JP2013521305A - ラキニモドを用いるループス関節炎の治療 - Google Patents
ラキニモドを用いるループス関節炎の治療 Download PDFInfo
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- JP2013521305A JP2013521305A JP2012556214A JP2012556214A JP2013521305A JP 2013521305 A JP2013521305 A JP 2013521305A JP 2012556214 A JP2012556214 A JP 2012556214A JP 2012556214 A JP2012556214 A JP 2012556214A JP 2013521305 A JP2013521305 A JP 2013521305A
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- laquinimod
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Classifications
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Description
ここで用いられるように、他に明記しない限り、以下の用語の各々は、下に示す定義を有するものとする。
0.存在しない。
グレード「A」=高用量ステロイド(>20mg/日の経口プレドニソロンもしくは同等物またはIVパルス投与>500mg MP)、全身性免疫調節薬または高用量抗凝血による治療を必要とする重症疾患活動性
グレード「B」=低用量経口ステロイド(<20mg/日のプレドニソロンまたは同等物)、IMもしくはIAステロイド(MP<500mgと同等)、局所ステロイドもしくは免疫調節薬、抗マラリア薬または対症療法(例えばNSAID)による治療を必要とする中等度の疾患活動性。
り組み込まれる。
実施例1:動物モデルでのSLEについてのラキニモドの効果の評価
全身性エリテマトーデス(SLE)は、欠陥T細胞媒介応答および自己抗原または変化した自己抗原に反応性である様々な抗体の形成を特徴とする、全身性自己免疫の障害である。SLEは、抗DNA抗体の存在を主な特徴とする。これらの自己抗体のいくつかは対応する自己抗原と合わさり、循環血液中に、または組織中に直接的に免疫複合体を形成し、重度傷害をもたらす。免疫複合体によって誘発される糸球体腎炎は、実際、SLE患者で主要な死因である。(NZBxNZW)F1は、抗dsDNA抗体(Ab)、タンパク尿症および免疫複合体沈着物(ICD)を含むSLE様疾患を自然発生的に発症する、ループスを起こしやすいマウスである。(NZBxNZW)F1(NZB/W)マウスモデルは、自然発生SLEの証明モデルである。
この試験はSLEのマウスモデルでSLEの免疫調節薬ラキニモドの効果を調査し、その治療効果を参照物質CTXおよびMTXと比較した。CTXは、最も重症型のループスの疾患管理のための標準的なケアになっているアルキル化剤である。MTXは、癌および自己免疫性疾患の治療で用いられる代謝拮抗薬である。それはジヒドロ葉酸レダクターゼの阻害を通して葉酸の代謝を阻害することによって作用し、急増殖細胞でDNA合成を妨害する。これらの作用には、免疫抑制が含まれる。CTXとMTXの両方は、先行研究で効力を示している。
これは、(NZBxNZW)F1マウスで症状を抑制することにおいてラキニモドが有効かどうか決定する生存用量応答試験であった。用いた陽性対照はCytoxanであった。
この試験は、ラキニモド(0.2および5mg/kg)対CTXおよび媒体治療(NZBxNZZW)F1マウスの効果を検討した。
この試験は、MRL/lprループスマウスモデルでのラキニモドの効力を評価する。
活動性ループス関節炎を有する全身性エリテマトーデス(SLE)患者でラキニモド(0.5mg/日および1mg/日)の安全性と、許容度と、バイオマーカーと、臨床効果とを評価するために、多施設ランダム化二重盲検プラセボ比較臨床試験を行う。
約90人の活動性ループス関節炎を有する全身性エリテマトーデス患者が組み入れられる。(治療群につき約30人の対象者)。脱落例は、交換されない。
全体の試験期間は最高20週であり、スクリーニング期間は2週まで、治療期間は12週であり、経過観察期間は4週である。
ラキニモド/マッチングプラセボ
ラキニモド0.5mgおよび/またはマッチングプラセボを含有するカプセルを、1日1回経口投与する:
1.ラキニモド0.5mg群−ラキニモド0.5mgのカプセル1つおよびマッチングプラセボカプセル1つ。
組入基準
全ての対象は、適格となるために、下記の全ての組入基準を満たさなければならない:
1.スクリーニング検診のときまでにSLEのThe American College of Rheumatologyの少なくとも4つの分類基準(1997年版)を満たした、SLEと診断された対象。全ての対象は、異常な抗核抗体力価を有するべきである。[ケースバイケースで、スクリーニングとベースラインとの間で抗核抗体または抗dsDNAを再評価することができる]。
a.スクリーニングおよびベースライン診察時に少なくとも4つの圧痛および4つの腫脹のある関節[評価した28個の関節中]。
以下のいずれも試験への組入れから対象を除外する:
1.スクリーニング診察時にMDRD式によって計算される30ml/分/1.73m2以下のGFR。
a.試験プロトコルによって許される標準治療によってうまく制御することができない心臓血管または肺の障害。
14.MTXで治療された対象であって、この治療はスクリーニングの前の12週以内に開始された。
これは、活動性ループス関節炎を有する全身性エリテマトーデス患者でラキニモドの2つの用量の安全性と、許容度と、薬物動態と、バイオマーカーと、臨床効果とを評価するための、ランダム化二重盲検プラセボ比較第IIa相試験である。この試験は、活動性ループス関節炎を有する全身性エリテマトーデス患者でラキニモドの2つの用量(0.5mgおよび1mg/日)の安全性と許容度とを評価する。この試験はまた、活動性ループス関節炎を有する全身性エリテマトーデス患者でラキニモド(0.5mgおよび1mg/日)のバイオマーカーと臨床効果とを評価する。
1.ラキニモド0.5mg。
許可される併用投薬の用量は、試験全体で(試験プロトコルで規定されるスクリーニングから経過観察期間の完了まで)安定して保たれる。試験治療全期間中の試験プロトコルによって許可されないSLEのためのいかなる新規投薬/治療または用量の増加も、重大なプロトコル違反になり、治療失敗とみなされる。試験治療全期間中の試験プロトコルによって許可されない用量または投与療法の減少も、重大なプロトコル違反になる。さらに、試験治療全期間中の任意のときに対象に投与されるいかなる新規の生物的治療、新規の免疫抑制剤もしくは細胞毒性薬、血漿交換法またはIV−Igも治療失敗とみなされ、早期の治療中止をもたらす。
経口コルチコステロイドの許可されたバックグラウンド用量(最高10mgプレドニゾン/プレドニソロンまたは同等物)は、試験全体で安定したままである。安定用量は、ベースラインと比較して5mg未満のプレドニゾン/プレドニソロン(または同等物)の変化と定義される。IV、IMまたは関節内(IA)投薬は、許可されない。
1.試験プロトコルによって許可される免疫抑制治療(AZA、6MP、MTX、MMF)は、試験全体で安定に保たれる。治療期間中の新規の免疫抑制剤または細胞毒性薬による治療は早期の治療中止をもたらし、治療失敗とみなされる。治療期間中の用量増加は、治療失敗とみなされる。
1.抗炎症薬(NSAID)またはCOX2阻害剤による治療は、試験中、安定に保たれる。治療全期間中の新規の治療または用量の変化は、治療失敗とみなされる。
経過観察全期間中、治療期間中に処方されるバックグラウンド投薬(例えばNSAID、COX2阻害剤、抗マラリア薬、ステロイド、免疫抑制剤)または任意の他の薬剤の安定用量を維持させるあらゆる試みがなされる。
1.上記のもの以外のループス関節炎の治療のための薬剤は、試験の過程中許可されない。
薬物動態学(PK)/集団PK試験(PPK):
PK評価のための血液試料は、以下の通りに全ての対象から収集される:4週目診察−下記時点での完全なPKプロファイル:投薬前、投薬の15、30分後、1、1.5、2、3、4、6および24時間後;2週目および12週目診察−投薬前(トラフ血漿レベル)。
下記事象のいずれかで、試験への対象の協力は直ちに中止される。対象は、症状または臨床検査異常の解消または安定化まで追跡される。
1.以下のいずれかと組み合わせたULNの3倍以上へのALTまたはASTの増加:
a.ワルファリン無治療対象でULNの1.5倍以上のINRの上昇。
1.好中球減少−絶対好中球数<1000/mm3。
1.試験中の任意の時点で、ベースラインと比較した腫脹または圧痛の関節点数の50%の増加を有する対象は、治療失敗とみなされて試験を中止される。
応答の定義
・BILAG MSK応答は、ベースライン時の筋骨格AまたはBからLOV時のCまたはDへの変化と定義される。
・以下のいずれかで定義される薬/介入性フレア
−以前の用量と比較して、またはベースラインか任意のIV、IMもしくは関節内用量と比較して少なくとも5mg/日のステロイド増加。
ループス関節炎
1.12週目の腫脹関節数の変化
12週目の腫脹関節数の記述統計ならびにベースラインからの変化が、表およびグラフ形式で治療群別に示される。
12週目の圧痛関節数の記述統計ならびにベースラインからの変化が、表およびグラフ形式で治療群別に示される。
12週目の圧痛関節数と腫脹関節数の記述統計ならびにベースラインからの変化が、表およびグラフ形式で治療群別に示される。
ランダム化集団から計算される、12週目にBILAG MSK応答にあり、治療失敗を経験していない対象の数および百分率が、治療群別に表とグラフの両方の形式で示される。
1.12週目の実質的BILAG応答者の割合および治療失敗の欠如
ランダム化集団から計算される、12週目に実質的BILAG応答を有し、治療失敗を経験していない対象の数および百分率が、治療群別に表とグラフの両方の形式で示される。
ランダム化集団から計算される、12週目にSLEDAI応答を有し、治療失敗を経験していない対象の数および百分率が、治療群別に表とグラフの両方の形式で示される。
ランダム化集団から計算される、治療全期間(12週)中に任意の系で新規のBILAG AまたはBを経験した対象の数および百分率が、治療群別に表とグラフの両方の形式で示される。
ランダム化集団から計算される、治療期間中にいつでも新規の薬介入性フレアを有する対象の数および百分率が、治療群別に表とグラフの両方の形式で示される。
12週目のPGAおよびEGAの記述統計ならびにベースラインからの変化が、表およびグラフ形式で治療群別に示される。
SLEDAI 2Kの記述統計ならびにベースラインからの変化が、表およびグラフ形式で試験週および治療群別に示される。
抗dsDNA、C3、C4およびCH50の記述統計ならびにベースラインからの変化が、表およびグラフ形式で試験週および治療群別に示される。同様に、ベースライン時の正常から異常へ移行した対象の数および百分率が、表形式で試験週および治療群別に示される。
12週目のバイオマーカーの記述統計ならびにベースラインからの変化が、表およびグラフ形式で試験週および治療群別に示される。
安全性
1.有害事象(AE)の発生率、頻度および重症度。
1.治療を早期に中止する対象の割合。
この試験は、活動性ループス関節炎を有する全身性エリテマトーデス(SLE)患者で、プラセボと比較したラキニモドの0.5mgおよび1.0mgの日用量の効力と、許容度と、安全性とを評価する。
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Claims (19)
- 活動性ループス関節炎で苦しむ対象を治療する方法であって、ラキニモドまたは薬学的に許容されるその塩の、前記対象を治療するのに有効な量を前記対象に定期的に投与することを含む方法。
- ラキニモドまたは薬学的に許容されるその塩の前記量が、前記対象で活動性ループス関節炎の臨床徴候または症状を低減するのに有効である、請求項1に記載の方法。
- ラキニモドの前記薬学的に許容される塩がラキニモドナトリウムである、請求項1または2に記載の方法。
- ラキニモドまたは薬学的に許容されるその塩の前記定期投与が経口的に実行される、請求項1〜3のいずれか一項に記載の方法。
- 投与されるラキニモドの前記量が0.5〜1.0mg/日である、請求項1〜4のいずれか一項に記載の方法。
- 投与されるラキニモドの前記量が0.5mg/日である、請求項5に記載の方法。
- 投与されるラキニモドの前記量が1.0mg/日である、請求項5に記載の方法。
- コルチコステロイド、免疫抑制剤、抗マラリア薬、非ステロイド系抗炎症薬、COX2阻害剤、アバタセプト、リツキシマブおよび/またはベリムマブの投与をさらに含む、請求項1〜7のいずれか一項に記載の方法。
- 前記免疫抑制剤がアザチオプリン、メトトレキセート、6−メルカプトプリン、レフルノミド、サイクロスポリンまたは他のカルシニューリン阻害剤である、請求項8に記載の方法。
- 前記定期投与が少なくとも12週間の間継続する、請求項1〜9のいずれか一項に記載の方法。
- 前記ラキニモドまたは薬学的に許容されるその塩が、活動性ループス関節炎のための単独療法として投与される、請求項1〜10のいずれか一項に記載の方法。
- 前記ラキニモドまたは薬学的に許容されるその塩が、別の活動性ループス関節炎療法の補助療法として投与される、請求項1〜10のいずれか一項に記載の方法。
- ラキニモドまたは薬学的に許容されるその塩の前記定期投与が、前記対象の腫脹関節数を低減する、請求項1〜12のいずれか一項に記載の方法。
- ラキニモドまたは薬学的に許容されるその塩の前記定期投与が、前記対象の圧痛関節数を低減する、請求項1〜13のいずれか一項に記載の方法。
- ラキニモドまたは薬学的に許容されるその塩の前記定期投与が、前記対象のBILAG MSK応答を改善する、請求項1〜14のいずれか一項に記載の方法。
- ラキニモドまたは薬学的に許容されるその塩の前記定期投与が、前記対象のBILAGスコアを改善する、請求項1〜15のいずれか一項に記載の方法。
- 前記対象がヒトである、請求項1〜16のいずれか一項に記載の方法。
- 活動性ループス関節炎で苦しむ対象の治療において用いるための、ラキニモドまたは薬学的に許容されるその塩。
- 活動性ループス関節炎で苦しむ対象の治療において用いるための量のラキニモドまたは薬学的に許容されるその塩を含む医薬組成物。
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US33935510P | 2010-03-03 | 2010-03-03 | |
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JP2016196473A (ja) * | 2010-03-03 | 2016-11-24 | テバ ファーマシューティカル インダストリーズ リミティド | ラキニモドを用いるループス関節炎の治療 |
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Cited By (1)
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JP2016196473A (ja) * | 2010-03-03 | 2016-11-24 | テバ ファーマシューティカル インダストリーズ リミティド | ラキニモドを用いるループス関節炎の治療 |
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EA201290859A1 (ru) | 2013-04-30 |
JP2016196473A (ja) | 2016-11-24 |
CN102781239A (zh) | 2012-11-14 |
PL2542080T3 (pl) | 2017-02-28 |
CA2791711A1 (en) | 2011-09-09 |
ZA201207125B (en) | 2014-06-25 |
CN102781239B (zh) | 2015-01-21 |
US20130184310A1 (en) | 2013-07-18 |
WO2011109536A1 (en) | 2011-09-09 |
MX2012010071A (es) | 2012-10-03 |
EP2542080B1 (en) | 2016-08-31 |
EP2542080A4 (en) | 2013-07-17 |
US20150086549A1 (en) | 2015-03-26 |
US20160213663A1 (en) | 2016-07-28 |
AU2011223702A1 (en) | 2012-10-25 |
ES2601819T3 (es) | 2017-02-16 |
PE20130496A1 (es) | 2013-05-08 |
BR112012022064A2 (pt) | 2015-09-08 |
CL2012002422A1 (es) | 2012-12-21 |
US20110217295A1 (en) | 2011-09-08 |
PT2542080T (pt) | 2016-11-16 |
HK1177876A1 (zh) | 2013-08-30 |
SG10201501539SA (en) | 2015-04-29 |
EP2542080A1 (en) | 2013-01-09 |
KR20130036217A (ko) | 2013-04-11 |
MX342001B (es) | 2016-09-09 |
SG183515A1 (en) | 2012-10-30 |
NZ602512A (en) | 2014-07-25 |
AU2011223702B2 (en) | 2016-07-14 |
CO6630086A2 (es) | 2013-03-01 |
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