JP7022136B2 - 非アルコール性脂肪性肝炎の治療のための方法及び医薬組成物 - Google Patents
非アルコール性脂肪性肝炎の治療のための方法及び医薬組成物 Download PDFInfo
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Description
本出願は、2016年9月28日に提出された米国仮出願第62/400,963号明細書;2017年2月17日に提出された米国仮出願第62/460,606号明細書;及び2017年3月10日に提出された米国仮出願第62/469,722号明細書に対する優先権を主張する。尚、これら文献の各々の全内容をあらゆる目的のために参照により本明細書に組み込むものとする。
非アルコール性脂肪性肝疾患(NAFLD)は、単純な脂肪症から非アルコール性脂肪性肝炎(NASH)、線維症、及び硬変まで、広範囲の肝疾患である。NASHの重要な組織学的特徴としては、脂肪症、肝細胞風船様腫大、及び実質炎症が挙げられ、一般に線維症も観察される。Takahashi et al.,World J Gastroenterol,2014,20:15539-15548.
本明細書で使用する用語は、特定の実施形態を表すことを目的とし、限定を意図するものではない。本明細書及び続く特許請求の範囲では、いくつかの用語に言及がなされるが、これらの用語は、以下に記載する定義を有すると規定される。別に定義されない限り、本明細書で使用される全ての技術及び科学用語は、本発明が属する技術分野の当業者により一般に理解されるものと同じ意味を有する。文脈から明らかに反対の解釈が要求されない限り、単数形は複数形も含む。従って、文脈から明らかに反対の解釈が要求されない限り、単数形「1つの(a)」、「1つの(an)」及び「その(the)」は、複数の指示物も含む。
一態様では、本開示は、NASHの治療のための療法を提供し、これは、治療が必要な患者に、治療有効量のウベニメクスを投与するステップを含む。一部の実施形態では、治療が必要な患者は、NASHと診断された患者である。一部の実施形態では、本明細書に記載のウベニメクスによる治療は、NASH疾患の進行を遅延、停止、又は逆転させる。
本開示の治療法から利益を受ける可能性がある患者は、本明細書で論じる、又は当業者には周知の様々な手段によって容易に識別することができる。加えて、患者がこの治療法に応答しているか否かを決定するための方法も提供する。一部の実施形態では、超音波試験、コンピュータ断層撮影(CT)、及び/又は磁気共鳴イメージング(MRI)をはじめとする腹部画像検査を用いて、疾患を有する患者を診断する、例えば、疾患が存在するか否か、及びその重症度を評価することができる。こうした非侵襲性診断は、要望されれば、肝生検によってさらに決定的に確認することができる。一部の実施形態では、1つ若しくは複数のバイオマーカを用いて、NAFLD又はNASHを診断する。一部の実施形態では、本開示に従って治療しようとする患者は、NASH又はNAFLDの一次診断を受けており、現時点で治療の必要が示される、又は臨床的に発症しているいずれか他の状態(例えば、特定の癌患者、PAH適応、若しくはリンパ浮腫適応)についてウベニメクスによる治療を受けていない。
一部の実施形態では、約1000mg未満(例えば、900mg未満、800未満、750未満、700未満、600mg未満、又は500mg未満)の総1日用量でウベニメクスを投与する。本明細書に記載される場合、用量は、1用量当たり投与される活性成分の量を指し、医薬製剤の量ではない。一部の実施形態では、約5mg~約450mg、例えば、約10mg~約450mg、約20mg~約450mg、約30mg~約450mg、約10mg~約350mg、約20mg~約350mg、約30mg~約350mg、約10mg~約250mg、約20mg~約250mg、又は約30mg~約250mgの総1日用量でウベニメクスを投与する。この1日用量は、1度に全部:1日1回で投与してもよいが、一部の実施形態では、1日1回用量(QD投与)は、少なくとも30mg以上であり得る。BID投与の場合、1日用量は、1日2回10~450mg、例えば、5~225mgであり得るが、一部の実施形態では、BID投与の場合、用量は、少なくとも15mg以上であり得る。TID投与の場合、一部の実施形態では、1日用量は、1日3回15~450mg、例えば、5~150mgであり得るが、一部の実施形態では、TID投与の場合、用量は、少なくとも10mg以上であり得る。一部の実施形態では、少なくとも20mg、少なくとも30mg、少なくとも40mg、又は少なくとも50mgの1日用量でウベニメクスを投与する。一部の実施形態では、約20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、又は450mgの1日用量でウベニメクスを投与する。
一部の実施形態では、ウベニメクス(及び任意選択で第2治療薬)による治療は、予定期間にわたって、不定期間にわたって、又はエンドポイントが達成されるまで投与する。一部の実施形態では、治療は、少なくとも30日若しくは1ヶ月、少なくとも60日若しくは2ヶ月、少なくとも90日若しくは3ヶ月、少なくとも120日若しくは4ヶ月、少なくとも150日若しくは5ヶ月、又は少なくとも180日若しくは6ヶ月にわたる。一部の実施形態では、治療は、少なくとも6ヶ月~1年間継続する。一部の実施形態では、ウベニメクスを少なくとも1ヶ月、少なくとも3ヶ月、又は少なくとも6ヶ月~少なくとも1年にわたって投与する(例えば、本明細書に記載するように、ウベニメクスの継続的な毎日の投与により)。他の実施形態では、患者の生涯にわたって又は投与が有意な治療利益をもたらす上でもはや有効ではなくなるまで、治療を継続する。一部の実施形態では、治療は、継続的に毎日投与する。一部の実施形態では、治療は、ほぼ継続的に毎日投与する(例えば、ウベニメクスを毎日患者に投与するが、患者が1日の処置を受けそこなう場合もある)。
別の態様では、本明細書に記載の方法で使用するためのウベニメクスを含む組成物、単位剤形、医薬品パッケージ、及びキットが提供される。一部の実施形態では、製剤、単位剤形、医薬品パッケージ、及び/又はキットは、NASHの治療に使用することを目的とする。一部の実施形態では、製剤、単位剤形、医薬品パッケージ、及び/又はキットは、NAFLDを有する対象におけるNAFLDからNASHへの進行を遅延又は予防に使用することを目的とする。
別の態様では、ウベニメクスは、1又は複数種の追加治療薬と組み合わせて投与する。一部の実施形態では、NASH(及び/又はNAFLD)を治療する方法は、本開示に従って、さらに併用療法を含んでもよく、併用療法では、治療が必要な患者に、NASH(今日、存在しないが、そのような薬剤は、もしあれば、後に承認されることになる臨床試験中の薬剤を含む)、及び/又はNASHに関連する状態、又はそれらの組合せの治療のために承認される1若しくは複数種の薬剤と組み合わせて、ウベニメクスを投与する。NASHの治療のための併用療法は、さらに1又は複数のライフスタイルの変化と組み合わせてウベニメクスの投与を含んでもよく、そうした変化として、例えば、体重を減らすための運動並びに/又は身体及び/若しくは精神的健康を改善するための活動がある。
STAM(商標)マウスは、約8週間でNASHを発現するC57BL/6マウスへの化学及び食餌介入の組合せにより作出されたNASHのモデルであり、NASHは、約12週間で線維症に進行した後、約16週間でHCCに進行する。Saito et al.,Sci.Rep.2015,5:12466を参照。NASHの治療におけるウベニメクスの効果を実証するために、このモデルを本試験で使用した。
NASHに罹患したヒト対象の2つ以上の群の各々に、ウベニメクスを含む30mgの薬学的有効量を投与するが、1群はQD投与(すなわち、総1日用量30mg)を受け、他の群はBID(すなわち、総1日用量60mg)を受ける。NASHに罹患したヒト対照群にはプラセボを投与する。試験は約6ヶ月にわたって実施し、その間、参加者は、NAFLD活動性スコア、脂肪症スコア、炎症スコア、及び風船様腫大スコアの少なくとも1つの改善についてモニターされる。処置は、前記スコアの1つ又は複数を改善することが予想される。
この試験では、複数の投与レジメンで、NASH線維症のSTAMモデルにおけるウベニメクスの効果を調べた。
生後2日で200μgのストレプトゾトシン(STZ,Sigma-Aldrich,USA)溶液の単回皮下注射を実施し、4週齢後に高脂肪飼料(HFD、57kcal%脂肪、Cat♯HFD32、CLEA Japan Inc.、日本)を給餌することによって40匹の雄マウスにNASHを誘導した。
試験群:以下の試験群を使用した。群1(ビヒクル):8匹のNASHマウスに、10mL/kgの量でビヒクル(RO水)を6~11週齢まで1日2回経口投与した。群2(ウベニメクスQD、5週間):8匹のNASHマウスに、5mg/kgの用量でウベニメクスを添加したビヒクルを6~11週齢まで1日1回経口投与した。群3(ウベニメクスBID、5週間):8匹のNASHマウスに、5mg/kgの用量でウベニメクスを添加したビヒクルを6~11週齢まで1日2回経口投与した。群4(ウベニメクスBID、2週間):8匹のNASHマウスに、5mg/kgの用量でウベニメクスを添加したビヒクルを9~11週齢まで1日2回経口投与した。群5(テルミサルタン、5週間):8匹のNASHマウスに、5mg/kgの用量でテルミサルタンを添加した純水を6~11週齢まで1日1回経口投与した。
犠牲日の平均体重、平均肝臓重量、及び平均肝臓-体重比を全5群について以下の表5に示す。犠牲日の平均体重は、ビヒクル群と比較して、ウベニメクスBID5週間群及びテルミサルタン陽性対照群で有意に低かった。犠牲日の平均体重は、ビヒクル群と比較して、ウベニメクスQD群で減少する傾向があった。ビヒクル群とウベニメクスBID2週間群の間で犠牲日の平均体重に有意な差はなかった。肝臓重量については、テルミサルタン群が、ビヒクル群と比較して平均肝臓重量に有意な減少を示した。平均肝臓重量は、ビヒクル群と比較して、ウベニメクスQD及びウベニメクスBID5週間群で減少する傾向があった。ビヒクル群とウベニメクスBID2週間群の間で、平均肝臓重量に有意な差はなかった。テルミサルタン群は、ビヒクル群と比較して、平均肝臓-体重比に有意な減少を示した。ビヒクル群とウベニメクス処置群の間で、平均肝臓-体重比に有意な差はなかった。
Claims (37)
- 非アルコール性脂肪性肝炎(NASH)を対象において治療するための、治療有効量のウベニメクスを含む医薬。
- 対象が、早期又は中期NASHを有する、請求項1に記載の医薬。
- ウベニメクスが、5mg~1000mgの範囲の総1日用量で投与される、請求項1又は2に記載の医薬。
- ウベニメクスが、約5mg~約450mgの1日用量で投与される、請求項1~3のいずれか1項に記載の医薬。
- ウベニメクスが、約20mg~約450mgの用量でQD投与される、請求項4に記載の医薬。
- ウベニメクスが、約10mg~約200mgの用量でBID投与される、請求項4に記載の医薬。
- ウベニメクスが、約10mg~約150mgの用量でTID投与される、請求項4に記載の医薬。
- ウベニメクスが、少なくとも4週間投与される、請求項1~7のいずれか1項に記載の医薬。
- ウベニメクスが、少なくとも12週間投与される、請求項8に記載の医薬。
- 対象の血漿CK-18レベルの低下をもたらす、請求項1~9のいずれか1項に記載の医薬。
- 対象の肝細胞風船様腫大の軽減をもたらす、請求項1~10のいずれか1項に記載の医薬。
- ウベニメクスが、第2治療薬と組み合わせて投与される、請求項1~11のいずれか1項に記載の医薬。
- 第2治療薬が、ファルネソイドX受容体(FXR)アゴニスト、ペルオキシソーム増殖因子活性化受容体(PPAR)アゴニスト、アラムコール、カスパーゼ阻害剤、ガレクチン3阻害剤、マイトジェン活性化タンパク質キナーゼ5(MAPK5)阻害剤、線維芽細胞増殖因子19(FGF19)アゴニスト、FGF21アゴニスト、ロイコトリエンD4(LTD4)受容体アンタゴニスト、ニアシン類似体、頂端側ナトリウム胆汁酸共輸送体(ASBT)阻害剤、アポトーシスシグナル調節キナーゼ1(ASK1)阻害剤、アンジオテンシン変換酵素(ACE)阻害剤、アンジオテンシン受容体遮断薬、ケモカイン受容体阻害剤、チオゾリジンジオン、GLP-1類似体、ビグアニド、又は非ステロイド性抗炎症薬(NSAID)である、請求項12に記載の医薬。
- 非アルコール性脂肪性肝疾患(NAFLD)を有する対象においてNAFLDからNASHへの進行を遅延させる、又は予防するための、治療有効量のウベニメクスを含む医薬。
- 対象の肝細胞風船様腫大の軽減をもたらす、請求項14に記載の医薬。
- ウベニメクスが、5mg~1000mgの範囲の総1日用量で投与される、請求項14又は15に記載の医薬。
- ウベニメクスが、約5mg~約450mgの1日用量で投与される、請求項14~16のいずれか1項に記載の医薬。
- ウベニメクスが、約20mg~約450mgの用量でQD投与される、請求項17に記載の医薬。
- ウベニメクスが、約10mg~約200mgの用量でBID投与される、請求項17に記載の医薬。
- ウベニメクスが、約10mg~約150mgの用量でTID投与される、請求項17に記載の医薬。
- ウベニメクスが、少なくとも4週間投与される、請求項14~20のいずれか1項に記載の医薬。
- ウベニメクスが、少なくとも12週間投与される、請求項21に記載の医薬。
- NASHを有する対象の肝細胞風船様腫大を低減するための、ウベニメクスを含む医薬であって、治療有効量のウベニメクスが、少なくとも4週間投与される、医薬。
- ウベニメクスが、少なくとも12週間投与される、請求項23に記載の医薬。
- NASHを有する対象の線維症を低減するための、ウベニメクスを含む医薬であって、治療有効量のウベニメクスが、少なくとも24週間投与される、医薬。
- ウベニメクスが、少なくとも48週間投与される、請求項25に記載の医薬。
- ウベニメクスが、第2治療薬と組み合わせて投与される、請求項14~26のいずれか1項に記載の医薬。
- 第2治療薬が、FXRアゴニスト、PPARアゴニスト、アラムコール、カスパーゼ阻害剤、ガレクチン3阻害剤、MAPK5阻害剤、FGF19アゴニスト、FGF21アゴニスト、LTD4受容体アンタゴニスト、ニアシン類似体、ASBT阻害剤、ASK1阻害剤、ACE阻害剤、アンジオテンシン受容体遮断薬、ケモカイン受容体阻害剤、チオゾリジンジオン、GLP-1類似体、ビグアニド、又はNSAIDである、請求項27に記載の医薬。
- NASHを治療する、又はNAFLDからNASHへの進行を遅らせるための、ウベニメクス及び第2治療薬を含む医薬であって、第2治療薬が、FXRアゴニスト、PPARアゴニスト、アラムコール、カスパーゼ阻害剤、ガレクチン3阻害剤、MAPK5阻害剤、FGF19アゴニスト、FGF21アゴニスト、LTD4受容体アンタゴニスト、ニアシン類似体、ASBT阻害剤、ASK1阻害剤、ACE阻害剤、アンジオテンシン受容体遮断薬、ケモカイン受容体阻害剤、チオゾリジンジオン、GLP-1類似体、ビグアニド、又はNSAIDである、医薬。
- ウベニメクスが、少なくとも4週間投与される、請求項29に記載の医薬。
- ウベニメクスが、少なくとも12週間投与される、請求項30に記載の医薬。
- ウベニメクスが、少なくとも24週間投与される、請求項31に記載の医薬。
- NASHを治療する、又はNAFLDからNASHへの進行を遅らせるための、ウベニメクスの単位製剤を含み、第2治療薬の単位製剤をさらに含む医薬品パッケージであって、第2治療薬が、FXRアゴニスト、PPARアゴニスト、アラムコール、カスパーゼ阻害剤、ガレクチン3阻害剤、MAPK5阻害剤、FGF19アゴニスト、FGF21アゴニスト、LTD4受容体アンタゴニスト、ニアシン類似体、ASBT阻害剤、ASK1阻害剤、ACE阻害剤、アンジオテンシン受容体遮断薬、ケモカイン受容体阻害剤、チオゾリジンジオン、GLP-1類似体、ビグアニド、又はNSAIDである、医薬品パッケージ。
- ウベニメクスの各単位製剤が、約5mg~約450mgの量でウベニメクスを含む、請求項33に記載の医薬品パッケージ。
- ウベニメクスが、即放用に製剤化される、請求項33又は34に記載の医薬品パッケージ。
- ウベニメクスが、制御放出用に製剤化される、請求項33又は34に記載の医薬品パッケージ。
- ウベニメクスが、錠剤、カプセル、又は丸薬の形態である、請求項33~36のいずれか1項に記載の医薬品パッケージ。
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US201762460606P | 2017-02-17 | 2017-02-17 | |
US62/460,606 | 2017-02-17 | ||
US201762469722P | 2017-03-10 | 2017-03-10 | |
US62/469,722 | 2017-03-10 | ||
PCT/US2017/054087 WO2018064373A1 (en) | 2016-09-28 | 2017-09-28 | Methods and pharmaceutical compositions for the treatment of non-alcoholic steatohepatitis |
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EP3518918A4 (en) | 2016-09-28 | 2020-04-22 | Eiger Biopharmaceuticals, Inc. | METHOD AND PHARMACEUTICAL COMPOSITIONS FOR TREATING NON-ALCOHOLIC STEATOHEPATITIS |
JP2021504479A (ja) * | 2017-11-28 | 2021-02-15 | アイガー・バイオファーマシューティカルズ・インコーポレイテッドEiger Biopharmaceuticals, Inc. | 非アルコール性脂肪性肝炎の処置のための方法および医薬組成物 |
EP3784657A4 (en) * | 2018-04-24 | 2022-02-09 | pH Pharma Co., Ltd. | USE OF NEUTROPHIL ELASTASE INHIBITORS IN LIVER DISEASE |
EP3811937A1 (en) * | 2019-10-24 | 2021-04-28 | Sorbonne Universite | Compounds for use in the prevention and/or treatment of non-alcoholic fatty liver disease |
US11478533B2 (en) | 2020-04-27 | 2022-10-25 | Novo Nordisk A/S | Semaglutide for use in medicine |
WO2023076679A1 (en) | 2021-11-01 | 2023-05-04 | Alkahest, Inc. | Benzodioxane modulators of leukotriene a4 hydrolase (lta4h) for prevention and treatment of aging-associated diseases |
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US11571403B2 (en) | 2023-02-07 |
US10588880B2 (en) | 2020-03-17 |
JP2019529566A (ja) | 2019-10-17 |
CN109862888A (zh) | 2019-06-07 |
US20190307714A1 (en) | 2019-10-10 |
KR102399254B1 (ko) | 2022-05-17 |
WO2018064373A1 (en) | 2018-04-05 |
EP3518918A1 (en) | 2019-08-07 |
KR20190058532A (ko) | 2019-05-29 |
US20200237696A1 (en) | 2020-07-30 |
EP3518918A4 (en) | 2020-04-22 |
CN109862888B (zh) | 2022-08-12 |
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