CN116761597A - 司拉德帕治疗胆管病 - Google Patents
司拉德帕治疗胆管病 Download PDFInfo
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- CN116761597A CN116761597A CN202280012684.XA CN202280012684A CN116761597A CN 116761597 A CN116761597 A CN 116761597A CN 202280012684 A CN202280012684 A CN 202280012684A CN 116761597 A CN116761597 A CN 116761597A
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- A—HUMAN NECESSITIES
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
司拉德帕及其盐在治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者中的胆管病中有效。
Description
技术领域
本发明涉及对奥贝胆酸和/或贝特类药物不耐受或不充分应答(inadequateresponse)的受试者的胆管病(cholangiopathies)的治疗。
背景技术
胆管病
胆管细胞是肝内和肝外胆管衬里的上皮细胞,在那里它们参与胆汁的产生和稳态。在健康肝脏中,胆管细胞通过碳酸氢盐和水的净释放促进胆汁分泌。胆管细胞通过胆汁酸非依赖性胆汁流发挥作用,胆汁流由电解质的主动转运驱动。胆管细胞在被称为胆管病的各种人类疾病中受损。胆汁淤积是胆汁从肝脏流向十二指肠的流动减慢或受阻的病况:在胆汁淤积中,胆汁积聚在肝实质中。胆汁淤积可以方便地分为两种类型:肝内胆汁淤积,在肝脏内部,胆汁形成受到诸如各种疾病的病况、延长静脉营养或诸如某些药物(如某些抗生素)的副作用干扰;以及肝外胆汁淤积,发生在肝外,通常胆汁流因胆管的机械部分或完全闭合而受阻,如胆管肿瘤、囊肿、胆管结石、狭窄或胆管受压;尽管原发性硬化性胆管炎(PSC)可能是肝内或肝外。胆汁淤积的常见症状包括疲劳、瘙痒症(发痒)、黄疸和黄瘤(皮肤下富含胆固醇的物质沉积)。胆汁淤积的影响深远并且很广泛,导致肝脏疾病恶化,伴有全身性疾病、肝衰竭,需要进行肝移植。作为一个群体,胆管病约占成人肝移植的18%,并且占儿童肝移植的大多数。
肝内胆管病按频率递减顺序包括原发性胆汁性胆管炎(PBC,以前称为原发性胆汁性肝硬化);原发性硬化性胆管炎(PSC),如上所述,这些也可能是肝外;进行性家族性肝内胆汁淤积;和Alagille综合征(AS)。其他胆管病包括囊性纤维化相关胆管病和免疫介导的胆管病自身免疫性胆管炎和涉及肝脏的移植物抗宿主病。其他胆管病在例如方框1中提到:Banales等人,“Cholangiocyte pathobiology”,Nature Rev.Gastroenterol.Hepatol.,第16卷,第269-281页(2019)中的第272页中选择的胆管病,或其他关于胆管病的参考文献。
PBC是一种自身免疫性肝脏病况,其特征是肝脏小胆管缓慢进行性破坏,小叶内导管在病况早期受累。当这些导管受损时,胆汁会在肝脏中积聚(胆汁淤积),并随着时间的推移损害组织,这可能导致瘢痕、纤维化和肝硬化。最近的研究表明,它可能影响多达3,000-4,000人中的1人,男女性别比例为至少9:1。PBC没有治愈方法,肝移植往往成为必要;但是药物,如减少胆汁淤积和改善肝功能的熊去氧胆酸(UDCA,熊二醇)、吸收胆汁酸的消胆胺、治疗疲劳的莫达非尼和脂溶性维生素(维生素A、D、E和K,因为胆汁流量减少使这些维生素难以被吸收)可能会减缓进展,以允许正常的寿命和生活质量。UDCA在美国被批准用于治疗PBC,但据报道,约40%的患者对UDCA不充分应答,并且据报道约5%的患者对UDCA治疗不耐受。日本研究人员报道称,在UDCA中添加苯扎贝特、一种过氧化物酶体增殖物激活受体(PPAR)泛激动剂和妊娠X受体激动剂有助于治疗UDCA单药治疗难治的患者,改善血清胆汁酶、胆固醇和甘油三酯;韩国研究人员报道在UDCA中添加非诺贝特或苯扎贝特;并且BEZURSO研究了在UDCA中添加苯扎贝特。奥贝胆酸(OCA,6α-乙基鹅去氧胆酸,Intercept’sOCALIVA)是一种半合成胆汁酸类似物,它是一种高度强效法尼醇X受体激动剂,于2016年在美国被批准用于PBC的治疗,或者作为UDCA的补充,或者作为UDCA不耐受时的唯一治疗方法。然而,据报道,约50%的患者对OCA不充分应答,而OCA被广泛报道会加剧瘙痒,瘙痒是PBC的症状之一。根据OCALIVA处方信息,在一项针对216名患者的为期12个月的双盲随机对照试验中,OCALIVA 10mg组中的23%的患者、OCALIVA滴定组中的19%的患者和安慰剂组中的7%的患者出现严重瘙痒。前瞻性、观察性、多中心研究报告称,OCA停药率为12%至17%,其中很大一部分患者(45%至71%)因治疗引起的瘙痒而停药。
PSC是一种慢性胆汁淤积性肝病,其特征是肝内或肝外胆管炎症和纤维化,最终导致肝硬化。炎症的根本原因被认为是自身免疫;大约四分之三的PSC患者患有炎症性肠病,通常是溃疡性结肠炎,尽管据报道,这一比例因国家而异,患病率(通常报告为约万分之一)和性别比例(通常报告主要为男性)也是如此。标准治疗包括UDCA,它已被证明可以降低PSC患者肝酶数量的升高,但不能提高肝脏生存率或总生存率;还包括止痒药、消胆胺、脂溶性维生素和治疗感染(细菌性胆管炎)的抗生素。在2009年报道的一项研究中,长期高剂量UDCA治疗与PSC的血清肝试验改善有关,但不能提高生存率,并且与更高的严重不良事件发生率有关。已在PSC中单独测试了非诺贝特(NCT01142323);据报道,在对UDCA不充分应答的患者中,在UDCA中添加了非诺贝特或苯扎贝特。肝移植是唯一被证实的长期治疗方法。
PFIC是指一组与肝内胆汁淤积相关的儿童常染色体隐性遗传疾病的三种类型:家族性肝内胆汁胆汁淤积1缺乏症(PFIC-1)、胆汁盐外运泵缺乏症(PFIC-2)和多药耐药蛋白3缺乏症(PFIC-3)。它们的总发病率为五万-十万分之一。这种病况通常在2岁之前发病,PFIC-3通常最早出现,但患者甚至在青春期就被诊断为PFIC。患者通常表现为胆汁淤积、黄疸和发育停滞;强烈瘙痒是其特征。可能出现脂肪吸收不良和脂溶性维生素缺乏。生化标记物包括PFIC1和PFIC2中正常的γ-谷氨酰转肽酶(GGT),但PFIC3中GGT显著升高;同时血清胆汁酸水平显著升高;尽管血清胆固醇水平通常不会升高,这在胆汁淤积中通常可见,因为这种病况是由转运蛋白引起的,而不是胆汁细胞的解剖问题。这种病况通常在没有肝移植的情况下进行,导致儿童肝衰竭和死亡;并且肝细胞癌可能在很小的年龄就在PFIC2中发展。UDCA药物治疗很常见;由PFIC-1中的脂溶性维生素、消胆胺和胰酶补充。
AS,也称为Alagille-Watson综合征、综合征性胆管缺乏和动脉肝脏发育不良,是一种常染色体显性遗传疾病,与肝脏、心脏、眼睛和骨骼异常以及特征性面部特征有关;发病率为约十万分之一。肝脏异常是肝脏内胆管狭窄和畸形;这些会导致胆汁流动受阻,引起肝硬化(瘢痕)。AS主要是由位于20号染色体上的Jagged1基因的变化引起的。在3-5%的病例中,整个基因从20号染色体的一个拷贝中删除(缺失);在其余部分中,Jagged1 DNA序列存在变化或突变。在极少数病例(少于1%)中,另一个基因Notch2的变化会导致AS。在大约三分之一的病例中,突变是遗传性的;在大约三分之二的病例中,这种突变是该病例中新出现的。AS没有治愈方法,尽管肝病的严重程度通常在3至5岁时达到峰值,通常在7至8岁时消退。在一些人中,肝病会发展到终末期肝病,可能需要肝移植;大约15%的AS患者需要肝移植。许多不同的药物,例如UDCA,已被用于改善胆汁流量和减少瘙痒,许多患者服用了高剂量的脂溶性维生素。
囊性纤维化相关胆管病,更常见的是囊性纤维化肝病或CFLD,是囊性纤维的一种并发症,据报道约30%的囊性纤维化患者会受到影响,并且是囊质纤维化患者第三常见的死亡原因。CFLD可通过肝脂肪变性(可选伴有肝炎)发展为局灶性胆汁性肝硬化和多小叶性肝硬变。在一些成年CFLD患者中,症状与PSC相似。UDCA是一种常见的治疗方法,补充脂溶性维生素也是如此。
根据Heathcote,“Autoimmune cholangitis”,Clinics Liver Dis.,第2(2)卷,303-311(1998),“术语“自身免疫性胆管炎”描述了慢性肝病患者具有原发性胆汁性肝硬化(PBC)典型的胆汁模式,但与自身免疫性肝炎典型的非器官特异性抗体相关。有些人认为这种病况是典型的I型自身免疫性肝炎的变体;其他人认为它是PBC的变体,因为缺乏血清线粒体抗体。”UDCA和免疫抑制剂如硫唑嘌呤或皮质类固醇如泼尼松已被建议用于治疗。
移植物抗宿主病(GVHD)是异基因造血细胞移植(HCT)后的常见并发症,通常表现为皮肤、胃肠道粘膜和肝脏损伤。肝脏的慢性GVHD更典型地是一种与皮肤、口腔粘膜和泪腺异常相关的惰性胆汁淤积综合征,在同种异体HCT后第100天出现。常见的治疗方法是免疫抑制治疗。
碱性磷酸酶(ALP)和GGT是胆汁淤积的关键标记物。虽然其中一个单独升高并不表示胆汁淤积,并且需要其他参数来确认,但ALP和GGT的升高都表示胆汁淤积;两者的减少表明胆汁淤积的改善。因此,ALP和GGT水平是肝内胆管病中存在胆道病理生理学的生化标记物,ALP水平已被用作肝内胆管病(如PBC)临床研究的主要结果标记物(包括引发美国批准OCA的研究)。其他相关标记物可能包括胆管退化的生物标记物,如CK19、miR-506和其他(参见例如,Baghdasaryan等人,“Inhibition of intestinal bile acid absorptionimproves cholestatic liver and bileduct injury in a mouse model of sclerosingcholangitis”,J.Hepatology,第64卷,第674-681(2016)和Erice等人,“MiRNA-506promotes primary biliary cholangitis-like features in cholangiocytes andimmune activation”,Hepatology,第67(4)卷,第1420-1440(2018)),肝损伤标记物如天冬氨酸转氨酶(AST)和丙氨酸转氨酶(ALT),以及纤维化标记物如Col1α1,因为纤维化在肝外胆管病中比在肝内胆管病中更常见。反映治疗的临床标记物可能包括上述生物标记物、缺乏纤维化进展或进展为肝硬化;基于血液的纤维化标记物如ELF、Pro-C3和Pro-C5减少;以及缺乏与肝脏相关的不良事件,如胆管炎、腹水、静脉曲张出血或MELD进展。
胆管病的治疗
如上所述,UDCA是胆管病的常见治疗方法,因为它的作用可以减少胆汁淤积和改善肝功能。然而,2012年对PBC中UDCA的Cochrane综述发现,尽管UDCA显示肝脏病理、黄疸和腹水的生物标记物减少,但医学文献中没有证据表明UDCA对死亡率或肝移植有任何益处,而它的使用与体重增加和成本有关。虽然UDCA也用于其他胆管病,但许多胆管病患者唯一的长期治疗方法是肝移植。
此外,如上所述,OCA于2016年在美国被批准用于PBC的治疗,或者作为UDCA的补充,或者作为UDCA不耐受时的唯一治疗。贝特类药物如非诺贝特和苯扎贝特也被使用,如OCA,或者作为UDCA的补充,或者作为UDCA不耐受或提供的不充分应答时的唯一治疗。其他药物,如PPARα/δ激动剂elafibranor已在PBC中进行了测试,非诺贝特和苯扎贝特两者也在PSC中进行了测试。其他治疗胆管病的药物,特别是例如治疗PFIC和AS的药物,通过抑制顶端钠-胆汁酸转运蛋白ASBT[也称为回肠胆汁酸转运蛋白(IBAT)],靶向与这些疾病相关的胆汁淤积性瘙痒。这些包括在美国被批准为Albireo的BYLVAY用于治疗PFIC的奥维昔巴特,以及在美国被批准为为Mirum的LIVMARLI的用于治疗AS的maralixabat。
然而,OCALIVA当前的美国标签包含“黑盒子”警告,禁止用于患有失代偿性肝硬化(如Child-Pugh B级或C级)或既往失代偿事件或有门静脉高压证据的代偿性肝硬化的PBC患者;而当前对非诺贝特(AbbVie的TRICOR)的美国标签规定,它在活动性肝病患者中禁用,包括在原发性胆汁性肝硬化和不明原因的持续性肝功能异常患者中禁用。苯扎贝特在美国未被批准,但对缓释苯扎贝特(Allergan的BEZALIP SR)的当前加拿大标签规定,它在肝损伤(包括原发性胆汁性肝硬化)中禁用。
对于对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者,开发治疗胆管病的药物治疗方法是可取的。
司拉德帕(Seladelpar)
司拉德帕(Seladelpar)(国际非专利名称-INN)的化学名称为[4-({(2R)-2-乙氧基-3-[4-(三氟甲基)苯氧基]丙基}硫烷基)-2-甲基苯氧基]乙酸[WHO推荐的IUPAC名称INN:列表77]和代码编号MBX-8025。司拉德帕及其合成、制剂和用途公开于例如美国专利号7301050(表1中的化合物15,实施例M,权利要求49)、美国专利号7635718(表1的化合物15、实施例M)和美国专利号8106095(表1中的化合物15、实施例M、权利要求14)。司拉德帕的赖氨酸(l-赖氨酸)盐和相关化合物公开在美国专利号7709682中(整个实施例中的司拉德帕-l-赖氨酸盐,要求保护的结晶形式)。
司拉德帕是一种口服活性、强效(2nM)PPARδ激动剂。它具有特异性(与PPARα和PPARγ受体相比,分别为大于600-倍和大于2500-倍)。PPARδ激活刺激脂肪酸氧化和利用,改善血脂和脂蛋白代谢、葡糖利用和线粒体呼吸,并保持干细胞稳态。根据美国专利号7301050,PPARδ激动剂如司拉德帕,被建议用于治疗PPARδ介导的病况,包括“糖尿病、心血管疾病、代谢X综合征、高胆固醇血症、次高密度脂蛋白(HDL)-胆固醇血症、超低密度脂蛋白(LDL)-胆固醇症、血脂异常、动脉粥样硬化和肥胖”,血脂异常据说包括高甘油三酯血症和混合性高脂血症。
美国专利号9486428和PCT国际公开号WO 2015/143178公开了用司拉德帕及其盐治疗肝内胆汁淤积病,例如原发性胆汁性胆管炎、原发性硬化性胆管炎、进行性家族性肝内胆汁淤积和Alagille综合征;美国专利号10272058和PCT国际公开号WO 2017/209865公开了用较低剂量的司拉德帕及其盐(例如5mg/天和10mg/天的司拉德帕)治疗相同疾病;以及美国申请公开号2019/0105291和PCT国际公开号WO 2019/06373公开了用司拉德帕及其盐治疗胆汁淤积性瘙痒。
司拉德帕已在原发性胆汁性胆管炎(PBC)中进行了研究,50mg/天和200mg/天的结果在Jones等人,“Seladelpar(MBX-8025),a selective PPAR-δagonist,in patientswith primary biliary cholangitis with an inadequate response toursodeoxycholic acid:a double-blind,randomised,placebo-controlled,phase 2,proof-of-concept study”,Lancet Gastroenterol.Hepatol.,2(10),716-726(2017)中报道,并且2mg/天、5mg/天和10mg/天的结果在法国巴黎主办(2018年4月11日至4月15日)的欧洲肝病研究协会(EASL)的The International Liver CongressTM上:在海报LBP-2中(Hirschfield等人,“Treatment Efficacy and Safety of Seladelpar,a SelectivePeroxisome Proliferator-Activated Receptor Delta agonist,in Primary BiliaryCholangitis Patients:12-and 26-Week Analyses of an Ongoing,International,Randomized,Dose Ranging Phase 2Study”),以及在海报THU-239中(Boudes等人,“Seladelpar’s Mechanism of Action as a Potential Treatment for PrimaryBiliary Cholangitis and Non-Alcoholic Steatohepatitis”)报道,两者均可在https://ir.cymabay.com/presentations;以及在以后的简报中可获得。在2b期研究中,发现司拉德帕在52周时间内使ALP和GGT显著降低,同时ALT和稳定的总胆红素水平统计学上显著降低;而即使在Child-Pugh A肝硬化的亚组中甚至也观察到类似的结果。司拉德帕也被建议用于其他胆管病。
发明内容
本发明是通过施用司拉德帕或其盐治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者的胆管病的方法。
在各个方面中,本发明包括:
用于治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者的胆管病的司拉德帕或其盐;
司拉德帕或其盐用于治疗或制备用于治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者的胆管病或在制备用于其治疗的药物中的用途;和
用于治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者的胆管病的包含司拉德帕或其盐的药物组合物或药物。
鉴于司拉德帕在治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者中的原发性胆汁性胆管炎的已证明的疗效,如实施例1所示,以及胆管病的常见因素,司拉德帕预期在治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者中的其他胆管病方面具有活性。鉴于在胆管病(如PBC)中使用这些药物的警告和禁忌症,这种活性被认为是特别有利的。无论受试者是否对熊去氧胆酸不敏感,或是否对熊去氧胆酸不耐受或不充分应答,都可以预期这种活性。
本发明的优选实施方案的特征在于所提交的本申请的权利要求1至20的说明书和特征。
具体实施方式
定义
背景技术中标题为“胆管病”和“胆管病的治疗”的章节中描述了胆管病及其治疗。
背景技术中标题为“司拉德帕”的小节中描述了司拉德帕。
在本发明中包括司拉德帕的盐(例如,药学上可接受的盐),并且这些盐可用于本申请中描述的方法。这些盐优选与药学上可接受的酸形成。例如,参见“Handbook ofPharmaceutically Acceptable Salts”,Stahl和Wermuth编辑,Verlag HelveticaChimica Acta,Zürich,Switzerland,了解有关药用盐及其选择、制备和使用的广泛讨论。除非上下文另有要求,否则对司拉德帕的任何提及都是对该化合物及其盐的提及。
由于司拉德帕含有羧基,因此当存在的酸性质子与无机或有机碱反应时,它可能会形成盐。通常,司拉德帕用过量的碱性试剂处理,如含有适当阳离子的氢氧化物、碳酸盐或醇盐。阳离子如Na+、K+、Ca2+、Mg2+、和NH4 +是存在于药学上可接受的盐中的阳离子的实例。因此,合适的无机碱包括氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。也可以使用有机碱来制备盐,例如伯胺、仲胺和叔胺的盐,包括天然存在的取代胺的取代胺,和环状胺,包括异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺、胆碱、甜菜碱、乙二胺、葡萄糖胺、N-烷基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶等。预期有用的盐包括l-赖氨酸盐;并且如“司拉德帕”小节中所述,目前司拉德帕被配制为其l-赖氨酸二水合物盐。
“另一种抗胆汁淤积剂”是指用于治疗胆管病的药物,它既不是司拉德帕或司拉德帕盐,也不是奥贝胆酸或贝特类药物。这类试剂包括熊去氧胆酸(UDCA),如背景技术中所述。
术语“贝特类药物(fibrate)”包括纤维酸的两种衍生物,如吉非罗齐、氯贝特、非诺贝特、苯扎贝特、氯贝胺、环丙贝特、克利贝特、氯烟贝特和双贝特,以及作为PPARα激动剂的非纤维酸衍生物化合物(包括混合激动剂,前提是它们具有显著的PPARα激动作用),如elafibranor、拉尼兰诺和沙罗格列扎;特别是非诺贝特、苯扎贝特和elafibranor。
就奥贝胆酸和/或贝特类药物而言,“不耐受”或“不耐性”或类似术语是指为治疗胆管病而被施用奥贝胆酸或贝特类药物的受试者出现了导致受试者停止奥贝胆酸和/或贝特类药物治疗的副作用。可能导致受试者被认为对奥贝胆酸不耐受的示例性副作用包括肝脏相关的不良反应、瘙痒和HDL-C减少,例如如OCALIVA的当前标签中所述,通过引用并入本申请。可能导致受试者被认为对贝特类药物不耐受的示例性副作用包括肌肉毒性/肌痛、肌酸酐激酶升高、横纹肌溶解、肾毒性(如血清肌酸酐或尿素氮升高、肾小球滤过率下降、ALT、AST或总胆红素(TBIL)升高)。“奥贝胆酸和/或贝特类药物”和“奥贝胆酸和贝特类药物中的至少一种”是指所有的奥贝胆酸、单一贝特类药物、多于一种贝特类药物、奥贝胆酸与单一贝特类药物以及奥贝胆酸与多于一种贝特类药物。
关于奥贝胆酸和/或贝特类药物的“不充分应答”、“不完全反应”或类似术语,是指为治疗胆管病而被施用奥贝胆酸或贝特类药物的受试者未能对其胆管病进行充分治疗。不充分应答可以通过受试者未能实现胆管病的生物化学标记物的充分降低来评估,例如,受试者未实现ALP低于正常上限1.67倍、ALP充分降低(例如,至少15%)和/或总胆红素低于正常值上限中的至少一种,通常是多于一种。
由于熊去氧胆酸被视为许多胆管病的一线治疗方法,因此通常需要在对熊去氧胆酸不耐受或不充分应答的受试者中测试其他治疗方法,如奥贝胆酸;或者作为熊去氧胆酸的附加组分(add-on)进行测试,例如在BEZURSO和POISE研究中。因此,基本上无法获得对熊去氧胆酸不敏感(即未经熊去氧胆酸治疗)的受试者的经验。然而,预期司拉德帕对对熊去氧胆酸不敏感的受试者以及对熊去氧胆酸不耐受或不充分应答的受试者同样有效。
司拉德帕和另一种抗胆汁淤积剂(如熊去氧胆酸)的“伴随施用”是指在胆管病治疗过程中施用的司拉德帕和另一种抗胆汁淤积剂。这种伴随施用可能涉及在施用司拉德帕之前、期间和/或之后施用另一种抗胆汁淤积剂,从而维持每种化合物的治疗有效水平。伴随施用可以通过施用司拉德帕和另一种抗胆汁淤积剂来完成,每种都以其常规剂量施用;但是,如果两者都是口服生物可利用的并且方便地每天口服给药,则伴随施用可能还包括联合剂型的施用。司拉德帕和另一种抗胆汁淤积剂的“联合治疗”与“伴随施用”具有相同的含义。
司拉德帕或其盐的“治疗有效量”是指当用于治疗对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者(即人)的胆管病时,足以有效治疗胆管病的量。
受试者胆管病的“治疗(Treating)”或“治疗(treatment)”包括以下一种或多种:
(1)预防或降低发展为胆管病的风险,即,使可能易患胆管病但尚未经历或表现出胆管病症状的受试者中不发展胆管病的临床症状(即,预防);
(2)抑制胆管病,即阻止或减少胆管病或其临床症状的发展;和
(3)缓解胆管病,即引起胆管病的消退、逆转或改善,或减少其临床症状的数量、频率、持续时间或严重程度。
“治疗(treatment)”并不一定意味着“治愈”或完全治疗,例如治疗胆管病的所有临床症状,尽管“治疗(treatment)”可能包括“治愈”。相反,当与不施用司拉德帕相比时,“治疗(treatment)”意味着施用司拉德帕提供临床益处;并且治疗还可以通过正在接受治疗的胆管病的生物标记物的改善来评估。
特定受试者的治疗有效量取决于待治疗的受试者健康和身体状况、胆管病的程度、对医疗状况的评估以及其他相关因素。预期治疗有效量将落在可通过常规试验确定的相对较宽的范围内。
如果司拉德帕与另一种不是奥贝胆酸也不是贝特类药物的抗胆汁淤积剂伴随施用,则司拉德帕或与司拉德帕伴随施用的另一种抗胆汁淤积剂的“治疗有效量”是指每一种的量,当司拉德帕和另一种抗胆汁淤积剂伴随施用给受试者用于治疗胆管病时足以实现对胆管病的有效治疗。
“包括(comprising)”或“含有(containing)”及其语法变体是包含式而非限制性的单词,并且意思是指定所述组分、分组、步骤等的存在,但不排除其他组分、分组、步骤等的存在或添加。因此,“包括(comprising)”并不意味着“由...组成(consisting of)”、“基本上由...组成(consisting substantially of),或“仅由...组成(consisting onlyof);并且例如,“包括(comprising)”一种化合物的制剂必须含有该化合物,但也可能含有其他活性成分和/或赋形剂。除非上下文另有要求,单数形式“一个(a)”、“一个(an)”和“该(the)”包括复数所指物。因此,例如,“另一种抗-胆汁淤积剂”表示一种或多种另一种抗-胆汁淤积剂;并且“选自司拉德帕及其盐的化合物”表示选自司拉德帕及司拉德帕的盐的一种或多种化合物。
制剂和施用
司拉德帕可以通过任何适合接受治疗的受试者和受试者病况性质的途径施用。施用途径包括口服施用(如果可用,通常优选);注射施用,包括静脉内、腹腔内、肌肉内和皮下注射;通过跨粘膜(例如,鼻内、颊、舌下、直肠或阴道)或透皮(局部)递送;等。制剂可以是口服制剂(例如,片剂、胶囊或口服溶液或悬浮液);注射制剂(例如,溶液);以及设计用于跨粘膜或透皮施用药物的制剂。用于这些给药方法中每一种的合适制剂可以在例如“Remington:The Science and Practice of Pharmacy”,20th ed.,Gennaro,ed.,Lippincott Williams&Wilkins,Philadelphia,Pa.,U.S.A中找到。由于司拉德帕是口服可利用的,因此典型的制剂是口服的,并且典型的剂型是用于口服施用的片剂或胶囊剂。正如“司拉德帕”小节中提到的,司拉德帕是以胶囊形式配制的,用于临床试验。静脉内制剂可特别适用于急性疾病受试者的施用,例如患有急性酒精性肝炎或酒精性纤维化或肝硬化的受试者,例如那些可能住院治疗的受试者。
取决于预期的施用方式,药物组合物可以是固体、半固体或液体剂型的形式,优选为适合单次施用精确剂量的单位剂型形式。除了有效量的司拉德帕外,组合物还可包含合适的药学上可接受的赋形剂,包括有助于将活性化合物加工成可药学上使用的制剂的佐剂。“药学上可接受的赋形剂”是指不会干扰活性化合物(多种)的生物活性的有效性,并且对它所施用给的受试者无毒或在其他方面不希望有的赋形剂或赋形剂混合物。
对于固体组合物,常规赋形剂包括例如,医药级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖、碳酸镁等。液体药理学上可施用的组合物可以例如通过将本文所述的活性化合物和任选的药物佐剂溶解、分散等在水中或水性赋形剂(诸如例如水、盐水、水性葡萄糖等)中以形成溶液或悬浮液来制备。如果需要,待施用的药物组合物还可以含有少量无毒的辅助赋形剂,例如润湿剂或乳化剂、pH缓冲剂等,例如乙酸钠、脱水山梨糖醇单月桂酸酯、三乙醇胺乙酸钠、三乙醇胺油酸酯等。
对于口服施用,组合物通常采取片剂或胶囊的形式;或者,特别是对于儿科使用,它可以是水溶液或非水溶液、悬浮液或糖浆。片剂和胶囊是优选的口服施用形式。用于口服使用的片剂和胶囊通常包括一种或多种常用赋形剂,如乳糖和玉米淀粉。通常还加入润滑剂,例如硬脂酸镁。当使用液体悬浮液时,活性剂可以与乳化和悬浮赋形剂结合。如果需要,也可以添加调味剂、着色剂和/或甜味剂。用于掺入到口服制剂中的其他任选赋形剂包括防腐剂、悬浮剂、增稠剂等。
通常,司拉德帕的药物组合物或包含司拉德帕组合物的试剂盒被包装在具有标签或说明书或两者的容器中,指示药物组合物或试剂盒在治疗酒精性肝病中的用途。
药物制剂领域的普通技术人员将能够通过选择合适的剂型、赋形剂、包装等来制备司拉德帕的合适的药物组合物,以实现治疗有效的制剂,而无需过度的实验并且依赖于个人知识和本申请的公开内容。
针对对奥贝胆酸和/或贝特类药物不耐受或不充分应答的成年受试者,用于口服给药的合适量(即治疗有效量)的司拉德帕或其盐预期等同于至少0.5mg/天,例如至少1mg/天、例如至少2mg/天或至少5mg/天的司拉德帕;但相当于不大于50mg/天,例如不大于25mg/天,如不大于15mg/天,或不大于10mg/天的司拉德帕;例如,在由“至少”值之一和“不大于”值之一定义的任何范围内,例如至少1mg/天且不大于25mg/天(即1-25mg/天)或至少2mg/天且不大于10mg/天;例如2mg/天、5mg/天或10mg/天,取决于胆管病的程度和严重程度以及诸如肝和肾功能的因素。也就是说,用于成人口服给药的司拉德帕以治疗诸如PBC的病况的合适剂量预期与对奥贝胆酸和/或贝特类药物不耐受或不充分应答的类似受试者大致相同。对于患有诸如PFIC和AS的疾病的儿童受试者,将根据年龄和体重等其他因素;以及在患有严重肝损伤的受试者,如取决于损伤程度为Child-Pugh B级和C级的受试者中,将剂量适当减少至上述外部范围的下限或低于该下限。这些量表示平均每日剂量,而不一定是单次给药给予的量。给药频率可能高达多于一次/天(其中数量或每日剂量将在每天的施用次数之间分配),但更通常为一次/天(其中该数量在单次施用中给予)。任选地,特别是在严重肝损伤的情况下,给药频率可以低于一次/天,例如在一次/周和每隔一天之间,例如一次/周、两次/周(尤其是间隔至少三天的剂量)、三次/周(特别是间隔至少两天的剂量)或每隔一天;因此,例如,受试者可以以1.4mg/天的量(日剂量)每周接受两次5mg。“相当于”司拉德帕特定量的司拉德帕盐量是指所述特定量乘以盐的配方重量与司拉德帕的配方重量比率的盐量。例如,如果使用司拉德帕l-赖氨酸二水合物盐,由于司拉德帕l-赖氨酸二水合物盐的配方重量是司拉德帕的配方重量的约1.41倍,因此司拉德帕l-赖氨酸二水合物盐的约14.1mg/天的量将相当于司拉德帕的10mg/天的量。
当司拉德帕或司拉德帕盐和另一种抗胆汁淤积剂伴随施用时,适当量的司拉德帕或司拉德帕盐预期与单独施用司拉德帕或司拉德帕盐时相同;并且适当量的另一种抗胆汁淤积剂预期与如背景技术中所述的临床试验中批准或使用的量相似。也就是说,达到联合治疗的治疗有效量的司拉德帕或司拉德帕盐和另一种抗胆汁淤积剂的适当量将类似于临床试验中使用的量。然而,任何一种在联合治疗中的治疗有效量都可能低于作为单药治疗使用的量时,因为它们中的每一种都预期有效治疗胆管病。
胆管病治疗领域的普通技术人员将能够确定司拉德帕或司拉德帕盐的治疗有效量,当单独使用或与另一种抗胆汁淤积剂以及当伴随施用使用时用于胆管病的特定患者和阶段的另一种防胆汁淤积剂同时使用时,以获得治疗有效量,而不需要过度实验并且依赖于个人知识和本申请的公开内容。
实施例
实施例1:原发性胆汁性胆管炎
合并了在对熊去氧胆酸不耐受或不充分应答的受试者中入选司拉德帕的开放标签2期研究(NCT02955602,EudraCT 2016-002996-91)或随机安慰剂对照3期研究(NCT03602560,EudraCT 2018-001171-20)的原发性胆汁性胆管炎受试者;并且选择对奥贝胆酸和/或贝特类药物不耐受或不充分应答的受试者进行分析。试验受试者为成年、男性或女性,根据以下三项标准中的至少两项诊断为PBC:(a)ALP高于正常(ULN)上限至少六个月的病史,(b)免疫荧光阳性抗线粒体抗体滴度>1/40或酶联免疫吸附测定M2阳性或PBC特异性抗核抗体阳性,以及(c)记录的肝活检结果与PBC一致,在过去12个月内服用稳定和推荐剂量的UDCA或UDCA不耐受,且ALP≥1.67×ULN。排除标准包括AST或ALT≥3×ULN,TBIL≥2×ULN、自身免疫性肝炎或有慢性病毒性肝炎病史、PSC、目前使用了贝特类药物或辛伐他汀、前两个月使用了秋水仙碱、甲氨蝶呤、硫唑嘌呤或全身性类固醇、使用了PBC的实验性治疗以及使用了实验性或未经批准的免疫抑制剂。受试者每天口服一次胶囊形式的司拉德帕l-赖氨酸二水合物盐,其量相当于10mg/天或5mg/天的司拉德帕(S)或安慰剂。对治疗三个月的受试者进行疗效评估。联合终点是受试者达到ALP<1.67×ULN、ALP降低>15%且TBIL≤ULN的应答率。其他终点是ALP≤ULN,基线ALP变化以及其他肝功能标记物。对安全性进行超过一年的评估。
在这两项研究中,384名入选受试者中,共有71名受试者对OCA(47)、贝特类药物(16)或两者(8)均不耐受或不充分应答。51名受试者接受了为期3个月的治疗;且37名受试者接受了评估;结果如下表所示:
对所有71名受试者进行安全性分析。四名受试者出现严重不良事件(三名服用5mg/天司拉德帕,一名服用安慰剂),均与司拉德帕无关;两名受试者因不良事件停止治疗:一名受试者因ALT/AST升高而停止治疗,另一名受试者因胃食管反流病而停止治疗。在对奥贝胆酸和/或贝特类药物不耐受或不充分应答的PBC受试者中,司拉德帕似乎是安全的、耐受性良好的,并且在胆汁淤积的生化标记物方面表现出有意义的改善。
实施例2:原发性硬化性胆管炎
试验受试者为成年、男性或女性,根据以下三项标准中的至少两项诊断为PSC:(a)任何既往实验室结果显示AP>ULN升高的历史证据,(b)与PSC一致的肝活检,以及(c)通过MRCP、ERCP或经皮肝穿刺胆管造影测量的与PSC一致的异常胆管造影;在过去六个月或UDCA治疗后至少十二周内,UDCA的稳定和推荐剂量≤20mg/Kg/天;以及对奥贝胆酸和/或贝特类药物不耐受或不充分应答。其他标准包括ALP≥1.5×ULN,TBIL≤2×ULN,ALT和AST两者≤5×ULN,eGFR>60mL/min/1.73m2,血小板≥140×103/μL,INR≤1.3(在没有华法林或其他抗凝血疗法的情况下)和白蛋白≥3.5g/dL。排除标准包括病因非PSC的临床显著急性或慢性肝病、自身免疫性肝炎(AIH)和PSC重叠的诊断、继发性或IgG4相关的硬化性胆管炎、小管PSC、胆管造影或MRI上是否存在胆管癌、胆管支架术、病史、迹象、或高度怀疑胆管癌或其他肝胆恶性肿瘤,12周内推定或诊断为急性胆管炎,以及代偿性或失代偿性肝硬化迹象。主要研究终点是第24周基线血清ALP的相对变化;且次要终点是治疗引发的不良事件的发生率、PSC相关症状或程序的发生率和严重程度,以及肝病进展事件的发生率。受试者随机接受安慰剂或司拉德帕或其盐,其量相当于5、10或20mg/天的司拉德帕,每天口服一次,为期24周。受试者表现出ALP的剂量相关降低,并表现出PSC相关症状的改善。
Claims (20)
1.一种选自司拉德帕及其盐的化合物,用于治疗对奥贝胆酸和贝特类药物中的至少一种不耐受或不充分应答的受试者的胆管病的用途。
2.根据权利要求1所述的用于用途的化合物,其中所述化合物为司拉德帕L-赖氨酸盐。
3.根据权利要求2所述的用于用途的化合物,其中所述化合物为司拉德帕L-赖氨酸二水合物盐。
4.根据权利要求1至3中任一项所述的用于用途的化合物,其中所述化合物是口服施用的。
5.根据权利要求1至4中任一项所述的用于用途的化合物,其中所述化合物的量相当于0.5-50mg/天的司拉德帕。
6.根据权利要求5所述的用于用途的化合物,其中所述化合物的量相当于1-25mg/天的司拉德帕。
7.根据权利要求6所述的用于用途的化合物,其中所述化合物的量相当于2-10mg/天的司拉德帕。
8.根据权利要求7所述的用于用途的化合物,其中所述化合物的量相当于5mg/天或10mg/天的司拉德帕。
9.根据权利要求1至8中任一项所述的用于用途的化合物,其中所述化合物每天施用一次。
10.根据权利要求1至9中任一项所述的用于用途的化合物,其中所述胆管病为原发性胆汁性胆管炎。
11.根据权利要求1至9中任一项所述的用于用途的化合物,其中所述胆管病为原发性硬化性胆管炎。
12.根据权利要求1至9中任一项所述的用于用途的化合物,其中所述胆管病为进行性家族性肝内胆汁淤积。
13.根据权利要求1至9中任一项所述的用于用途的化合物,其中所述胆管病为Alagille综合征。
14.根据权利要求1至9中任一项所述的用于用途的化合物,其中所述胆管病为囊性纤维化相关胆管病。
15.根据权利要求1至9中任一项所述的用于用途的化合物,其中所述胆管病为自身免疫性胆管炎。
16.根据权利要求1至9中任一项所述的用于用途的化合物,其中所述胆管病是涉及肝脏的移植物抗宿主病。
17.根据权利要求1至16中任一项所述的用于用途的化合物,其中所述受试者对熊去氧胆酸不敏感。
18.根据权利要求1至16中任一项所述的用于用途的化合物,其中所述受试者对熊去氧胆酸不耐受或对其不充分应答。
19.根据权利要求1至18中任一项所述的用于用途的化合物,其中所述受试者对奥贝胆酸不耐受或对其不充分应答。
20.根据权利要求1至19中任一项所述的用于用途的化合物,其中所述受试者对贝特类药物不耐受或对其不充分应答。
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