CN115551510A - 用于治疗由冠状病毒引起的肺炎和/或心肌炎的azd1656 - Google Patents
用于治疗由冠状病毒引起的肺炎和/或心肌炎的azd1656 Download PDFInfo
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Abstract
本发明涉及AZD1656或其药学上可接受的盐,用于治疗可能与冠状病毒感染相关联或由冠状病毒感染引起的肺炎和/或心肌炎。
Description
技术领域
本发明涉及肺炎(肺部的破坏性炎症)和/或心肌炎(心脏的破坏性炎症)的治疗。
背景技术
肺炎是指代肺组织的炎症的通用术语。肺炎的常见原因包括通过空气传播的刺激物或某些药物治疗的副作用。
肺炎最常见的症状是呼吸急促,其可能伴有干咳。如果肺炎未被发现或未得到治疗,则患者可能会发展为慢性肺炎,这可能导致肺部瘢痕形成(纤维化)。
心肌炎是心脏肌肉(心肌)的炎症。心肌炎可能会影响心肌和心律,降低心脏的泵血能力并导致快速或异常的心律(心律失常)。
肺炎和心肌炎可能与病毒感染相关联。一种这样的病毒感染是冠状病毒,如Covid-19。在当前的冠状病毒大流行中,病毒感染导致的死亡原因是肺炎和/或心肌炎,并且因此需要新的药物来治疗这些病况。
葡萄糖激酶是一种促进葡萄糖磷酸化成6-磷酸葡萄糖的酶。葡萄糖激酶出现在人类和大多数其他脊椎动物的肝脏和胰腺中的细胞中。在这些器官中的每一个中,它通过充当葡萄糖传感器、响应于如在饭后或在空腹时发生的葡萄糖水平的上升或下降而触发代谢或细胞功能的变化而在调节碳水化合物代谢中起着重要作用。对于这种酶,基因突变可能引起不寻常形式的糖尿病或低血糖。葡萄糖激酶(GK)是一种己糖激酶同工酶,与至少三种其他己糖激酶同源相关。
AZD1656是一种体外人和大鼠葡萄糖激酶的强效的、选择性的(〉100倍于己糖激酶1和2以及药理学筛选组)激活剂;对于重组酶,EC50分别为0.057和0.072μM,其转化为细胞系统(在人和大鼠肝细胞中,EC50分别为1.39和0.47μM)。当急性给药时和当每天一次给药持续长达28天时,AZD1656在血糖正常的胰岛素抗性大鼠和糖尿病小鼠中以剂量依赖性方式降低血浆葡萄糖水平,起效迅速。
AZD1656已在健康志愿者中进行了以高达180mg的单剂量和150mg BID的多剂量持续8天的研究,以及在糖尿病患者中进行了以每天200mg单独和与其他血糖控制剂组合持续长达6个月持续时间的研究。在健康志愿者和糖尿病患者两者中,除了葡萄糖下降外,没有注意到显著的临床效果。
已经执行了长达12个月的临床前研究。这些显示了强效的葡萄糖下降效果,并且从而,在健康动物中的慢性毒理学研究结果被较高剂量下的严重低血糖症和后遗症(如沃勒型神经变性(Wallerian type nerve degeneration)和骨骼肌纤维变性)所混淆。在肝脏中看到附加的变化,也被认为是继发于低血糖症(肝细胞糖原的损耗)。
在日本2型糖尿病受试者的第2期研究中,AZD1656,其在4个月内以高(40-200mg/天)、中(20-140mg/天)和低(10-80mg/天)剂量给予BID,已发现50mg剂量会降低HbA1c和空腹血浆(FPG)葡萄糖水平,从而在血浆中产生约2×EC50的化合物水平。然而,这种效果在第8周和第16周之间呈短暂的给药前水平趋势,并且在4个月时,HbA1c或FPG与基线相比没有统计学上的显著变化。
当以40mg或80mg的剂量施用时,AZD1656在健康、非糖尿病患者中已被证明不会引起低血糖(低血糖在研究中定义为2.7mmol/l)(Norjavaara E.等人,《临床内分泌学与新陈代谢杂志(J Clin Endocrinol Metab)》,2012,97(9):3319-3325)。
AZD1656具有系统名称3-{[5-(氮杂环丁-1-基羰基)吡嗪-2-基]氧基}-5-{[(1S)-1-甲基-2-(甲基氧基)乙基]氧基}-N-(5-甲基吡嗪-2-基)苯甲酰胺。
AZD1656具有以下结构:
发明内容
本发明是AZD1656或其药学上可接受的盐,用于治疗具体地说由于冠状病毒感染而造成的肺炎和/或心肌炎。
AZD1656是一种分子,它是调节性T细胞(Treg)中葡萄糖激酶的激活剂。这些细胞是一种用以免疫反应的特殊的T细胞亚群。在不适当的炎症中,Treg可以抑制T细胞增殖和细胞因子产生。这在临床上可能是有益的。
因此,预测AZD1656的施用,特别是当口服、经皮或静脉内给予时,将有效治疗肺炎和/或心肌炎,特别是与如Covid-19的冠状病毒感染相关联的肺炎和/或心肌炎。
本发明的第一方面是用于治疗肺炎和/或心肌炎的AZD1656或其药学上可接受的盐。
本发明的第二方面是AZD1656或其药学上可接受的盐的用途,用于制造用于治疗肺炎和/或心肌炎的药物。
本发明的第三方面提供了一种治疗肺炎和/或心肌炎的方法,包含向患者施用AZD1656或其药学上可接受的盐。
具体实施方式
如本文所用,术语“治疗(treatment)”或“治疗(treating)”是指治疗性(治愈性)治疗,包括改善。治疗还包括阻止疾病发展或减缓疾病的进一步进展。例如,治疗可能包括防止症状恶化。“改善”是患者病况的改善或感知到的改善,或使患者病况或副作用变得越来越可以忍受的患者病况的变化。
肺炎和/或心肌炎通常由病毒感染引起。因此,在一个实施例中,肺炎和/或心肌炎的特征在于是病毒感染,优选地冠状病毒感染,例如SARS(严重急性呼吸综合征)或SARS-CoV-2,并且优选地COVID-19或长期Covid的结果或与其相关联。
在一个实施例中,要治疗的受试者感染或疑似感染冠状病毒,如Covid-19。在另一实施例中,感染或疑似感染冠状病毒的受试者在WHO临床改进顺序量表上被分类为3、4或5阶段。WHO临床改进顺序量表衡量随时间推移的疾病严重程度(Michael O'Kelly和SiyingLi(2020),《生物医药研究中的统计学(Statistics in Biopharmaceutical Research)》,12:4,451-460)。
“Covid-19”是指由病毒严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2)引起的传染病。
“长期Covid”或“Covid后综合征”是指在符合COVID-19的感染期间或之后出现的体征和症状,其持续超过12周并且无法通过替代诊断来解释。这种病况通常会呈现一系列症状,通常是重叠的,这些症状可能会随着时间的推移而改变,并可能影响身体内的任何系统。许多患有COVID后综合征的人还可能会遭受全身疼痛、疲劳、持续高温和精神问题。
术语“患者”和“受试者”可互换使用,并且指要施用AZD1656的受试者。优选地,受试者是人。
本发明适用于糖尿病患者和非糖尿病患者。在一些实施例中,受试者患有糖尿病,优选地1型或2型糖尿病。
在一些实施例中,受试者的血糖水平等于或高于4mmol/L。
在一些实施例中,受试者患有糖尿病和/或已经历肾移植。
如本文所用,药学上可接受的盐是具有药学上可接受的酸或碱的盐。药学上可接受的酸包括无机酸,如盐酸、硫酸、磷酸、二磷酸、氢溴酸或硝酸;以及有机酸,如柠檬酸、富马酸、马来酸、苹果酸、抗坏血酸、琥珀酸、酒石酸、苯甲酸、乙酸、甲磺酸、乙磺酸、水杨酸、硬脂酸、苯磺酸或对甲苯磺酸。药学上可接受的碱包括碱金属(例如,钠或钾)和碱土金属(例如,钙或镁)氢氧化物和有机碱,如烷基胺、芳基胺或杂环胺。
熟练的从业人员会理解,本发明的化合物可以配制为包含AZD1656或其药学上可接受的盐的药物组合物。在一个实施例中,AZD1656是组合物中唯一的活性剂。唯一的活性剂意指,所述组合物不含可用于治疗肺炎和/或心肌炎和/或病毒感染的其他组分。
包含AZD1656或其药学上可接受的盐的组合物可以含有药学上可接受的载剂。“药学上可接受的载剂”意指与组合物的其他成分相容且对接受者无害的任何稀释剂或赋形剂,如填充剂或粘合剂。药学上可接受的载剂可以根据所需的施用途径,按照标准药学实践进行选择。
在本发明中,AZD1656可以以多种剂型施用。在一个实施例中,AZD1656可以配制成适合于口服、直肠、肠胃外、鼻内或经皮施用或通过吸入或通过栓剂施用的形式。
AZD1656可以例如以片剂、含片、锭剂、水性或油性悬浮液、可分散粉末或颗粒的形式口服施用。优选地,将AZD1656配制成使得其适合于口服施用,例如片剂和胶囊。
AZD1656还可以肠胃外施用,无论是皮下施用、静脉内施用、肌内施用、胸骨内施用、经皮施用还是通过输注技术。AZD1656还可以以栓剂的形式施用。
AZD1656还可以通过吸入施用。与通过口服途径摄取的许多药物相比,吸入药物的优点在于其直接递送到血液供应丰富的区域。由于肺泡具有巨大的表面积和丰富的血液供应,并且绕过首过代谢,因此吸收非常迅速。
本发明还提供了含有AZD1656的吸入装置。通常,所述装置是定量吸入器(metereddose inhaler,MDI),其含有用于将药物推出吸入器的药学上可接受的化学推进剂。
AZD1656还可以通过鼻内施用进行施用。鼻腔的高度可渗透组织非常易于接受药物并且快速且有效地吸收药物。与注射相比,鼻腔药物递送的痛苦和侵入性更小,从而减少患者的焦虑。通过这种方法,吸收会非常迅速并且通常会绕过首过代谢,从而降低患者间的变异性。此外,本发明还提供了含有AZD1656的鼻内装置。
AZD1656还可以通过经皮施用进行施用。对于局部递送,可以使用经皮和经粘膜贴剂、乳膏、软膏、凝胶剂、溶液或悬浮液。因此,本发明还提供一种含有AZD1656的经皮贴剂。
AZD1656还可以通过舌下施用进行施用。因此,本发明还提供了一种包含AZD1656的舌下片剂。
AZD1656也可以与通过除了患者的正常代谢之外的过程减少物质的降解的药剂一起配制,如抗菌剂或可能存在于患者体内或活于患者身上或体内的共生或寄生虫有机体中的蛋白酶抑制剂,并且所述蛋白酶能够降解所述化合物。
用于口服施用的液体分散体可以是糖浆、乳液和悬浮液。
悬浮液和乳液可以含有例如天然树胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇作为载剂。用于肌内注射的悬浮液或溶液可以与活性化合物一起含有药学上可接受的载剂,例如无菌水、橄榄油、油酸乙酯、二醇(例如,丙二醇),以及如果需要的话,合适量的盐酸利多卡因。
用于注射或输注的溶液可以含有例如无菌水作为载剂,或者优选地所述溶液可以呈无菌、水性、等渗盐水溶液的形式。
在本发明的实施例中,以有效量施用AZD1656以治疗肺炎和/或心肌炎的症状。有效剂量对于本领域的技术人员而言将是显而易见的,并且取决于医学从业者将能够确定的许多因素,包括年龄、性别、体重。
在优选的实施例中,AZD1656是以0.5到400mg,更优选地1到400mg,更优选地2.5到400mg,更优选地5mg到400mg,更优选地50mg到300mg,最优选地150mg到300mg的剂量施用的。剂量下限优选地为0.5mg、1mg、1.5mg、2mg、2.5mg、3mg、4mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg或200mg。剂量上限优选地为400mg、390mg、380mg、370mg、360mg、350mg、340mg、330mg、320mg、310mg、300mg、290mg、280mg、270mg、260mg、250mg、240mg、230mg、220mg或210mg。任何上述范围的下限或上限可以彼此组合,并且在本文中公开。在一些实施例中,剂量为150mg到300mg。在一些实施例中,剂量为2到100mg或约2.5mg。
任何上述剂量可以每天一次、每天两次、每天三次或每天四次施用。
在本发明的实施例中,AZD1656每天至少施用一次。优选地,其以单个日剂量的形式施用。优选地,单个日剂量为200mg到400mg或2到100mg。优选地,单个日剂量为2.5mg、200mg、300mg或400mg。
应当理解,小儿患者可能需要较低的剂量。
在本发明的实施例中,AZD1656每日施用两次。优选地,每个剂量为1到20mg或150mg到200mg,其中总日剂量为2到40mg或300mg到400mg。
替代地,其可以每天施用三次。优选地,每个剂量为1到20mg或100mg到130mg。
可替代地,其可以每天施用四次。优选地,每个剂量为1到20mg或75mg到100mg。
优选地,剂量方案使得AZD1656的总日剂量不超过400mg,更优选地300mg。
为了治疗肺炎和/或心肌炎,在慢性剂量方案中使用AZD1656,即慢性、长期治疗。
本发明还涉及AZD1656或其药学上可接受的盐的用途,用于制造用于治疗肺炎和/或心肌炎的药物。本发明的此实施例可以具有上述任何优选特征。
在一个实施例中,肺炎和/或心肌炎与冠状病毒感染相关联,例如Covid-19或长期Covid。
本发明还涉及一种治疗肺炎和/或心肌炎的方法,所述方法包含向患者施用AZD1656或其药学上可接受的盐。本发明的此实施例可以具有上述任何优选特征。施用方法可以根据上述任何途径。
为了避免疑问,本发明还涵盖在体内反应以得到本发明的化合物的前药。
以下实例展示本发明。
实例
研究
第一项临床试验是在已证实感染冠状病毒的糖尿病患者中进行的。与非糖尿病患者相比,这些患者的死亡风险增加。终点是肺成像、血液中的炎症标志物、动脉氧浓度和心脏射血分数以及存活率。所述化合物的后续试验将在糖尿病和非糖尿病患者首次出现症状时进行。所述化合物应预防并治疗冠状病毒感染中的肺病和心脏病。
第一个(II期)临床试验目前正在英国(UK)、罗马尼亚(Romania)和捷克共和国(Czech Republic)进行,以评测因疑似或确诊COVID-19而住院的AZD1656的安全性和功效。在提交本申请时,试验数据尚未揭盲。然而,初步观察结果是可用的。截至2021年3月9日,已有116名患者进入试验,并且报告有5人死亡。在2021年2月26日的独立安全审查委员会(theindependent Safety Review Committee,SRC)会议上,在没有打破盲法的情况下,从安全的角度对迄今为止完成试验的60名患者的数据进行了检查。数据的质量被认为是高的。在当时完成试验方案的60名患者中,有5人死亡。委员会没有安全问题。患者进入特征在测试组和对照组之间平均分布。
法国Coronad对Covid-19糖尿病患者的研究报告称,在28天内,因Covid-19住院的糖尿病患者死亡率为五分之一。因此,根据Coronad研究数据,在2月26日之前完成当前试验的60名患者中,预计有12人死亡。如果死亡人数在试验的测试组和对照组之间随机分布,则根据Coronad研究的数据,预计测试组有6人死亡,对照组有6人死亡。然而,截至2月26日,试验组和对照组总共有5人死亡(而不是12人)。对照组接受了非活性安慰剂,因此根据Coronad研究数据提出安慰剂组的死亡率为6是合理的。测试组接受了已知可激活Treg淋巴细胞的AZD1656剂量,所述Treg淋巴细胞抑制不适当的炎症。这一假设在Covid-19疾病中的可信度得到了资助该试验的英国政府UKRI和英国监管机构MHRA的支持。因此,在截至2月26日的研究中,AZD1656组中发生的预期死亡率从预期12人降至5人,这是毫无疑问的。有人认为,这些发现支持AZD1656在患有Covid-19疾病的人糖尿病患者中的功效。
研究设计
这是一项评测AZD1656对已知或疑似COVID-19的住院糖尿病患者的COVID-19心肺并发症的安全性和功效的II期、随机、安慰剂对照、双盲临床试验。
所有患者都将接受常规护理以及AZD1656或安慰剂。世界卫生组织(WHO)临床改进8点顺序量表被用作衡量患者最终结果的标准方法。
主要终点:
主要终点是将AZD1656治疗与安慰剂进行比较,根据WHO临床改进8点顺序量表,以第14天属于1-3类的受试者百分比来衡量的临床改进。
次要终点:
(a)将AZD1656治疗与安慰剂进行比较,在第7天、第14天和第21天在WHO 8点顺序量表上分类为每个严重度等级的患者与基线相比的百分比来衡量的临床改进。
(b)与安慰剂相比,通过接受AZD1656的患者为维持适当的血糖水平而增加基线药物需求的需要或添加附加的糖尿病药物的需要来衡量的血糖控制程度。
(c)与安慰剂相比,在接受AZD1656的患者中导致研究药物停药的治疗紧急不良事件(TEAE)的比例。
(d)与安慰剂相比,接受AZD1656的患者中严重不良事件(SAE)的比例。
(e)与安慰剂相比,接受AZD1656的患者从入院到出院的时间(以小时为单位)。
(f)与安慰剂相比,接受AZD1656的患者从入院到接受插管/机械通气的时间。
(g)与安慰剂相比,接受AZD1656的患者的死亡率。
探索性终点:
(a)与安慰剂相比,接受AZD1656的患者在治疗的前7天期间的血浆AZD1656水平。
(b)将通过流式细胞术进行的免疫表型专题讨论:T、B和NK细胞(包括特定Treg和记忆T细胞群)水平的组间比较(AZD1656与安慰剂);单核细胞、中性粒细胞和嗜酸性粒细胞计数,包括中性粒细胞(CD11b)和单核细胞亚群的激活标志物(CD14/CD16鉴定,包括6-Sulfo LacNAc(SLAN))。
(c)用于评测以下生物标志物的要使用MSD U-Plex多重检定进行的免疫化学专题讨论:G-CSF、GM-CSF、IL-1B、IL-4、IL-6、IL-8、IL-10、IL-12和MIP-1a。
(d)测量hsTroponin和NTproBNP以确定接受AZD1656的患者与安慰剂相比的心脏损伤程度。
(e)在治疗之前测量25-羟基维生素D水平以确定维生素D水平与临床结果之间是否存在任何相关性。
(f)临床结果与患者种族的相关性。
研究方案
已经筛选了大约165名患者,以达成150名患者随机分配给AZD1656或安慰剂。所有患者都接受常规护理以及AZD1656或安慰剂。
纳入标准
1.男性或女性。
2.18岁及以上。
3.患有1型或2型糖尿病。
4.入组时因疑似或确诊的新型冠状病毒(严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2))感染住院,在WHO临床改进顺序量表上分类为3、4或5阶段。
5.血糖水平等于或高于4mmol/L。
6.能够服用药物的口服(片剂)配制物。
7.患者能够在任何研究程序开始之前提供书面知情同意书。
剂量
AZD1656口服施用,为50mg薄膜衣片剂,以100mg BID给药(总日剂量为200mg)。
片剂由Patheon制造。
持续时间
已选择21天的治疗持续时间来探究AZD1656对安全性和功效的影响。在之前的试验中已经评估了长达6个月的治疗持续时间,因此根据需要COVID-19住院治疗的糖尿病患者的预期住院持续时间,该试验的持续时间被认为是安全的,并且适合该患者群体。
研究有3个阶段:
1.筛选/随机化(第-2天到第1天)
2.双盲治疗(第1天到第21天)
3.安全性随访(研究治疗完成后7天)
所述研究评估了一系列评测的功效,评估了临床改进、血糖控制、从入院到出院的时间以及从入院到接受插管/机械通气的时间。
Claims (19)
1.一种AZD1656或其药学上可接受的盐,其用于治疗肺炎和/或心肌炎。
2.根据权利要求1所述的供使用的AZD1656,其中治疗受试者患有糖尿病,优选地1型或2型糖尿病。
3.根据权利要求1或2所述的供使用的AZD1656,其中所述治疗受试者是人。
4.根据权利要求1至3中任一项所述的供使用的AZD1656,其中AZD1656的剂量为1mg到400mg,优选地50mg到400mg,优选地50mg到300mg,最优选地150mg到300mg。
5.根据前述权利要求中任一项所述的供使用的AZD1656,其中施用通过单个日剂量进行。
6.根据权利要求5所述的供使用的AZD1656,其中所述单个日剂量为1mg到400mg,优选地300mg到400mg。
7.根据权利要求1至4中任一项所述的供使用的AZD1656,其中施用通过一剂量每天两次进行。
8.根据权利要求7所述的供使用的AZD1656,其中所述剂量为1mg到5mg或150mg到200mg。
9.根据权利要求1至7中任一项所述的供使用的AZD1656,其中所述剂量为40到300mg。
10.根据权利要求1至7中任一项所述的供使用的AZD1656,其中剂量的下限为80mg,且剂量的上限为210mg。
11.根据前述权利要求中任一项所述的供使用的AZD1656,其通过口服施用。
12.根据权利要求1至10中任一项所述的供使用的AZD1656,其通过肠胃外、经皮、舌下、直肠或吸入施用进行施用。
13.根据前述权利要求中任一项所述的供使用的AZD1656,其中所述肺炎和/或心肌炎与如Covid-19的冠状病毒感染相关联或由冠状病毒感染引起。
14.根据前述权利要求中任一项所述的供使用的AZD1556,其中要治疗的所述受试者感染或疑似感染冠状病毒,如Covid-19。
15.根据前述权利要求中任一项所述的供使用的AZD1556,其中要治疗的所述受试者患有长期COVID。
16.一种AZD1656或其药学上可接受的盐的用途,其用于制造用于治疗肺炎和/或心肌炎的药物。
17.根据权利要求16所述的AZD1656或其药学上可接受的盐的用途,其具有根据权利要求2至15所述的任一个附加特征。
18.一种治疗肺炎和/或心肌炎的方法,其包含向患者施用AZD1656或其药学上可接受的盐。
19.根据权利要求18所述的方法,其具有根据权利要求2至15所述的任一个附加特征。
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