JP2013516455A - Vb−201を用いた治療 - Google Patents
Vb−201を用いた治療 Download PDFInfo
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Abstract
Description
本発明は、その一部の態様において、酸化型リン脂質VB-201の新規の剤形および治療レジメンに関する。酸化型リン脂質VB-201の新規の剤形および治療レジメンは、炎症関連疾患および炎症関連障害、例えば、アテローム性動脈硬化症および関連障害、炎症性腸疾患、ならびに自己免疫疾患または自己免疫障害、例えば、乾癬および関節炎を治療または予防するために効果的に使用することができる。
血漿中濃度の測定:
血漿中VB-201濃度は、HPLC-MS/MS(高速液体クロマトグラフィーとタンデム質量分析検出)アッセイを用いて求めた。較正は、低用量では5〜500ng/ml、高用量では50〜5000ng/mlに対して行った。
薬物動態学的パラメータは、AUC(曲線下面積)以外はノンコンパートメント法を用いることによって見積もった。AUC(曲線下面積)は、(log-)台形公式を用いて、以前のトラフレベルを上回る面積として求めた。
血漿試料中のC反応性タンパク質(CRP)濃度は、CRP Latexアッセイキット(Olympus)およびAU400(登録商標)immuno-analyzer(Olympus)を用いて測定した。
インターロイキン-23(IL-23)およびインターフェロン-γ(IFN-γ)の血漿中濃度は、前記サイトカインに対するFlowCytomix human simplex kit(Bender Medsystems)を用いて製造業者の説明書に従って求めた。試料の取得は、FacsCalibur(Becton Dickinson)を用いて行った。結果は、FlowCytomix Pro 2.2ソフトウェアを用いて解析した。
ヒト単球(CD14+細胞)を健康ドナーの全血から単離した。Ficoll-Paqueおよびleucosepチューブを用いて全血からPBMC(末梢血単核球)を分離した後に、特異的CD14マイクロビーズ(Miltenyi Biotech)を用いて、CD14+細胞を分離した。特異的モノクローナルCD14抗体を用いたFACS分析によって、CD14+集団の純度を検証した。化学誘引物質については、RANTES(100ng/ml)、MIP-1α(マクロファージ炎症性タンパク質-1α;50ng/ml)、MCP-1(単球走化性タンパク質-1;50ng/ml)、またはMCP-3(50ng/ml)を2%胎仔ウシ血清/RPMI-1640に溶解し、QCM(商標)24ウェル遊走アッセイプレート(Corning-Costar)の下部チャンバーに入れた。CD14+細胞を、溶媒(1%エタノール/PBS)または8μMのVB-201(もしくは1.7〜17μMの様々な濃度のVB-201、示さず)と30分間プレインキュベートした。300,000個の処理細胞を上部チャンバーに播種し、その後に、3〜4時間インキュベートすることによって、遊走アッセイを行った。この後に、FACS(蛍光標識細胞分取)によって遊走細胞数を求めた。
VB-201の安全性および耐容性は、以下の測定値における異常知見の発生率を評価することによって判断した:
生命徴候:収縮期血圧および拡張期血圧、脈拍数、呼吸数、体温;
理学的検査;
12誘導心電図;
以下についての血液試料臨床検査:全血球数、プロトロンビン時間/部分トロンボプラスチン時間、LDL-コレステロールおよびHDL-コレステロール、総コレステロール、トリグリセリド、グルコース、血中尿素窒素、ナトリウム、カリウム、クレアチニン、カルシウム、リン、クレアチニンホスホキナーゼ、乳酸デヒドロゲナーゼ、アスパラギン酸トランスアミナーゼ、アラニントランスアミナーゼ、γ-グルタミルトランスフェラーゼ、アルカリホスファターゼ、タンパク質、アルブミン、総ビリルビン、総IgM抗体および総IgG抗体、インターロイキン-12/23 p40、腫瘍壊死因子-α、およびインターロイキン-6、ならびに日常的な尿検査;ならびに
全ての有害事象が、Good Clinical Practiceの基準に従って、重篤とみなされるかどうか、治験薬との関連性があるかどうか。
単回投与のVB-201の安全性、耐容性、および薬物動態
試験デザイン:
経口摂取された単回投与のVB-201の安全性、耐容性、および薬物動態を調べるために、無作為化二重盲式プラセボ対照試験を行った。
VB-101血漿中濃度の平均を図1に経時的に示した。
AUC(0-168)=0時間から168時間までの濃度時間曲線下面積
AUC(0-最後 非BLQ)=0時間から定量限界以上であった最後の測定値までの濃度時間曲線下面積
AUC(0-無限大)=0時間から無限大までの濃度時間曲線下面積
Cmax=最大血漿中濃度
Cavg(0-168)=0時間から168時間までの平均濃度
T1/2=排出半減期
Tmax=最大血漿中濃度に到達するまでの時間
AUMC=濃度時間曲線のモーメント曲線下面積
MTT=平均通過時間
Ke=排出速度定数
Cl/F=クリアランス
Vz/F=経口投与後の終末相のみかけの分布容積
安全性および耐容性を前記のように決定した。
反復投与のVB-201の安全性、耐容性、および薬物動態
試験デザイン:
経口摂取された毎日反復投与のVB-201の安全性、耐容性、および薬物動態を調べるために、無作為化二重盲式プラセボ対照試験を行った。対象は全員、健康なボランティアであった。6人の対象からなるコホートにそれぞれ、14日間にわたって、少なくとも10時間絶食させ後に、午前中に、一日量5mg、10mg、20mg、および30mgのVB-201を与えた。10人の対象にはプラセボを与えた。VB-201を、Opadry AMBおよびAcryleze Whiteによって腸溶コーティングされたゼラチンカプセルに入れて製剤化した。
1日目および14日目のそれぞれについて24時間にわたる濃度時間曲線を作成した。1日目および14日目の間のVB-101血漿中濃度の平均を図2に示した。
AUC(0-24)=0時間から投与後24時間までの濃度時間曲線下面積
AUC(0-無限大)=0時間から無限大までの濃度時間曲線下面積
Cmax=最大血漿中濃度
Tmax=最大血漿中濃度に到達するまでの時間
T1/2=排出半減期
T1/2(回復相)=回復相の排出半減期
AUMC(0-24)=0時間から投与後24時間までの濃度時間曲線のモーメント曲線下面積
AUMC(0-無限大)=0時間から無限大までの濃度時間曲線のモーメント曲線下面積
MTT=平均通過時間
Ke=排出速度定数
Cl/F(0-24)=0時間から投与後24時間までのクリアランス
Vd/F=分布容積
Accum.=蓄積
NA=該当なし
安全性および耐容性を前記のように決定した。
単回投与のVB-201の安全性、耐容性、および薬物動態に対する食事およびカプセルコーティングの効果
試験デザイン:
健康対象における二重盲式プラセボ対照試験において、腸溶性VB-201カプセルおよび非コーティングVB-201カプセルの薬物動態に対する食事の効果を調べた。6人の対象からなるコホートにそれぞれ、午前中に、単回投与の10mg、2x10mg、または20mgのVB-201を与えた。それぞれの投与量レベルについて、1つのコホートに腸溶性カプセルを与え、1つのコホートに非コーティングカプセルを与えた。12人の対象にプラセボを与えた。
144時間までの期間について濃度時間曲線を作成した。薬物動態学的パラメータを、最初の24時間および全144時間のデータに基づいて計算した。144時間をカバーするデータから計算したパラメータを用いると、さらに正確な代謝パラメータ推定値が得られる。それでもなお、パラメータと以前の研究を比較するために、最初の24時間をカバーするデータからもパラメータを計算した。
AUC(0-24)=0時間から投与後24時間までの濃度時間曲線下面積
AUC(0-144)=0時間から投与後144時間までの濃度時間曲線下面積
AUC(0-無限大,24から)=0時間から無限大までの濃度時間曲線下面積、0時間から24時間までのデータに基づいて計算した
AUC(0-無限大,144から)=0時間から無限大までの濃度時間曲線下面積、0時間から144時間までのデータに基づいて計算した
Cmax=最大血漿中濃度
Tmax=最大血漿中濃度に到達するまでの時間
T1/2(24から)=0時間から24時間時間までのデータに基づいて計算した排出半減期
T1/2(144から)=0時間から144時間までのデータに基づいて計算した排出半減期
AUMC(0-24)=0時間から投与後24時間までの濃度時間曲線のモーメント曲線下面積
AUMC(0-無限大)=0時間から無限大までの濃度時間曲線のモーメント曲線下面積(0時間から144時間までのデータに基づいて計算した)
MTT(0-24)=0時間から24時間にわたって計算した平均通過時間
MTT(144から)=0時間から144時間までのデータに基づいて計算した平均通過時間
Ke(24から)=0時間から24時間のデータに基づいて計算した排出速度定数
Ke(144から)=0時間から144時間までのデータに基づいて計算した排出速度定数
Cl/F(0-24)=0時間から投与後24時間にわたって計算したクリアランス
Cl/F(144から)=0時間から144時間までのデータに基づいて計算したクリアランス
Vd/F(0-24)=0時間から投与後24時間にわたる分布容積
Vd/F(144から)=0時間から144時間までのデータに基づいて計算した分布容積
Vd/F(144から)=0時間から144時間までのデータに基づいて計算した分布容積
安全性および耐容性を前記のように決定した。
反復高用量投与VB-201の安全性、耐容性、薬物動態、およびC反応性タンパク質濃度に対する効果
試験デザイン:
経口摂取された反復一日量VB-201の安全性、耐容性、および薬物動態を調べるために、無作為化二重盲式プラセボ対照試験を行った。対象は全員、健康なボランティアであった。6人の対象からなるコホートにそれぞれ、14日間にわたって、少なくとも10時間の絶食後、午前中に、一日量40mgまたは80mgのVB-201を与えた。6人の対象にプラセボを与えた。VB-201を非腸溶性カプセルに入れて製剤化した。
40mgコホートの1日目および14日目ならびに80mgコホートの14日目について、投与後24時間の間のVB-201血漿中濃度の平均を求めた。これらの期間のそれぞれに相当するデータについて薬物動態学的パラメータを求めた。血漿中濃度の平均を図4に示した。
AUC(0-24)=0時間から投与後24時間までの濃度時間曲線下面積
AUC(0-無限大)=0時間から無限大までの濃度時間曲線下面積
Cmax=最大血漿中濃度
Tmax=最大血漿中濃度に到達するまでの時間
Τ1/2=排出半減期
MTT(0-24)=0時間から24時間にわたって計算した平均通過時間
MTT(0-無限大)=0時間から無限大にわたって計算した平均通過時間
Ke=排出速度定数
Cl/F(0-24)=0時間から投与後24時間にわたって計算したクリアランス
Cl/F(0-無限大)=0時間から無限大にわたって計算したクリアランス
Vd/F(0-24)=0時間から投与後24時間にわたって計算した分布容積
Vd/F(0-無限大)=0時間から無限大にわたって計算した分布容積
NA=該当なし
C反応性タンパク質(CRP)は公知の炎症プロセスマーカーである。
安全性および耐容性を前記のように決定した。
サイトカイン濃度に対する80mg/日VB-201の効果
インターロイキン-23(IL-23)は感染に抵抗する炎症応答の重要な部分であり、非常に多くの炎症性分子の産生を促進する。IL-23は多発性硬化症および炎症性腸疾患の症状の発症において重要な役割を果たし、このことは炎症性疾患経路におけるIL-23の重要性を強調している。
活動性慢性関節リウマチ(RA)患者におけるVB-201とメトトレキセート(MTX)の効力
VB-201は、アジュバント誘発関節炎およびコラーゲン誘発関節炎のインビボ動物モデルにおいて有効であることが以前に示された。VB-201はまた、慢性関節リウマチ(RA)の進行を遅延し得る免疫調節作用を有することも示されている。従って、ヒトでのRA治療におけるVB-201の効力を調べる。
尋常性乾癬を有する患者におけるVB-201の効力
中程度から重度の尋常性乾癬を有する対象において、この状態の治療におけるVB-201の効力を決定するために無作為化二重盲式第II相試験が行われる。
ベースライン18FDGスキャンが異常な患者における頚動脈および上行大動脈18FDG取り込みに対するVB-201の効果
頚動脈炎症および上行大動脈炎症に対する、20mg/日および80mg/日のVB-201を用いた治療の効果が調べられる。炎症は、18FDG(18F-フルデオキシグルコース)取り込みを標的対バックグラウンド比(TBR)を定量するポジトロン放出コンピュータ断層撮影法(PET-CT)によって測定される。
単球遊走に対するVB-201の効果
細胞遊走は、発生および成人期の多くの段階の必須のプロセスである。細胞は個々の細胞として遊走することができる、または組織の状況において移動することができる。移動は内部シグナルおよび外部シグナルによって制御される。内部シグナルおよび外部シグナルは、極めて動的かつ局所的な細胞骨格リモデリング、細胞間相互作用、および細胞-基質相互作用をもたらす複雑なシグナル伝達カスケードを活性化する。化学誘引物質は、構造上関連するヘテロ三量体グアニンヌクレオチド結合タンパク質(Gタンパク質)共役受容体の特異なファミリーを活性化することによって細胞遊走を誘導する。ケモカインすなわち走化性サイトカインは、DCを含む白血球の遊走および活性化だけでなく、ストローマ細胞の遊走および活性化も調節する8〜10kDa分泌タンパク質である。化学誘引は細胞外空間におけるケモカインの局所勾配に応じて起こる。
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US7807847B2 (en) | 2004-07-09 | 2010-10-05 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
US9006217B2 (en) | 2007-01-09 | 2015-04-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
US8569529B2 (en) | 2007-01-09 | 2013-10-29 | Vascular Biogenics Ltd. | High-purity phospholipids |
WO2010041242A2 (en) * | 2008-10-08 | 2010-04-15 | Vascular Biogenics Ltd. | Oxidized thiophospholipid compounds and uses thereof |
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WO2013033642A1 (en) | 2011-09-01 | 2013-03-07 | Vascular Biogenics Ltd. | Formulations and dosage forms of oxidized phospholipids |
US20150320773A1 (en) * | 2011-12-12 | 2015-11-12 | Vascular Biogenics Ltd. | Treatment of inflammation |
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US9763992B2 (en) | 2014-02-13 | 2017-09-19 | Father Flanagan's Boys' Home | Treatment of noise induced hearing loss |
US9771385B2 (en) | 2014-11-26 | 2017-09-26 | Vascular Biogenics Ltd. | Oxidized lipids |
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