JP7369033B2 - 線維症の治療 - Google Patents
線維症の治療 Download PDFInfo
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- JP7369033B2 JP7369033B2 JP2019524917A JP2019524917A JP7369033B2 JP 7369033 B2 JP7369033 B2 JP 7369033B2 JP 2019524917 A JP2019524917 A JP 2019524917A JP 2019524917 A JP2019524917 A JP 2019524917A JP 7369033 B2 JP7369033 B2 JP 7369033B2
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Description
線維状結合組織の形成は、損傷または炎症による組織損傷後の正常な治癒過程の一部である。この過程の間、マクロファージなどの活性化免疫細胞は、線維芽細胞の増殖および活性化を刺激し、次に、結合組織を沈着させる。しかし、結合組織の異常なまたは過剰な産生は、線維状物質の蓄積に繋がり得、その結果、組織の正常な機能を妨害する。線維増殖は拡大し、健康な周囲組織を侵害し得る。修復または反応性過程で発生するこのような異常な過剰結合組織の形成は、線維化と呼ばれる。
肝臓の線維化は、本明細書では肝線維症とも呼ばれ、様々な種類の慢性肝損傷により、特に、炎症性要素が伴う場合に、引き起こされ得る。自己限定性の、急性肝損傷(例えば、急性ウイルス性肝炎A)は、劇症型であっても、足場構造を変型させるとは限らず、したがって、通常、肝細胞が減少にもかかわらず、線維症を生じない。しかし、慢性アルコール症、栄養障害、血色素症、および毒物、毒素または薬物への曝露などの因子は、肝細胞障害型の化学物質への曝露が原因で、慢性肝損傷および肝線維症をもたらす場合がある。手術または機械的な胆管閉塞に関連する他の形態の損傷により引き起こされる肝臓瘢痕もまた、肝線維症につながり得る。
種々の障害の治療用の抗線維化薬の開発の対する試みが報告されてきた。しかし、数ヶ月また数年にわたる慢性または反復損傷後に形成された、既発症線維症の治療は、未だ難題として残されたままである。その初期段階では、原因が可逆的な場合(例えば、ウイルスクリアランスにより)、肝線維症は、退行する。したがって、大部分の利用可能な治療選択肢は、慢性ウイルス性肝炎のB型肝炎ウイルスまたはC型肝炎ウイルスの除去、アルコール性肝疾患における禁酒、血色素症における鉄またはウィルソン病における銅などの重金属の除去、および胆管閉塞における胆管の除圧などにより肝損傷の根源を除去するように設計されている。
肝疾患の治療用の特定の抗線維化薬の開発の対する試みが報告されてきた。例えば、米国特許第8、729、046号は、核酸または核酸類似体の組み合わせを用いた、肝臓の線維化を含む組織の線維化を治療する方法に関する。具体的には、核酸またはその類似体は、miR23bクラスターのマイクロRNAを標的とする。米国特許第6、562、829号は、肝線維症を治療する組成物および該組成物の使用および製造方法、キナゾリノン誘導体、好ましくはハロフジノンを含む組成物を開示している。米国特許第8、858、954号は、肝線維症または非アルコール性脂肪性肝疾患を予防および治療するための医薬組成物に関し、該組成物は、50~90重量%の冬虫夏草菌糸体粉末、および10~50重量%の濃縮レンゲソウ粉末を含む。
脂肪酸胆汁酸塩コンジュゲートは、脂肪酸胆汁酸コンジュゲート(Fatty Acid Bile Acid Conjugate)(FABAC)とも呼ばれ、胆汁酸またはコレステロール代謝に関連する状態を改善するために使用され得る合成分子のファミリーである。FABACは、血中コレステロール濃度を下げ、肝脂肪レベルを低減し、胆石を溶解すると考えられている(Gilat et al.、Hepatology 2003;38:436-442;and Gilat et al.、Hepatology 2002;35:597-600)。FABACは、アラムコールとしても知られる、3β-アラキジルアミド-7α,12α-ジヒドロキシ-5β-コラン-24-酸を含む。
アラムコールは、化学名3β-アラキジルアミド-7α,12α-ジヒドロキシ-5β-コラン-24-酸であり、次の化学構造により表される:
W-X-G (I)
本発明は、報告された脂肪肝および脂肪症に対する作用とは別に、アラムコールが効力の高い抗線維化効果を発揮し、種々の実験モデルにおいて線維化を低減するという意外な発見に、一部は基づいている。具体的には、アラムコール(5mg/kg)による治療は、インビボチオアセタミド(TAA)モデルで、毒素誘導による肝硬変、壊死および肝線維症の発症を有意に抑制した。アラムコールはまた、意外にも、オベチコール酸(OCA)よりすぐれていることが明らかになった。OCAは、試験した実験条件下で、これらのパラメーターの統計的に有意な低減を誘導しなかった。さらに、アラムコールは、PPARγの上方制御によりLX-2ヒト肝臓星状細胞中のCOL1A1発現を有意に低減させたこの場合も、アラムコールは、意外にも、既発症線維症を元に戻し、特に星状細胞中のコラーゲンの産生を低減させるのに効果的であることが明らかになった。
いくつかの実施形態では、投与される化合物(例えば、アラムコール)は、治療有効量の少なくとも1種の前記化合物を含む組成物(本発明の組成物と呼ばれる)の形態である。本明細書で使用される場合、「有効量」という用語は、本明細書に記載の障害または症状を軽減および/または弱めることができる化合物の量を意味する。本発明により投与される化合物の特定の投与量は、無論、例えば、投与される化合物、投与経路、対象の生理学的状態、および治療される状態を含む、特定の周辺環境により決定されるであろう。
ある実施形態では、対象の治療は、対象のNAFLD活性(NAS)スコアの悪化のないことを含む。
アラムコールの投与開始時のレベルまたは比率に比べて、対象の、
a.ヘモグロビンA1CまたはHOMA-IRのレベルを低減する;
b.フィブリノーゲン、CK-18、C反応性タンパク質(CRP)、TNFα、IL6および線維症試験(NFS)のレベルを低減する;
c.レプチンのアジノペクチンに対する比率を低減する;または
d.前記アジノペクチンのレベルを高める;
ことを含む。
a.アラムコールの投与の開始時のヒト対象の体重に比べて、ヒト対象の体重を低減する;
b.アラムコールの投与の開始時のヒト対象の胴回りに比べて、ヒト対象の胴回りを低減する;または
c.アラムコールの投与の開始時のヒト対象の脂肪肝指数に比べて、ヒト対象の脂肪肝指数を低減する、
ことを含む。
a.ヘモグロビンA1CまたはHOMA-IRのレベルを低減する;
b.フィブリノーゲン、CK-18、C反応性タンパク質(CRP)、TNFα、IL6および線維症試験(NFS)のレベルを低減する;
c.レプチンのアジノペクチンに対する比率を低減する;または
d.アジノペクチンのレベルを高める;
のに効果的である。
a.投与の開始時のヒト対象の体重に比べて、ヒト対象の体重を低減する;
b.投与の開始時のヒト対象の胴回りに比べて、ヒト対象の胴回りを低減する;または
c.投与の開始時のヒト対象の脂肪肝指数に比べて、ヒト対象の脂肪肝指数を低減する、のに効果的である。
C-Cモチーフケモカイン受容体CCR5は、AIDSの原因となるウイルスのHIVが細胞に侵入するプロセスに関与する。CCR5受容体アンタゴニストは、CCR5受容体をアンタゴナイズする小分子の種類である。したがって、この受容体のアンタゴニストは、進入阻害剤であり、HIV感染症の治療において潜在的治療用途を有する。C-Cケモカイン受容体2型(CCR2)は、ヒト中でCCR2遺伝子によりコードされるタンパク質である。この遺伝子は、単球およびマクロファージなどの細胞の走化性を特異的に媒介するケモカインである、単球化学誘引物質タンパク質1(CCL2)の受容体の2つのアイソフォームをコードする。セニクリビロック((S、E)-8-(4-(2-ブトキシエトキシ)フェニル)-1-イソブチル-N-(4-(((1-プロピル-1H-イミダゾール-5-イル)メチル)スルフィニル)フェニル)-1、2、3、4-テトラヒドロベンゾ[b]アゾシン-5-カルボキサミド、CAS番号497223-25-3)は、CCR2およびCCR5受容体の両方の阻害剤である。
実施例は、本発明のより完全な理解を容易にするために以下に提供されている。以下の実施例は、例示方式により本発明の作製および実施について示す。しかし、本発明の範囲は、例示のみを目的とするこれらの実施例で開示される特定の実施形態に限定されるものではない。
TAA(20mg/100g体重)の週2回、10週にわたる腹腔内注射により、肝線維症をウィスターラットで誘導した。TAAの腹腔内適用は、肝臓小葉中心壊死、アミノ基転移酵素活性上昇および堅牢な肝線維症を生じる。治療群には、さらにアラムコール(1または5mg/kg経口)またはオベチコール酸(OCA、5mg/kg)の同時投与を含めた。対照群の生理食塩水処理ラット(TAA投与なし)をさらに含めた。その後、ラットを屠殺し、肝臓の肝硬変および壊死性病変の徴候を目視で観察し、マッソンゴールドナー染色後に、顕微鏡で観察した。0~4のスケールで計算した線維症スコアを、それぞれの試料に対し決定した。この場合、0は線維症なしで、4は進行型線維症および肝硬変を示す。
LX2細胞(150、000個の細胞/ウエル)を抗生物質、グルタミンおよびウシ胎仔血清含有DMEM培地に播種した。24時間のインキュベーション後、培地を0%血清に変更し、さらに追加の16時間にわたりインキュベートした。その後、アラムコール(10mM)を加え、24時間後、RNAをトリゾールで抽出した。
以下に記載の試験は、0.1%メチオニンおよびコリン欠乏(0.1MCD)食NASHマウスモデルを用いて、アラムコールの作用機序および線維症に対するその潜在的作用を調査する。
概要
これは、多施設第IIb相ランダム化二重盲検プラセボ対照試験であり、試験に入る前の6ヶ月の期間中に実施された肝臓生検により確認された非アルコール性脂肪性肝炎(NASH)の、体重過剰または肥満症で前糖尿病またはII型糖尿病の18~75歳の被験者に対する2種のアラムコール投与量の効力と安全性を評価するように設計された試験である。
薬物:アラムコール
a.1錠のアラムコール400mgおよびアラムコールと釣り合う用量の1錠のプラセボ。
b.1錠のアラムコール400mgおよび1錠のアラムコール200mg。
c.アラムコールと釣り合う用量の2錠のプラセボ。錠剤は朝の朝食後30分以内にコップ1杯の水(250ml)と共に経口摂取するとよい。
実験:アラムコール600mg
a.1錠のアラムコール400mgおよび1錠のアラムコール200mg。
b.介入:薬物:アラムコール
a.1錠のアラムコール400mgおよび1アラムコールと釣り合う用量の1錠のプラセボ。
b.介入:薬物:アラムコール
a.アラムコールと釣り合う用量の2錠のプラセボ。
b.介入:薬物:アラムコール
240人
18歳~75歳の男性または女性。
除外基準:
これは、多施設第IIb相ランダム化二重盲検プラセボ対照試験であり、試験に入る前の6ヶ月の期間中に実施された肝臓生検により確認された非アルコール性脂肪性肝炎(NASH)の、体重過剰または肥満症で前糖尿病またはII型糖尿病の18~75歳の被験者に対する2種のアラムコール投与量の効力と安全性を評価するように設計された試験である。
a.バイタルサインが各試験来診時に測定される。
b.身体検査が、スクリーニング来診時、24週目、治療の終わり/早期終了時、および65週目の来診時に実施される。
主要および副次評価項目(400mg群)
400mgのアラムコールによる治療は、磁気共鳴分光法(MRS)により測定して、肝臓トリグリセリド比率を有意に低減する。
400mgのアラムコールによる治療は、被験者の肝臓トリグリセリドに対するアラムコールの効果に基づく予測を有意に超えて、被験者の線維症スコアの悪化を抑制する。
600mgのアラムコールによる治療は、磁気共鳴分光法(MRS)により測定して、肝臓トリグリセリド比率を有意に低減する。
600mgのアラムコールによる治療は、被験者の肝臓トリグリセリドに対するアラムコールの効果に基づく予測を有意に超えて、被験者の線維症スコアの悪化を抑制する。
本明細書に記載の調査に基づいて、アラムコールは、意外にも、強力な抗線維化および抗肝硬変剤であることが明らかになった。アラムコールはまた、意外にも、OCAより優れており、肝線維症に対する改善された効果的な治療を提供することも明らかになった。したがって、アラムコールは、急性または致命的肝不全および/または肝性脳症または門脈体循環性脳症、例えば、毒素による肝不全および/または肝性脳症を防止するために使用し得る。
Claims (1)
- 肝線維症に罹患しているヒト対象の肝線維症を治療するための薬剤を調製するための、1日当たり350mgないし1200mgの用量の、3β-アラキジルアミド-7α,12α-ジヒドロキシ-5β-コラン-24-酸(アラムコール)、またはその薬学的に許容可能な塩の使用であって、
前記肝線維症の治療は、前記対象の肝臓におけるコラーゲン産生の下方制御を含み、それによって前記対象の前記肝線維症を治療し、
前記肝線維症が、機械的な閉塞、受動的充血、毒物または毒素への曝露、梅毒、毒素による肝炎、貯蔵または代謝肝障害、先天性肝線維症、薬剤誘発性肝炎、寄生虫性肝炎、原発性硬化性胆管炎、バッド・キアリ症候群、肝静脈閉塞症、または門脈血栓症を原因とする、使用。
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MA47558A (fr) | 2019-09-18 |
BR112019009516A2 (pt) | 2019-07-30 |
CA3152584A1 (en) | 2018-05-17 |
AU2017357867A1 (en) | 2019-06-27 |
JP2019534311A (ja) | 2019-11-28 |
KR20190083659A (ko) | 2019-07-12 |
AU2017357867B2 (en) | 2023-12-14 |
EP3538158B1 (en) | 2023-11-01 |
CN110191724A (zh) | 2019-08-30 |
MA46788A (fr) | 2019-09-18 |
IL309558A (en) | 2024-02-01 |
CA3226066A1 (en) | 2018-05-17 |
KR20210042421A (ko) | 2021-04-19 |
EP3538158A1 (en) | 2019-09-18 |
JP2021178863A (ja) | 2021-11-18 |
JP7313405B2 (ja) | 2023-07-24 |
CA3043284A1 (en) | 2018-05-17 |
CA3043284C (en) | 2022-06-28 |
MX2019005533A (es) | 2020-02-07 |
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