JP2021514358A - アピリモドとグルタミン酸作動薬を用いた併用療法 - Google Patents
アピリモドとグルタミン酸作動薬を用いた併用療法 Download PDFInfo
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Abstract
Description
[04]グルタメート(グルタミン酸とも呼ばれる)はヒトの主要な興奮性神経伝達物質である。それはまた、神経細胞の興奮性を調節する主要な抑制性神経伝達物質、GABA(γ−アミノ酪酸)の合成における基質でもある。
[14]実施態様において、神経疾患又は神経障害はレット症候群である。
[16]実施態様において、対象はヒトである。
[17]本開示はまた、筋萎縮性側索硬化症(ALS)の治療を、それを必要とする対象においてするための方法も提供し、該方法は、アピリモド又はその薬学的に許容可能な塩を含む医薬組成物をリルゾール及びトリグリルゾールから選ばれるグルタミン酸作動薬と組み合わせて対象に投与することを含む。
[28]アピリモドは、例えば、米国特許第7,923,557号及び7,863,270号、ならびにWO2006/128129号に記載されている方法に従って製造できる。
[42]本開示は、神経疾患又は神経障害、又はがんの治療を、それを必要としている対象においてするための方法を提供し、該方法は、アピリモド、又はその薬学的に許容可能な塩、溶媒和物、包接化合物、水和物、多形、代謝産物、プロドラッグ、類似体又は誘導体をグルタミン酸作動薬と組み合わせて投与することを含む。本開示はさらに、神経疾患又は神経障害、又はがんの治療に有用な医薬の製造のために、アピリモド、又はその薬学的に許容可能な塩、溶媒和物、包接化合物、水和物、多形、代謝産物、プロドラッグ、類似体又は誘導体をグルタミン酸作動薬と組み合わせて使用することを提供する。
[47]本明細書中に記載の方法は、アピリモドと少なくとも一つのグルタミン酸作動薬とを用いる併用療法に関する。用語“併用療法”又は“共同療法(co-therapy)”は、本明細書中に記載の化合物、例えばアピリモド、又はその薬学的に許容可能な塩、溶媒和物、包接化合物、水和物、多形、代謝産物、プロドラッグ、類似体又は誘導体を、少なくとも一つの追加の薬剤、例えばグルタミン酸作動薬と共に、これらの化合物の共同作用(co-action)から得られる有益効果を提供する目的で特定の治療計画の一部として投与することを含む。有益効果は、神経疾患又は神経障害、又はがんの進行の緩徐化、及び/又は神経疾患又は神経障害、又はがんの一つ又は複数の症状の緩和をもたらしうる。組合せ(併用)の有益効果は、組合せから得られる薬物動態的又は薬力学的共同作用を含むが、これに限定されない。組合せの有益効果は、組合せ中の別の薬剤に関連する毒性、副作用、又は有害事象の軽減にも関連しうる。“併用療法”は、本開示の組合せを偶然及び任意にもたらす別個の単独療法計画の一部として二つ以上のこれらの治療化合物を投与することを包含しないものとする。
[54]本明細書中に記載の方法に従って治療できる神経変性疾患及び障害は、例えば、アルツハイマー病(AD)、筋萎縮性側索硬化症(ALS)、びまん性レビー小体病、運動ニューロン疾患、多発性硬化症(MS)、パーキンソン病(PD)、フリードライヒ失調症、プリオン病、脊髄小脳失調症(SCA)、及び脊髄性筋萎縮症(SMA)などである。治療できるその他のあまり一般的でない神経変性疾患及び障害は、例えば、クロイツフェルト・ヤコブ病(CJD)、進行性核上まひ(PSP、スティール・リチャードソン・オルゼウスキー症候群)、老人性舞踏病、ハンチントン舞踏病、脊髄小脳失調症(SCA)を含む脊髄性運動失調症、フリードライヒ失調症、亜急性硬化性全脳炎、前頭側頭葉変性症、及びハレルフォルデン・スパッツ病(パントテン酸キナーゼ関連神経変性、PKAN)などである。ALS又は前頭側頭型認知症の治療の実施態様において、その治療を必要としている患者は、C9ORF72遺伝子に反復配列異常伸長(repeat expansion)を有する者である。
[58]本明細書中に記載の方法に従って、神経疾患又は神経障害は、双極性障害、治療抵抗性うつ病及び大うつ病、全般性不安障害、パニック障害、社会不安、気分障害、認知障害、激越、無気力、精神病、外傷後ストレス障害、過敏(irritability)、脱抑制、学習障害、記憶喪失、パーソナリティ障害、双極性障害、摂食障害、行為障害、疼痛性障害、譫妄、薬物中毒、耳鳴り、精神遅滞、頸椎性脊髄症、脊髄損傷、遺伝性小脳性運動失調症、トゥレット症候群、自閉症スペクトラム障害、統合失調症、脆弱性X症候群、パーキンソン病及びハンチントン病から選ぶこともできる。
[77]本開示は、神経疾患又は神経障害の治療、又はがんの治療において、グルタミン酸作動薬との併用療法で使用するための、アピリモド、又はその薬学的に許容可能な塩、溶媒和物、包接化合物、水和物、多形、代謝産物、プロドラッグ、類似体又は誘導体を含む医薬組成物を提供する。
[91]医薬組成物は、非経口投与に適切な無菌の水溶液又は分散液の形態でもよい。本明細書中で使用されている非経口という用語は、皮下、皮内、静脈内、筋肉内、関節内、動脈内、滑液嚢内、胸骨内、髄腔内、病巣内及び頭蓋内注射又は注入技術を含む。
[97]アピリモドで治療された患者では、血漿中を循環する各種タンパク質に変化が見られる。これらのうちの一つは、糖タンパク質非転移性メラノーマプロテインB(Glycoprotein Nonmetastatic Melanoma Protein B,GPNMB)で、メラノーマ細胞で最初に同定されたI型膜タンパク質である。それは、細胞表面上での発現に加えて、ADAM10及びADAM12などのマトリックスメタロプロテアーゼの活性によって細胞から放出(又は発散)されることもある。
[100]SOMAscanTMプラットフォームを用いて、アピリモド投与により患者の血漿中で変化した被検体を同定した。SOMAscanTMは、SomaLogic社製のアプタマーベースのプロテオミクスアッセイで、血清又は血漿中の1,305種類のヒトタンパク質被検体を高感度かつ特異的に測定できる。臨床試験指定NCT02594384号に登録された患者の血漿を、投与前(アピリモドの初回投与前)と、アピリモド投与14日後の15日目に採取した。Ritchieらにより、Nucleic Acids Research,43(7),pp.e47(2015)に記載されている“Limma R”ソフトウェアパッケージを用い、マイクロアレイデータの線形モデルのための対応ある実験設計によりディファレンシャル・プロテイン・アナリシスを行った。
Claims (39)
- 神経疾患又は神経障害の治療を、それを必要とする対象においてするための方法であって、アピリモド又はその薬学的に許容可能な塩を含む医薬組成物を、グルタミン酸作動薬と組み合わせて当該対象に投与することを含む、前記方法。
- アピリモドがアピリモドジメシレートである、請求項1に記載の方法。
- グルタミン酸作動薬が、グルタミン酸トランスポーター調節薬及びグルタミン酸受容体アンタゴニストから選ばれる、請求項1又は2に記載の方法。
- グルタミン酸トランスポーター調節薬が興奮性アミノ酸再取込み阻害薬である、請求項3に記載の方法。
- グルタミン酸受容体アンタゴニストが、N−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニストである、請求項3に記載の方法。
- グルタミン酸受容体アンタゴニストが、AP5(R−2−アミノ−5−ホスホノペンタノエート)、AP7(2−アミノ−7−ホスホノヘプタン酸)、CNQX(6−シアノ−7−ニトロキノキサリン−2,3−ジオン)、CPPene(3−[(R)−2−カルボキシピペラジン−4−イル]−プロパ−2−エニル−1−ホスホン酸)、NBQX(2,3−ジヒドロキシ−6−ニトロ−7−スルファモイル−ベンゾ[f]キノキサリン−2,3−ジオン)、及びセルフォテル(CGS−19755)から選ばれる、請求項3に記載の方法。
- グルタミン酸受容体アンタゴニストが、アマンタジン、アトモキセチン、AZD6765、アグマチン、ガシクリジン、ケタミン、メマンチン、エリプロジル、デルセミンから選ばれる、請求項3に記載の方法。
- グルタミン酸作動薬が、BHV−5000、ラモトリギン、ラニセミン、リルゾール、トリグリルゾール、及びトピラメートから選ばれる、請求項1又は2に記載の方法。
- 医薬組成物が、経口剤形又は舌下剤形である、請求項1〜8のいずれか1項に記載の方法。
- グルタミン酸作動薬が、アピリモドと同じ又は異なる剤形で投与される、請求項1〜9のいずれか1項に記載の方法。
- 神経疾患又は神経障害が、アルツハイマー病、筋萎縮性側索硬化症(ALS)、注意欠陥多動性障害、自閉症、小脳性運動失調症、シャルコー・マリー・ツース病、クロイツフェルト・ヤコブ病、認知症、てんかん、フリードライヒ失調症、ハンチントン病、多発性硬化症、強迫性障害(OCD)、パーキンソン病、レット症候群、老人性舞踏病、脊髄性運動失調症、脊髄損傷、核上まひ、外傷性脳損傷から選ばれる、請求項1〜10のいずれか1項に記載の方法。
- 神経疾患又は神経障害が認知症である、請求項11に記載の方法。
- 認知症が、エイズ認知症コンプレックス(ADC)、アルツハイマー病(AD)に伴う認知症、ボクサー認知症、びまん性レビー小体病、前頭側頭型認知症、混合型認知症、レビー小体型老年性認知症、及び血管性認知症から選ばれる、請求項12に記載の方法。
- 神経疾患又は神経障害が筋萎縮性側索硬化症(ALS)である、請求項11に記載の方法。
- 神経疾患又は神経障害がレット症候群である、請求項11に記載の方法。
- 神経疾患又は神経障害が強迫性障害(OCD)である、請求項11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1項に記載の方法。
- 筋萎縮性側索硬化症(ALS)の治療を、それを必要とする対象においてするための方法であって、アピリモド又はその薬学的に許容可能な塩を含む医薬組成物を、リルゾール及びトリグリルゾールから選ばれるグルタミン酸作動薬と組み合わせて当該対象に投与することを含む、前記方法。
- アルツハイマー病の治療を、それを必要とする対象においてするための方法であって、アピリモド又はその薬学的に許容可能な塩を含む医薬組成物を、リルゾール及びトリグリルゾールから選ばれるグルタミン酸作動薬と組み合わせて当該対象に投与することを含む、前記方法。
- 強迫性障害(OCD)の治療を、それを必要とする対象においてするための方法であって、アピリモド又はその薬学的に許容可能な塩を含む医薬組成物を、リルゾール及びトリグリルゾールから選ばれるグルタミン酸作動薬と組み合わせて当該対象に投与することを含む、前記方法。
- レット症候群の治療を、それを必要とする対象においてするための方法であって、アピリモド又はその薬学的に許容可能な塩を含む医薬組成物を、BHV−5000及びラニセミンから選ばれるグルタミン酸作動薬と組み合わせて当該対象に投与することを含む、前記方法。
- がんの治療を、それを必要とする対象においてするための方法であって、アピリモド又はその薬学的に許容可能な塩を含む医薬組成物を、リルゾール及びトリグリルゾールから選ばれるグルタミン酸作動薬、好ましくはトリグリルゾールと組み合わせて当該対象に投与することを含む、前記方法。
- がんが、脳腫瘍、乳がん、子宮頸がん、結腸直腸がん、白血病、肺がん、リンパ腫、メラノーマ又はその他の皮膚がん、卵巣がん、前立腺がん、腎がん、及び精巣がんから選ばれる、請求項22に記載の方法。
- アピリモドがアピリモドジメシレートである、請求項18〜23のいずれか1項に記載の方法。
- 前記対象がヒトである、請求項18〜24のいずれか1項に記載の方法。
- 神経疾患又は神経障害の治療においてグルタミン酸作動薬との併用療法で使用するための、アピリモドを含む医薬組成物。
- アピリモドがアピリモドジメシレートである、請求項26に記載の医薬組成物。
- グルタミン酸作動薬が、グルタミン酸トランスポーター調節薬及びグルタミン酸受容体アンタゴニストから選ばれる、請求項26又は27に記載の医薬組成物。
- グルタミン酸トランスポーター調節薬が興奮性アミノ酸再取込み阻害薬である、請求項28に記載の医薬組成物。
- グルタミン酸受容体アンタゴニストが、N−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニストである、請求項28に記載の医薬組成物。
- グルタミン酸受容体アンタゴニストが、アマンタジン、アトモキセチン、AZD6765、アグマチン、ガシクリジン、メマンチン、エリプロジル、デルセミンから選ばれる、請求項28に記載の医薬組成物。
- グルタミン酸作動薬が、リルゾール、トリグリルゾール、BHV−5000、及びラニセミンから選ばれる、請求項26又は27に記載の医薬組成物。
- アピリモドとグルタミン酸作動薬が同じ剤形に含有される、請求項26〜32のいずれか1項に記載の医薬組成物。
- 神経疾患又は神経障害が、アルツハイマー病、筋萎縮性側索硬化症(ALS)、注意欠陥多動性障害、自閉症、小脳性運動失調症、シャルコー・マリー・ツース病、クロイツフェルト・ヤコブ病、認知症、てんかん、フリードライヒ失調症、ハンチントン病、多発性硬化症、強迫性障害(OCD)、パーキンソン病、レット症候群、老人性舞踏病、脊髄性運動失調症、脊髄損傷、核上まひ、及び外傷性脳損傷から選ばれる、請求項26〜33のいずれか1項に記載の医薬組成物。
- 神経疾患又は神経障害が認知症である、請求項34に記載の医薬組成物。
- 認知症が、エイズ認知症コンプレックス(ADC)、アルツハイマー病(AD)に伴う認知症、ボクサー認知症、びまん性レビー小体病、前頭側頭型認知症、混合型認知症、レビー小体型老年性認知症、及び血管性認知症から選ばれる、請求項35に記載の医薬組成物。
- 神経疾患又は神経障害が筋萎縮性側索硬化症(ALS)である、請求項34に記載の医薬組成物。
- 神経疾患又は神経障害がレット症候群である、請求項34に記載の医薬組成物。
- 神経疾患又は神経障害が強迫性障害(OCD)である、請求項34に記載の医薬組成物。
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MX2020008680A (es) | 2020-09-25 |
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RU2020130837A (ru) | 2022-03-21 |
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KR20200138714A (ko) | 2020-12-10 |
RU2020130837A3 (ja) | 2022-03-21 |
CN111801098A (zh) | 2020-10-20 |
CA3090807A1 (en) | 2019-08-29 |
BR112020016256A2 (pt) | 2020-12-15 |
JP7354123B2 (ja) | 2023-10-02 |
AU2019223014A1 (en) | 2020-08-20 |
TW202000205A (zh) | 2020-01-01 |
WO2019164861A1 (en) | 2019-08-29 |
US11957688B2 (en) | 2024-04-16 |
IL276609A (en) | 2020-09-30 |
US10751345B2 (en) | 2020-08-25 |
EP3755332A1 (en) | 2020-12-30 |
US20190255061A1 (en) | 2019-08-22 |
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