JP7479278B2 - Acc阻害剤を含む併用療法 - Google Patents
Acc阻害剤を含む併用療法 Download PDFInfo
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- JP7479278B2 JP7479278B2 JP2020519118A JP2020519118A JP7479278B2 JP 7479278 B2 JP7479278 B2 JP 7479278B2 JP 2020519118 A JP2020519118 A JP 2020519118A JP 2020519118 A JP2020519118 A JP 2020519118A JP 7479278 B2 JP7479278 B2 JP 7479278B2
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Description
本出願は、米国特許法第119条(e)下で、その全体が本明細書に参照により組み込まれる、2017年10月6日に出願した米国仮特許出願第62/569,375号、2017年12月1日に出願した米国仮特許出願第62/593,806号、および2018年4月10日に出願した米国仮特許出願第62/655,704号に対する利益を主張する。
本明細書では、非アルコール性脂肪肝疾患(NAFLD)を処置する、安定化させる、またはその重症度もしくは進行を軽減する、薬物の組合せおよび方法が提供される。
非アルコール性脂肪肝疾患(NAFLD)は、比較的良性の脂肪症からより重症の非アルコール性脂肪肝炎(NASH)までの範囲にわたる状態からなり、後者は、未処置である場合、線維症、肝硬変症、肝不全、または肝細胞癌をもたらす可能性がある。NAFLDは、米国において慢性肝疾患の最も一般的な原因であり、肥満、2型糖尿病、およびメタボリックシンドロームに密接に関連している。
一部の態様では、非アルコール性脂肪肝疾患を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、アセチル-CoAカルボキシラーゼ(ACC)阻害剤を、ペルオキシソーム増殖因子活性化受容体アルファ(PPARα)アゴニストまたは魚油と組み合わせて投与することを含む方法が本明細書に提供されている。
特定の実施形態では、例えば、以下が提供される:
(項目1)
非アルコール性脂肪肝疾患を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、化合物1または化合物2を、PPARαアゴニストまたは魚油と組み合わせて投与することを含み、前記PPARαアゴニストが、アルミニウムクロフィブレート、ベザフィブレート、シプロフィブレート、コリンフェノフィブレート、クリノフィブレート、クロフィブレート、クロフィブリド、フェノフィブレート、ゲムフィブロジル、ペマフィブレート、ロニフィブレート、シンフィブレート、オメガ-3脂肪酸、ピリニクス酸、GW409544、AZ242、LY518674、NS-220、AVE8134、BMS-711939、アレグリタザル、およびムラグリタザルからなる群から選択される、方法。
(項目2)
高トリグリセリド血症の出現を低減もしくは除外、またはその重症度を軽減しながら、非アルコール性脂肪肝疾患を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、化合物1または化合物2をPPARαアゴニストまたは魚油と組み合わせて投与することを含む方法。
(項目3)
前記NAFLDが、脂肪症、非アルコール性脂肪肝炎、非アルコール性脂肪肝炎によって引き起こされる肝線維症、非アルコール性脂肪肝炎によって引き起こされる肝硬変、および非アルコール性脂肪肝炎によって引き起こされる肝細胞癌からなる群から選択される、項目1または2に記載の方法。
(項目4)
非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、化合物1または化合物2を、PPARαアゴニストまたは魚油と組み合わせて投与することを含み、前記PPARαアゴニストが、アルミニウムクロフィブレート、ベザフィブレート、シプロフィブレート、コリンフェノフィブレート、クリノフィブレート、クロフィブレート、クロフィブリド、フェノフィブレート、ゲムフィブロジル、ペマフィブレート、ロニフィブレート、シンフィブレート、オメガ-3脂肪酸、ピリニクス酸、GW409544、AZ242、LY518674、NS-220、AVE8134、BMS-711939、アレグリタザル、およびムラグリタザルからなる群から選択される、方法。
(項目5)
高トリグリセリド血症の出現を低減もしくは除外、またはその重症度を軽減しながら、非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、化合物1または化合物2をPPARαアゴニストまたは魚油と組み合わせて投与することを含む方法。
(項目6)
前記患者が非肝硬変である、項目1から5のいずれか一項に記載の方法。
(項目7)
前記患者がステージ1~4の線維症を有する、項目1から6のいずれか一項に記載の方法。
(項目8)
前記患者が、ベースラインにおいて少なくとも約8%の磁気共鳴画像法プロトン密度脂肪画分(MRI-PDFF)を有する、項目1から7のいずれか一項に記載の方法。
(項目9)
前記患者が、ベースラインにおいて少なくとも約2.5kPaの肝硬度を有する、項目1から8のいずれか一項に記載の方法。
(項目10)
前記患者が、ベースラインにおいて少なくとも約150mg/dLの血漿トリグリセリドレベルを有する、項目1から9のいずれか一項に記載の方法。
(項目11)
処置が、前記患者の前記MRI-PDFFをベースラインと比較して少なくとも約20%低減させる、項目1から10のいずれか一項に記載の方法。
(項目12)
前記処置した患者の少なくとも約3人に1人が、ベースラインと比較してMRI-PDFFの約30%の低減を達成する、項目1から11のいずれか一項に記載の方法。
(項目13)
前記処置が、前記患者の組織メタロプロテイナーゼ阻害物質-1(TIMP-1)の血清レベルをベースラインと比較して少なくとも約5%低減させる、項目1から12のいずれか一項に記載の方法。
(項目14)
前記処置が、前記患者のN末端プロコラーゲンIII-ペプチド(PIII-NP)の血清レベルをベースラインと比較して少なくとも約9%低減させる、項目1から13のいずれか一項に記載の方法。
(項目15)
前記処置した患者の前記血漿トリグリセリドレベルが、前記処置中に有意に増加しない、項目1から14のいずれか一項に記載の方法。
(項目16)
前記処置した患者が、グレード3または4のトリグリセリド上昇を経験しない、項目1から15のいずれか一項に記載の方法。
(項目17)
前記PPARαアゴニストが選択的PPARαアゴニストである、項目1から16のいずれか一項に記載の方法。
(項目18)
前記PPARαアゴニストが、アルミニウムクロフィブレート、ベザフィブレート、シプロフィブレート、コリンフェノフィブレート、クリノフィブレート、クロフィブレート、クロフィブリド、フェノフィブレート、ゲムフィブロジル、ペマフィブレート、ロニフィブレート、シンフィブレート、オメガ-3脂肪酸、GW409544、AZ242、LY518674、NS-220、AVE8134、BMS-711939、アレグリタザル、ムラグリタザルおよびサログリタザルからなる群から選択される、項目2、3、5から16のいずれか一項に記載の方法。
(項目19)
前記PPARαアゴニストが、アルミニウムクロフィブレート、ベザフィブレート、シプロフィブレート、コリンフェノフィブレート、クリノフィブレート、クロフィブレート、クロフィブリド、フェノフィブレート、ゲムフィブロジル、ペマフィブレート、ロニフィブレート、シンフィブレート、オメガ-3脂肪酸、GW409544、AZ242、LY518674、NS-220、AVE8134、BMS-711939、アレグリタザル、ムラグリタザル、サログリタザル、およびエラフィブラノールからなる群から選択される、項目2、3、5から16のいずれか一項に記載の方法。
(項目20)
前記PPARαアゴニストがフィブレートである、項目1から16のいずれか一項に記載の方法。
(項目21)
前記PPARαアゴニストがフェノフィブレートである、項目1から16のいずれか一項に記載の方法。
(項目22)
化合物1が投与される、項目1から21のいずれか一項に記載の方法。
(項目23)
化合物1が毎日1回約20mgの量で投与される、項目22に記載の方法。
(項目24)
化合物2が投与される、項目1から21のいずれか一項に記載の方法。
(項目25)
非アルコール性脂肪肝炎を有する非肝硬変患者において、非アルコール性脂肪肝炎を処置する方法であって、それを必要とする前記患者に、毎日1回約20mgの化合物1を投与することを含む方法。
(項目26)
前記患者がステージ1~3の線維症を有する、項目25に記載の方法。
(項目27)
前記患者が、ベースラインにおいて少なくとも約8%の磁気共鳴画像法プロトン密度脂肪画分(MRI-PDFF)を有する、項目25または26に記載の方法。
(項目28)
前記患者が、ベースラインにおいて少なくとも約2.5kPaの肝硬度を有する、項目25から27のいずれか一項に記載の方法。
(項目29)
前記患者が、約250mg/dL未満のベースライン血漿トリグリセリドレベルを有する、項目25から28のいずれか一項に記載の方法。
(項目30)
前記処置が、前記患者のMRI-PDFFをベースラインと比較して少なくとも約20%低減させる、項目25から29のいずれか一項に記載の方法。
(項目31)
化合物1で処置した前記患者の少なくとも約3人に1人が、ベースラインと比較してMRI-PDFFの約30%の低減を達成する、項目25から30のいずれか一項に記載の方法。
(項目32)
前記処置が、前記患者の組織メタロプロテイナーゼ阻害物質-1(TIMP-1)の血清レベルをベースラインと比較して少なくとも約5%低減させる、項目25から31のいずれか一項に記載の方法。
(項目33)
前記処置が、前記患者のN末端プロコラーゲンIII-ペプチド(PIII-NP)の血清レベルをベースラインと比較して少なくとも約9%低減させる、項目25から32のいずれか一項に記載の方法。
(項目34)
化合物1または化合物2が毎晩1回投与される、項目1から33のいずれか一項に記載の方法。
(項目35)
非アルコール性脂肪肝炎(NASH)に起因する代償性肝硬変を有する患者において、NASHを処置する方法であって、それを必要とする前記患者に、毎日1回約20mgの化合物1を投与することを含む方法。
本明細書に記載されているように、一部の実施形態では、本発明は、非アルコール性脂肪肝疾患(NAFLD)を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、ACC阻害剤をPPARαアゴニストと組み合わせて投与することを含む方法を提供する。
「含む(comprise)」という用語およびその変化形、例えば、「含む(comprises)」および「含んでいる(comprising)」は、オープンの、包括的な意味、すなわち、「~を含むが、これらに限定されない」と解釈されるべきである。さらに、単数形「a」、「an」、および「the」は、文脈で明確に他であると指示されていない限り、複数の指示対象を含む。したがって、「薬剤」についての言及は複数のこのような薬剤を含む。
一部の態様では、非アルコール性脂肪肝疾患(NAFLD)を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、ACC阻害剤をPPARαアゴニストと組み合わせて投与することを含む方法が提供される。一部の実施形態では、非アルコール性脂肪肝疾患を処置する、安定化させる、またはその重症度もしくは進行を軽減する方法であって、それを必要とする患者に、ACC阻害剤をPPARαアゴニストと組み合わせて投与することを含み、PPARαアゴニストが、アルミニウムクロフィブレート、ベザフィブレート、シプロフィブレート、コリンフェノフィブレート、クリノフィブレート、クロフィブレート、クロフィブリド、フェノフィブレート、ゲムフィブロジル、ペマフィブレート、ロニフィブレート、シンフィブレート、オメガ-3脂肪酸(例えば、イコサペント酸エチル(icosapent ethyl)(Vascepa(登録商標))、またはドコサヘキサエン酸)、ピリニクス酸(pirinixic acid)、GW409544、AZ242、LY518674、NS-220、AVE8134、BMS-711939、アレグリタザル、およびムラグリタザル(muraglitzar)からなる群から選択される、方法が提供される。
・ステージ1:線維症による門脈域の拡大;
・ステージ2:門脈域間に稀に架橋を有する門脈域から伸びる線維症;
・ステージ3:肝臓の門脈域と中心静脈域(central area)を連結する線維症の多くの架橋
・ステージ4:<50%の生検の線維症を有する明らかな肝硬変。
化合物1は、化学名(R)-2-(1-(2-(2-メトキシフェニル)-2-((テトラヒドロ-2H-ピラン-4-イル)オキシ)エチル)-5-メチル-6-(オキサゾール-2-イル)-2,4-ジオキソ-1,2-ジヒドロチエノ[2,3-d]ピリミジン-3(4H)-イル)-2-メチルプロパン酸および以下の構造:
化合物2
上に全般的に記載されているように、提供される方法は、ACC阻害剤、例えば、化合物1または化合物2、およびペルオキシソーム増殖因子活性化受容体アルファ(PPARα)アゴニストを含む組合せを含む。
一部の実施形態では、本明細書に提供されている処置の方法は、患者に、1種または複数種の追加の治療剤を投与することをさらに含む。ある特定の実施形態では、1種または複数種の追加の治療剤は、独立して、アンジオテンシンII受容体アンタゴニスト、アンジオテンシン変換酵素(ACE)阻害剤、オートタキシン阻害剤、カスパーゼ阻害剤、カテプシンB阻害剤、CCR2ケモカインアンタゴニスト、CCR5ケモカインアンタゴニスト、クロライドチャネル刺激物質、コレステロール溶解剤、ジアシルグリセロールO-アシルトランスフェラーゼ1(DGAT1)阻害剤、ジアシルグリセロールO-アシルトランスフェラーゼ2(DGAT2)阻害剤 ジペプチジルペプチダーゼIV(DPPIV)阻害剤、ファルネソイドX受容体(FXR)アゴニスト、FXR/TGR5二重アゴニスト、ガレクチン-3阻害剤、グルカゴン様ペプチド1(GLP1)アゴニスト、グルタチオン前駆体、C型肝炎ウイルスNS3プロテアーゼ阻害剤、HMG CoA還元酵素阻害剤、11β-ヒドロキシステロイドデヒドロゲナーゼ(11β-HSD1)阻害剤、IL-1βアンタゴニスト、IL-6アンタゴニスト、IL-10アゴニスト、IL-17アンタゴニスト、回腸の胆汁酸ナトリウム共輸送体阻害剤、レプチン類似体、5-リポキシゲナーゼ阻害剤、LPL遺伝子刺激物質、リシルオキシダーゼホモログ2(LOXL2)阻害剤、リゾホスファチジン酸受容体アンタゴニスト、PDE3阻害剤、PDE4阻害剤、ホスホリパーゼC(PLC)阻害剤、Rho関連タンパク質キナーゼ2(ROCK2)阻害剤、ナトリウムグルコーストランスポーター-2(SGLT2)阻害剤、ステアロイルCoAデサチュラーゼ-1阻害剤、甲状腺ホルモン受容体βアゴニスト、腫瘍壊死因子α(TNFα)リガンド阻害剤、ケトヘキソキナーゼ阻害剤、トランスグルタミナーゼ阻害剤、トランスグルタミナーゼ阻害剤前駆体、血管接着タンパク質(VAP-1)、血小板由来成長因子アンタゴニスト、結合(cynnective)組織成長因子アンタゴニスト、PTP1b阻害剤、およびASK1阻害剤からなる群から選択される。
それを必要とする患者に、約20mgの化合物1を、PPARαアゴニストまたは魚油、および必要に応じて、セロンセルチブ、FXRアゴニスト、またはこれらの組合せから選択される追加の治療剤と組み合わせて投与することを含み、
患者が、投与前に<250mg/dLの血清トリグリセリドレベルを有する、方法が本明細書に提供されている。
それを必要とする患者に、約20mgの化合物2を、PPARαアゴニストまたは魚油、および必要に応じて、セロンセルチブ、FXRアゴニスト、またはこれらの組合せから選択される追加の治療剤と組み合わせて投与することを含み、
患者が、投与前に<250mg/dLの血清トリグリセリドレベルを有する、方法が本明細書に提供されている。
それを必要とする患者に、約20mgの化合物1を、PPARαアゴニストまたは魚油、および必要に応じて、セロンセルチブ、FXRアゴニスト、またはこれらの組合せから選択される追加の治療剤と組み合わせて投与することを含み、
PPARαアゴニストが、フェノフィブレート、ベザフィブレート、エラフィブラノール(elafinbranor)、またはサログリタザルであり、
患者が、PPARαアゴニストまたは魚油と組み合わせた化合物1の投与前に、<250mg/dLの血清トリグリセリドレベルを有する、方法が本明細書に提供されている。
それを必要とする患者に、約20mgの化合物2を、PPARαアゴニストまたは魚油、および必要に応じて、セロンセルチブ、FXRアゴニスト、またはこれらの組合せから選択される追加の治療剤と組み合わせて投与することを含み、
PPARαアゴニストが、フェノフィブレート、ベザフィブレート、エラフィブラノール、またはサログリタザルであり、
患者が、PPARαアゴニストまたは魚油と組み合わせて化合物2を投与する前に、<250mg/dLの血清トリグリセリドレベルを有する、方法が本明細書に提供されている。
それを必要とする患者に、約20mgの化合物1を、PPARαアゴニストまたは魚油、および必要に応じて、セロンセルチブ、FXRアゴニスト、またはこれらの組合せから選択される追加の治療剤と組み合わせて投与することを含み、
PPARαアゴニストが、フェノフィブレート、ベザフィブレート、エラフィブラノール、またはサログリタザルであり、
患者が、化合物1の投与前にPPARαアゴニストまたは魚油を投与される(必要に応じてPPARαアゴニストまたは魚油と組み合わせて)、方法が本明細書に提供されている。
それを必要とする患者に、約20mgの化合物2を、PPARαアゴニストまたは魚油、および必要に応じて、セロンセルチブ、FXRアゴニスト、またはこれらの組合せから選択される追加の治療剤と組み合わせて投与することを含み、
PPARαアゴニストが、フェノフィブレート、ベザフィブレート、エラフィブラノール、またはサログリタザルであり、
患者が、化合物2の投与前にPPARαアゴニストまたは魚油を投与される(必要に応じてPPARαアゴニストまたは魚油と組み合わせて)、方法が本明細書に提供されている。
本明細書に記載されているように、提供される方法は、投与を必要とする患者に、ACC阻害剤、例えば、化合物1または化合物2を、PPARαアゴニストまたは魚油、および必要に応じて1種または複数種の追加の治療剤と組み合わせて投与することを含む。本明細書で使用される場合、ACC阻害剤、例えば、化合物1または化合物2、PPARαアゴニストまたは魚油、および必要に応じた1種または複数種の治療剤の投与に関する「組み合わせて」という用語は、ACC阻害剤、例えば、化合物1または化合物2、PPARαアゴニストまたは魚油、および必要に応じた1種または複数種の治療剤のそれぞれを、患者に、単一組成物、製剤、または単位剤形で、任意の順序(すなわち、同時にまたは逐次)または一緒に投与することができることを意味する。
一部の実施形態では、PPARαアゴニストまたは必要に応じた追加の治療剤は、約0.1mg/日~約1200mg/日の量で投与される。一部の実施形態では、PPARαアゴニストまたは1種または複数種の必要に応じた追加の薬剤のそれぞれは、1mg/日~約100mg/日、約10mg/日~約1200mg/日、約10mg/日~約100mg/日、約100mg/日~約1200mg/日、約400mg/日~約1200mg/日、約600mg/日~約1200mg/日、約400mg/日~約800mg/日または約600mg/日~約800mg/日の量で投与される。一部の実施形態では、本明細書で開示されている方法は、0.1mg/日、0.5mg/日、1mg/日、10mg/日、15mg/日、20mg/日、30mg/日、40mg/日、45mg/日、50mg/日、60mg/日、75mg/日、100mg/日、125mg/日、150mg/日、200mg/日、250mg/日、300mg/日、400mg/日、600mg/日または800mg/日のPPARαアゴニストおよび必要に応じて治療剤の、それを必要とする患者への投与を含む。
一部の実施形態では、PPARαアゴニストおよび1種または複数種の必要に応じた追加の治療剤のそれぞれは、約0.1mg~約2000mg、約1mg~200mg、約35mg~約1400mg、約125mg~約1000mg、約250mg~約1000mg、または約500mg~約1000mgの間のPPARαアゴニストまたは治療剤を含む単位投与量製剤で投与される。
一部の実施形態では、提供される方法は、PPARαアゴニストもしくは魚油または1種もしくは複数種の追加の治療剤を含む薬学的に許容される組成物を1日1回、2回、3回、または4回投与することを含む。
一部の実施形態では、本発明は、本明細書に記載されている方法における使用のための、化合物1もしくは化合物2のいずれか、またはPPARαアゴニストの薬学的に許容される組成物を含む薬学的に許容される組成物を提供する。一部の実施形態では、化合物1または化合物2を含む組成物は、PPARαアゴニストを含む組成物とは別々になっている。一部の実施形態では、化合物1または化合物2、およびPPARαアゴニストは、同じ組成物中に存在する。
NASHを有する患者の第2相、無作為化、プラセボ対照試験における化合物1
方法:この二重盲検プラセボ対照試験において、MRIプロトン密度脂肪画分(PDFF)≧8%およびMRエラストグラフィー(MRE)による肝硬度≧2.5kPaによってNASHを有すると非侵襲性的に診断された、または過去の肝生検がNASHおよびステージ1~3の線維症と一致した、126名の非肝硬変被験体を2:2:1に無作為化して、化合物1、20mg、化合物1、5mg、またはプラセボを経口的にQDで12週間(W12)与えた。中央読影MRI-PDFFおよびMRE、ならびにFibroScanおよび線維症の血清マーカーをベースラインおよびW12において測定した。幾人かの被験体において、トランジェントエラストグラフィー(FibroScan(登録商標);Echosens、Paris、France)を使用して、制御減衰パラメータ(CAP)による肝硬度および肝臓脂肪含有量をベースライン(すなわち第0週)および第12週において評価した。
化合物2およびフェノフィブレート:雄のC57B1/6マウスにおける脂肪肝のファストフード食餌モデルを使用した14日間の経口およびフィード薬理学研究
目的:この研究の目的は、マウスの非アルコール性脂肪症のファストフード食餌誘発性モデルにおける10~14日間の化合物2の投与後の血漿および肝臓TGへの重水素取り込みならびに肝臓の分子生物学に対する化合物2の効果を評価することである。この研究に登録したマウスには、研究開始前のほぼ9カ月間ファストフード食餌を給餌した。主要評価項目は、血漿TGへの重水素取り込み、全血漿TG、ならびに肝臓からのPPARα、肝臓X受容体(LXR)、およびレチノイン酸X受容体アルファ(RXRα)のクロマチン免疫沈降(IP)である。
雄のC57B1/6マウスの脂肪肝のファストフード食餌モデルを使用した、固形飼料で毎日1回投与した化合物2およびフェノフィブレート:14日間の薬理学研究
目的:この研究の目的は、脂肪、コレステロール、およびフルクトース(ファストフード食餌、FFD)の高い食餌を給餌したマウスにおいて、経口投与した化合物2(10mg/kg、QD)、またはフェノフィブレート(固形飼料で0.1%投与)、または組合せの10~14日間後の血漿および肝臓TGならびに肝臓の分子生物学に対する化合物2の効果を評価することであった。この研究に登録したマウスには、研究開始前のほぼ9カ月間ファストフード食餌を給餌した。主要評価項目は、血漿トリグリセリド、肝臓トリグリセリド、肝臓コレステロール、および肝臓Xレセプターα(LXRα)の肝臓遺伝子発現、およびqPCRによるステロール応答エレメント結合タンパク質-1c(SREBP1c)標的遺伝子であった。
NASHに起因する代償性肝硬変を有する患者における化合物1
方法:概念実証研究において、NASHに起因する代償性肝硬変(Child-Turcotte-Pugh[CTP]-A)の疑いのある10人の被験体(生検、磁気共鳴エラストグラフィーによる肝硬度[MRE]≧4.67kPaまたはトランジェントエラストグラフィー≧14.0kPa、またはFibrotest≧0.75のいずれか1つにより定義される)には、化合物1、20mgを経口的に毎日1回12週間与えた。中央読影磁気共鳴画像法-プロトン密度脂肪画分(MRI-PDFF)およびMRE、ならびに線維症の血清マーカーをベースライン(BL)、第4週(W4)、および第12週(W12)において測定した。DNL決定のために、重水(2H2O、35mL)を、ベースライン、W4、およびW12の前に、毎日3回、1週間のサイクルの間投与した。パルミテートへの重水素取り込みをGC/MSにより空腹時血漿試料中において測定し、質量アイソトポマー分布分析を使用して、肝臓のDNLおよび化合物1によるその阻害を計算した。
患者における化合物1
脂肪症(MRI-PDFF≧10%)およびF1~F3線維症(MRE≧2.88kPaであるが、FibroText<0.75、過去のイメージングおよび肝生検に基づく非肝硬変)を有する10人の被験体を20mgの化合物1で12週間処置した。
NASHを有する患者における化合物1
F3~F4 NASH線維症と共に代償性肝機能(非侵襲性マーカーおよび6カ月以内のスクリーニングによる過去の生検によって決定してもよい)を示す被験体を含めた、既存のフィブレートまたは魚油を受けていない被験体に、20mgの化合物1および投与量強度で与えられるフェノフィブレート(例えば、145mg)を投与する。トリグリセリド>250mg/dLを有する被験体が数名(ほぼ75%)登録されてもよいが、トリグリセリド(trigliceride)>750mg/dLを有する被験体は除外され得る。肝臓生化学(ALT、AST、GGT)、線維症の血清マーカー(例えば、ELFおよびその構成成分)および代謝(例えば、HBA1C、インスリン、グルコース、アシルカルニチン)、およびイメージング(例えば、MRI-PDFF、MRE、Fibroscan)を、様々な時間間隔、例えば、第0週、第4週、第8週、第12週、および第24週で測定する。
化合物2およびフェノフィブレートの毎日1回の経口投与:雄のC57BL/6マウスにおいて脂肪肝のファストフード食餌モデルを使用した15日の薬理学研究
目的:この研究の目的は、高脂肪、高コレステロール、および高フルクトース(ファストフード食餌、FFD(研究食餌D12079B))の食餌を給餌したマウスにおいて、化合物2(5mg/kg、QD)、フェノフィブレート(25mg/kgおよび50mg/kg、QD)、または組合せ(化合物2(5mg/kg、QD)+フェノフィブレート(50mg/kg、QD))の15日間の経口投与(「PO」)後、化合物2の血漿および肝臓トリグリセリド(TG)ならびに肝臓の分子生物学に対する効果を評価することであった。この研究に登録したマウスには、研究開始前のほぼ9カ月間FFDを給餌した。主要評価項目は、血漿TG、肝臓TG、肝臓ケトン体、血漿肝臓酵素、肝臓の酸化ストレスならびに肝臓Xレセプターα(LXRα)およびPPARα標的の肝臓遺伝子発現、ならびにqPCRによる線維化促進マーカーであった。
Claims (18)
- 非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減するための組み合わせ物であって、前記組み合わせ物は、(i)化合物1:
- 高トリグリセリド血症の重症度を軽減しながら、非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減するための組み合わせ物であって、前記組み合わせ物は、(i)化合物1:
- 前記ヒト患者が、少なくとも約150mg/dLの血漿トリグリセリドレベルを有する、請求項1から2のいずれか一項に記載の組み合わせ物。
- 前記ヒト患者が、NASHに起因する代償性肝硬変を有する、請求項1から3のいずれか一項に記載の組み合わせ物。
- 毎日1回約20mgの化合物1が投与されることを特徴とする、請求項1から4のいずれか一項に記載の組み合わせ物。
- 非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減するための組成物であって、前記組成物は、化合物1:
- 非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減するための組成物であって、前記組成物は、フェノフィブレートまたはその塩を含み、前記組成物は、それを必要とする患者に、化合物1:
- 高トリグリセリド血症の重症度を軽減しながら、非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減するための組成物であって、前記組成物は、化合物1:
- 高トリグリセリド血症の重症度を軽減しながら、非アルコール性脂肪肝炎を処置する、安定化させる、またはその重症度もしくは進行を軽減するための組成物であって、前記組成物は、フェノフィブレートまたはその塩を含み、前記組成物は、それを必要とする患者に、化合物1:
- 1日当たり約48mgのフェノフィブレートが投与されることを特徴とする、請求項1または請求項2に記載の組み合わせ物。
- 1日当たり約145mgのフェノフィブレートが投与されることを特徴とする、請求項1または請求項2に記載の組み合わせ物。
- 前記組み合わせ物が、FXRアゴニストと組み合わせて投与されることを特徴とし、前記FXRアゴニストがオベチコール酸またはPX-102である、請求項10または請求項11に記載の組み合わせ物。
- フェノフィブレートの投与が、化合物1の投与前に開始され、必要に応じて、前記化合物1の投与の少なくとも一部の間継続されることを特徴とする、請求項1または請求項2に記載の組み合わせ物。
- フェノフィブレートの投与と化合物1の投与が同時である、請求項1または請求項2に記載の組み合わせ物。
- 1日当たり約30mgの前記FXRアゴニストが投与されることを特徴とする、請求項12に記載の組み合わせ物。
- 1日当たり約30mg~約200mgのフェノフィブレートが投与されることを特徴とする、請求項1または2に記載の組み合わせ物。
- 前記ヒト患者が、少なくとも約150mg/dLの血漿トリグリセリドレベルを有する、請求項6から9のいずれか一項に記載の組成物。
- 前記組成物が約20mgの化合物1を含む、請求項6から9のいずれか一項に記載の組成物。
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CA2971640C (en) | 2015-07-06 | 2020-09-22 | Gilead Sciences, Inc. | Cot modulators and methods of use thereof |
CA3055581C (en) | 2017-03-28 | 2023-03-14 | Gilead Sciences, Inc. | Methods of treating liver disease |
WO2019071216A1 (en) * | 2017-10-06 | 2019-04-11 | Gilead Sciences, Inc. | POLYTHERAPY COMPRISING AN ACC INHIBITOR |
TWI770527B (zh) | 2019-06-14 | 2022-07-11 | 美商基利科學股份有限公司 | Cot 調節劑及其使用方法 |
AR119594A1 (es) | 2019-08-09 | 2021-12-29 | Gilead Sciences Inc | Derivados de tienopirimidina como inhibidores acc y usos de los mismos |
KR20220161438A (ko) | 2020-03-30 | 2022-12-06 | 길리애드 사이언시즈, 인코포레이티드 | Cot 억제제 화합물, (S)-6-(((1-(바이사이클로[1.1.1]펜탄-1-일)-1H-1,2,3-트라이아졸-4-일)2-메틸-1-옥소-1,2-다이하이드로아이소퀴놀린-5-일)메틸)))아미노8-클로로-(네오펜틸아미노)퀴놀린-3-카르보니트릴의 고체 형태 |
WO2021202688A1 (en) | 2020-04-02 | 2021-10-07 | Gilead Sciences, Inc. | Process for preparing a cot inhibitor compound |
US11478533B2 (en) | 2020-04-27 | 2022-10-25 | Novo Nordisk A/S | Semaglutide for use in medicine |
WO2022192428A1 (en) | 2021-03-11 | 2022-09-15 | Gilead Sciences, Inc. | Glp-1r modulating compounds |
KR20230158542A (ko) | 2021-03-29 | 2023-11-20 | 길리애드 사이언시즈, 인코포레이티드 | Khk 억제제 |
TW202304435A (zh) | 2021-06-04 | 2023-02-01 | 美商基利科學股份有限公司 | 治療nash之方法 |
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US20190134041A1 (en) | 2019-05-09 |
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