JP2019065044A - 神経疾患を治療するための方法 - Google Patents
神経疾患を治療するための方法 Download PDFInfo
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Abstract
Description
本願は、2014年3月21日提出の米国仮特許出願番号US 61/968,595からの優先権を主張するものであり、該仮出願の内容を本明細書の一部として援用する。
Val−APS:
以下の定義が本開示に関連して使用される。他に定義されない限り、本明細書中で使用される「被験者」の用語は、哺乳動物、例えばヒト、マウス、ラット、モルモット、イヌ、ネコ、ウマ、牛、ブタ、またはサル、チンパンジー、またはヒヒなどの非ヒト霊長類である。一実施形態において、該被験者はヒトである。
アポリポタンパク質E遺伝子のε4対立遺伝子は、遅発性AD患者についての最強の遺伝的危険因子である。少なくとも1つのε4対立遺伝子を有するApoE4+被験者は、健常者の25%の有病率に対して、AD症例では50%〜60%を占める。ApoE4+のAD患者は、発症年齢の低下、重症度の増加及び加速したAD進行を示す。2つのε4対立遺伝子を有する被験者はADの10%〜14%を占め、更なる攻撃的な疾患進行を示す。ε4対立遺伝子は、増加した脳Aβアミロイド沈着、増加したCSFタウ及びp−タウ、より速い認知機能低下を導く。加えて、ApoEの1つまたは2つのε4対立遺伝子をもつ認知症患者はADを有する可能性が高く、患者の臨床試験において疾患の誤診の顕著な低下をもたらす(非ApoE4患者の42%に対して2%)。
本明細書では、ApoE4対立遺伝子の1つまたは2つのコピーを有する患者においてアルツハイマー病を治療及び/または予防する方法が開示される。治療及び予防のための組成物もまた開示される。3−アミノ−1−プロパンスルホン酸(3−APS、トラミプロゼート、アルツヘムド(商標)[AlzhemedTM])は、北米及び欧州での第III相臨床試験を受けているアルツハイマー病治療のための有望な治験薬候補である(Wright,T.M.,Drugs of Today(2006),42(5):291−298)。この製品は、ニューロケム社(Neurochem Inc.)(ラヴァル、QC、カナダ)が開発したものであり、可溶性Aβモノマーへの結合を介して脳におけるアミロイド凝集、堆積及び/またはアミロイドの負荷を軽減することにより作用すると考えられている。3−APS治療の有効性を高めるためには、経口投与後の親(parent)の露出、代謝安定性及び/または3−APS暴露を増加させ、また被験者間での薬物動態変動を最小化することが望ましいであろう。これらの必要性及び他の必要性は、3−アミノ−1−プロパンスルホン酸(3−APS)のプロドラッグ化合物、その医薬組成物によって満たされる。有利なことに、これらの薬剤を用いた特定のサブ集団の治療は顕著な効果を示す。具体的には、本明細書に開示されるのは、ApoE4対立遺伝子についてホモ接合またはヘテロ接合である患者において、アルツハイマー病を治療及び/または予防するための方法である。
一実施形態において、投与される化合物は次式Iのもの、並びにその医薬的に許容可能な塩、水和物、及び溶媒和物であり、ここでのAA1及びAA2はアミノ酸である:
投与の目的のために、特定の実施形態において、本明細書に記載の化合物は未加工の化学物質として投与されるか、または医薬組成物として製剤化される。本開示の医薬組成物は、式I及びIIの化合物、並びに1以上の薬学的に許容可能な担体を含有する。式I及びIIの化合物は、目的とする特定の疾患または状態を治療するために有効な量で、組成物中に存在する。式I及びIIの化合物の活性は、例えば以下の実施例に記載されるように当業者が決定できる。適切な濃度及び投与量は、当業者が容易に決定できる。
本開示はまた、ApoE4陽性のアルツハイマー病患者の治療のための薬剤の製造における、本明細書に開示された化合物の使用を提供する。本開示はまた、上記疾患の治療または予防のための方法であって、それを必要とする被験者、好ましくはヒト被験者に対して、治療的有効量の化合物またはこれを含有する組成物を投与することを含む方法を提供する。従って、本開示の関連する態様は、それを必要とするヒト被験者に対して本開示の化合物または組成物の有効量を投与することによる、ApoE4陽性のヒトにおけうアツハイマー病の予防及び/または治療に関する。
3APS治療は、ApoE4+の全ての来訪(ヘテロ接合及びホモ接合)被験者においてADAS−Cogスコアを向上させる
患者は、150mgBID及び100mgBIDで3APSを投与され、またはプラセボが与えられた。ADAS−Cogの結果を測定した。データにより、スコアの減少が3APSにより遅延されることが確立された。図1及び以下の表を参照されたい。第13週おいて、ADAS−Cogの小さな改善が観察された。時間の経過と共にその差は増大した。約第52週から、プラセボ患者は、本研究の両方の治療アーム(即ち、100mgBID及び150mgBID)に比較して、実質的により大きな認知の減少を示した。
組み合わせデータセットにおけるApoE4サブグループによるADAS−Cog
Val−APSは、3APSに対して改善された脳蓄積及び改善された血漿半減期を示す
図4は、Val−APSプロドラッグ対トラミプロゼートでの、得られた脳内の改善された蓄積を示している。プロドラッグを使用することにより、作用部位での増強された蓄積が達成される。図5は更に、Val−APSの改善された薬理学的性質を示している。トラミプロゼートがVal−APS(NRM8499)として投与されたとき、APSは、延長されたt1/2を示す。図7は、カプセル及び錠剤の形態での3APS(トラミプロゼート)を凌駕する、緩く充填されたVal−APSカプセルの改善された性質を示すデータを要約している。このデータは、Val−APSは緩く充填されたカプセルで投与されたときに、t1/2の14.9±3.9への増加を示している。
3APSは、ApoE4陽性の患者において顕著な効果を示す
患者は3APSを投与され、ADAS−Cogの結果が様々な時点で得られた。次いで、患者はApoE4対立遺伝子の存在を検出するために、遺伝子型を決定された。図8は、ApoE4の状態に基づいて分離された特定のサブ集団における、トラミプロゼート、即ち、Val−APSの活性剤の有利な効果を示している。このデータは、経時的にプラセボに対して実質的に改善されたADAS−cogスコアを確立した。データは、第13週、第26週、第39週、第52週、第65週、及び第78週に提示される。最初の柱は、ApoE4についてホモ接合(「ApoE4+/+」)の患者を示し、2番目の柱はApoE4についてヘテロ接合及びホモ接合の患者「ApoE4の全来訪者」からの合併されたデータを示し、3番目の柱はApoE4について陰性の患者(非ApoE4を)を示す。ApoE4有病率は改善された認知スコアと相関する。明らかに、E4対立遺伝子についてヘテロ接合であった患者は特に顕著な改善を示した。総合して考慮すると、これらのデータは、ApoE4ホモ接合患者における認知に関してプラセボ(トラミプロゼート;150mgBID,n=34)に対して4ポイントの改善を示し、治療18ヶ月後のADAS−cogに関しては4.62ポイントに達した(p<0.01)。
例えば、本発明は以下の項目を提供する。
(項目1)
ApoE4陽性の患者においてアルツハイマー病を治療する方法であって:
(i)アルツハイマー患者をApoE4対立遺伝子について試験する工程と、
(ii)ApoE4対立遺伝子を有する患者をApoE4陽性として特徴付けする工程と、
(iii)該ApoE4陽性患者に対して、ある期間に亘って、次式Iの化合物を投与する工程を具備し、
前記期間は少なくとも13週間であり、
前記期間の終点においてADAS−cogスコアが試験され、前記同じ期間にわたるApoE4陽性患者へのプラセボの投与に比較して、少なくとも約1.5倍改善される方法。
(項目2)
前記アルツハイマー患者はApoE4対立遺伝子についてヘテロ接合である項目1に記載の方法。
(項目3)
前記アルツハイマー患者はApoE4対立遺伝子についてホモ接合である項目1に記載の方法。
(項目4)
前記期間は少なくとも26週間であり、前記改善は少なくとも約2.20倍である項目1に記載の方法。
(項目5)
前記期間は少なくとも39週間であり、前記改善は少なくとも約3.0倍である項目1に記載の方法。
(項目6)
前記期間は少なくとも65週間であり、前記改善は少なくとも約4.5倍である項目1に記載の方法。
(項目7)
AA1及びAA2は、アラニン(Ala)、システイン(Cys)、アスパラギン酸(Asp)、グルタミン酸(Glu)、フェニルアラニン(Phe)、グリシン(Gly)、ヒスチジン(His)、イソロイシン(Ile)、リシン(Lys)、ロイシン(Leu)、メチオニン(Met)、アスパラギン(Asn)、プロリン(Pro)、グルタミン(Gln)、アルギニン(Arg)、セリン(Ser)、トレオニン(Thr)、バリン(Val)、トリプトファン(trp)、チロシン(Tyr)、β−アラニン(β−ALA)、及びγ−アミノ酪酸(GABA)からなる群から独立に選択される項目1に記載の方法。
(項目8)
ApoE4陽性の患者においてアルツハイマー病を治療する方法であって:
(i)アルツハイマー患者をApoE4対立遺伝子について試験する工程と、
(ii)ApoE4対立遺伝子を有する患者をApoE4陽性として特徴付けする工程と、
(iii)該ApoE4陽性患者に対して、ある期間に亘って、次式Iの化合物を投与する工程を具備し、
前記期間は少なくとも13週間であり、
前記期間の終点においてADAS−cogスコアが試験され、前記同じ期間にわたるApoE4陽性患者へのプラセボの投与に比較して、少なくとも約1.5倍改善される方法。
(項目9)
前記アルツハイマー患者はApoE4対立遺伝子についてヘテロ接合である項目8に記載の方法。
(項目10)
前記アルツハイマー患者はApoE4対立遺伝子についてホモ接合である項目8に記載の方法。
(項目11)
前記期間は少なくとも26週間であり、前記改善は少なくとも約2.20倍である項目8に記載の方法。
(項目12)
前記期間は少なくとも39週間であり、前記改善は少なくとも約3.0倍である項目8に記載の方法。
(項目13)
前記期間は少なくとも65週間であり、前記改善は少なくとも約4.5倍である項目8に記載の方法。
(項目14)
AA1は、アラニン(Ala)、システイン(Cys)、アスパラギン酸(Asp)、グルタミン酸(Glu)、フェニルアラニン(Phe)、グリシン(Gly)、ヒスチジン(His)、イソロイシン(Ile)、リシン(Lys)、ロイシン(Leu)、メチオニン(Met)、アスパラギン(Asn)、プロリン(Pro)、グルタミン(Gln)、アルギニン(Arg)、セリン(Ser)、トレオニン(Thr)、バリン(Val)、トリプトファン(trp)、チロシン(Tyr)、β−アラニン(β−ALA)、及びγ−アミノ酪酸(GABA)からなる群から選択される項目8に記載の方法。
(項目15)
AA1は、アラニン(Ala)、イソロイシン(Ile)、ロイシン(Leu)、セリン(Ser)、及びバリン(Val)からなる群から選択される項目14に記載の方法。
(項目16)
AA1はバリン(Val)である項目15に記載の方法。
(項目17)
前記化合物は1日1回投与される項目8に記載の方法。
Claims (1)
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US20220087967A1 (en) * | 2018-08-01 | 2022-03-24 | Alzheon, Inc. | Sulfopropanoic acid derivatives for treating neurodegenerative disorders |
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