CN110352059A - 非酒精性脂肪性肝炎(nash)和肝纤维化的联合疗法 - Google Patents
非酒精性脂肪性肝炎(nash)和肝纤维化的联合疗法 Download PDFInfo
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Abstract
本发明涉及一种用于治疗CCR5和/或CCR2介导的疾病如非酒精性脂肪性肝炎(NASH)的方法,包括施用有效量的C‑C趋化因子受体5(CCR5)拮抗剂(例如,马拉韦罗或维立韦罗或赛尼克韦罗)和/或有效量的C‑C趋化因子受体2(CCR2)拮抗剂,或CCR5/CCR2拮抗剂连同有效量的法呢酯X受体(FXR)激动剂(例如,奥贝胆酸(OCA))。“有效量”可以是FXR受体激动剂和/或CCR5/CCR2拮抗剂中单独的任一种药剂的常规临床剂量或它们的减少剂量。该联合有效治疗NASH,伴有:(1)增强的功效;(2)大幅减少副作用,特别是与施用OCA或其类似物相关的副作用,即对肝酶升高的影响更小;和瘙痒的严重程度和频率更低(3)。固定剂量联合提供更好的功效和安全性。
Description
技术领域
本申请要求2016年12月28日提交的美国临时申请序列号62/439,666的权益,其全部教导通过引用并入本文。
背景技术
非酒精性脂肪性肝炎(NASH)是一种潜伏的且进展缓慢的疾病,对生活质量有显著影响。它最终可导致肝硬化,失代偿性肝病和/或肝细胞癌。其本质特征是脂肪变性、炎性趋化因子的释放、炎症和纤维化造成的不断损害。与炎症相关的纤维化是疾病进展的关键驱动因素。已经在临床试验中测试了具有不同机制的多种药物,但尚未批准有效的治疗方法。
现在有许多新分子处于对NASH临床研发的不同阶段,但仅报道了边际/轻微效应(1,2)。
CCR5拮抗剂最初被开发为用于治疗HIV的HIV进入抑制剂。马拉韦罗(maraviroc)是第一个被批准用于该适应症的分子。已经表明,肝脏脂肪变性与趋化因子的升高有关,趋化因子包括CCL5/rantes及其受体CCR5(3)。CCR5的其他配体包括CCL3、CCL4、CCL7、CCL13和CCL16。通过马拉韦罗对CCR5的抑制已被证明在动物模型中有效降低NAS评分和纤维化(4)。在患有HCV感染同时接受马拉韦罗治疗的HIV患者中观察到肝纤维化减少(5)。最近的研究表明,靶向CCR5和CCR2两者的赛尼克韦罗(cenicriviroc)对NASH具有边际效应,对纤维化具有相对更显著的作用(2,6)。赛尼克韦罗正处于NASH的临床开发。另一个临床阶段的CCR5拮抗剂是维立韦罗(vicroviroc)。CCR5拮抗剂对NASH的主要疗效主要体现在其对纤维化的影响,对NAS评分具有较小的影响(2)。据报道,CCR2也是肝纤维化的重要参与者(7)。
奥贝胆酸(obeticholic acid(OCA))是一种半合成的胆汁酸类似物,具有6ɑ-乙基-鹅去氧胆酸的化学结构。作用机制是通过激活法呢酯X受体(FXR)。它正在作为几种肝病和相关障碍的药物制剂进行临床开发。它已于2016年被美国FDA批准用于治疗原发性胆汁性胆管炎(8)。NASH的临床项目正处于3期开发。
临床前毒理学研究已经表明,OCA的毒性靶向系统是肝胆系统。在大鼠的26周口服毒性研究中,用OCA处理产生了临床化学参数的变化(例如,ALT、AST和ALP增加),肝脏重量增加和胆管增生(9)。在狗的9个月口服毒性研究中,OCA产生了可能与肝功能(皮肤、粘膜和眼睛的黄色变色)和ALT水平升高相关的临床毒性迹象。在临床试验中也报道了肝脏毒性;肝脏生化测试中所有严重的和其他临床上显著的肝脏相关不良反应的暴露调整发生率和单独升高,每100名患者暴露年份(PEY)为:与安慰剂组中的2.4相比,10mg组为5.2,25mg组为19.8%,50mg组为54.5%(10)。
OCA已被表明会引起剂量相关的副作用,包括瘙痒和HDL的减少。瘙痒是OCA最常见的不良事件之一;据报道,频率高达80%;还报道了因瘙痒引起的剂量相关的中断。严重瘙痒OCA美国包装插页中被列为警告和预防措施之一;有时会需要减少剂量和/或临时给药中断(8)。还有一些靶向FXR的新分子实体处于不同的研发阶段。
临床和临床前数据均表明,使用OCA作为FXR激动剂,通过CCR5或CCR2/5拮抗剂或FXR途径靶向实现轻微至中等功效(1,2)。这可能是OCA处于2000名NASH患者临床试验的原因之一(10),患者在治疗18个月后出读数。临床前,疗效也是轻微的。临床前和人类数据表明,使用CCR5或CCR2/5拮抗剂靶向CCR5或CCR2/5有效减少纤维化,但NAS评分或脂肪变性的效果要小得多(2)。NASH是一种慢性疾病,大多数患者都有这种疾病的良性病因;因此,必须有一个除了有效之外还非常安全的治疗方案。因此,需要治疗NASH/肝纤维化的改进方法,以提高总体功效并改善安全性。
发明内容
现在已经发现,CCR5或CCR2抑制剂或靶向CCR2/5的分子和FXR激动剂的组合比任何一种单独的药剂更有效地治疗NASH,副反应更少,即使在以低于全剂量的剂量给药FXR时也是如此。
特别地,当CCR5抑制剂马拉韦罗和FXR激动剂奥贝胆酸(OCA)在NASH的小鼠模型中各自单独和联合施用时,进行以下观察(参见实施例):
·联合疗法比任何单独的单一药剂更有效地降低NAS评分(图1A)。
·联合疗法比任何单独的单一药剂更有效地减少肝纤维化(图3A)。
·联合疗法比任何单独的单一药剂更有效地减少肝脏炎症评分(图4A)。
·联合疗法比任何单独的单一药剂更有效地降低肝细胞气球样变性评分(ballooning score)(图5A),并显示出对气球样变性的协同作用。此外,当两种药物均施用一半剂量时,未观察到气球样变性。
·联合疗法比任何单独的单一药剂更有效地降低肝脂肪变性评分(图6A)。
·剂量减少的OCA(半剂量或剂量减少更多的OCA)与全剂量CCR5/CCR2拮抗剂可以产生足够的疗效,但在长期慢性治疗环境中毒性降低。
此外,在用MVC和OCA两者处理的小鼠中未观察到在用OCA处理的小鼠中观察到的AST和ALP肝酶的升高(图7A-8A),表明由OCA引起的不良肝毒性可通过与MVC的同时治疗来减轻。基于这些发现,本文公开了用CCR5拮抗剂(和/或CCR2拮抗剂)和FXR激动剂(例如OCA)治疗NASH和其他C-C趋化因子受体5(CCR5)介导的(和/或CCR2介导的)炎性疾病的方法。当施用CCR2拮抗剂MK 0812代替CCR5拮抗剂MVC(图7B和图8B),或使用CCR5抑制剂马拉韦罗和CCR2拮抗剂MK 0812的组合用CCR2/5治疗(数据未显示)时,观察到类似的观察结果。
本发明的一个实施方案是治疗患有以下疾病的人类患者的方法:C-C趋化因子受体5(CCR5)介导的炎性疾病;CCR2受体介导的炎性疾病;或CCR2/5受体介导的炎性疾病。该方法包括向患者施用有效量的CCR5拮抗剂(如马拉韦罗、维立韦罗或赛尼克韦罗);或CCR2拮抗剂,例如(MLN-1202(AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812、PF-04634817);或者CCR2/5拮抗剂如(赛尼克韦罗)和有效量的法呢酯X受体(FXR)激动剂。
本发明的另一个实施方案是治疗患有C-C趋化因子受体5(CCR5)介导的炎性疾病的人类患者的方法,包括向患者施用有效量的CCR5拮抗剂和有效量的法呢酯X受体激动剂。本发明的另一个实施方案是治疗患有C-C趋化因子受体2(CCR2)介导的炎性疾病的人类患者的方法,包括向患者施用有效量的CCR2拮抗剂和有效量的法呢酯X受体激动剂。本发明的另一个实施方案是治疗患有C-C趋化因子受体CCR2/5介导的炎性疾病的人类患者的方法,包括向患者施用有效量的CCR2/CCR5拮抗剂和有效量的法呢酯X受体激动剂。
本发明的另一个实施方案是通过FXR激动剂治疗FXR介导的疾病如NASH或胆汁性肝硬化或适用的适应症的方法。该方法包括联合施用有效量的法呢酯X受体(FXR)激动剂和有效量的CCR5拮抗剂,以改善FXR激动剂的安全性和/或功效。
本发明的另一个实施方案是通过FXR激动剂治疗FXR介导的疾病如NASH或胆汁性肝硬化或适用的适应症的方法。该方法包括联合施用有效量的法呢酯X受体(FXR)激动剂和有效量的CCR2拮抗剂,以改善FXR激动剂的安全性和/或功效。
本发明的另一个实施方案是通过FXR激动剂治疗FXR介导的疾病如NASH或胆汁性肝硬化或适用的适应症的方法。该方法包括联合施用有效量的法呢醇X受体(FXR)激动剂与有效量的CCR2/5拮抗剂,以改善FXR激动剂的安全性和/或功效。
所公开的联合疗法可有效治疗CCR5和/或CCR2介导的炎性疾病或FXR介导的疾病,例如NASH,并伴有:(1)增强的功效,和(2)副作用的显著减少,特别是与OCA或其类似物的施用相关的副作用,即对肝酶升高的影响较小,瘙痒的严重程度和频率较低,和(3)可以降低FXR激动剂的全剂量以在减少副作用的同时达到联合疗效。利用所公开的联合疗法,预期需要较低剂量的OCA以实现与单独施用OCA时相当的疗效。
附图说明
图1A是条形图,显示在NASH小鼠模型中单独施用OCA和MVC与NAS评分的轻微降低相关,但当联合施用OCA和MVC两者例如全剂量联合和半剂量联合时获得更显著的效果。图1B是条形图,显示在NASH小鼠模型中单独施用OCA和CCR2拮抗剂(MR 0812)与NAS评分的轻微降低相关,但当联合施用OCA和MK 0812两者时,获得了更显著的效果。考虑到单独的CCR2拮抗剂或半剂量的OCA收效甚微,当以半剂量15mg/mg而不是30mg/kg的OCA与MK 0812(10mg,每天两次)一起施用时,注意到特别值得注意的效果。
图2A是肝脏组织学,显示通过胶原染色证实在NASH小鼠模型中单独施用OCA和MVC与纤维化减少相关,但是当联合施用OCA和MVC两者时观察到更显著的效果。图2B是肝脏组织学,显示在NASH小鼠模型中单独施用OCA和MK 0812与纤维化的减少相关,如通过单独或联合的胶原染色所证明的。
图3A是条形图,显示在NASH小鼠模型中单独施用OCA和MVC与纤维化评分的降低相关,但是当联合施用OCA和MVC两者时观察到更显著的效果。图3B是条形图,显示在NASH小鼠模型中单独施用OCA和MK 0812与纤维化评分的降低相关,但是当联合施用OCA和MK 0812两者时观察到更显著的效果。值得注意的是,半剂量的OCA(15mg/mg而不是30mg/kg)与MK0812(10mg,每天两次)一起施用。
图4A是条形图,显示在NASH小鼠模型中单独施用OCA和MVC与肝脏炎症的减少相关,但当联合施用OCA和MVC两者时获得更显著的效果。图4B是条形图,显示在NASH小鼠模型中单独施用OCA和MK 0812与肝脏炎症的减少相关,但当联合施用OCA和MK0812两者时出现更显著的效果。
图5A是条形图,显示在NASH的小鼠模型中,MVC与肝细胞气球样变性评分的降低相关,但是当联合施用OCA和MVC时观察到更显著的效果。注意到OCA对肝细胞气球样变性仅有边际效应。当使用MVC和OCA两者时,对气球样变性的效果大于单独的单一药剂。此外,令人惊讶的是当MVC和OCA都施用半剂量时,没有检测到气球样变性。图5B是条形图,显示在NASH的小鼠模型中,MK 0812和OCA都与肝细胞气球样变性评分的降低相关。
图6A是条形图,显示NASH小鼠模型中的OCA与脂肪变性减少有关,而单独的MVC仅观察到对脂肪变性的边际效应。当联合施用OCA和MVC两者时,获得了对脂肪变性的更显著的效果。图6B是条形图,显示NASH小鼠模型中的OCA与脂肪变性减少相关,然而单独的MK0812或半剂量OCA没有观察到对脂肪变性的明显效果。但是,半剂量的OCA与MK 0812的联合与全剂量的OCA一样有效。
图7A是条形图,显示在NASH小鼠模型中单独施用OCA与肝酶AST的升高相关。在单独使用MVC或使用OCA和MVC处理的小鼠中未观察到这种不良反应。在用OCA处理的小鼠和用OCA/MVC处理的小鼠之间的AST差异在统计学上是显著的。图7B是条形图,显示在NASH小鼠模型中单独施用OCA与肝酶AST的升高有关。在用单独的MK 0812或用OCA和MK 0812处理的小鼠中未观察到这种不良反应。用OCA处理的小鼠和用OCA/MK 0812处理的小鼠之间的AST差异在统计学上是显著的。
图8A是条形图,显示在NASH小鼠模型中单独施用的OCA与肝酶ALP的升高相关,但在用MVC或用OCA和MVC处理的小鼠中并非如此。用OCA处理的小鼠和用OCA/MVC处理的小鼠之间的ALP差异在统计学上是显著的。图8B是条形图,显示在NASH小鼠模型中单独施用的OCA与肝酶ALP的升高相关,但在用MK 0812处理的小鼠中并非如此。
具体实施方式
“C-C趋化因子受体5(CCR5)介导的炎性疾病”是指以以下为特征的疾病或病症:至少部分由CCR5-轴(包括CCR5的配体,例如CCL3、CCL4、CCL5、CCL X和CCR5受体)的异常活性引起的炎症或其症状可至少部分地通过抑制CCR5来缓解。CCR5介导的炎性病症的实例包括非酒精性脂肪性肝炎(NASH)、纤维化疾病(例如,肝纤维化、肾纤维化和肺纤维化)和原发性胆道硬化。“C-C趋化因子受体2(CCR2)介导的炎性疾病”是指以至少部分由CCR2-轴的异常活性引起的炎症为特征的疾病或病症。“CCR5/CCR2介导的炎性疾病”是指以至少部分由CCR5-轴和/或CCR2轴的异常活性引起的炎症为特征的疾病或病症。
FXR介导的疾病是指至少部分由FXR的异常活性引起的疾病,例如NASH或原发性胆道硬化。
“CCR5/CCR2拮抗剂”是指抑制CCR5和/或CCR2的化合物。
“CCR5拮抗剂”是指抑制CCR5的高度同源的物种特异性拮抗剂家族,包括马拉韦罗(MVC)、维立韦罗和centiviroc。
马拉韦罗目前由纽约州纽约Pfizer授权,商品名为Selentry,用于治疗HIV适应症。
维立韦罗是一种CCR5拮抗剂,由legacy Schering-Plough研发,目前被Merck/MSD,Kenilworth NJ搁置。
赛尼克韦罗是处于由Tobira,南旧金山,CA 94080研发的用于治疗NASH和HIV的CCR5和CCR2双重拮抗剂。
CCR2拮抗剂是指抑制CCR2的高度同源物种特异性拮抗剂家族,包括:MLN-1202(AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812或PF-04634817。
FXR激动剂包括奥贝胆酸(OCA),其是Intercept Pharmaceuticals,450W 15thstreet,Suite 505,floor 5,New York,NY 10011批准用于原发性胆汁性胆管炎的临床阶段化合物,OCA正处于NASH的第3期临床研发阶段。还包括PX104,其是由德国Ludwigshafen的Phenex与Gilead,Forest City,CA合作研发的FXR激动剂;和AKN-083,其由AkarnaTherapeutics研发,由Allergan,Irvine,CA收购。
该专利还包括氘代形式的CCR5、CCR2或CCR2/5拮抗剂例如马拉韦罗和维立韦罗和赛尼克韦罗。这些氘代CCR5、CCR2或CCR2/5拮抗剂具有通过CCR5、CCR2或CCR2/5拮抗作用的作用机制,分别类似于相应的非氘代形式的CCR5、CCR2或CCR2/5拮抗剂。
“有效量”是指当向患有CCR5/CCR2介导的炎性疾病或FXR介导的疾病的人类患者施用时,达到所需的治疗效果的CCR5拮抗剂的量、CCR2拮抗剂的量或CCR2/5拮抗剂的量和FXR激动剂的量,例如,不同的CCR5拮抗剂以不同的剂量施用:对于马拉韦罗,剂量为100mg至300mg每天两次或200至600mg每天一次,对于维立韦罗,剂量为5mg至50mg,每天一次,赛尼克韦罗为50mg至400mg,每天一次,MK 0812为2mg至50mg,每天一次或两次。可选择地,为了确定有效量,技术人员可以参考每种批准药物的产品标签,即CCR5拮抗剂以临床上批准剂量或较低剂量与OCA联合施用,例如每天口服一次。CCR5拮抗剂如马拉韦罗或维立韦罗可以单独施用或以固定剂量与OCA联合施用。靶向CCR2或CCR2/5的药剂可以单独施用或以固定剂量与OCA联合施用。
临床上批准的10mg OCA,以10mg的起始剂量或滴定剂量的施用,与剂量相关的副作用有关。最显著的不良事件是瘙痒和HDL的减少。据报道,与来自安慰剂组的38%相比,每天一次10mg和滴定方案中瘙痒分别为56%和70%。据报道,接受OCA的患者中约有19-23%患有严重的瘙痒(7)。还报道了HDL的剂量相关降低。通过CCR5拮抗剂或CCR2拮抗剂或CCR5/CCR2拮抗剂的联合,预期需要较小剂量的OCA以实现与当单独施用OCA时相当的功效。在这种情况下,与CCR5拮抗剂或CCR2拮抗剂或CCR2/5激动剂联合使用时,2-10mg、2-8mg、2-7mg、4-6mg或5mg或剂量小于10mg的OCA将是未来的临床剂量。
本文引用的所有参考文献均通过引用并入本文。
实施例
我们已经使用了经过充分验证的小鼠模型,其中通过顺序诱导糖尿病和高脂肪饮食诱导NASH和纤维化(14)。在第2天,给C59BL/6J小鼠注射链脲佐菌素,然后从第4周到第9周用高脂肪饮食处理。干预治疗从第5周开始直到第9周。在第9周,对这些小鼠实施安乐死。NASH及其随后的疾病过程的干预通过单独或联合施用4周的CCR5拮抗剂马拉韦罗(剂量45mg/kg,每天口服一次)和OCA(30mg/kg,每天一次)来进行。
如图1A所示,单独的CCR5拮抗剂马拉韦罗对NAS评分的影响有限,并且单独的OCA仅引起NAS评分的轻微降低。CCR5拮抗剂与OCA联合导致NAS评分显著降低,并且比任何单独的单一药剂更有效地降低NAS评分。根据非酒精性脂肪性肝炎临床研究网络的共识确定NAS评分(13)。
如图2A所示,CCR5拮抗剂马拉韦罗和OCA均有效减少纤维化,如胶原染色所证实(图2A)。基于这一证据,马拉韦罗比OCA更有效地减少纤维化。CCR5拮抗剂与OCA联合导致对纤维化减少的显著效果。根据非酒精性脂肪性肝炎临床研究网络(13)的共识确定纤维化评分。如图3A所示,对纤维化的效果也通过纤维化评分来量化,并且马拉韦罗和OCA联合导致纤维化评分减少约80%。如图4A所示,单独的OCA和MVC的联合与肝脏炎症的减少相关,但是当联合施用OCA和MVC两者时观察到更显著的效果。如图5A所示,MVC与肝细胞气球样变性评分的降低相关,但当联合施用OCA和MVC两者时观察到更显著的效果。注意到OCA对肝细胞气球样变性仅有边际效应。如图6A所示,OCA与脂肪变性的轻微减少相关,然而注意到MVC对脂肪变性仅有边际效应。当联合施用OCA和MVC时,获得了对脂肪变性的更显著的影响。当使用CCR2拮抗剂如MK 0812时获得了相当的结果(图3B至7B)。
在临床前动物研究中,单独使用OCA治疗会导致临床化学参数变化(例如,ALT、AST和ALP增加),肝脏重量增加和胆管增生,相对于推荐的人类剂量,安全范围仅为2.3倍(8)。临床试验也报道了肝脏毒性;肝脏生化检测中所有严重和其他临床上显著的肝脏相关不良反应的暴露调整发生率和单独升高,每100名患者暴露年份(PEY)为:与安慰剂组中的2.4相比,10mg组为5.2,25mg组为19.8%和50mg组为54.5%(9)。在该研究中,用OCA处理产生AST和ALP升高,但在用MVC和OCA两者处理的小鼠中未观察到这种升高(图7A-8A),并且在CCR2拮抗剂MK 0812处理的小鼠中观察到类似的发现,表明通过用MVC或MK 0812同时治疗可以减轻由OCA引起的不希望的肝毒性。
非专利引用
参考文献:
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4.Laura Pérez-Martínez,Patricia Pérez-Matute,Javier Aguilera- Lizarraga,et e al:Maraviroc,a CCR5antagonist,ameliorates the development ofhepatic steatosis in a mouse model of non-alcoholic fatty liver disease(NAFLD),J.Antimicrob.Chemother.(2014)doi:10.1093/jac/dku071
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Claims (38)
1.一种治疗患有FXR介导的疾病或C-C趋化因子受体5(CCR5)/CCR2介导的炎性疾病的人类患者的方法,包括向所述患者施用有效量的CCR5/CCR2拮抗剂和有效量的法呢酯X受体(FXR)激动剂。
2.根据权利要求1所述的方法,其中所述CCR5介导的炎性疾病或FXR介导的疾病是非酒精性脂肪性肝炎(NASH)。
3.根据权利要求1所述的方法,其中所述CCR5/CCR2介导的炎性疾病是纤维化疾病。
4.根据权利要求3所述的方法,其中所述纤维化疾病是肝纤维化。
5.根据权利要求1所述的方法,其中所述FXR介导的疾病是原发性胆道硬化。
6.根据权利要求3所述的方法,其中所述纤维化疾病是肺纤维化或肾纤维化。
7.根据权利要求1-6中任一项所述的方法,其中所述CCR5/CCR2拮抗剂是马拉韦罗、维立韦罗或赛尼克韦罗、MLN-1202(AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812或PF-04634817。
8.根据权利要求1-7中任一项所述的方法,其中所述FXR激动剂是奥贝胆酸(OCA)、PX104或AKN-083。
9.根据权利要求1-7中任一项所述的方法,其中所述CCR5拮抗剂是马拉韦罗,所述FXR激动剂是OCA。
10.根据权利要求1-7中任一项所述的方法,其中所述CCR5/2拮抗剂是赛尼克韦罗,所述FXR激动剂是OCA。
11.根据权利要求8、9或10所述的方法,其中每天一次向所述患者施用2-10mg OCA。
12.一种CCR5/CCR2拮抗剂,其与法呢酯X受体(FXR)激动剂联合用于治疗患有C-C趋化因子受体5(CCR5)/CCR2介导的炎性疾病或FXR介导的疾病的人类患者。
13.根据权利要求12所述的CCR5/CCR2拮抗剂,其中所述CCR5介导的炎性疾病或FXR介导的疾病是非酒精性脂肪性肝炎(NASH)。
14.根据权利要求12所述的CCR5/CCR2拮抗剂,其中所述CCR5/CCR2介导的炎性疾病是纤维化疾病。
15.根据权利要求14所述的CCR5/CCR2拮抗剂,其中所述纤维化疾病是肝纤维化。
16.根据权利要求12所述的CCR5/CCR2拮抗剂,其中所述FXR介导的疾病是原发性胆道硬化。
17.根据权利要求14所述的CCR5/CCR2拮抗剂,其中所述纤维化疾病是肺纤维化或肾纤维化。
18.根据权利要求12-17中任一项所述的CCR5/CCR2拮抗剂,其中所述CCR5/CCR2拮抗剂是马拉韦罗、维立韦罗或赛尼克韦罗、MLN-1202(AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812或PF-04634817。
19.根据权利要求12-18中任一项所述的CCR5/CCR2拮抗剂,其中所述FXR激动剂是奥贝胆酸(OCA),PX104或AKN-083。
20.根据权利要求12-18中任一项所述的CCR5/CCR2拮抗剂,其中所述CCR5拮抗剂是马拉韦罗,所述FXR激动剂是OCA。
21.根据权利要求12-18中任一项所述的CCR5/CCR2拮抗剂,其中所述CCR5拮抗剂是赛尼克韦罗,所述FXR激动剂是OCA。
22.根据权利要求19、20或21所述的CCR5/CCR2拮抗剂,其中每天一次向所述患者施用2-10mg的OCA。
23.一种药物组合物,其包含有效量的CCR5拮抗剂、CCR2拮抗剂或CCR5/CCR2拮抗剂,和有效量的法呢酯X受体(FXR)激动剂。
24.根据权利要求23所述的药物组合物,其中所述FXR激动剂是奥贝胆酸(OCA)、PX104或AKN-083。
25.根据权利要求23所述的药物组合物,其中所述FXR激动剂是奥贝胆酸(OCA)。
26.根据权利要求25所述的药物组合物,其中所述药物组合物物包含2-10mg的OCA。
27.根据权利要求25所述的药物组合物,其中所述药物组合物包含1-5mg OCA。
28.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含有效量的马拉韦罗。
29.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含100-300mg的马拉韦罗。
30.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含200-600mg的马拉韦罗。
31.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含有效量的维立韦罗。
32.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含5-50mg维立韦罗。
33.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含有效量的赛尼克韦罗。
34.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含50mg-400mg的赛尼克韦罗。
35.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含有效量的MK 0812。
36.根据权利要求23-27中任一项所述的药物组合物,其中所述药物组合物包含2mg-50mg的MK 0812。
37.根据权利要求25所述的药物组合物,其中所述药物组合物包含2-8mg、2-7mg、4-6mg或5mg的OCA。
38.根据权利要求23-27或37所述的药物组合物,其中所述药物组合物包含有效量的MLN-1202(AB)、CCX-140、PF-4136309、JNJ-17166864、AZD-2423、INCB-003284、BMS-741672、MK-0812、PF-04634817、马拉韦罗(MVC)、维立韦罗或赛尼克韦罗。
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