TWI833753B - 用於治療hcv之組合療法 - Google Patents
用於治療hcv之組合療法 Download PDFInfo
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- TWI833753B TWI833753B TW108116038A TW108116038A TWI833753B TW I833753 B TWI833753 B TW I833753B TW 108116038 A TW108116038 A TW 108116038A TW 108116038 A TW108116038 A TW 108116038A TW I833753 B TWI833753 B TW I833753B
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- Taiwan
- Prior art keywords
- hcv
- pharmaceutically acceptable
- acceptable salt
- inhibitor
- compound
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- 238000002648 combination therapy Methods 0.000 title abstract description 29
- 238000011282 treatment Methods 0.000 title abstract description 24
- 239000003112 inhibitor Substances 0.000 claims abstract description 125
- 229940126062 Compound A Drugs 0.000 claims abstract description 51
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 51
- 241000711549 Hepacivirus C Species 0.000 claims description 128
- 150000003839 salts Chemical class 0.000 claims description 103
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Abstract
本文揭示了藉由投與化合物A及一第二HCV抑制劑來治療或預防HCV之組合治療方法。
Description
本發明係關於藉由投與化合物A及第二HCV抑制劑來治療或預防HCV的組合療法。
C型肝炎病毒(HCV)為屬於黃病毒科之C型肝炎病毒屬(Hepacivirus
)中的一種被膜正義單股RNA病毒。HCV感染為人體內肝病及肝硬化之主要原因。感染通常為無症狀的,或者症狀為輕微的,且約15-20%之感染者能夠在不進行治療的情況下清除病毒。然而,其餘80-85%感染者之感染發展為持續性感染,其可能為終生的,導致肝病,其會引起肝硬化及肝細胞癌。HCV感染為美國最常見之慢性血源性疾病,影響約4百萬人,且每年造成約12,000人死亡。「評估急性C型肝炎感染監測(Evaluation of Acute Hepatitis C Infection Surveillance)-美國,2008,」MMWR
,2010年11月5日,59(43)。全世界約有1.7億人具有慢性C型肝炎感染。Chen等人,《醫學科學國際雜誌(Int J Med Sci
)》,2006,3(2):47-52。
HCV具有簡單的基因組,其駐存於約9.6 kb之單開放閱讀框中。在受感染之細胞中轉譯基因組以產生約3000個胺基酸之單聚合蛋白,然後藉由宿主與病毒酶處理蛋白分解以產生至少10種結構及非結構(NS)蛋白-包膜蛋白EL與E2、膜結合蛋白p7及非結構蛋白NS2、NS3、NS4A、NS4B、NS5A及NS5B。病毒在受感染之人中多樣化為16種不同之抗原及/或基因上可鑑別之亞型或基因型,其中一些進一步細分為亞型。
HCV在複製時迅速突變,並且被認為以病毒準種之形式存在,其意味著其在複製時快速突變以產生具有相當進化適應度的病毒的諸多競爭性基因變種。在單個感染者中此內部產生之諸多變種使得分離單一變種以開發疫苗非常困難,並且被認為與以下有關:開發疫苗的困難、病毒對特定醫藥的耐藥性的發展及病毒在宿主中之持久性。病毒可能在宿主免疫反應之壓力下發展成免疫學上相異準種,藉此使其存活並持續存在。
批准之醫藥治療包含注射干擾素,通常為聚乙二醇化形式,其包含聚乙二醇干擾素α-2a(Pegasys®)或聚乙二醇干擾素α-2b(PegIntron®)。聚乙二醇化干擾素之臨床應用於2001年獲得FDA批准。利巴韋林(Ribavirin)(例如,Ribasphere®、Virazole®、Copegus®、Rebetol®),一種對病毒具有廣譜活性之鳥苷類似物,用於治療HCV感染,但當用作單一療法時似乎對HCV無效。目前的標準護理療法包含將聚乙二醇干擾素與利巴韋林組合投與。由於副作用(如流感樣症狀、白細胞減少、血小板減少、抑鬱與貧血),此療法受到限制,並且只有中等功效;成功部分取決於患者中占主導地位之基因型。參見Ghany等人,《肝臟病學(Hepatology
)》,2011,54(4):1433-44。通常,根據HCV基因型,用peg IFN-α與利巴韋林子組合治療C型肝炎24或48週。對功效及耐受性仍然存在實質性限制,因為諸多使用者遭受副作用且病毒自身體中消除通常不完全。
治療之目標為持續的病毒反應(「SVR」)〜意味著在療法完成後HCV在患者的血液中為不可量測的。SVR12,定義為療法後12週不可檢測之HCV RNA,被認為基本上為臨床治癒。用聚乙二醇化干擾素α及利巴韋林組合治療後,治療24週內HCV基因型2與3之患者持續治癒率(持續病毒反應)為約75%或更高,治療48週HCV基因型1之彼等為約50%,治療48週內HCV基因型4之彼等為約65%。
波普瑞韋(Boceprevir)與特拉匹韋(telaprevir)被批准用於治療HCV基因型1(「GT1」)。兩種藥劑均為HCV NS3/4A蛋白酶之抑制劑,並與peg IFN及利巴韋林組合使用。
索非布韋(Sofosbuvir)為NS5B之口服尿苷核苷酸前藥抑制劑,被批准用於治療慢性C型肝炎。對於感染HCV GT1或GT4之患者,治療療法包含索非布韋與peg IFN-α及利巴韋林組合持續十二(12)週。對於感染HCV GT2之患者,治療療法包含索非布韋與利巴韋林組合持續十二(12)週。對於感染HCV GT3之患者,治療療法包含索非布韋與利巴韋林組合持續二十四(24)週。
一種單片劑,其為一種口服之索非布韋及利帕斯韋(ledipasvir)之組合(一種NS5A抑制劑)被批准用於感染HCV GT1之患者。對於沒有肝硬化之患者,治療療法包含索非布韋與利帕斯韋組合持續十二(12)週。對於經歷過治療之肝硬化患者,治療療法包含索非布韋與利帕斯韋組合持續二十四(24)週。此外,索非布韋(片劑)與西咪匹韋(simeprevir)(膠囊)之所有口服組合(一種NS3A/4A蛋白酶抑制劑)被批准用於感染HCV GT1之患者。對於沒有肝硬化之患者,治療療法包含索非布韋與西咪匹韋組合持續十二(12)週。對於具有肝硬化之患者,治療療法包含索非布韋與西咪匹韋組合持續二十四(24)週。
需要HCV抑制劑之組合療法來治療HCV。
本文提供了治療或預防受試者中之C型肝炎病毒(HCV)感染之方法,其包括向所述受試者投與(1)化合物A或其醫藥學上可接受之鹽及(2)第二HCV抑制劑,其量可有效治療或預防受試者中之HCV。第二HCV抑制劑可包括一種或多種抑制劑。在一些情況下,第二HCV抑制劑包括NS5B抑制劑。在一些情況下,第二HCV抑制劑包括NS5A抑制劑。在一些情況下,第二HCV抑制劑包括蛋白酶抑制劑。在一些情況下,第二HCV抑制劑包括NS5A及NS5B抑制劑。NS5A抑制劑,NS5B抑制劑及蛋白酶抑制劑,如下文詳細論述。
本文還提供了治療或預防受試者中之C型肝炎病毒(HCV)感染之方法,其包括向所述受試者投與(1)化合物A或其醫藥學上可接受之鹽及(2)包括HCV NS5A 抑制劑與HCV NS5B抑制劑之組合,其量可有效治療或預防所述受試者中之HCV。在一些情況下,HCV NS5A抑制劑包括達拉他韋(daclatasvir)、艾巴司韋(elbasvir)、利帕斯韋、奧拉斯韋(odalasvir)、奧匹替韋(ombitasvir)、匹布他韋(pibrentasvir)、瑞達斯韋(ravidasvir)、如雜斯韋(ruzasvir)、薩馬他韋(samatasvir)、維帕他韋(velpatasvir)或其組合或其醫藥學上可接受之鹽。在各種情況下,HCV NS5A抑制劑包括達拉他韋或維帕他韋或其醫藥學上可接受之鹽。在一些情況下,HCV NS5B抑制劑包括貝拉布韋(beclabuvir)、達薩布韋、德里布韋(deleobuvir)、非利布韋(filibuvir)、司屈布韋(setrobuvir)、索非布韋、瑞達布韋(radalbuvir)、阿瑞布韋(uprifosbuvir)或其組合或其醫藥學上可接受之鹽。在各種情況下,HCV NS5B抑制劑為索非布韋或其醫藥學上可接受之鹽。在各種情況下,所述組合包括維帕他韋與索非布韋或達拉他韋與索非布韋或其醫藥學上可接受之鹽。在各種情況下,所述方法包括向受試者投與(1)400 mg化合物A及(2)固定劑量組合,其包括100 mg維帕他韋與400 mg索非布韋。
本文還提供了用於治療或預防受試者中之C型肝炎病毒(HCV)感染之組合,其包括(1)化合物A或其醫藥學上可接受之鹽及(2)一組合,其包括HCV NS5A抑制劑及HCV NS5B抑制劑,其量可有效治療或預防所述受試者中之HCV。
本文提供了藉由投與化合物A或其醫藥學上可接受之鹽及第二HCV抑制劑或其醫藥學上可接受之鹽來治療或預防受試者中之HCV感染的組合療法的方法。
如本文所用,術語「醫藥學上可接受之鹽」係指合理醫療判斷範疇內合適用於接觸人類及低等動物之組織而無不當副作用(諸如毒性、刺激、過敏反應及類似者)且與合理利益/風險比相當的化合物之鹽。
醫藥學上可接受之鹽在此項技術中已熟知。例如, S. M. Berge等人在以引用之方式併入本文中之醫藥科學雜誌(J. Pharmaceutical Sciences
),1977, 66, 1-19中詳細地描述醫藥學上可接受之鹽。本文所描述之化合物之醫藥學上可接受之鹽包含衍生自合適無機酸及鹼以及有機酸及鹼之彼等鹽。可在化合物之最終分離及純化期間就地製備此等鹽。
在本文所描述之化合物含有鹼基或足夠鹼性之生物電子等排物體的情況下,酸加成鹽可藉由1)使呈其游離鹼形式之經純化化合物與合適有機或無機酸反應及2)分離因此形成之鹽來製備。在實踐中,酸加成鹽可為供使用之更適宜形式,且所述鹽之使用相當於游離鹼形式之使用。
醫藥學上可接受之無毒酸加成鹽之實例為胺基與無機酸(諸如鹽酸、氫溴酸、磷酸、硫酸及過氯酸)或有機酸(諸如乙酸、草酸、順丁烯二酸、酒石酸、檸檬酸、琥珀酸或丙二酸)形成之鹽,或藉由使用本領域中所用之其它方法(諸如離子交換)形成之鹽。其它醫藥學上可接受之鹽包含己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘油磷酸鹽、羥乙酸鹽、葡糖酸鹽、羥乙酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基-乙烷磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲烷磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酸鹽、過氧硫酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、水楊酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一烷酸鹽、戊酸鹽及其類似物。
在本文所描述之化合物含有羧基或足夠酸性之生物電子等排物體的情況下,鹼加成鹽可藉由1)使呈其酸形式之經純化化合物與合適有機或無機鹼反應及2)分離因此形成之鹽來製備。在實務中,鹼加成鹽之使用可為更適宜形式,且所述鹽形式本身之使用相當於游離酸形式之使用。衍生自合適鹼之鹽包含鹼金屬(例如鈉、鋰及鉀)、鹼土金屬(例如鎂及鈣)、銨及N+
(C1
-4
烷基)4
鹽。本發明亦涵蓋本文中所揭示化合物之含任何鹽基態氮之基團之四級銨化。藉由此類四級銨化可以獲得水溶性或油溶性或可分散之產物。
鹼性加成鹽包含醫藥學上可接受之金屬鹽及胺鹽。合適金屬鹽包含鈉、鉀、鈣、鋇、鋅、鎂及鋁。鈉鹽及鉀鹽通常為較佳的。在適當時,其它醫藥學上可接受之鹽包含使用諸如鹵化物、氫氧化物、羧酸鹽、硫酸鹽、磷酸鹽、硝酸鹽、低碳數烷基磺酸鹽及芳基磺酸鹽之相對離子形成之無毒銨、四級銨及胺陽離子。合適無機鹼加成鹽由金屬鹼製備,所述金屬鹼包含氫化鈉、氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鋁、氫氧化鋰、氫氧化鎂、氫氧化鋅及類似物。合適胺鹼加成鹽由因其低毒性及醫療用途之可接受性而時常用於藥物化學的胺製備。氨、乙二胺、N-甲基-葡糖胺、離胺酸、精胺酸、鳥胺酸、膽鹼、N,N'-二苯甲基乙二胺、氯普魯卡因、二乙醇胺、普魯卡因、N-苯甲基苯乙基胺、二乙胺、哌嗪、三(羥基甲基)-胺基甲烷、四甲基銨氫氧化物、三乙胺、二苯甲基胺、二苯羥甲胺、去氫樅胺、N-乙基哌啶、苯甲胺、四甲銨、四乙銨、甲胺、二甲胺、三甲胺、乙胺、鹼性胺基酸、二環己胺及類似物。
其它酸及鹼在其本身並非醫藥學上可接受時可用於製備在獲得本文所描述之化合物及其醫藥學上可接受之酸或鹼加成鹽時用作中間物的鹽。化合物 A
用於本文揭示之方法的化合物A為具有以下結構的HCV抑制劑:。
化合物A可作為游離酸或可作為醫藥學上可接受之鹽。所述化合物可與藥理學上可接受之陽離子形成鹼鹽。此類鹽之非限制性實例包含鹼金屬或鹼土金屬鹽,且具體地鈣、鎂、鈉、鋰、鋅、鉀胡鐵鹽以及四烷基銨鹽。關於醫藥學上可接受之鹽之一般資訊可在Stahl PH及Wermuth CG編的醫藥鹽之手冊:特性、選擇及使用(Handbook of Pharmaceutical Salts: Properties, Selection and Use
),2002, Wiley-VCH/VHCA Weinheim/Zürich中找到。通篇中所論述之用於化合物A的所有重量均以游離酸化合物計,不包含任何鹽陽離子。
在所揭示之方法中向受試者投與之化合物A或其鹽的量可為任何合適之量,諸如以化合物之游離酸的重量計,劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,化合物A可以以100 mg至1000 mg,或300 mg至700 mg,或400 mg至600 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於化合物A之每日總劑量為為400 mg。在某些實施例中,用於化合物A之每日總劑量為600 mg。在某些情況下,化合物A一次/天投與。在一些情況下,400 mg化合物A一次/天投與。在一些情況下,600 mg化合物A一次/天投與。在某些情況下,化合物A兩次/天投與。在一些情況下,200 mg化合物A兩次/天投與,每日總劑量為400 mg。第二 HCV 抑制劑
在所揭示之方法中使用的第二HCV抑制劑可為抑制HCV的任何化合物、抗體、核酸或蛋白質。例如此類HCV抑制劑可為干擾素、利巴韋林、核苷HCV NS5B聚合酶抑制劑、非核苷HCV NS5B聚合酶抑制劑、HCV NS3-4A蛋白酶抑制劑、HCV NS5A抑制劑、HCV進入抑制劑、HCV NS3抑制劑、HCV NS3解螺旋酶抑制劑、HCV NS4B抑制劑及/或人親環蛋白抑制劑。當術語「第二HCV抑制劑」以單數使用時,除非另外說明,否則其意欲包含單第二HCV抑制劑或第二HCV抑制劑之組合兩者。
例示性干擾素包含但不限於天然、重組及改性(例如PEG-連接、白蛋白連接)干擾素分子。干擾素包含但不限於干擾素α-2a(Roferon®)、干擾素α-2b(Intron®)、干擾素α-1(Infergen®)、聚乙二醇干擾素α-2a(Pegasys®)或聚乙二醇干擾素α-2b(PegIntron®)、重組α干擾素(BLX-883;Locteron®)及白蛋白干擾素α 2b(Zalbin®)。在某些情況下,干擾素亦與利巴韋林一起投與。
預期NS3-4A蛋白酶抑制劑(替代地被稱作「蛋白酶抑制劑」)包含但不限於特拉匹韋(Incivek™;VX-950;Vertex)、波普瑞韋(Victrelis™;SCH503034;默克公司(Merck))、西咪匹韋(TMC435;強生公司(Janssen)/Tibotec/Medevir))、丹諾普韋(danoprevir)(ITMN-191/RG7227;Hoffmann-La Roche/Genentech)、法達瑞韋(faldaprevir)(BI 201335;Boehringer Ingelheim)、BI 12202(Boehringer Ingelheim)、瓦尼普韋(vaniprevir)(MK-7009;默克公司)、MK-5172(默克公司)、帕瑞普韋(paritaprevir)(ABT-450;Abbvie);格卡匹韋(gelcaprevir)(Abbvie)、VX500(Vertex)、PHX1766(Phenomix)、BILN2061(Boehringer Ingelheim)、GS-9256(吉利德(Gilead))、GS-9451(吉利德)、阿蘇普韋(asunaprevir)(BMS-650032;Bristol-Myers Squibb),VX-985(Vertex)、沙普瑞韋(sovaprevir)(ACH-1625;Achillion)、ACH-2684(Achillion)及那拉匹韋(narlaprevir)(SCH900518;默克公司)。在一些情況下,蛋白酶抑制劑為格卡匹韋、格佐匹韋(grazoprevir)、帕瑞普韋、西咪匹韋或沃西拉韋(voxilaprevir)或其醫藥學上可接受之鹽。
預期NS4B抑制劑包含克立咪唑(clemizole)(Eiger生物藥劑);及宿主細胞進入抑制劑,例如ITX5061(iTherX)。
預期親環蛋白抑制劑包含親環蛋白-A抑制劑,例如Debio 025(阿拉泊韋)、SCY-635、NIM811及其它環孢菌素(環孢菌素)衍生物。
預期NS5A抑制劑包含達拉他韋(BMS-790052;布里斯托爾-邁爾斯斯奎布(Bristol-Myers Squibb))、BMS-824383(布里斯托爾-邁爾斯斯奎布)、AZD7295(阿斯利康(AstraZeneca))、PPI-461(Presidio)、PPI-688(Presidio)、GS-5885(吉利德)、ACH-2928(Achillion)、IDX-719(Idenix),奧匹替韋(ABT-267;Abbvie);利帕斯韋(GS-5885;吉利德)、ACH-3102(Achillion)、GS-5816(吉利德)、JNJ-56914845(GSK 2336805;強生公司)、MK-8742(默克公司)及匹布他韋(Abbvie)。在一些情況下,NS5A抑制劑為達拉他韋、艾巴司韋、利帕斯韋、奧匹替韋、匹布他韋或維帕他韋或其醫藥學上可接受之鹽。在某些情況下,NS5A抑制劑包括達拉他韋、艾巴司韋、利帕斯韋、奧拉斯韋、奧匹替韋、匹布他韋、瑞達斯韋、如雜斯韋、薩馬他韋、維帕他韋或其組合或其醫藥學上可接受之鹽。在一些情況下,NS5A抑制劑包括達拉他韋或維帕他韋或其醫藥學上可接受之鹽。
NS5B的抑制劑可大致分類成三組:核苷類似物(NI)、非核苷類似物(NNI)及焦磷酸鹽化合物(PPi)。
核苷類似物化合物(NI)在酶活性位點結合並與天然核苷三磷酸競爭,干擾病毒RNA合成。預期核苷抑制劑包含但不限於IDX184(Idenix)、梅利他濱(mericitabine)(RG7128、R-7128、RO5024048;Hoffmann-La Roche/Genentech)、PSI-7851(Pharmasset)、PSI-938(Pharmasset)、索非布韋(SOVALDI®,PSI-7977;吉利德/Pharmasset)、TMC647055(強生公司);及VX-135(Vertex),以及胺基磷酸酯核苷酸類似物諸如INX-189(Inhibitex)、TMC649128(Tibotec/Medevir)。
預期NNI化合物包含但不限於JTK-109(日本菸草)、BILB-1941(Boehringer Ingelheim)、MK-3281(默克公司)、BI 207127(Boehringer Ingelheim);非利布韋(PF-868554;輝瑞(Pfizer))、VX-759(VCH-759;Vertex)、VCH-916(Vertex)、VX-222(VCH-222;Vertex)、GS-9669(吉利德);GSK625433(Glaxo SmithKline)、ANA-598(Anadys/Roche)、達薩布韋(ABT-333;Abbvie),ABT-072(阿博特(Abbott))、司屈布韋(ANA-598l;Hoffmann-La Roche/Genentech);HCV-796(ViroPharma/Wyeth)、特哥布韋(tegobuvir)(GS-9190;吉利德)、IDX375(Idenix)、非利布韋(輝瑞)、特哥布韋(GS 9190;吉利德)、VX-222(Vertex)、A-837093(阿博特)、ABT-072(阿博特)、ABT-333(阿博特)及PF-868554(輝瑞)。NS5B的其它非核苷抑制劑包含噻吩-2-羧酸及其衍生物(參見例如WO 2002/100846、WO 2002/100851、WO 2004/052879、WO 2004/052885、WO 2006/072347、WO 2006/119646、WO 2008/017688、WO 2008/043791、WO 2008/058393、WO 2008/059042、WO 2008/125599、WO 2009/000818、US 6,881,741、US 7,402,608、US 7,569,600、US 6,887,877及US 6,936,629,其各者以引用之方式併入本文中)。
在一些情況下,NS5B抑制劑包括貝拉布韋、達薩布韋、德里布韋、非利布韋、司屈布韋、索非布韋、瑞達布韋、阿瑞布韋或其組合或其醫藥學上可接受之鹽。
在一些情況下,第二HCV抑制劑包括索非布韋。索非布韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,索非布韋可以以100 mg至1000 mg,或100 mg至500 mg,或200 mg至400 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於索非布韋之每日總劑量為200 mg。在某些實施例中,用於索非布韋之每日總劑量為400 mg。在某些情況下,索非布韋一次/天投與。在某些情況下,400 mg索非布韋一次/天投與。
在一些情況下,第二HCV抑制劑包括維帕他韋。維帕他韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,維帕他韋可以以50 mg至500 mg,或50 mg至200 mg,或50 mg至100 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於維帕他韋之每日總劑量為100 mg。在某些情況下,維帕他韋一次/天投與。在某些情況下,100 mg維帕他韋一次/天投與。
在一些情況下,第二HCV抑制劑包括利帕斯韋。利帕斯韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg to 30 mg/kg。作為非限制性實例,利帕斯韋可以以50 mg至500 mg,或50 mg至200 mg,或50 mg至100 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於利帕斯韋之每日總劑量為90 mg。在某些情況下,利帕斯韋一次/天投與。在某些情況下,90 mg利帕斯韋一次/天投與。
在一些情況下,第二HCV抑制劑包括匹布他韋。匹布他韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,匹布他韋可以以50 mg至500 mg,或50 mg至200 mg,或100 mg至150 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於匹布他韋之每日總劑量為120 mg。在某些情況下,匹布他韋一次/天投與。在某些情況下,120 mg匹布他韋一次/天投與。
在一些情況下,第二HCV抑制劑包括格卡匹韋。格卡匹韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,格卡匹韋可以以100 mg至1000 mg,或100 mg至500 mg,或200 mg至400 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於格卡匹韋之每日總劑量為200 mg。在某些實施例中,用於格卡匹韋之每日總劑量為300 mg。在某些情況下,格卡匹韋一次/天投與。在某些情況下,300 mg格卡匹韋一次/天投與。
在一些情況下,第二HCV抑制劑包括化合物B,其具有結構或其醫藥學上可接受之鹽。在一些情況下,第二HCV抑制劑包括化合物C,其具有結構或其醫藥學上可接受之鹽。
化合物B與C之任何一種可以以任何合適之量投與,諸如以化合物之游離酸或鹼之重量計劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,化合物B或C可以以100 mg至1000 mg,或300 mg至700 mg,或400 mg至600 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於化合物B或C之每日總劑量為400 mg。在某些實施例中,用於化合物B或C之每日總劑量為600 mg。在某些情況下,化合物B或C一次/天投與。在某些情況下,400 mg化合物B或C一次/天投與。在某些情況下,600 mg化合物B或C一次/天投與。在某些情況下,化合物B或C兩次/天投與。200 mg化合物B或C兩次/天投與,每日總劑量為400 mg。
在一些情況下,第二HCV抑制劑包括達拉他韋或其醫藥學上可接受之鹽。達拉他韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,達拉他韋可以以30 mg至300 mg,或30 mg至200 mg,或30 mg至80 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於達拉他韋之每日總劑量為60 mg。在某些情況下,達拉他韋一次/天投與。在某些情況下,60 mg達拉他韋一次/天投與。
在一些情況下,第二HCV抑制劑包括阿蘇普韋或其醫藥學上可接受之鹽。阿蘇普韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,阿蘇普韋可以以100 mg至1000 mg,或100 mg至500 mg,或100 mg至300 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於阿蘇普韋之每日總劑量為200 mg。在某些情況下,阿蘇普韋兩次/天投與。在一些情況下,100 mg阿蘇普韋兩次/天投與,每日總劑量為200 mg。
在一些情況下,第二HCV抑制劑包括西咪匹韋或其醫藥學上可接受之鹽。西咪匹韋可以以任何合適之量投與,諸如劑量為0.1 mg/kg至200 mg/kg體重,或0.25 mg/kg至100 mg/kg,或0.3 mg/kg至30 mg/kg。作為非限制性實例,西咪匹韋可以以50 mg至500 mg,或50 mg至200 mg,或100 mg至200 mg或其間的任何量的每日總劑量投與。在某些實施例中,用於西咪匹韋之每日總劑量為150 mg。在某些情況下,西咪匹韋一次/天投與。在某些情況下,150 mg西咪匹韋一次/天投與。
在一些情況下,第二HCV抑制劑包括利巴韋林或其醫藥學上可接受之鹽。利巴韋林可包含任何合適之利巴韋林形式或調配物。利巴韋林之例示性調配物包含COPEGUS®、REBETOL®及RIBASPHERE®。利巴韋林之例示性前藥為他瑞韋林(taribavirin),其具有化學名稱1-β-D-呋喃核糖基-l,2,4-三唑-3-甲脒。利巴韋林及他瑞韋林可根據此項技術中熟知之利巴韋林及他瑞韋林投與來進行投與。在一些實施例中,COPEGUS®或REBETOL®以每日劑量500 mg至1500 mg以一劑量或分次劑量投與。在一些實施例中,COPEGUS®或REBETOL®以800 mg之每日劑量進行投與。在一些實施例中,REBETOL®以1000 mg之每日劑量進行投與。在一些實施例中,COPEGUS®或REBETOL®以1200 mg之每日劑量進行投與。在一些實施例中,REBETOL®以1400 mg之每日劑量進行投與。利巴韋林之合適劑量取決於受試者之重量,例如1000-1200 mg。利巴韋林之合適每日總劑量包含但不限於一日400 mg至1400 mg,替代地800 mg至1400 mg/天,替代地400 mg至1200 mg,替代地800 mg至1200 mg。
在一些情況下,第二種HCV抑制劑包括NS5B抑制劑及NS5A抑制劑。在此等情況之一些特定情況下,NS5B抑制劑為核苷抑制劑。在此等情況之一些特定情況下,NS5B抑制劑包括索非布韋或其醫藥學上可接受之鹽。在此等情況之一些特定情況下,NS5A抑制劑包括維帕他韋或其醫藥學上可接受之鹽。在此等情況之一些特定情況下,NS5A抑制劑包括利帕斯韋或其醫藥學上可接受之鹽。在一些情況下,NS5A抑制劑包括維帕他韋並且NS5B抑制劑包括索非布韋或其醫藥學上可接受之鹽。在一些情況下,NS5A抑制劑包括達拉他韋並且NS5B抑制劑包括索非布韋或其醫藥學上可接受之鹽。在一些情況下,向受試者投與400 mg化合物A及固定劑量組合,其包括100 mg維帕他韋及400 mg索非布韋。
在一些情況下,第二HCV抑制劑包括NS5A抑制劑及蛋白酶抑制劑。在此等情況之一些特定情況下,NS5A抑制劑包括匹布他韋或其醫藥學上可接受之鹽。在此等情況之一些特定情況下,蛋白酶抑制劑包括格卡匹韋或其醫藥學上可接受之鹽。
在一些情況下,第二HCV抑制劑包括NS5A抑制劑、NS5B抑制劑及蛋白酶抑制劑。在此等情況之一些特定情況下,NS5B抑制劑為核苷抑制劑。在此等情況之一些特定情況下,NS5B抑制劑包括索非布韋或其醫藥學上可接受之鹽。在此等情況之一些特定情況下,NS5A抑制劑包括維帕他韋或其醫藥學上可接受之鹽。在此等情況之一些特定情況下,NS5A抑制劑包括利帕斯韋或其醫藥學上可接受之鹽。在此等情況之一些特定情況下,NS5A抑制劑包括匹布他韋或其醫藥學上可接受之鹽。在此等情況之一些特定情況下,蛋白酶抑制劑包括格卡匹韋或其醫藥學上可接受之鹽。用於 HCV 感染之組合療法
本文揭示之方法考慮使用HCV抑制劑之任何組合來治療HCV感染。所述方法包括向有此需要之HCV患者投與有效量的此組合。在一些實施例中,患者感染有HCV基因型1。在其它實施例中,患者感染有HCV基因型2。在又其它實施例中,患者感染有HCV基因型3。在又其它實施例中,患者感染有HCV基因型4。在又其它實施例中,患者感染有HCV基因型5。在又其它實施例中,患者感染有HCV基因型6。
在一些情況下,患者為HCV未經治療之患者、HCV-經歷治療之患者、干擾素無反應者(例如零反應者)或非干擾素治療之候選人。如本申請案中所用,干擾素非反應患者包含部分干擾素反應者及干擾素反彈患者。參見工業指南-慢性C型肝炎病毒感染:開發直接治療抗病毒治療藥物(GUIDANCE FOR INDUSTRY - CHRONIC HEPATITIS C VIRUS INFECTION: DEVELOPING DIRECT-ACTING ANTIVIRAL AGENTS FOR TREATMENT)(FDA,2010年9月,指南草案),用於未經治療、部分反應者、反應者復發者(亦即,反彈)及零反應者患者之定義。干擾素非反應患者亦包含零反應患者。在本文所描述之任何方法中,所治療之患者可為未進行治療之患者。
在本文所描述之任何方法中,所治療之患者可為干擾素無反應者。在本文所描述之任何方法中,所治療之患者可為干擾素零反應者。在本文所描述之任何方法中,所治療之患者可無肝硬化。在本文所描述之任何方法中,所治療之患者可為肝硬化患者。在本文所描述之任何方法中,所治療之患者可為患有補償性肝硬化之患者。
所揭示之組合療法通常構成完整的治療療法,並且在一些實施例中,沒有意欲之後續療法(例如,沒有後續的干擾素療法)。因此,在一些情況下,本文所描述之治療或用途不包含任何後續治療。較佳地,本文所描述之治療或用途不包含任何後續的含干擾素及/或利巴韋林的治療。
在某些實施例中,化合物A及另外HCV抑制劑或抑制劑可以以實質上同步方式(例如彼此在約5分鐘內)、以依序方式或兩者投與。預期此類組合療法可包含在其它投與之間多次投與一種治療劑。各藥劑之投與之間的時間段可在幾秒(或更短)至幾個小時或天之範圍內,且取決於例如各組合物及活性成份之特性(例如效能、可溶性、生物可用性、半衰期及動態曲線)以及患者的情況。在一些情況下,化合物A及另外HCV抑制劑或抑制劑依序及彼此在30分鐘、60分鐘、2小時、4小時、6小時、8小時、10小時、12小時、18小時、24小時、36小時或48小時內投與。在一些情況下,化合物A在另外HCV抑制劑或抑制劑之前投與,而在其它情況下,化合物A在另外HCV抑制劑或抑制劑之後投與。在一些情況下,化合物A及另外HCV抑制劑或抑制劑實質上同步及彼此在10分鐘、5分鐘或1分鐘內投與。在各種情況下,化合物A及另外HCV抑制劑或抑制劑根據不同的給藥排程投與,例如一種療法一天一次投與,而另一種療法一天兩次投與。在一些情況下,化合物A及另外HCV抑制劑或抑制劑根據相同的給藥排程投與。在一些特定情況下,各療法一天一次投與。
本揭示案亦部分針對醫藥組合物,其包括化合物A與用於所揭示組合的另外HCV抑制劑或抑制劑。例如,本文所提供之組合療法包含醫藥組合物,所述醫藥組合物包括化合物A、索非布韋及維帕他韋或利帕斯韋或其醫藥學上可接受之鹽。本文所提供之組合療法亦包含醫藥組合物,所述醫藥組合物包括化合物A、格卡匹韋及/或匹布他韋或其醫藥學上可接受之鹽。在一些情況下,本文所提供之組合療法包括化合物A、格卡匹韋與匹布他韋。在一些情況下,組合療法包括化合物A、100 mg格卡匹韋與40 mg匹布他韋之固定劑量組合。在一些情況下,本文所提供之組合療法包括化合物A、維帕他韋與索非布韋。在一些情況下,組合療法包括化合物A、100 mg維帕他韋與400 mg索非布韋之固定劑量組合。
化合物A及另外HCV抑制劑或抑制劑可投與任何合適之時間,諸如至少4週、至少6週或至少8週。在某些實施例中,組合療法投與不超過24週。在某些實施例中,組合療法投與不超過12週。在某些實施例中,組合療法投與不超過8週。在某些實施例中,組合療法投與不超過6週。
通常,相比於各療法單獨實現的程度,組合療法不能改良對有需要的受試者的療效,相比於或任一單獨療法,組合療法僅適當地改良療效。然而,與各單獨療法之抑制相比,本文揭示之使用組合療法之方法可導致對相加的HCV的抑制。因此,組合療法產生的療效大於任一單獨治療劑的個別效果。例如,相比於單獨之治療劑之一(例如化合物A)的療效,本文揭示之組合療法可具有至少10%改良療效的相加效應。在一些情況下,相比於單獨之治療劑之一(例如化合物A),相加效應為至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少50%、至少60%改良。
在一些情況下,與單獨之各療法之抑制相比,結果為協同的。因此,組合療法產生的療效大於各治療劑的個別效果的總和。在一些情況下,相比於治療劑之總和,協同效應為至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少50%、至少60%改良。
在一些情況下,所揭示之組合療法的活性使得治療可以比單獨的組合療法的任一組分投與更短的時間。
考慮到下文提供之實例中描述的測定,可以進行如本文所揭示之組合療法的協同及/或相加結果量測。
可以使用各種量測來表達本文所揭示之方法的效果。一種此類量測為SVR,如本文所用,其意指在療法結束時及療法結束後至少6週(SVR6);療法結束後至少8週(SVR8)病毒不可檢測;較佳地,在療法結束時及療法結束後至少12週(SVR12)病毒不可檢測;更佳地,在療法結束時及療法結束後至少16週(SVR16)病毒不可檢測;並且極佳地,在療法結束時及療法結束後至少24週(SVR24)病毒不可檢測。SVR24常視為對治癒之功能性定義;且治療後少於24週時之SVR (例如SVR8或SVR12)的高比率可預測SVR24之高比率。
參照詳述例示性實施例之以下實例更全面地理解本揭示案。然而,其不應解釋為限制本揭示案之範疇。整個本揭示案之所有引用在此均明確地以引用之方式併入。
實例
材料:細胞-藉由WuXi AppTec產生並提供HCV GT1b(Con1,HCV-1b)複製子細胞。HCV-1b複製子細胞為用含有HCV亞基因組、耐藥性選擇基因NEO及報導基因螢火蟲螢光素酶之HCV GT1b複製子穩定轉染之Huh7細胞。
化合物-根據先前所揭示之合成製備測試化合物或從商業源購買。
試劑-使用之主要試劑為為達爾伯克最小基本培養基(DMEM);胎牛血清(FBS);格魯塔瑪(GlutaMax);遺傳黴素選擇性抗生素(G418);青黴素-鏈黴素;MEM非必需胺基酸;達爾伯克磷酸鹽緩衝鹽水(DPBS);0.05%胰蛋白酶-EDTA;二甲亞碸(DMSO);亮-Glo;以及CellTiter-氟。
設備-使用之主要設備為自動液體工作站(Labcyte,Echo555)及微板讀取器設想(Microplate Reader Envision)(Perkin Elmer,2104)。
軟體-使用MacSynergy™ II軟體分析HCV複製子資料。
方法:此研究旨在評估化合物A與其它HCV抗病毒劑在HCV GT1b複製子測定中對HCV複製子複製的組合效果。
2-藥物組合實驗使用以下設計:各藥劑的7種藥物濃度的檢查板交叉模式,包含各單獨藥劑,一式三份,用自動液體工作站(Labcyte,Echo555)電鍍。測試化合物之濃度為0.125、0.25、0.5、1、2、4、8x EC50
值。在單獨的HCV GT1b複製子測定中測定測試化合物的EC50
值。化合物組合之療法列於表1中-其中各療法包含化合物A作為第一化合物。化合物之測試濃度如下表所示。細胞培養基中DMSO之最終濃度為0.5%。
表1
HCV-1b細胞以8000個細胞/孔之密度在96孔盤中接種並在5% CO2
及37℃下在含有10% FBS之DMEM中培養。用化合物治療複製子細胞3天。
根據藉由供應商提供之方案,用CellTiter-氟評估細胞存活率。將CellTiter-氟試劑添加到孔中並在5% CO2
及37℃下孵育1小時。用Envision(Perkin Elmer,USA)量測螢光信號。原始螢光信號資料(RFU)用於使用以下等式計算細胞存活率:,其中CPD為來自含有測試化合物之孔的信號;HPE為來自培養基孔的信號的平均值;以及ZPE為來自DMSO對照孔的信號的平均值。
藉由使用亮Glo根據藉由供應商提供之方案監測複製子報導基因螢火蟲螢光素酶的活性來測定化合物的抗病毒活性。使用MacSynergy™ II軟體計算組合指數。正組合指數值表示協同作用,且負組合指數值表示拮抗作用。
檢測的所有組合療法在測試濃度下未顯示明顯的細胞毒性。如下表所示,化合物A在基於HCV複製子細胞的測定中顯示出與HCV NS5B核苷抑制劑、NS5A抑制劑、NS3蛋白酶抑制劑、NS3解螺旋酶抑制劑及利巴韋林的相加或協同作用。
表2-化合物A與NS5B核苷抑制劑之組合
表3-化合物A與NS5A抑制劑之組合
表4-化合物A與NS3蛋白酶抑制劑之組合
表5-比較組合療法
Claims (21)
- 如請求項1之用途,其中所述醫藥品係提供作醫藥組合物,該組合物包括(1)化合物A或其醫藥學上可接受之鹽及(2)一NS5B抑制劑或一NS5A抑制劑。
- 如請求項1之用途,其中(1)所述NS5B抑制劑為索非布韋(sofosbuvir)或其醫藥學上可接受之鹽;或(2)所述NS5A抑制劑為維帕他韋(velpatasvir)或其醫藥學上可接受之鹽。
- 如請求項1之用途,其中所述第二HCV抑制劑包括: (1)索非布韋與維帕他韋中之每一者或其醫藥學上可接受之鹽;(2)利帕斯韋(ledipasvir)或其醫藥學上可接受之鹽;(3)索非布韋與利帕斯韋中之每一者或其醫藥學上可接受之鹽;(4)匹布他韋(pibrentasvir)或其醫藥學上可接受之鹽;(5)格林匹韋(glecaprevir)或其醫藥學上可接受之鹽;(6)匹布他韋與格林匹韋中之每一者或其醫藥學上可接受之鹽;(7)化合物B或其醫藥學上可接受之鹽:
- 如請求項1之用途,其中所述受試者為一干擾素無反應者及其中所述干擾素無反應個體係經投與化合物A或其鹽及一蛋白酶抑制劑及一NS5A抑制劑。
- 如請求項5之用途,其中所述無反應受試者係進一步經投與一NS5B核苷抑制劑。
- 如請求項1之用途,其中所述第二HCV抑制劑包括一HCV NS5A抑制劑與一HCV NS5B抑制劑之一組合,其量可有效治療或預防所述受試者中之HCV。
- 如請求項7之用途,其中所述HCV NS5A抑制劑包括達拉他韋、艾巴司韋、利帕斯韋、奧拉斯韋(odalasvir)、奧匹替韋、匹布他韋、瑞達斯韋(ravidasvir)、如雜斯韋(ruzasvir)、薩馬他韋(samatasvir)、維帕他韋(velpatasvir)或其組合或其醫藥學上可接受之鹽。
- 如請求項8之用途,其中所述HCV NS5A抑制劑包括達拉他韋或維帕 他韋或其醫藥學上可接受之鹽。
- 如請求項8或9之用途,其中所述HCV NS5B抑制劑包括貝拉布韋(beclabuvir)、達薩布韋、德里布韋(deleobuvir)、非利布韋(filibuvir)、司屈布韋(setrobuvir)、索非布韋、瑞達布韋(radalbuvir)、阿瑞布韋(uprifosbuvir)或其組合或其醫藥學上可接受之鹽。
- 如請求項10之用途,其中所述HCV NS5B抑制劑為索非布韋或其醫藥學上可接受之鹽。
- 如請求項7之用途,其中所述組合包括維帕他韋與索非布韋或達拉他韋與索非布韋或其醫藥學上可接受之鹽。
- 如請求項12之用途,其包括向所述個體投與(1)400mg化合物A及(2)包括100mg維帕他韋與400mg索非布韋之一固定劑量組合。
- 如請求項1之用途,其中所述第二HCV抑制劑包括(1)化合物A或其醫藥學上可接受之鹽及(2)包括格卡匹韋及匹布他韋之一組合或(3)包括維帕他韋及索非布韋之一組合,其量可有效治療或預防所述受試者中之HCV。
- 如請求項14之用途,其包括: (1)包括100mg格卡匹韋及40mg匹布他韋之一固定劑量組合;或(2)包括100mg維帕他韋及400mg索非布韋之一固定劑量組合。
- 如請求項1之用途,其中所述治療或預防一受試者中之C型肝炎病毒(HCV)感染包括投與所述療法4至8週。
- 如請求項1之用途,其中所述治療或預防一受試者中之C型肝炎病毒(HCV)感染包括以400至600mg/天之總每日劑量投與化合物A或其鹽。
- 如請求項1之用途,其中所述治療或預防一受試者中之C型肝炎病毒(HCV)感染包括每天一次或每天兩次投與化合物A或其鹽。
- 如請求項1之用途,其中所述受試者罹患HCV基因型1、HCV基因型2、HCV基因型3、HCV基因型4、HCV基因型5或HCV基因型6。
- 如請求項19之用途,其中所述受試者共同感染HIV。
- 如請求項19或20之用途,其中所述受試者共同感染HBV。
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US20170014394A1 (en) * | 2015-07-16 | 2017-01-19 | Cipla (UK) Limited | Thienopyridine derivative for the treatment of hepatitis c infections |
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CN112203652A (zh) | 2021-01-08 |
JP2021523129A (ja) | 2021-09-02 |
AU2019265740A1 (en) | 2020-10-29 |
JP7381493B2 (ja) | 2023-11-15 |
US11752166B2 (en) | 2023-09-12 |
EP3790542A1 (en) | 2021-03-17 |
TW202015672A (zh) | 2020-05-01 |
KR20210018806A (ko) | 2021-02-18 |
EP3790542B1 (en) | 2023-07-19 |
CA3096916A1 (en) | 2019-11-14 |
US20210161935A1 (en) | 2021-06-03 |
WO2019217643A1 (en) | 2019-11-14 |
MX2020011912A (es) | 2021-01-29 |
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