QC 試料の分析結果から、分析性能に問題はないと考えられた。 033 試験及び 365 試験で用いた生体試料分析法（PK、ADA 及び NAb 分析を含む）を Table 1.2-1 に 示す。 4 2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 abatacept Table 1.2-1: 生体試料測定法 Clinical PK Assay ADA Assay NAb Assay Study IM101-033 ELISA (BMS), ELISA, Cell-based Bioassay, Manual Method Method Method ELISA ( ), Method IM101-365 ELISA, ECL, Cell-based Bioassay, Method Method Method Source: ELISA (BMS) Manual Method【皮下注 CTD モジュール 5.3.1.4.1.1、5.3.1.4.1.2、5.3.1.4.1.3、 5.3.1.4.1.4、5.3.1.4.1.5】、ELISA () 【皮下注 CTD モジュール 5.3.1.4.3.1、 5.3.1.4.3.2、5.3.1.4.3.3】、Method 【モジュール 5.3.1.4-1、5.3.1.4-2】【点滴静注用 CTD モジュール 2.7.2、4.1.1.1 項】、Method 【モジュール 5.3.1.4-3、5.3.1.4-4】【点 滴静注用 CTD モジュール 2.7.2、4.1.1.1 項】、Method 【点滴静注用 CTD モジュール 2.7.2、 4.1.1.2 項】、Method 【モジュール 5.3.1.4-5】【皮下注 CTD モジュール 5.3.1.4.5、5.3.1.4.1.1、 5.3.1.4.1.2、5.3.1.4.1.3、5.3.1.4.1.4、5.3.1.4.1.5】、Method 【モジュール 5.3.1.4-6、5.3.1.4-7】【皮下注 CTD モジュール 5.3.1.4.6】 Note: The ELISA assay methods used at BMS and ( ) were considered to yield results that were comparable【点滴静注用 CTD モジュール 2.7.1、1.1.2.3 項】. Abbreviations: ADA = anti-drug antibody; BA = bioanalytical; BMS = Bristol-Myers Squibb; ECL = electrochemiluminescence; ELISA = enzyme-linked immunosorbent assay; MSD = MesoScale Discovery; NAb = neutralizing antibodies; PK = pharmacokinetic(s); = 1.2.1 ヒト血清中アバタセプトの定量 本剤の開発当初に、ヒト血清試料中のアバタセプト濃度を測定するために、ブリストル・マイヤー ズ スクイブ社（以下、BMS）においてマニュアル及びオートメーションの 2 つの酵素免疫吸着測定 法（以下、ELISA）による定量法を開発した【点滴静注用 CTD モジュール 2.7.1、1.1.1 項】。 本剤の第 3 相臨床試験に向けて、BMS で開発した ELISA 法のクロスバリデーションを 社（San Diego、CA、以下、 社）にて実施した（点滴静注用 CTD モジュー ル 2.7.1、1.1.2 項）。 社の ELISA 法（ 法）の分析性能は BMS の ELISA 法と同等であ り、033 試験におけるヒト血清試料中のアバタセプト濃度の定量に本法を用いた【点滴静注用 CTD モジュール 2.7.1、1.1.2.3 項】。 さらに、BMS の ELISA 法のクロスバリデーションを 社（旧 社、Trenton、 NJ）にて実施し【「オレンシア皮下注 125mg シリンジ 1mL」承認申請 CTD（以下、皮下注 CTD） モジュール 2.7.1、1.2.1 項】、 社の ELISA 法（ 法）を 365 試験におけるヒト血 清試料中のアバタセプト濃度の定量に用いた。 皮下注製剤の申請以降、本申請までに更新された分析性能に関わる情報は、ヒト血清中のアバタセ プトの長期安定性が−20°C で 6.5 ヵ月間まで確認できたことである【モジュール 5.3.1.4-5】。血清中 5 2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 abatacept アバタセプト濃度はすべて、対象物質の安定性が確認されている上記期間中に測定した。バリデー トされた分析法の分析性能を Table 1.2.1-1 に示す。 Table 1.2.1-1: 生体試料中薬物濃度分析法の分析性能 Number of Accuracy (%Bias)a Precision (%CV)b Clinical Study Assay Method Runs for Assay QCs for Assay QCs IM101-033 ELISA (BMS), Manual 2 -2.1 to 5.7 0.0 to 2.9 ELISA ( ), 157 1.9 to 4.7 3.9 to 8.0 IM101-365 ELISA, 21 -8.7 to 1.8 1.2 to 10.3 Source: ELISA BMS【モジュール 5.3.5.1-1、IM101033H】、ELISA 【モジュール 5.3.5.1-1、IM101033I、 IM101033J 】、 【モジュール 5.3.5.2-1、 13-095】 a Accuracy acceptance criteria: ± 15% and ± 20% of nominal for Study IM101-033 and Study IM101-365, respectively b Precision acceptance criteria: ± 20% Abbreviations: = ; BMS = Bristol-Myers Squibb; CV = coefficient of variation; ELISA = enzyme-linked immunosorbent assay; QC = quality control; = 1.2.2 ヒト血清中の抗薬物抗体の検出 2 つの ELISA 法（ 法及び 法）のバリデーションを 社（以下、 社）（旧 社、Whitesboro、NY）にて実施 し、033 試験におけるヒト血清試料中の ADA（抗アバタセプト抗体*及び抗 CTLA4-T 抗体）の検出 に用いた【点滴静注用 CTD モジュール 2.7.2、4.1.1 項】。 その後、メソスケールディスカバリー（MSD）システムを使用した、より感度の高い電気化学発光 （以下、ECL）免疫測定法のバリデーションを 社にて実施し、365 試験【モジュール 5.3.5.2-1】におけるヒト血清試料中の ADA［抗 CTLA4 抗体†（Ig 領域に対しても抗体反応を示して いる可能性がある）並びに抗 Ig 及び／又は結合領域抗体］の検出に用いた（皮下注 CTD モジュー ル 2.7.2、4.1.1 項）。ECL 法による ADA 測定は、ADA 濃度 2000 ng/mL の測定にアバタセプト 100 μg/mL までの影響を受けないことが示されている。また、低濃度 ADA（250 ng/mL）は、アバタ セプト濃度 40 μg/mL まで影響を受けないことが示された【皮下注 CTD モジュール 5.3.1.4.6、モジ ュール 5.3.1.4-6、5.3.1.4-7】。 1.2.3 ヒト血清中アバタセプト中和抗体の検出 アバタセプトの CTLA-4 領域に特異的な抗体（033 試験では抗 CTLA4-T 抗体、365 試験では抗 CTLA4 抗体）に対して陽性を示し、かつ血清中アバタセプト濃度が 1 μg/mL 以下であったヒト血清 試料について、バリデートされた in vitro 細胞培養アッセイ法（ 法）を用いて NAb の有 無を分析することとした【点滴静注用 CTD モジュール 2.7.2、4.1.1.2 項】。 * 点滴静注用 CTD では「抗アバタセプト分子抗体」と記載。 † 皮下注 CTD では「抗 CTLA-4 及び Ig 様抗体」と記載。 6 2.7.1 生物薬剤学試験及び関連する分析法 JIA BMS-188667 abatacept 2 個々の試験結果の要約 初回申請時と同じ製剤を使用しているため、新たな生物薬剤学試験は実施していない。 3 全試験を通しての結果の比較と解析 JIA 患者を対象としたアバタセプトの開発プログラムにおいて、血清中アバタセプトの定量並びに ADA 及び NAb の検出に用いた分析法は、十分な真度及び精度を示し、優れた選択性及び特異性を 有していた。 7 2.7.2 臨床薬理試験 JIA BMS-188667 abatacept Table of Contents 1 背景及び概観 ................................................................................................................................. 5 1.1 薬物動態評価を含む試験の概要 ................................................................................................. 5 1.2 薬物動態解析の概要 ..................................................................................................................... 7 1.3 免疫原性解析の概要 ..................................................................................................................... 7 1.4 用量選択及びその根拠の概要 ..................................................................................................... 7 2 個々の試験結果の要約 ................................................................................................................. 7 2.1 海外第 3 相試験（IM101-033 試験） .......................................................................................... 7 2.2 国内第 3 相試験（IM101-365 試験） .......................................................................................... 8 3 全試験を通しての結果の比較と解析 ......................................................................................... 9 3.1 薬物動態パラメータの試験間比較 ............................................................................................. 9 3.2 JIA 患者を対象とした母集団薬物動態解析の要約 ................................................................ 10 3.2.1 体重の影響................................................................................................................................... 13 3.2.2 年齢の影響................................................................................................................................... 13 3.2.3 疾患及び人種の影響 ................................................................................................................... 15 3.3 推奨用量の設定根拠 ................................................................................................................... 18 3.3.1 非臨床試験の結果 ....................................................................................................................... 18 3.3.2 IM101-365 試験の用量設定の根拠 ............................................................................................ 18 3.3.3 日本人 JIA 患者における推奨臨床用量の妥当性 ................................................................... 19 3.3.4 日本人 JIA 患者における推奨用量設定根拠の要約 ............................................................... 20 4 特別な試験................................................................................................................................... 21 4.1 免疫原性....................................................................................................................................... 21 4.2 免疫原性が薬物動態に及ぼす影響 ..........................................................................................
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