JP2018526407A - 特定の患者集団において神経変性障害を処置する方法 - Google Patents
特定の患者集団において神経変性障害を処置する方法 Download PDFInfo
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
【選択図】図1
Description
また、出願人らは、臨床データに基づいて、軽度ADまたは軽度〜中等度ADを有するAPOE4/4ホモ接合患者が、他のAD患者(例えば、より中等度のADを有するAPOE4/4ホモ接合患者)よりも、トラミプロセートまたはそのプロドラッグ(例えば、ALZ−801)による処置に対して予想外にも応答することを驚くべきことに発見した。特に、軽度AD(ベースラインMMSEスコア20〜26)を有するAPOE4/4ホモ接合患者及び軽度〜中等度AD(ベースラインMMSEスコア18〜19)を有するAPOE4/4ホモ接合患者は、ベースラインでMMSE<18を有する患者よりも、150mg BIDにおいてトラミプロセートに対してより高い改良を示す傾向にある。さらに、ベースラインMMSE≧22を有するApoE4/4ホモ接合患者は、78週の研究にわたって、プラセボと比較して、最も高い有効性及び認知機能の漸進的な増加を示した。同じことが、等価用量(265mg BID)のALZ−801−トラミプロセートプロドラッグについて予期される。
a.トラミプロセート、バリル−3−アミノ−1−プロパンスルホン酸またはこれらのいずれかの薬学的に許容可能な塩を含む医薬組成物を、(i)APOE4ヘテロ接合であり中等度アルツハイマー病を有する;または(ii)APOE4/4ホモ接合体であり軽度もしくは軽度〜中等度アルツハイマー病を有すると決定された対象に投与するステップと;
b.対象に、医薬組成物を、対象が(i)APOE4陰性である;(ii)APOE4ヘテロ接合であり中等度アルツハイマー病に罹患していない;または(iii)APOE4/4ホモ接合であり軽度もしくは軽度〜中等度アルツハイマー病に罹患していないと決定されるときには投与しないステップとを含む、上記方法を提供する。これらの実施形態の一態様において、対象が(i)APOE4陰性;(ii)APOE4ヘテロ接合であり中等度アルツハイマー病に罹患していない;または(iii)APOE4/4ホモ接合であり軽度もしくは軽度〜中等度アルツハイマー病に罹患していないと決定されるとき、対象に、トラミプロセート、バリル−3−アミノ−1−プロパンスルホン酸または上記のいずれかの薬学的に許容可能な塩以外の治療薬が投与される。
以下の定義を本開示に関連して使用する。
ADに現在罹患している個体は、特徴的な認知症、ならびに以下に記載されている危険因子の存在から認識され得る。また、認知及び神経学的検査に基づく多くの診断試験は、ADを有する個体を識別するのに利用可能である。例えば、ADに罹患している個体は、以下に議論されているように、CDRスケール、MMSE、ADAS−Cog、または当該分野において公知のいずれか他の試験によって診断され得る。MMSE及びADASを含めた好適な測定基準に基づくベースラインスコアは、より正常な集団を評価するように設計されている他の測定基準と共に、危険な状態にある集団を見出すのに使用され得る。ADAS−Cog、CDR−SB及びNPIの値が高いほど、より重篤度が高いことを示しているが、DAD及びMMSEの値が低いほど、より重篤度が高いことを示している。
アルツハイマー病を処置するためのトラミプロセートの第3相ヒト臨床試験を、100mg BID及び150mg BIDの用量で最大78週間、北米及び欧州の両方で行った(合計1691患者が登録された)。両試験におけるプラセボは、単独またはメマンチンとの組み合わせのいずれかのドネペジルによる処置であった。ADAS−Cogスコア及びCDR−SBスコアを、試験に残った患者について13週毎に得た。患者はAPOE4の遺伝子型であり、疾患の重篤度を処置の開始の前にMMSEを使用して測定した。両試験からのデータをある特定の統計分析用に統合した。これらのデータの最初の統計分析は、APOE4ステータスに焦点を当てたものであり、プラセボと比較した100mg処置群及び150mg処置群の両方の統計的に有意な効果を、APOE4+サブ群におけるADAS−Cog及びCDR−SBの両方について観察した。
ベースラインMMSEに基づいた、APOE4/4ホモ接合体対象におけるトラミプロセートの有効性の分析を実施して、軽度患者と中等度患者との間の薬物応答の差について評価した。MMRM分析を以下のベースラインMMSEカテゴリー:軽度〜中等度AD集団(ベースラインMMSE16〜26(境界含む))、軽度AD集団(ベースラインMMSE20〜26(境界含む))、及びより軽度のAD集団(ベースラインMMSE22〜26(境界含む));において実施した。データを図7、パネルA及びBにおいて以下に示す。
ALZ−801の臨床開発を第3相に進めるために、本発明者らは、安全性、耐容性及び薬物動態を評価するために、健常なより高齢のボランティアにおいて単回用量及び14日の複数用量漸増の第1相ブリッジング試験を終了させた。経口トラミプロセートと比較して、単回用量の経口ALZ−801は、50%超がより低い被験者間変動で等しい血漿中曝露量のトラミプロセートを送達した(以下の表5を参照されたい)。経口ALZ−801もまた、一旦定常状態に達したら、血漿トラミプロセートの終末相半減期を約24時間に延長した(以下の表6を参照されたい)。複数用量漸増試験において観察されたより長い半減期はBID投薬の14日後に得られ、これは、単回用量試験と比較して、この試験でなされた採血の時点がより延びていたという事実に起因するものであった。複数用量漸増試験において、BID投薬の7日目にALZ−801の定常状態に達し、Cmax及びAUCの両方の患者間変動が定常状態で24〜28%の間であった。
Claims (17)
- 対象においてアルツハイマー病を処置する方法であって、バリル−3−アミノ−1−プロパンスルホン酸またはその薬学的に許容可能な塩を含む医薬組成物を、(i)APOE4ヘテロ接合であり中等度アルツハイマー病を有する;または(ii)APOE4/4ホモ接合であり軽度もしくは軽度〜中等度アルツハイマー病を有すると決定された対象に投与することを含む、前記方法。
- 対象においてアルツハイマー病を処置する方法であって:
a.トラミプロセート、バリル−3−アミノ−1−プロパンスルホン酸またはこれらのいずれかの薬学的に許容可能な塩を含む医薬組成物を、(i)APOE4ヘテロ接合であり中等度アルツハイマー病を有する;または(ii)APOE4/4ホモ接合であり軽度もしくは軽度〜中等度アルツハイマー病を有すると決定された対象に投与するステップと;
b.前記対象に、前記医薬組成物を、前記対象が(i)APOE4陰性である;(ii)APOE4ヘテロ接合であり中等度アルツハイマー病に罹患していない;または(iii)APOE4/4ホモ接合であり軽度もしくは軽度〜中等度アルツハイマー病に罹患していないと決定されるときに投与しないステップと
を含む、前記方法。 - 前記対象におけるアルツハイマー病の重篤度が、前記組成物の最初の投与の前の60日以内になされたミニメンタルステート検査(MMSE)におけるスコアによって決定されており:
a.前記対象が16〜19の範囲のミニメンタルステート検査(MMSE)スコアを有したときに前記対象が中等度アルツハイマー病を有すると決定されており;
b.前記対象が20〜26の範囲のミニメンタルステート検査(MMSE)スコアを有したときに前記対象が軽度アルツハイマー病を有すると決定されており;
c.前記対象が18〜19の範囲のミニメンタルステート検査(MMSE)スコアを有したときに前記対象が軽度〜中等度アルツハイマー病を有すると決定されている、
請求項1または2に記載の方法。 - 前記対象がAPOE4ヘテロ接合であり、ベースラインMMSEスコア16〜19によって示される中等度アルツハイマー病を有する、請求項3に記載の方法。
- 前記対象がAPOE4/4ホモ接合であり、ベースラインMMSEスコア18〜26によって示される軽度〜中等度または軽度アルツハイマー病を有する、請求項3に記載の方法。
- 前記対象がAPOE4/4ホモ接合であり、ベースラインMMSEスコア20〜26によって示される軽度アルツハイマー病を有する、請求項3に記載の方法。
- 前記対象がAPOE4+ホモ接合であり、ベースラインMMSEスコア22〜26によって示されるより軽度のアルツハイマー病を有する、請求項3に記載の方法。
- 前記医薬組成物が、100mg〜150mg/用量の範囲の用量のトラミプロセートを送達する、請求項1〜7のいずれか一項に記載の方法。
- 前記医薬組成物が、260mgと270mgとの間のバリル−3−アミノ−1−プロパンスルホン酸またはその薬学的に許容可能な塩を含む、請求項8に記載の方法。
- 前記組成物が265mgのバリル−3−アミノ−1−プロパンスルホン酸を含み、前記組成物が、即時放出の経口錠剤またはカプセルとして製剤化される、請求項9に記載の方法。
- 前記医薬組成物が、毎日2回投与される、請求項1〜10のいずれか一項に記載の方法。
- 前記対象が85歳以下である、請求項1〜11のいずれか一項に記載の方法。
- 前記処置が、前記対象における認知低下を減少させる、請求項1〜12のいずれか一項に記載の方法。
- バリル−3−アミノ−1−プロパンスルホン酸による処置に関する対象の適合性を決定する方法であって、前記対象のAPOE4ステータス、及び前記対象のアルツハイマー病の重篤度を決定することを含み、a)前記対象がAPOE4ヘテロ接合であり中等度アルツハイマー病を有するとき;またはb)前記対象がAPOE4/4ホモ接合であり軽度もしくは軽度〜中等度アルツハイマー病を有するとき、前記対象が処置に適合していると決定される、前記方法。
- 260mgと270mgとの間のバリル−3−アミノ−1−プロパンスルホン酸と;薬学的に許容可能な担体とを含む医薬組成物であって、即時放出の経口錠剤またはカプセルとして製剤化されている、前記組成物。
- アルツハイマー病を処置する方法であって、これを必要とする対象に請求項15の医薬組成物を投与することを含む、前記方法。
- 前記医薬組成物が1日に2回投与される、請求項16に記載の方法。
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