CN114423430A - 使用核心蛋白别构调节剂治疗hbv感染的方法 - Google Patents
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Abstract
本发明涉及一种治疗人类患者的HBV感染的方法,其中所述方法包括施用治疗有效量的化合物(I),或其药用盐。
Description
本发明涉及治疗人类患者的HBV感染的方法,其中该方法包括施用治疗有效量的核心蛋白别构调节剂。
技术领域
乙型肝炎病毒(HBV)感染是世界范围内的主要公共卫生问题,大约30%的世界人口显示出当前或过去感染的血清学证据。尽管在1980年代初期引入了针对该病毒的安全有效的预防性疫苗,但据估计全球仍有超过2.57亿慢性HBV携带者,其中很大一部分最终会发展为肝硬化或肝细胞癌(HCC)(WHO乙型肝炎情况说明书N°204)。在2010年全球疾病负担研究(R Lozano,等人,Lancet,380(2012),2095–2128)中,HBV感染位居世界卫生优先事项之列,是第十大死亡原因(每年780,000人死亡)。HBsAg的持续清除已被证明可预防疾病进展和HBV并发症(包括肝硬化、肝功能衰竭和HCC)的发展。因此,HBsAg消失(功能性治愈)被认为是慢性乙型肝炎(CHB)患者的最佳终点。功能性治愈定义为在完成有限疗程后,血清中持续的、无法检测到的HBsAg和HBV DNA,有或没有血清转化为抗HBs(LokAS、Zoulim F、Dusheiko G等人,乙型肝炎治愈:从发现到监管部门的批准(Hepatitis B cure:fromdiscovery to regulatory approval)。J Hepatol 2017;67:847-861)。
目前,有两种治疗类别可用于CHB的治疗:皮下施用的干扰素-α(IFN-α)制剂(常规或PEGIFN-IFN-α)和口服施用的核苷(酸)类似物(NUC),诸如替诺福韦(tenofovir)、恩替卡韦(entecavir)、阿德福韦(adefovir)、替比夫定(telbivudine)和拉米夫定(lamivudine)。两种治疗都没有达到很高的功能治愈率(HBsAg持续消失,有或没有血清转换)。此外,基于IFN的疗法与许多副作用有关,而NUC经常需要延长治疗或可能终身治疗,并且有些与病毒耐药性的高风险有关。
最近,开发了一种CpAM(核心蛋白别构调节剂)用于治疗HBV感染患者。化合物(I)是一种用于通过靶向HBV衣壳来治疗和/或预防人类的CpAM,该CpAM在WO2015132276公开,结构如下所示:
已完成三项临床研究(YP39364(NCT02952924)、YP39406(NCT03570658)和YP40218(NCT03717064)的第1部分和第2部分)以在健康志愿者和慢性乙型肝炎患者中表征化合物(I)的安全、耐药性、药代动力学(PK)和药效动力学(PD)。短期PD标志物(HBV DNA和HBVRNA)在化合物(I)治疗4周期间显示出强劲下降,但在此持续时间未观察到HBsAg显著下降。因此,对于用化合物(I)进行治疗的新方法存在未满足的医学需求,该方法可以在有限的治疗持续时间和优异的耐受性下实现更高的功能性治愈率。
发明内容
在本发明中,开发了化合物(I)单药治疗和化合物(I)与其他抗HBV药剂联合治疗12-144周的方法。化合物(I)在慢性乙型肝炎患者中安全且耐受性良好。与当前的NUC治疗相比,本发明的当前有限治疗方法使耐药性风险最小化并减少NUC治疗的副作用(例如肾损伤、骨密度损失和肌酸激酶升高等的风险)。
就功效而言,本发明的治疗方法在患者中表现出强烈的HBV DNA和HBV RNA下降。此外,化合物(I)与其他抗HBV药剂联合治疗12-144周导致乙型肝炎表面抗原(HBsAg)显著下降或丢失。此外,目前还没有针对免疫耐受患者(定义为具有高复制性(HBV DNA水平升高)和低炎症(ALT水平正常或肝活检无明显炎症或纤维化迹象)的患者)的有效抗病毒治疗。然而,本发明用化合物(I)治疗的方法也可以在这些患者中诱导强烈的HBV DNA和HBVRNA下降。
具体实施方式
定义
术语“NUC”表示用作HBV疗法的核苷(酸)类似物,包括但不限于拉米夫定、阿德福韦酯、恩替卡韦(ETV)、替比夫定、富马酸替诺福韦酯(TDF)和艾拉酚胺替诺福韦(TAF)。
术语“空腹”是指一段时间内不进餐施用,可以是下一餐前或最后一餐后12小时内的任何时间。
术语“食物”指任何种类的食物,包括但不限于高脂肪食物、清淡食物或标准食物。
术语“皮下注射”或“SC”是指通过短针将药物输送到患者皮肤和肌肉之间的组织层,皮下剂量将在任何适当的部位施用,例如腹部或大腿上部。对于多次给药,施用部位应轮换。
术语“静脉注射”或“IV”是指使用针头或管子将药物直接输送到患者的静脉中。
术语“TLR激动剂”表示一类toll样受体激动剂,该toll样受体激动剂可以促进抗病毒细胞因子的产生和自然杀伤细胞、B细胞和T细胞的活化,这些免疫反应可能在实现CHB(即HBsAg消失)的功能性治愈的方面发挥作用。TLR 激动剂的示例包括但不限于TLR 7激动剂GS-9620(Gilead Sciences Incs)、TLR 8激动剂GS-9688(Gilead Sciences Incs)、TLR7激动剂JNJ-64794964(Janssen Research&Development LLC)和TLR9调节剂AIC649(AiCuris Anti-infective Cures GmbH)。
术语“视黄酸诱导基因I”或“RIG-I”表示启动针对许多RNA病毒的免疫反应的胞质病原体识别受体。RIG-I调节剂表示可以通过视黄酸诱导基因-I(RIG-I)介导的HBV前基因组RNA 5'-ε区的感应来诱导III型和I型干扰素的分子。RIG-I调节剂的示例包括但不限于来自斯布林邦克药物(Spring Bank Pharmaceuticals)的Inarigivir(SB9200)。(SatoS、LiK、Kameyama T等人,RNA传感器RIG-I具有先天传感器和直接抗乙型肝炎病毒因子的双重功能(The RNA sensor RIG-I dually functions as an innate sensor and directantiviral factor for hepatitis B virus)。免疫2015;42:123-32)。
术语“小干扰RNA”或“siRNA”表示小干扰核糖核酸,它是一类双链RNA分子。siRNA靶向任何病毒转录物并通过RISC/Ago2复合物诱导其降解,从而导致基因沉默。siRNA的示例包括但不限于ARB-1467(Arbutus Biopharma)、ARO-HBV(Arrowhead Pharma)、AB-729(Arbutus Biopharma)、DCR-HBVS(Dicerna)、Vir-2218(Alnylam和Vir Biotech)、BB-103(Benitec)和Lunar-HBV(Arcturus,USA with Janssen)。
术语“HBV LNA”表示一种分子,该分子是一种含N-乙酰半乳糖胺(GalNAc)靶向锁定核酸(LNA)的单链寡脱氧核糖核苷酸,与乙型肝炎病毒(HBV)基因组衍生的mRNA种类互补,旨在用于治疗CHB感染。
术语“HBsAg抑制剂”表示可以干扰HBsAg的组装/释放、产生或进入的分子。HBsAg抑制剂的示例包括但不限于REP 2139(Replicor)和REP 2165(Replicor),以及MyrcludexB(MYR Pharma)。
术语“HBV治疗性疫苗”或“HBV疫苗”表示可以刺激或增强宿主免疫反应以恢复免疫控制,从而持续抑制HBV复制并最终导致HBsAg消失的分子。HBV疫苗的示例包括但不限于ABX203(Center for Genetic Engineering and Biotechnology)、INO-1800(Inovio)、HB-110(Ichor Medical Systems with Janssen)、TG1050(Transgene)和HepTcell(Altimmune)。
术语“治疗有效量”是表示本发明的化合物或分子的量,当将其施用于受试者时,(i)治疗或预防特定疾病、病症或疾患,(ii)减弱、改善或消除特定疾病、病症或疾患的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、病症或疾患的一种或多种症状的发作。治疗有效量取决于化合物,所治疗的疾病状态,所治疗疾病的严重程度,受试者的年龄和相对健康状况,给药途径和形式,主治医学或兽医的判断和其他因素。
术语“药物组合物”表示包含治疗有效量的活性药物成分和一起施用于有此需要的哺乳动物(例如人)的药用赋形剂的混合物或溶液。
治疗的组分
另一个实施方案提供含有本发明化合物和治疗惰性载体,稀释剂或赋形剂的药物组合物或药物,以及使用本发明化合物制备此类组合物和药物的方法。在一个示例中,化合物(I)可通过在环境温度下适当的pH和期望的纯度下与生理学上可接受的载体(即在所用剂量和浓度下对接受者无毒的载体)混合而配制为盖伦(galenical)施用形式。制剂的pH主要取决于化合物的具体用途和浓度,但是优选地在约3至约8的范围内。在一个示例中,将化合物(I)在pH5的乙酸盐缓冲液中配制。在另一个实施方案中,化合物(I)是无菌的。该化合物可以例如作为固体或无定形组合物、作为冻干制剂或作为水溶液储存。
组合物以符合良好医疗实践的方式配制、给药和施用。在该背景下需要考虑的因素包括所治疗的具体疾患、所治疗的具体哺乳动物、个体患者的临床状况、疾患的原因、药剂的递送部位、施用方法、施用的时间安排以及执业医师已知的其他因素。待施用的化合物的“有效量”将由这些考虑因素决定,并且是有效作为CpAM所需的最小量,其可用于但不限于治疗或预防乙型肝炎病毒感染的患者。
本发明的化合物可通过任何合适的方式施用,包括口服、局部(包括含服和舌下)、直肠、阴道、透皮、肠胃外、皮下、腹膜内、肺内、皮内、鞘内和硬膜外以及鼻内,并且如果需要局部治疗,则为病灶内施用。肠胃外输注包括肌内、静脉内、动脉内、腹膜内或皮下施用。
本发明化合物可以任何方便的施用形式施用,例如,片剂、粉剂、胶囊剂、溶液剂、分散剂、混悬剂、糖浆剂、喷雾剂、栓剂、凝胶剂、乳剂、贴剂等。此类组合物可以包含药物制剂中常规的组分,例如,稀释剂、载体、pH调节剂、甜味剂、填充剂和其他活性剂。
通过混合本发明的化合物和载体或赋形剂来制备通常的制剂。适合的载体和赋形剂是本领域技术人员熟知的,并且在例如Ansel、Howard C.等人,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.等人Remington:药剂学的科学和实践。Philadelphia:Lippincott,Williams&Wilkins,2000;以及Rowe,Raymond C.Handbook ofPharmaceutical Excipients.Chicago,Pharmaceutical Press,2005中有详细描述。该制剂还可以包含一种或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、不透明剂、助流剂、加工助剂、着色剂、甜味剂、加香剂、调味剂、稀释剂和其他已知的添加剂,以提供药物(例如,本发明的化合物或其药物组合物)的美观展示或有助于药物产品(例如,药物)的制造。
治疗方法
本发明涉及(i)一种治疗人类患者的HBV感染的方法,其包括在与或不与其他抗HBV药剂一起的情况下,以200mg QD或BID至1000mg QD或BID的量,向所述患者施用含有化合物(I)的活性成分的药物组合物12至144周;其中化合物(I)为3-[(8aS)-7-[[(4S)-5-乙氧基羰基-4-(3-氟-2-甲基-苯基)-2-噻唑-2-基-1,4-二氢嘧啶-6-基]甲基]-3-氧代-5,6,8,8a-四氢-1H-咪唑并[1,5-a]吡嗪-2-基]-15 2,2-二甲基-丙酸。
本发明的另一实施方案是(ii)根据(i)的方法,其中经口、SC或IV施用化合物(I)。
本发明的另一实施方案是(iii)根据(i)或(ii)的方法,其中空腹或随食物施用化合物(I)。
本发明的另一实施方案是(iv)根据(i)至(iii)中任一项的方法,其中,施用化合物(I)的量和频率为200mg QD或BID、400mg QD或BID、600mg QD或BID、800mg QD或BID、或1000mg QD或BID。
本发明的另一实施方案是(v)根据(i)至(iv)中任一项的方法,其中,施用化合物(I)12周、24周、36周、48周、52周、60周、72周、84周、96周、104周、108周、120周、132周或144周。
本发明的另一实施方案是(vi)根据(i)至(v)中任一项的方法,其中不与其他抗HBV药剂一起施用化合物(I)。
本发明的另一实施方案是(vii)根据(i)至(vi)中任一项的方法,其中与一种或两种其他抗HBV药剂一起施用化合物(I),其中所述其他抗HBV药剂独立地选自NUC、IFN-α、TLR激动剂、RIG-I调节剂、siRNA、HBV LNA寡核苷酸、HBsAg抑制剂和HBV疫苗。其他抗HBV药剂的治疗方法可根据现有的护理标准应用。
本发明的另一实施方案是(viii)根据(i)至(vii)中任一项的方法,其中与NUC一起施用化合物(I);其中NUC选自ETV、TAF和TDF。
本发明的另一实施方案是(ix)根据(i)至(viii)中任一项的方法,其中施用化合物(I)48-96周,特别是48周、52周、60周、72周、84周或96周。
本发明的另一实施方案是(x)根据(i)至(ix)中任一项的方法,其中以600mg QD经口且空腹与NUC一起施用化合物(I)48周;其中NUC选自ETV、TAF和TDF。
本发明的另一实施方案是(xi)根据(i)至(x)中任一项的方法,其中与NUC和IFN-α一起施用化合物(I);其中NUC选自ETV、TAF和TDF。
本发明的另一实施方案是(xii)根据(i)至(xi)中任一项的方法,其中,施用化合物(I)48-96周,特别是48周、52周、60周、72周、84周或96周。
本发明的另一实施方案是(xiii)根据(i)至(xii)中任一项的方法,其中以600mgQD经口且空腹与NUC和IFN-α一起施用化合物(I)48周;其中NUC选自ETV、TAF和TDF;其中,所述IFN-α选自和
本发明的另一实施方案是(xiv)根据(i)至(xiii)中任一项的方法,其中与NUC和TLR 激动剂一起施用化合物(I);其中所述NUC选自ETV、TAF和TDF;其中所述TLR激动剂选自GS-9620、GS-9688、JNJ-64794964和AIC649。
本发明的另一实施方案是(xv)根据(i)至(xiv)中任一项的方法,其中与NUC和RIG-I调节剂一起施用化合物(I);其中NUC选自ETV、TAF和TDF。
本发明的另一实施方案是(xvi)根据(i)至(xv)中任一项的方法,其中RIG-I调节剂是Inarigivir。
本发明的另一实施方案是(xvii)根据(i)至(xvi)中任一项的方法,其中,施用化合物(I)12-48周,特别是12周、24周、36周或48周。
本发明的另一实施方案是(xviii)根据(i)至(xvii)中任一项的方法,其中与NUC和siRNA一起施用化合物(I);其中NUC选自ETV、TAF和TDF。
本发明的另一实施方案是(xix)根据(i)至(xviii)中任一项的方法,其中siRNA选自ARB-1467、ARO-HBV、AB-729、DCR-HBVS、Vir-2218、BB-103和Lunar-HBV。
本发明的另一实施方案是(xx)根据(i)至(xix)中任一项的方法,其中与NUC和HBVLNA寡核苷酸一起施用化合物(I);其中NUC选自ETV、TAF和TDF;其中HBV LNA寡核苷酸为化合物(II),该化合物(II)为WO2015/173208或WO2014/179627中公开的化合物中的任一种。
本发明的另一实施方案是(xxi)根据(i)至(xx)中任一项的方法,其中,施用化合物(I)12-48周,特别是12周、24周、36周或48周。
本发明的另一实施方案是(xxii)根据(i)至(xxi)中任一项的方法,其中与NUC和HBsAg抑制剂一起施用化合物(I);其中NUC选自ETV、TAF和TDF;其中HBsAg抑制剂选自REP2139、REP 2165和Myrcludex B。
本发明的另一实施方案是(xxiii)根据(i)至(xxii)中任一项的方法,其中与另外的抗HBV药剂一起施用化合物(I),其中抗HBV药剂选自 Inarigivir、ARB-1467、ARO-HBV、AB-729、DCR-HBVS、Vir-2218、BB-103、Lunar-HBV、化合物(II)、REP 2139、REP 2165、Myrcludex B、GS-9620、GS-9688、JNJ-64794964、AIC649、ABX203、INO-1800、HB-110、TG1050和HepTcell。
实例
通过参考以下实例将更全面地理解本发明。但是,它们不应被解释为限制本发明的范围。
缩写
AASLD: 美国肝脏研究协会
APASL: 亚太肝脏研究协会
BID: 一天两次
CHB: 慢性乙型肝炎
EASL: 欧洲肝脏研究协会
ETV: 恩替卡韦
NUC: 核苷(酸)类似物
HBeAg: 乙型肝炎e抗原
HBsAg: 乙型肝炎表面抗原
HBV: 乙型肝炎病毒
HCC: 肝细胞性肝癌
PEG-IFN: 聚乙二醇化干扰素
QD: 一天一次
TAF: 替诺福韦艾拉酚胺。
TDF: 富马酸替诺福韦酯
WHO: 世界卫生组织
一般实验条件
研究人群:患有HBV的患者(Terrault NA、Lok ASF、McMahon BJ等人,慢性乙型肝炎预防、诊断和治疗的更新(Update on prevention,diagnosis,and treatment ofchronic hepatitis B):AASLD 2018乙型肝炎指南。肝病学。2018;67:1560-1599。欧洲肝脏研究协会。EASL 2017乙型肝炎病毒感染管理临床实践指南。J Hepatol.2017;67:370-398.)。
化合物:
化合物(I):3-[(8aS)-7-[[(4S)-5-乙氧基羰基-4-(3-氟-2-甲基-苯基)-2-噻唑-2-基-1,4-二氢嘧啶-6-基]甲基]-3-氧代-5,6,8,8a-四氢-1H-咪唑并[1,5-a]吡嗪-2-基]-152,2-二甲基-丙酸,其是具有如下所示结构的HBV CpAM:
化合物(II):HBV LNA寡核苷酸,其为Wo2015/173208或WO2014/179627中公开的化合物中的任一种。
Inarigivir:由斯布林邦克药物开发的一种小分子二核苷酸口服活性HBV抗病毒物质,具有直接作用和免疫调节活性,刺激宿主先天性抗病毒反应。它与胞质模式识别受体视黄酸诱导基因(RIG-I)结合,以增强RIG-I与HBV前基因组RNA的5'-ε区的结合。(WalshR.、Hammond R.、Jackson K.等人,SB9200(Inarigivir)对慢性乙型肝炎患者的免疫反应治疗(therapy on immune responses in patients with chronic hepatitis B)。肝病学杂志2018;68增刊1:S89-)。
REP 2139或REP 2165:由Replicor公司开发的一种核酸聚合物。它可以通过进入后机制、阻断HBV亚病毒颗粒的组装/释放,允许HBsAg从循环中清除来其作用(Bazinet M.、V.、Placinta G.等人,用REP 2139-MG/REP 2165-Mg、富马酸替诺福韦二吡呋酯和聚乙二醇化干扰素α-2a治疗HBeAg阴性慢性HBV感染后建立纤维化的高功能控制和逆转率(Establishment of high rates of functional control and reversal of fibrosisfollowing treatment of HBeAg negative chronic HBV infection with REP 2139-MG/REP2165-MG,tenofovir disoproxil fumarate and pegylated interferon alpha-2a)。肝病学2018;68增刊1:234A-235A)。
Gs-9620:由吉利德科学公司(Gilead Sciences Incs)开发的一种小分子TLR7激动剂。(Agarwal K.,Ahn SH,Elkhashab M.,vesatolimod(GS-9620)在目前未进行抗病毒治疗的慢性乙型肝炎患者中的安全性和功效(Safety and efficacy of vesatolimod(GS-9620)in patients with chronic hepatitis B who are not currently on antiviraltreatment)。病毒性肝炎杂志2018;25:1331-1340)。
GS-9688:由吉利德科学公司开发的一种强效选择性小分子TLR 8激动剂。(KhanamA.、Yoon J.A.、Poonia B.等人,GS-9688,一种toll样受体8激动剂,在慢性乙型肝炎患者中诱导先天性和适应性抗病毒免疫反应。肝病学2018;68增刊1:329A-330A)。
JNJ-64794964:一种口服toll样受体7激动剂旨在治疗慢性HBV,该激动剂目前由杨森研发有限责任公司(Janssen Research&Development LLC)开发。(Ed Gane、MinaPastagia、An De Creus等人,口服JNJ-64794964(Toll样受体7激动剂)在健康成年人中的安全性、耐受性、药代动力学和药效学的1期、双盲、随机、安慰剂对照、首次人体研究(APhase 1,Double-Blind,Randomised,Placebo-Controlled,First-in-Human Study ofthe Safety,Tolerability,Pharmacokinetics and Pharmacodynamics of oral JNJ-64794964,a Toll-like Receptor-7Agonist,in Healthy Adults)。肝病学杂志2019;70e141-e382:FRI-198)。
AIC649:一种灭活的绵羊副痘病毒颗粒制剂,其已被证明可直接解决宿主免疫防御的抗原呈递细胞臂,从而导致调节细胞因子释放和T细胞反应的激活。AIC649由艾克如斯抗感染治愈股份有限公司(AiCuris Anti-infective Cures GmbH)开发。(Ibironke Addy,Alen Jambrecina,Thomas Berg等人,首次在人中、单一剂量递增的AIC649在慢性肝炎患者中的临床试验(First in Human,single ascending dose clinical trial of AIC649 inpatients with chronic hepatitis)。肝病学杂志2019;70e141-e382:FRI-199)。
Myrcludex B:林吉特制药公司(MYR Pharma)拥有的一种抗HBV分子,该分子可以结合肝细胞表面蛋白牛磺胆酸钠共转运多肽并使之失活,从而将HBV错误导向至非生产性途径,从而防止细胞感染。(http://myr-pharma.com/science/about-myrcludex-b)。
DCR-HBVS:克纳制药股份有限公司(DicernaPharmaceuticals,Inc.)正在开发的试验药物。该试验药物由单个GalXC分子构成,该GalXC分子靶向HBsAg基因序列区域内的HBV信使RNA。
HBV疫苗:ABX203(Center for Genetic Engineering and Biotechnology)、INO-1800(Inovio)、HB-110(Ichor Medical Systems with Janssen)、TG1050(Transgene)或HepTcell(Altimmune)。
通用方法:为探索化合物(I)对HBsAg消失或下降的影响,按照表1中列出的剂量方案施用化合物(I)。主要测量是治疗后24周、定量HBsAg下降或HBsAg消失(<0.05IU/mL,由HBsAg II)测量)。
研究设计:为化合物(I)选择的剂量和用于本发明的方案总结在下表1中:
表1.化合物(I)的给药方案
Claims (23)
1.一种治疗人类患者的HBV感染的方法,其包括在与或不与其他抗HBV药剂一起的情况下,以200mg QD或BID至1000mg QD或BID的量,向所述患者施用含有化合物(I)的活性成分的药物组合物12至144周;其中化合物(I)为3-[(8aS)-7-[[(4S)-5-乙氧基羰基-4-(3-氟-2-甲基-苯基)-2-噻唑-2-基-1,4-二氢嘧啶-6-基]甲基]-3-氧代-5,6,8,8a-四氢-1H-咪唑并[1,5-a]吡嗪-2-基]-15 2,2-二甲基-丙酸。
2.根据权利要求1所述的方法,其中经口、SC或IV施用化合物(I)。
3.根据权利要求2所述的方法,其中空腹或随食物施用化合物(I)。
4.根据权利要求1至3中任一项所述的方法,其中,施用化合物(I)的量和频率为200mgQD或BID、400mg QD或BID、600mg QD或BID、800mg QD或BID、或1000mg QD或BID。
5.根据权利要求1至4中任一项所述的方法,其中施用化合物(I)12周、24周、36周、48周、52周、60周、72周、84周、96周、104周、108周、120周、132周或144周。
6.根据权利要求5所述的方法,其中不与其他抗HBV药剂一起施用化合物(I)。
7.根据权利要求5所述的方法,其中与一种或两种其他抗HBV药剂一起施用化合物(I),其中所述其他抗HBV药剂独立地选自:NUC、IFN-α、TLR激动剂、RIG-I调节剂、siRNA、HBV LNA寡核苷酸、HBsAg抑制剂和HBV疫苗。
8.根据权利要求7所述的方法,其中与NUC一起施用化合物(I);其中所述NUC选自ETV、TAF和TDF。
9.根据权利要求8所述的方法,其中施用化合物(I)48至96周,特别是48周、52周、60周、72周、84周或96周。
10.根据权利要求8或9所述的方法,其中以600mg QD与NUC一起经口且空腹施用化合物(I)48周;其中NUC选自ETV、TAF和TDF。
11.根据权利要求7所述的方法,其中与NUC和IFN-α一起施用化合物(I);其中NUC选自ETV、TAF和TDF。
12.根据权利要求12所述的方法,其中施用化合物(I)48至96周,特别是48周、52周、60周、72周、84周或96周。
14.根据权利要求7所述的方法,其中与NUC和TLR激动剂一起施用化合物(I);其中所述NUC选自ETV、TAF和TDF;其中所述TLR激动剂选自GS-9620、GS-9688、JNJ-64794964和AIC649。
15.根据权利要求7所述的方法,其中与NUC和RIG-I调节剂一起施用化合物(I);其中所述NUC选自ETV、TAF和TDF。
16.根据权利要求15所述的方法,其中所述RIG-I调节剂为Inarigivir。
17.根据权利要求16所述的方法,其中施用化合物(I)12至48周,特别是12周、24周、36周或48周。
18.根据权利要求7所述的方法,其中与NUC和siRNA一起施用化合物(I);其中所述NUC选自ETV、TAF和TDF。
19.根据权利要求18所述的方法,其中所述siRNA选自ARB-1467、ARO-HBV、AB-729、DCR-HBVS、Vir-2218、BB-103和Lunar-HBV。
20.根据权利要求7所述的方法,其中与NUC和HBV LNA寡核苷酸一起施用化合物(I);其中所述NUC选自ETV、TAF和TDF;其中所述HBVLNA寡核苷酸为化合物(II)。
21.根据权利要求20所述的方法,其中施用化合物(I)12至48周,特别是12周、24周、36周或48周。
22.根据权利要求7所述的方法,其中与NUC和HBsAg抑制剂一起施用化合物(I);其中所述NUC选自ETV、TAF和TDF;其中所述HBsAg抑制剂选自REP 2139、REP 2165和Myrcludex B。
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EP3503894A1 (en) * | 2016-08-24 | 2019-07-03 | H. Hoffnabb-La Roche Ag | Combination therapy of an hbv capsid assembly inhibitor and a nucleos(t)ide analogue |
WO2018050571A1 (en) * | 2016-09-13 | 2018-03-22 | F. Hoffmann-La Roche Ag | Combined treatment with a tlr7 agonist and an hbv capsid assembly inhibitor |
TW201907009A (zh) * | 2017-05-31 | 2019-02-16 | 加拿大商艾爾布圖斯生技公司 | 用於治療b型肝炎之治療組成物及方法 |
WO2019084020A1 (en) * | 2017-10-24 | 2019-05-02 | Gilead Sciences, Inc. | METHODS OF TREATING PATIENTS CO-INFECTED BY A VIRUS AND TUBERCULOSIS |
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2020
- 2020-09-18 WO PCT/EP2020/076065 patent/WO2021053126A1/en unknown
- 2020-09-18 TW TW109132236A patent/TW202126304A/zh unknown
- 2020-09-18 CN CN202080065852.2A patent/CN114423430A/zh active Pending
- 2020-09-18 EP EP20781313.0A patent/EP4031140A1/en active Pending
- 2020-09-18 US US17/761,521 patent/US20220370447A1/en active Pending
- 2020-09-18 JP JP2022517207A patent/JP2022548652A/ja active Pending
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US20220370447A1 (en) | 2022-11-24 |
EP4031140A1 (en) | 2022-07-27 |
JP2022548652A (ja) | 2022-11-21 |
WO2021053126A1 (en) | 2021-03-25 |
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