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CN1305382A - PEG－IFN－α和三唑核苷在治疗慢性丙型肝炎中的用途 - Google Patents

PEG－IFN－α和三唑核苷在治疗慢性丙型肝炎中的用途 Download PDF

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CN1305382A
CN1305382A CN99807170A CN99807170A CN1305382A CN 1305382 A CN1305382 A CN 1305382A CN 99807170 A CN99807170 A CN 99807170A CN 99807170 A CN99807170 A CN 99807170A CN 1305382 A CN1305382 A CN 1305382A
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Abstract

本发明提供了联合三唑核苷的PEG－IFN－α偶联物在制备用于治疗慢性丙型肝炎感染的药物中的用途。本发明还提供了在需要这种治疗的患者中治疗慢性丙型肝炎感染的方法,这种方法包括施用对治疗丙型肝炎有效的一定量的PEG－IFN－α偶联物和一定量的三唑核苷。

Description

PEG-IFN-α和三唑核苷在治疗慢性丙型肝炎中的用途
本发明涉及采用治疗丙型肝炎有效量的联合三唑核苷(Ribavirin)的PEG-IFN-α偶联物治疗慢性丙型肝炎感染的领域。
干扰素(IFN)是天然存在的具有抗病毒、抗增殖和免疫调节活性的蛋白质。已知人体当中存在四种不同的干扰素种类(Pestka等人(1987)生物化学年鉴(An.Rev.Biochem.)56,727-777以及Emanual和Pestka(1993)生物化学杂志(J.Biol.Chem.)268,12565-12569)。IFN-α家族代表由被刺激的外周血白细胞(Pestka等人.loc.cit.；Havell等人(1975)美国国家科学院学报(Proc.Natl.Acad.Sci.USA)72,2185-2187；Cavalieri等人(1977)美国国家科学院学报74,3287-3291)和淋巴母细胞和髓母细胞系(Familletti等人(1981)抗微生物药物和化学疗法(Antimicrob.Agents.Chemother.)20.5-9)产生的主要IFN类型。IFN-α的抗病毒作用不仅通过对病毒本身的直接影响，而且通过作用于他们的靶细胞免受病毒感染的能力这一活性来实现。干扰素可以对癌症肿瘤产生作用，而且能影响机体的免疫系统，例如它们激活巨噬细胞和NK细胞，并加强多种细胞膜的免疫学重要成分的表达。干扰素cDNA的制备及其直接表达，特别是在大肠杆菌(E.coli)中直接表达的细节已成为许多出版物的主题。因此，重组干扰素的制备是已知的，例如可以从自然(Nature)295(1982),503-508，自然284(1980),326-320，自然290(1981),20-26，核酸研究(Nucleic Acid,Res.)8(1980),4054-4074及欧洲专利32134、43980和211148中得知。
在治疗慢性丙型肝炎感染中已建议(欧洲专利申请第707855号)IFN-α与三唑核苷的联合治疗，然而这种治疗并不总有效。
PEG-IFN-α偶联物与三唑核苷的联合治疗可能比IFN-α与三唑核苷的联合治疗更有效。
在使用IFN-α的情况下，观察到PEG化能增加其循环半衰期和血浆停留时间，减少免疫原性，降低清除率并增强体内活性。
因此本发明提供了联合三唑核苷的PEG-IFN-α偶联物在制备用于治疗慢性丙型肝炎感染的药物中的用途。另外，本发明提供了在需要这种治疗的患者中治疗慢性丙型肝炎感染的方法，这种方法包括施用对治疗丙型肝炎有效剂量的联合三唑核苷的PEG-IFN-α偶联物。
在这当中用到的名词“PEG-IFN-α偶联物”包括从任何天然物质(例如，白细胞、成纤维细胞、淋巴细胞)或由其衍生的物质(例如，细胞系)或那些用重组DNA技术制备而得到的IFN-α。IFN-α克隆及其直接表达，特别是在大肠杆菌中表达的细节已经成为许多出版物的主题。重组IFN-α的制备是已知的，例如从Goeddel等人(1980)自然284,316-320和(1981)，自然290,20-26及欧洲专利第32134、43980和211148中可知。有许多类型的IFN-α，诸如IFN-αⅠ,IFN-α2；而且它们的亚型包括但不限于IFN-α2A,IFN-α2B,IFN-α2C和IFN-αⅡ(也命名为IFN-αⅡ或ω-IFN)。名词“IFN-α”也包括可以从Amgen或天然的和/或重组IFN-α的混合物中可得到的共有IFN-α。IFN-α2A的用途是优选的。欧洲专利第43980和211148号描述了IFN-α2A的制备。
IFN-α与多聚物如聚亚烷基二醇(取代的或未取代的)偶联，例如与聚乙二醇(PEG)偶联，形成PEG-IFN-α偶联物。偶联可以通过本领域已知的各种连接子完成，特别是通过那些在欧洲专利申请公开文件0510356、593868和809996中公开披露的连接子，PEG是优选的多聚物。多聚物的分子量可以从300到70000道尔顿，可以将一个或多个，优选一个到三个多聚物偶联到IFN-α上。优选的PEG-IFN-α偶联物具有这样的分子式：
Figure A9980717000041
其中R和R’是甲基，X是NH,n和n’独立地或全部为420或者为520。
三唑核苷即：1-β-D-呋喃核糖基-1H-1,2,4-三唑-3-羧酰胺，在第11版Merck目录中有描述，化合物号8199。美国专利4211771中有其制造和配制的描述。
依照这个发明，在患有慢性丙型肝炎感染的患者中可施用有效去除或缓解一种或多种慢性丙型肝炎征兆或症状之PEG-IFN-α偶联物和三唑核苷，所述征兆和症状包括ALT升高，抗HCV抗体测试阳性，通过HCV-RNA阳性实验证明HCV的存在，慢性肝脏疾病的临床特征(Stigmata)和肝细胞损伤。
对于实施本发明的联合治疗，不论体重，在每周1至2次施用当中PEG-IFN-α偶联物的剂量大约为每周33到540微克(mcg)。
对于实施本发明的三唑核苷的剂量是每天约400至1200mg，每周至少5天，优选每周7天。假定患者的体重在40和150kg之间，因此剂量范围在每天每公斤体重10到30mg之间。在一个较为具体的实施方案中，三唑核苷的每日剂量是800-1200mg。每日的剂量可以用单个剂量每天给药一次，或用分开的剂量每天给药两次或三次。优选的三唑核苷的每日剂量是用分开的剂量每天给药两次。
根据本发明，对患者施用三唑核苷是与PEG-IFN-α偶联物联合应用的。也就是说，在患者接受三唑核苷的相同或不同时期内施用PEG-IFN-α偶联物。在本发明的一个实施方案中，在同一周内，随着最少施用一剂PEG-IFN-α偶联物，最少施用一个每日剂量的三唑核苷。在一个更具体的实施方案中，在同一周内随着施用一次或多次PEG-IFN-α，施用大部分三唑核苷。在另外一个具体实施方案中，在同一周内随着施用一次或多次PEG-IFN-α，施用全部或几乎全部三唑核苷。现在PEG-IFN-α偶联物的制剂是口服给药无效的，故施用PEG-IFN-α偶联物的优选方法是非肠胃道给药，通过皮下(sc)或肌内(im)注射是优选的。三唑核苷可以胶囊或片剂的形式口服与非肠胃道给药的PEG-IFN-α偶联物联合应用。当然，也构思了两种药物的其它给药形式，只要是可得的。比如通过鼻喷雾、经皮、通过栓剂、通过缓释药剂形式等等。任何一种给药形式只要释放出合适的剂量而不破坏活性成分均可采用。
可用通过单独治疗和/或IFN-α与三唑核苷联合治疗与临床对照实验相比，来确定治疗的有效性。将联合治疗在缓解慢性丙型肝炎感染征兆和症状的效率，及其副作用的出现频率和严重性等方面与先前IFN-α单独治疗和/或IFN-α与三唑核苷联合治疗进行比较。三种患有慢性丙型肝炎感染的患者群体用于评价。运用联合治疗对只有一种或者全部三种患者群体进行研究：
1．事先未经治疗的患者。
2．事先用IFN-α和/或三唑核苷或任何其它药物治疗并且随后复发的患者。
3．事先用IFN-α和/或三唑核苷或任何其它药物治疗无反应的患者。
将通过事先描述的慢性肝炎的征兆和症状之缓解程度确定联合治疗的功效。
实施例比较联合应用PEG化IFN-α2A和三唑核苷与REBETRONTM在治疗慢性HCV感染(CHC)患者中的有效性和安全性Ⅲ期随机多中心研究
这项研究的主要目的是比较联合应用PEG-IFN-α2A和三唑核苷与REBETRON[IntronA+Rebetol(Schering/ICN牌三唑核苷)]在CHC治疗中的有效性和安全性。两组同样数量的患者(330名患者)持续48周接受联合应用PEG-IFN-α2A和三唑核苷，或者接受REBETRON。第三个患者组(165名患者)持续48周接受PEG-IFN-α2A加安慰剂。这个单独治疗的群体为PEG-IFN-α2A联合治疗群体提供了有效性和安全性的比较物。
IntronA的剂量是0.5ml溶液中3Mio.,每周三次(tiw)皮下(sc)给药，持续48周。
PEG-IFN-α2A的剂量是180μg，每周一次sc给药，与三唑核苷或安慰剂联合使用共48周。
根据体重，每天以分开的剂量使用三唑核苷和Rebetol的剂量是1000mg或1200mg。体重＜75kg(165磅)的患者每天接受1000mg(早上400mg，晚上600mg)，而体重≥75kg的患者每天接受1200mg(早上600mg，晚上600mg)。
主要的有效性参数是在持续(follow-up)的不治疗期结束时联合持续的病毒学反应(也就是通过AMPLICORTM PCR分析(灵敏度≥100拷贝/ml)检测不到HCV-RNA)和生物化学反应(血清ALT浓度正常化)。患者必须在第68周和72周具有正常血清丙氨酸转氨酶(ALT)活性，并且在第72周检测不到病毒，才能被视为反应者。
筛选中，在48周治疗期中的第1,2,4,6和8周及此后每4周在基线上进行安全性评估。安全性评估持续到其后的24周持续期。安全性测量包括副作用、生命指征和实验室化验及为了安全性或耐受性原因的剂量调整和从治疗中提前停止服药。
由事先未经任何形式的IFN-α2A或三唑核苷治疗的年满或超过18岁的CHC男性和女性患者组成患者群体。患者必须有在12个月内与CHC一致的可定量的HCV-RNA、持续异常的ALT和肝脏活检结果。排除患有其它形式的肝脏疾病、贫血、人类免疫缺陷病毒(HIV)感染、肝细胞癌、先前存在的严重的抑郁或其它精神疾病、心脏病、肾病、癫痫或严重的视网膜疾病的患者。
在试验(48周)治疗之前的筛选期(从第一次筛选评估到第一次施用实验药物的时间)长达35天。把满足所有合适条件的患者随机分配到三种治疗方案组中的一种中。
所有组中未证实有12周反应[定义为与基线相比，他们的HCV-RNA滴度下降至少1个log10单位或者其血清ALT下降至少50％(或正常化)]的患者不再继续治疗，并被视为非应答者。满足12周反应的定义但在第24周未证实或者没有可检测的HCV-RNA(＜100拷贝/ml)或者ALT正常化的患者不再继续治疗。此后仅仅为了安全性对那些不再继续治疗的患者进行跟踪。所有满足12周和24周反应标准的患者持续治疗48周。主要的有效性参数是在持续不治疗期(24周)结束时联合的病毒学和生物化学反应(HCV-RNA＜100拷贝/ml并且ALT正常化)。
目前已知的IntronA和Rebetol联合治疗的持续病毒学反应率和对PEG-IFN-α2A单独治疗48周(以从Ⅱ期研究中得到的数据为基准)以及PEG-IFN-α2A和三唑核苷联合应用的持续病毒学反应率的估计总结如下：
已知的和估计的病毒学反应率
治疗组 治疗持续时间 基因型1(A&B)EOT 基因型1(a&B)EOF 非1基因型EOT 非1基因型EOF 合并EOT 合并EOF
N(占总数的比例)           2/3      1/3          1/1
IntronA  48周 9％ 31％ 29％ 16％
IntronA加Rebetol  48周 29％ 65％ 51％ 41％
PEG-IFN  48周 60％ (29％)a 70％ (60％)a 62％ (40％)a
PEG-IFN加三唑核苷  48周 (61％)a (46％)a 70％ (70％)a (66％)a (53％)a
：园括弧内的百分数是以表中显示的其余已知反应率为基准估计的反应率。EOT：治疗结束时的病毒学反应率(病毒清除率)。EOF：持续期结束时的病毒学反应率(病毒清除率)。

Claims (10)

1．联合三唑核苷的PEG-IFN-α偶联物在制备用于治疗慢性丙型肝炎感染的药物中的用途。
2．根据权利要求1的用途，其中PEG-IFN-α偶联物的量为每周约33至540mcg。
3．根据权利要求1的用途，其中三唑核苷的量为每天400至1200mg。
4．根据权利要求1至3的用途，其中PEG-IFN-α偶联物为PEG-IFN-α2A偶联物，其分子式为：
Figure A9980717000021
其中R和R’是甲基，X是NH,n和n’独立地或全部为420或者520。
5．一种治疗慢性丙型肝炎感染的方法，包括施用对治疗慢性丙型肝炎有效的一定量的PEG-IFN-α偶联物和一定量的三唑核苷。
6．根据权利要求5的方法，其中在所述方法中施用的PEG-IFN-α偶联物的量为每周约33至540mcg。
7．根据权利要求5的方法，其中在所述方法中施用的三唑核苷的量为每天400至1200mg。
8．权利要求5至7中任何一个的方法，其中施用的PEG-IFN-α偶联物为上述PEG-IFN-α2A偶联物。
9．PEG-IFN-α偶联物和三唑核苷在治疗慢性丙型肝炎感染中的用途。
10．如此以前描述的发明。
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