JP2017526628A - 肝疾患又は肝機能異常を治療するためのアプレミラスト - Google Patents
肝疾患又は肝機能異常を治療するためのアプレミラスト Download PDFInfo
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- JP2017526628A JP2017526628A JP2016575180A JP2016575180A JP2017526628A JP 2017526628 A JP2017526628 A JP 2017526628A JP 2016575180 A JP2016575180 A JP 2016575180A JP 2016575180 A JP2016575180 A JP 2016575180A JP 2017526628 A JP2017526628 A JP 2017526628A
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- methoxyphenyl
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Abstract
Description
本明細書で提供されるのは、アプレミラストの投与により、それ単独で、又は他の治療法若しくは治療レジメンと組み合わせて、肝疾患又は肝機能異常を治療、予防及び/又は管理するための方法である。また、本明細書で提供されるのは、肝疾患又は肝機能異常を治療、予防及び/又は管理する方法における使用に適した、具体的な量のアプレミラストを含む医薬組成物及び剤形である。
脂肪性肝疾患(FLD)は、それがアルコール性FLD(AFLD)であるか非アルコール性FLD(NAFLD)であるかに関わらず、脂肪肝(hepatic steatosis)(脂肪肝(fatty liver))及び脂肪性肝炎の形態的スペクトル(morphological spectrum)を包含する。アルコールは成人における脂肪性肝疾患の周知の原因であり、脂肪症、脂肪性肝炎、及び肝硬変として組織学的に顕在化し得る。近年、別の実体、非アルコール性脂肪性肝疾患(NAFLD)が、典型的にはアルコールの乱用に関連する肝臓の変化の全スペクトルを模倣し得ることが明らかとなってきた。NAFLDは一まとめにメタボリック症候群と呼ばれるインスリン抵抗性、肥満、糖尿病、高血圧、及び脂質代謝異常と関連する。アルコール性脂肪性肝疾患及び非アルコール性脂肪性肝疾患の形態的変化は判別不可能である(Kumar、Abbas、Asterの文献、「ロビンス基礎病理学(Robbins Basic Pathology)」、第9版; Elsevier; 2013)。
本明細書で提供されるのは、それを必要とするヒトにおいて、肝疾患又は肝機能異常を治療、予防及び/又は管理するための方法である。肝機能異常を有する肝疾患には、これらに限定はされないが、遺伝性肝障害(例えば、ポルフィリン症、ウィルソン病、及びヘマクロマトーシス);急性肝炎(ウイルス又は細菌感染による肝炎、毒素への曝露による肝炎、及び薬剤誘発性肝炎);自己免疫性肝疾患(例えば、原発性胆汁性肝硬変及び狼瘡肝炎);並びに胆管疾患(例えば、硬化性胆管炎)がある。さらに、本明細書に記載されるのは、肝障害に関連する掻痒及び黄疸を治療するための方法である。該方法は、そのような治療、予防又は管理を必要とする患者に、治療上又は予防上有効な量のアプレミラスト、又はその医薬として許容し得るプロドラッグ、代謝産物、多形体、塩、溶媒和物(例えば、水和物)若しくは包接化合物を投与することを含む。また、本明細書で提供されるのは、先に記載の方法において使用するための治療上又は予防上有効な量の化合物であるが、該化合物はアプレミラスト、又はその医薬として許容し得るプロドラッグ、代謝産物、多形体、塩、溶媒和物(例えば、水和物)若しくは包接化合物であり、ここで、該方法はそのような治療、予防又は管理を必要とする患者に該化合物を投与することを含む。
(4.1. 定義)
本明細書で使用される用語「アプレミラスト」は、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンを指し、N-[2-[(1S)-1-(3-エトキシ-4-メトキシルフェニル)-2-(メチルスルホニル)エチル]-2,3-ジヒドロ-1,3-ジオキソ-1H-イソインドール-4-イル]アセトアミドとしても知られる。アプレミラストは下記の構造を有する:
本明細書で提供されるのは、肝疾患又は肝機能異常を治療、管理及び/又は予防する方法であって、そのような治療、管理又は予防を必要とする患者に治療上又は予防上有効な量の立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、又はその医薬として許容し得るプロドラッグ、代謝産物、多形体、塩、溶媒和物、又は包接化合物を投与することを含む、前記方法である。肝機能異常を有する肝疾患には、これらに限定はされないが、遺伝性肝障害(例えば、ポルフィリン症、ウィルソン病、及びヘマクロマトーシス); 急性肝炎(ウイルス又は細菌感染による肝炎、毒素への曝露による肝炎、及び薬剤誘発性肝炎); 自己免疫性肝疾患(例えば、原発性胆汁性肝硬変及び狼瘡肝炎); 及び胆管疾患(例えば、硬化性胆管炎)がある。
本実施態様により包含される特定の方法において、立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンは、肝疾患又は肝機能異常を治療、管理、及び/又は予防するための別の薬物(「第二活性剤」)と組み合わせて投与される。
理論に限定されることなく、アプレミラストは、下記の構造を有する2-[1-(3-エトキシ-4-メトキシフェニル)-2-メタンスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンの(+)鏡像異性体であると考えられている:
医薬組成物を、個別の単一単位剤形の製造に使用することができる。医薬組成物及び剤形は、アプレミラスト又はその医薬として許容し得る塩若しくは溶媒和物、及び第二活性剤を含むことができる。任意の第二活性剤の例が、本明細書で開示される(例えば、4.2.1節を参照されたい)。医薬組成物及び剤形は、1以上の担体、賦形剤、又は希釈剤をさらに含むことができる。
特定の実施態様において、活性成分は当業者に周知の制御放出手段又は送達装置により、投与することができる。制御放出手段又は送達装置の非限定的な例には、その各々が引用により本明細書に組み込まれている米国特許第3,845,770号; 第3,916,899号; 第3,536,809号; 第3,598,123号; 及び第4,008,719号、第5,674,533号、第5,059,595号、第5,591,767号、第5,120,548号、第5,073,543号、第5,639,476号、第5,354,556号、及び第5,733,566号に記載された制御放出手段又は送達装置がある。そのような剤形を使用して、例えばヒドロプロピルメチルセルロース(hydropropylmethyl cellulose)、他のポリマーマトリックス、ゲル、透過膜、浸透圧システム、多層コーティング、ミクロ粒子、リポソーム、ミクロスフェア、又は種々の比率で所望の放出プロファイルを提供するそれらの組み合わせを使用する、1以上の活性成分の遅延放出又は制御放出を提供することができる。本明細書に記載される制御放出製剤を含む、当業者に公知の適当な制御放出製剤は、該活性成分に使用するために容易に選択することができる。特定の実施態様において、本明細書で提供されるのは、経口投与に適した単一単位剤形、例えばこれらに限定はされないが、制御放出に適応した錠剤、カプセル剤、ゲルキャップ剤(gelcaps)、及びカプレット剤である。
一部の実施態様が以下の非限定的な実施例により例示される。この実施例はその範囲内に限定するものとして解釈されるべきではない。
関節炎病態は、炎症誘発性サイトカイン、インターフェロン(INF)γ、及び腫瘍壊死因子(TNF)-αの関与に起因するTh1自己免疫性疾患であると考えられている。環状ヌクレオチドであるアデノシン3',5'-環状一リン酸(cAMP)が上昇すると、TNF-αを含む炎症メディエータの放出が阻害される。cAMPの不活性化の細胞機構は、環状ヌクレオチドホスホジエステラーゼ(PDE)によるcAMPの分解である。PDE4の阻害は、炎症メディエータ放出の阻害において特に有効である。従って、PDE4を特異的に阻害する化合物は、望ましくない副作用を最低限にしながら炎症を阻害することができる。
乾癬性関節炎患者集団及び乾癬患者集団の両方における第3相試験、及びメトトレキサートを背景とするリウマチ性関節炎患者における第2相試験において、アプレミラストを試験した。これらの試験において、患者は肝機能の改善、並びに肝機能検査(LFT)における異常の減少を示した。アプレミラストの毎日の使用により、いかなる所定の身体活動、社会的習慣又は食習慣の変化も伴わずに、肝機能検査におけるベースラインでの軽度の異常の改善が観察された。乾癬性関節炎及び乾癬の試験の両方における患者集団の大部分が、被験者の平均BMIが30以上である体重過多であり、過半数が定期的にアルコール飲料を消費し、約60%が平均して1日15 mgの用量でメトトレキサートを服用し、70%が非ステロイド性抗炎症薬(NSAID)を使用していた。リスク因子(肥満及びアルコール消費は両方とも脂肪性肝疾患のリスク因子であり、NSAID及びメトトレキサートの使用は肝機能検査における異常のリスクを増加させる)の偏りなく振り分けたにもかかわらず、プールされた集団には、ベースラインで異常なLFTを有する被験者が同程度の数だけ含まれていた。試験クールの間、アプレミラスト処置群(20 mg BID及び30 mg BIDの両方)でより高い割合の被験者が、その後の偽薬を対照とした試験における第4週、第16週、及び第24週での通院において正常なLFT(すなわち、正常なレベルのALT及びAST)を有することが観察された(PALACE 1、2、及び3試験で得た表1〜10を参照されたい)。
表1:アプレミラスト処置の間のアラニンアミノトランスフェラーゼのパーセント変化の概要(PALACE 1、2、及び3)
表2:アプレミラスト処置の間のアスパラギン酸アミノトランスフェラーゼのパーセント変化の概要(PALACE 1、2、及び3)
アプレミラストを中程度から重度の尋常性乾癬を有する患者における、第3相試験で試験した。これらの試験において、患者は肝機能の改善並びに肝機能検査(LFT)の異常の減少を示した。アプレミラストの毎日の使用により、いかなる所定の身体活動、社会的習慣又は食習慣の変化も伴わずに、肝機能検査におけるベースラインでの軽度の異常の改善が観察された。試験クールの間、アプレミラスト処置群(30 mg BID)でより高い割合の被験者が、その後の偽薬を対照とした試験における第16週での通院において正常なLFT(すなわち、正常なレベルのALT及びAST)を有することが観察された。PSOR-008及びPSOR-009試験で得た表11〜16を参照されたい。
表11:偽薬群におけるアプレミラスト処置の第16週でのアラニンアミノトランスフェラーゼのレベル(PSOR-008及びPSOR-009)
アプレミラストを、メトトレキサートに対し不十分な反応を有していた、活動性の高い関節リウマチを有する患者における、第2相試験で試験した。これらの試験において、患者は肝機能の改善並びに肝機能検査(LFT)の異常の減少を示した。アプレミラストの毎日の使用により、いかなる所定の身体活動、社会的習慣又は食習慣の変化も伴わずに、肝機能検査におけるベースラインでの軽度の異常の改善が観察された。試験クールの間、30 mg BIDのアプレミラスト処置群でより高い割合の被験者が、その後の偽薬を対照とした試験における第16週での通院において正常なLFTを有することが観察された。RA-002試験で得た表17〜24を参照されたい。
表17:偽薬群におけるアプレミラスト処置の第16週でのアラニンアミノトランスフェラーゼのレベル(RA-002)
アプレミラストを、過去に疾患を軽減する抗リウマチ薬による治療を受けたことがない、活動性の高い乾癬性関節炎を有する患者における、第3相試験で試験した。これらの試験において、患者は肝機能の改善並びに肝機能検査(LFT)の異常の減少を示した。アプレミラストの毎日の使用により、いかなる所定の身体活動、社会的習慣又は食習慣の変化も伴わずに、肝機能検査におけるベースラインでの軽度の異常の改善が観察された。試験クールの間、20 mg BID及び30 mg BIDのアプレミラスト処置群の両方でより高い割合の被験者が、その後の偽薬を対照とした試験における第24週での通院において正常なLFT(すなわち、正常なレベルのALT及びAST)を有することが観察された。PSA-005試験で得た表25〜34を参照されたい。
表25:処置群による、アプレミラスト処置の様々な週での、アラニンアミノトランスフェラーゼレベルの変化を有する患者の割合(PSA-005)
2つの無作為化二重盲検偽薬対照多施設臨床試験を、体表面積(BSA)関与(body surface area (BSA) involvement)が≧10%、静的医師総合評価(static Physician Global Assessment)(sPGA)が≧3(中程度又は重度の疾患)、乾癬面積及び重症度指数(Psoriasis Area and Severity Index)(PASI)スコアが≧12であり、かつ光線療法又は全身療法の候補であった、中程度から重度の尋常性乾癬を有する患者において実施した。患者は無作為抽出されて初めの16週間は1日2回30 mgの量のアプレミラスト又は偽薬を伴い、第16週〜第32週には全ての患者が1日2回30 mgの量のアプレミラストを与えられた。
表35:ESTEEM 1及び2試験における第16週での臨床的奏効
Claims (54)
- 肝疾患又は肝機能異常を治療又は管理する方法における使用のための化合物であって、該方法が肝疾患又は肝機能異常を有する患者に有効量の該化合物を経口投与することを含み、該化合物が立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、又はその医薬として許容し得るプロドラッグ、多形体、塩又は溶媒和物である、前記使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが1日1回又は2回投与される、請求項1記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが1日1回約10 mg、約20 mg、約30 mg、又は約40 mgの量で投与される、請求項2記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが1日2回約10 mg、約20 mg、約30 mg、又は約40 mgの量で投与される、請求項2記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが、前記化合物の総重量パーセントに基づき約90重量%超の(+)異性体を含む、請求項1記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが、前記化合物の総重量パーセントに基づき約95重量%超の(+)異性体を含む、請求項1記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが、前記化合物の総重量パーセントに基づき約96重量%超の(+)異性体を含む、請求項1記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが、前記化合物の総重量パーセントに基づき約97重量%超の(+)異性体を含む、請求項1記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが、前記化合物の総重量パーセントに基づき約98重量%超の(+)異性体を含む、請求項1記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが、前記化合物の総重量パーセントに基づき約99重量%超の(+)異性体を含む、請求項1記載の使用のための化合物。
- 前記立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンが錠剤形態で投与される、請求項1記載の使用のための化合物。
- 前記錠剤が10 mg、20 mg、30 mg、又は40 mgの用量の立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンを含む、請求項11記載の使用のための化合物。
- 前記錠剤が10 mgの用量の立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンを含む、請求項12記載の使用のための化合物。
- 前記錠剤が20 mgの用量の立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンを含む、請求項12記載の使用のための化合物。
- 前記錠剤が30 mgの用量の立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンを含む、請求項12記載の使用のための化合物。
- 前記錠剤が40 mgの用量の立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンを含む、請求項12記載の使用のための化合物。
- 前記錠剤がラクトース一水和物、微結晶性セルロース、クロスカルメロースナトリウム、ステアリン酸マグネシウム、ポリビニルアルコール、二酸化チタン、ポリエチレングリコール、及びタルクをさらに含む、請求項12記載の使用のための化合物。
- 前記錠剤が赤酸化鉄をさらに含む、請求項17記載の使用のための化合物。
- 前記錠剤が赤酸化鉄及び黄酸化鉄をさらに含む、請求項17記載の使用のための化合物。
- 前記錠剤が赤酸化鉄、黄酸化鉄、及び黒酸化鉄をさらに含む、請求項17記載の使用のための化合物。
- 前記方法が治療上有効量の1以上の第二活性剤を前記患者に投与することをさらに含む、請求項1記載の使用のための化合物。
- 前記1以上の第二活性剤が肝疾患又は肝機能異常を治療するための薬剤である、請求項21記載の使用のための化合物。
- 前記肝疾患が脂肪性肝疾患である、請求項1記載の使用のための化合物。
- 前記肝疾患が肝線維症である、請求項1記載の使用のための化合物。
- 前記肝疾患が非アルコール性脂肪性肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患がアルコール性脂肪性肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患が薬剤誘発性肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患が毒素への曝露による肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患がヘモクロマトーシスである、請求項1記載の使用のための化合物。
- 前記肝疾患が急性ポルフィリン症である、請求項1記載の使用のための化合物。
- 前記肝疾患が自己免疫性肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患が硬化性胆管炎である、請求項1記載の使用のための化合物。
- 肝疾患が急性胆汁鬱滞性黄疸である、請求項1記載の使用のための化合物。
- 前記肝疾患が急性肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患が原発性胆汁性肝硬変である、請求項1記載の使用のための化合物。
- 前記肝疾患が狼瘡肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患がウィルソン病である、請求項1記載の使用のための化合物。
- 前記肝疾患がウイルス性肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患が細菌性肝炎である、請求項1記載の使用のための化合物。
- 前記肝疾患が脂肪肝である、請求項1記載の使用のための化合物。
- 前記肝疾患が掻痒と関連する、請求項1記載の使用のための化合物。
- 前記肝疾患が過去の治療に再発性又は不応性である、請求項1記載の使用のための化合物。
- 前記脂肪性肝疾患が非アルコール性脂肪性肝疾患である、請求項23記載の使用のための化合物。
- 前記脂肪性肝疾患がアルコール性脂肪性肝疾患である、請求項23記載の使用のための化合物。
- 前記非アルコール性脂肪性肝疾患が小児非アルコール性脂肪性肝疾患である、請求項43記載の使用のための化合物。
- 前記肝機能異常が前記患者における上昇したレベルのアラニンアミノトランスフェラーゼ又はアスパラギン酸アミノトランスフェラーゼを含む、請求項1記載の使用のための化合物。
- 前記方法が、実質的にいかなる塩、溶媒和物、又はプロドラッグの形態の(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンも含まない、立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンを投与することを含む、請求項1記載の使用のための化合物。
- 前記方法が立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンの医薬として許容し得る塩を投与することを含む、請求項1記載の使用のための化合物。
- 前記方法が立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンの医薬として許容し得る溶媒和物を投与することを含む、請求項1記載の使用のための化合物。
- 前記方法が前記患者におけるアラニンアミノトランスフェラーゼ又はアスパラギン酸アミノトランスフェラーゼのレベルを低下させる、請求項1記載の使用のための化合物。
- 前記方法が、前記患者に追加の治療を施すことをさらに含む、請求項1記載の使用のための化合物。
- 前記追加の治療が外科的矯正である、請求項51記載の使用のための化合物。
- 前記追加の治療が肝移植である、請求項51記載の使用のための化合物。
- 肝疾患又は肝機能異常に関連する掻痒を治療又は管理する方法における使用のための化合物であって、該方法が肝疾患又は肝機能異常を有する患者に有効量の該化合物を経口投与することを含み、該化合物が立体異性的に純粋な(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、又はその医薬として許容し得るプロドラッグ、多形体、塩又は溶媒和物である、前記使用のための化合物。
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