CN116096421A - 用于治疗缓解型多发性硬化的方法 - Google Patents
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Abstract
公开了一种治疗患有多发性硬化的人类受试者的方法。所述方法包括在不存在降胆固醇药物的情况下向所述受试者施用有效量的化合物1：
Description
相关申请
本申请根据35 U.S.C.§119(e)要求2020年8月19日提交的美国临时申请第63/067,727号的申请日的权益，所述美国临时申请的全部内容通过引用并入本文。
背景技术
多发性硬化(MS)是一种慢性致残性神经系统疾病，其在北美和西欧影响估计100万人。其特征在于影响脑白质和灰质、脊髓和视神经的显著脱髓鞘和轴突损失，并且临床上表现为可以复发-缓解模式和/或随时间持续进展而存在的神经功能丧失。大多数未经治疗的MS患者出现不可逆的失能，包括在诊断后15年内丧失独立行走能力。
髓鞘再生是人类CNS中的关键自然过程。三十多年来，已经知道，在MS中，在急性和慢性活动性病灶中都发生了大量且广泛的髓鞘再生。Prineas JW,Connell F.AnnNeurol.1979；5(1):22-31。这种髓鞘再生过程通过少突神经胶质细胞祖细胞(下文为“OPC”)的分化而发生。Blakemore WF,Keirstead HS,J Neuroimmunol.1999；98(1):69-76；Chang A,Nishiyama A,Peterson J等人,J Neurosci.2000；20(17):6404-12；Dawson MR,Levine JM,Reynolds R.J Neurosci Res.2000；61(5):471-9；Lucchinetti C,Bruck W,Parisi J等人,Brain 1999；122(Pt 12):2279-95；Raine CS,Moore GR,Hintzen R等人,Lab Invest.1988；59(4):467-76；以及Scolding N,Franklin R,Stevens S等人,Brain1998；121(Pt 12):2221-8。
在组织学上，髓鞘再生导致“阴影斑块”的形成，其对应于先前脱髓鞘与具有短节间的不成比例的薄髓鞘新形成的区域。髓鞘再生已证明可恢复实验动物中的传导阻滞。Smith KJ,Blakemore WF,McDonald WI,Brain 1981；104(2):383-404。传导阻滞的恢复可能是缓解方面的原因，它是疾病复发-缓解形式过程中的早期大多数MS发作的特征。然而，随着时间推移，大多数MS患者的髓鞘再生失败，正如尸体剖检时所研究的大多数慢性MS病灶中很少(如果存在)髓鞘再生的研究结果所表明。Chang A,Tourtellotte WW,Rudick R等人,N Engl J Med.2002；346(3):165-73；Chang KH,Lyu RK,Chen CM等人,MultScler.2006；12(4):501-6。
若干免疫调节药物经批准用于治疗MS，包括5种干扰素(IFN)-β疗法(3种IFNβ-1α和2种IFNβ-1β疗法)、醋酸格拉替雷(glatiramer acetate)、那他珠单抗(natalizumab)、米托蒽醌(mitoxanthrone)、芬戈莫德(fingolimod)、特立氟胺(teriflunomide)、富马酸二甲酯(dimethyl fumarate)、阿仑单抗(alemtuzumab)、克拉屈滨(cladribine)、奥瑞珠单抗(ocrelizumab)、辛波莫德(siponimod)、奥扎莫德(ozanimod)和富马酸地罗西美(diroximel fumarate)。尽管所有这些疾病改善疗法都是可降低可能导致临床恶化和失能的新MS病灶的频率和严重程度的抗炎疗法，但已知它们都不能增强受损MS组织的自然修复。因此，对特定改善组织修复，特别是髓鞘再生以及轴突和其神经元保存的MS疗法存在高度未满足的需求。
发明内容
现已发现，化合物1(其结构如下所示)是胆固醇生物合成途径中多种酶(包括LBR/TM7SF2和EBP)的抑制剂。具体而言，化合物1以剂量依赖性方式降低健康人类志愿者中的胆固醇水平(实施例1)并导致7-脱氢胆固醇(7-DHC)的积累。7-DHC的积累也在用化合物1处理的大鼠OPC中复制(实施例2)。在大鼠溶血磷脂酰胆碱诱导的脊髓和胼胝体脱髓鞘模型和小鼠铜腙(cuprizone)脱髓鞘模型中，化合物1增强髓鞘再生(参见实施例3)。化合物1也在OPC/大鼠背根神经节共培养测定中以剂量依赖性方式导致稳健的髓鞘形成(参见实施例4)和人类iPSC衍生的OPC至髓鞘形成少突神经胶质细胞的增强分化(参见实施例5)。
1-((6-(((1s,4s)-4-乙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
基于这些发现，本文公开了治疗多发性硬化的方法；由于化合物1的降胆固醇作用，所述方法在不存在另一种降胆固醇药物的情况下进行。或者，如果降胆固醇药物与化合物1共施用，则监测受试者的血浆胆固醇水平，并且在必要时调整降胆固醇药物的剂量，以使血浆胆固醇水平处于(期望的)目标范围内。
化合物1是神经鞘氨醇-1-磷酸受体4(下文为“S1P4”)的已知抑制剂，并且由于其髓鞘再生作用而可用于治疗MS。参见例如美国专利第9,340,527号。尽管据认为化合物1对S1P4受体的影响可能有助于髓鞘再生，但现已发现，与大鼠相比，S1P4在源自MS组织的人类CNS中(包括在人类OPC中)几乎不具有表达(实施例6)。根据此结果，化合物1的髓鞘再生作用不太可能主要经由CNS中的S1P4介导。相反，如上文所论述，现认为化合物1的髓鞘再生作用至少部分是由于其参与胆固醇生物合成途径的能力。基于这些发现，预计化合物1可以低剂量(例如每天10mg至60mg)在人体内实现OPC分化和髓鞘再生。根据人体试验已发现，在此范围外的较高剂量下，中性粒细胞减少的风险更大。
本公开的一个实施方案是治疗患有MS的人类受试者的方法。所述方法包括在不存在降胆固醇药物的情况下向所述受试者施用有效量的化合物1或其药学上可接受的盐。
本公开的另一个实施方案是治疗患有MS的人类受试者的方法。所述方法包括向所述受试者施用每天10mg至60mg化合物1(例如，每天10mg至20mg、每天20mg至30mg、每天30mg至40mg、每天40mg至50mg或每天50mg至60mg)或等效于每天10mg至60mg(例如，每天10mg至20mg、每天20mg至30mg、每天30mg至40mg、每天40mg至50mg或每天50mg至60mg)化合物1的量的其药学上可接受的盐。
本公开的另一个实施方案是治疗患有多发性硬化(MS)的人类受试者的方法，其中所述受试者正在用有效量的降胆固醇药物进行治疗。所述方法包括以下步骤：
i)向所述受试者施用有效量的化合物1：
或其药学上可接受的盐；
ii)评估所述受试者的血浆胆固醇水平；
iii)如果所述受试者的血浆胆固醇水平在目标范围之外，则调整施用至所述受试者的降胆固醇药物的量以使所述受试者的血浆胆固醇水平在目标范围内。可重复步骤ii)和iii)直至所述受试者血浆胆固醇水平在目标范围内。
本公开的另一个实施方案是用于在不存在降胆固醇药物的情况下治疗患有MS的人类受试者的化合物1或其药学上可接受的盐。
本公开的另一个实施方案是利用每天10mg至60mg(例如，每天10mg至20mg、每天20mg至30mg、每天30mg至40mg、每天40mg至50mg或每天50mg至60mg)化合物1或等效于每天10mg至60mg(例如，每天10mg至20mg、每天20mg至30mg、每天30mg至40mg、每天40mg至50mg或每天50mg至60mg)化合物1的量的其药学上可接受的盐在受试者中用于治疗具有MS的人类受试者的化合物1或其药学上可接受的盐。
本公开的另一个实施方案是化合物1或其药学上可接受的盐在制造用于在不存在降胆固醇药物的情况下治疗患有MS的受试者的药物中的用途。
本公开的另一个实施方案是化合物1在制造用于治疗患有MS的人类受试者的药物中的用途，其中所述受试者是用每天10mg至60mg化合物1或等效于每天10mg至60mg化合物1的量的其药学上可接受的盐进行治疗。
附图说明
图1显示了在28天时期内施用安慰剂、每天10mg、30mg或60mg化合物1的健康志愿者中的循环平均总胆固醇水平的降低的时程。
图2是显示在用化合物1治疗期间在药效稳态下施用安慰剂、每天1mg、3mg、10mg、30mg或60mg化合物1的受试者的循环胆固醇水平的预测稳态浓度的条形图。预测浓度是来自基于化合物1的三个I期试验的数据的模拟。
图3是显示用化合物1处理的大鼠OPC培养物中7-DHC、胆固醇和链甾醇水平的变化的条形图。
图4是显示胆固醇和链甾醇的生物合成途径的图。
图5是显示化合物1以剂量依赖性方式增强大鼠LPC脊髓脱髓鞘模型中的髓鞘再生的条形图。
图6是显示化合物1在小鼠铜腙模型中增强剂量依赖性髓鞘再生的条形图。
图7是用于确定OPC和背根神经节共培养物中髓鞘形成的MBP蛋白质印迹(Westernblot)的照片。
图8A是显示人类iPSC衍生的少突神经胶质细胞祖细胞中MBP+细胞的量化的条形图；p<0.0001，通过非配对t检验；并且图8B是显示人类iPSC衍生的少突神经胶质细胞祖细胞中MBP+有髓鞘轴突簇的量化的条形图；p<0.01，通过单向方差分析。
图9是显示S1P4在各种类型的大鼠细胞中表达的条形图。
具体实施方式
用化合物1进行治疗抑制胆固醇生物合成并因此导致患者体内胆固醇、特别是外周胆固醇的水平降低。化合物1也刺激和增强新少突神经胶质细胞的产生和内在髓鞘形成和/或髓鞘再生。因此，预期化合物1是MS的有效治疗剂。然而，由于其对胆固醇生物合成的抑制，希望将化合物1“在不存在降胆固醇药物的情况下”施用至MS患者。或者，将化合物1与降胆固醇药物共施用并监测受试者的血浆胆固醇水平，以评估受试者的血浆胆固醇水平是否在确定为受试者理想或正常的目标范围内。如果血浆胆固醇水平在目标范围之外，则调整施用的降胆固醇药物的量以使血浆胆固醇水平在目标范围内。胆固醇在体内执行各种重要的生物学功能，包括作为细胞膜的重要结构组分并且作为类固醇激素、胆酸和维生素D的生物合成的前体。另外，胆固醇是髓鞘的重要脂质组分。胆固醇不会穿过血脑障壁，并且中枢神经系统依赖于胆固醇的局部从头合成。脑胆固醇代谢的缺陷或中断与各种神经退行性疾病如阿尔茨海默病(Alzheimer's disease，AD)、亨廷顿病(Huntington's disease，HD)、帕金森病(Parkinson's disease，PD)和一些老年典型的认知缺陷有关(Juan Zhang和Qiang Liu,Protein Cell,6(4):254-264(2015))。因此，当患者用化合物1治疗时，将患者的胆固醇水平维持在目标范围内是至关重要的。根据本文所述的方法，在一些实施方案中，化合物1或其药学上可接受的盐降低人类的外周胆固醇，但根据动物数据并未显著降低中枢神经系统中的胆固醇。
“在不存在降胆固醇药物的情况下”施用意指受试者在开始用化合物1或其药学上可接受的盐治疗之前从未服用降胆固醇药物或停止服用降胆固醇药物，或者在开始用化合物1或其药学上可接受的盐治疗时停止服用降胆固醇药物。当受试者正在服用降胆固醇药物时，希望在开始用化合物1或其药学上可接受的盐治疗前1、2、3、4、5或6天；或者在开始用化合物1或其药学上可接受的盐治疗前至少1、2、3、4、5、6、7、8周或更多周；或者在开始用化合物1或其药学上可接受的盐治疗前至少1、2或3个月，终止施用降胆固醇药物。
“降胆固醇药物”是为降低胆固醇水平升高的人类患者的胆固醇而开具处方和/或施用的药物。实例包括他汀类药物、PCSK9抑制剂、选择性胆固醇吸收抑制剂、胆酸螯合剂、贝特类药物或降脂质疗法。
他汀类药物是通过抑制HMG-CoA还原酶而起作用的降胆固醇药物。实例包括阿托伐他汀(atorvastatin)
氟伐他汀(fluvastatin)(LESCOL
)、洛伐他汀(lovastatin)
匹伐他汀(pitavastatin)
普伐他汀(pravastatin)
瑞舒伐他汀(rosuvastatin)(
EZALLORTM)和辛伐他汀(simvastatin)
PCSK9抑制剂是通过抑制前蛋白转化酶枯草杆菌蛋白酶/kexin 9型丝氨酸蛋白酶而起作用的降胆固醇药物。实例包括阿利库单抗(alirocumab)和依伏库单抗(evolocumab)。
选择性胆固醇吸收抑制剂是通过抑制胆固醇在肠道中的吸收而起作用的降胆固醇药物。例如，依泽替米贝(ezetimibe)
是通过抑制转运蛋白Niemann-Pick C-1样1蛋白(NPC1L1)而起作用的选择性胆固醇吸收抑制剂。
胆酸螯合剂是通过结合肠道中的胆酸并增加粪便中胆酸的排泄而起作用的降胆固醇药物。这减少返回肝脏的胆酸量并迫使肝脏产生更多的胆酸来替代粪便中丢失的胆酸。为产生更多胆酸，肝脏将更多胆固醇转化为胆酸，从而降低血液中的胆固醇水平。实例包括消胆胺
考来替泊(colestipol)
和考来维仑(colesevelam)
苯氧酸(fibric acid)衍生物(贝特类药物)是一类降低血液甘油三酯水平的药物。贝特类药物通过减少肝脏产生VLDL(在血液中循环的携带甘油三酯的颗粒)以及加速从血液中去除甘油三酯来降低血液甘油三酯水平。贝特类药物在增加血液HDL胆固醇水平方面也有适度有效性。贝特类药物的实例包括吉非贝齐(gemfibrozil)
和非诺贝特(fenofibrate)
其他降胆固醇药物包括鱼油、尼亚新(niacin)(烟酸)cholestin、贝派地酸(bempedoic acid)
和普罗布考(probucol)。
受试者血浆胆固醇水平的“目标范围”是确定为受试者理想或正常的范围或确定为受试者整体健康和福祉最佳的范围。目标范围是根据治疗高胆固醇血症的医师的最佳实践确定，并且可根据医学专业组织和政府组织基于所述领域最新研究和经验的建议而改变。受试者血浆胆固醇的“目标范围”也可根据受试者的年龄和整体健康状况而变化。通常，正常范围是100mg/dL(毫克/分升)至200mg/dL，但对于某些受试者可为50mg/dL至200mg/dL、60mg/dL至200mg/dL、70mg/dL至200mg/dL、80mg/dL至200mg/dL、90mg/dL至200mg/dL、100mg/dL至200mg/dL、110mg/dL至200mg/dL、120mg/dL至200mg/dL、125mg/dL至200mg/dL、50mg/dL至175mg/dL、60mg/dL至175mg/dL、70mg/dL至175mg/dL、80mg/dL至175mg/dL、90mg/dL至175mg/dL、100mg/dL至175mg/dL、110mg/dL至175mg/dL、120mg/dL至175mg/dL或125mg/dL至175mg/dL。在医师办公室访视期间定期评估血浆胆固醇水平。
当受试者的血浆胆固醇水平在目标范围之外，例如低于目标范围时，可通过降低施用至受试者的降胆固醇药物的剂量来调节血浆胆固醇水平。相反，当血浆胆固醇水平高于目标范围时，可通过增加施用至受试者的降胆固醇药物的剂量来调节血浆胆固醇水平。
在所公开的方法中，可将有效量的用于治疗MS的其他药物与化合物1共施用。包括
富马酸二甲酯(例如
)，富马酸地罗西美
富马酸单甲酯(例如Bafiertam)，干扰素(例如聚乙二醇化或非聚乙二醇化干扰素，优选是干扰素β-1α或聚乙二醇化干扰素β-1α)，醋酸格拉替雷，改善血管功能的化合物，免疫调节剂(例如芬戈莫德、环孢素(cyclosporin)、雷帕霉素(rapamycin)或子囊霉素(ascomycin)，或其免疫抑制类似物，例如环孢素A、环孢素G、FK-506、ABT-281、ASM981、雷帕霉素、40-O-(2-羟基)乙基-雷帕霉素等)；皮质类固醇；环磷酰胺；硫唑嘌呤(azathioprine)；米托蒽醌(mitoxanthrone)，氨甲蝶呤(methotrexate)；来氟米特(leflunomide)；咪唑立滨(mizoribine)；霉酚酸(mycophenolic add)；吗替麦考酚酯(mycophenolate mofetil)；15-脱氧精胍；戊酸双氟可龙(difucortolone valerate)；二氟孕甾丁酯(difuprednate)；二丙酸阿氯米松(Alclometasone dipropionate)；安西奈德(amcinonide)；安吖啶(amsacrine)；天冬酰胺酶(asparaginase)；硫唑嘌呤；巴利昔单抗(basiliximab)；二丙酸倍氯米松(beclometasone dipropionate)；倍他米松(betamethasone)；二丙酸倍他米松；倍他米松磷酸钠；戊酸倍他米松；布地奈德(budesonide)；卡托普利(captopril)；盐酸氮芥(chlormethine chlorhydrate)；丙酸氯倍他索(clobetasol propionate)；醋酸可的松(cortisone acetate)；可的伐唑(cortivazol)；环磷酰胺(cyclophosphamide)；阿糖胞苷(cytarabine)；达利珠单抗(daclizumab)；放线菌素(dactinomycine)；地奈德(desonide)；去羟米松(desoximetasone)；地塞米松(dexamethasone)；醋酸地塞米松；异烟酸地塞米松；地塞米松间磺基苯甲酸钠；磷酸地塞米松；丁乙酸地塞米松；醋酸二氯松(dichlorisoneacetate)；盐酸多柔比星(doxorubicinee chlorhydrate)；盐酸表柔比星(epirubicinechlorhydrate)；氟氯缩松(fuclorolone acetonide)；醋酸氟氢可的松(fludrocortisoneacetate)；氟氢缩松(fludroxycortide)；新戊酸氟米松(flumetasone pivalate)；氟尼缩松(flunisolide)；醋酸氟轻松(fluocinolone acetonide)；氟轻松(fluocinonide)；氟可龙(fluocortolone)；己酸氟可龙；新戊酸氟可龙；氟米龙(fluorometholone)；醋酸氟泼尼定(fluprednidene acetate)；丙酸氟替卡松(fluticasone propionate)；盐酸吉西他滨(gemcitabine chlorhydrate)；哈西奈德(halcinonide)；氢化可的松(hydrocortisone)；醋酸氢化可的松；丁酸氢化可的松；半琥珀酸氢化可的松；美法仑(melphalan)；甲泼尼松(meprednisone)；巯嘌呤(mercaptopurine)；甲泼尼龙(methylprednisolone)；醋酸甲泼尼龙；半琥珀酸甲泼尼龙；米索前列醇(misoprostol)；莫罗单抗-cd3(muromonab-cd3)；吗替麦考酚酯；醋酸对米松(paramethansone acetate)；泼尼唑啉(prednazoline)，泼尼松龙(prednisolone)；醋酸泼尼松龙；己酸泼尼松龙；泼尼松龙间磺基苯甲酸钠；泼尼松龙磷酸钠；泼尼松(prednisone)；泼尼立定(prednylidene)；利福平(rifampicine)；利福平钠；他克莫司(tacrolimus)；特立氟胺(teriflunomide)；沙利度胺(thalidomide)；噻替派(thiotepa)；新戊酸替考托尔(tixocortol pivalate)；曲安西龙(triamcinolone)；半琥珀酸曲安奈德(triamcinolone acetonide hemisuccinate)；苯曲安奈德(triamcinolonebenetonide)；二醋酸曲安西龙；己曲安奈德(triamcinolone hexacetonide)；免疫抑制性单克隆抗体，例如针对白细胞受体的单克隆抗体，例如MHC、CD2、CD3、CD4、CD7、CD20(例如乌妥昔单抗(ublituximab)、利妥昔单抗(rituximab)和奥瑞珠单抗)、CD25、CD28、B7、CD40、CD45、CD56(例如达克珠单抗(daclizumab))，或CD58或其配体；或其他免疫调节化合物，例如CTLA41g，或其他粘附分子抑制剂，例如mAb或低分子量抑制剂，包括选择素拮抗剂和VLA-4拮抗剂(例如
)。在另一个实施方案中，与化合物1共施用的药物是干扰素β-1α、干扰素β-1β、醋酸格拉替雷、米托蒽醌、那他珠单抗、芬戈莫德、特立氟胺、富马酸二甲酯、富马酸地罗西美、阿仑单抗、奥瑞珠单抗、辛波莫德、克拉屈滨、奥扎莫德和奥瑞珠单抗。在一个方面，使用干扰素β-1β和醋酸格拉替雷。当与另一种可有效治疗MS的药物共施用时，化合物1和另一种药物可同时(在相同或不同的配制物中)或在不同时间施用。
“有效量”意指减轻疾病或疾患的一种或多种症状和/或减缓疾病或疾患的进展的药物量。关于用于治疗MS的化合物1，“有效量”包括在患有MS的人类受试者中诱导OPC分化和髓鞘再生的量。MS中化合物1的示例性有效量包括但不限于每天10mg至60mg(或等效于10至60mg化合物1的量的化合物1的药学上可接受的盐)，例如每天10mg、每天30mg或每天60mg。化合物1的药学上可接受的盐的示例性有效量包括但不限于等效于每天10mg至每天60mg的化合物1的量，例如等效于每天10mg、每天30mg或每天60mg的化合物1的量。在一些实施方案中，化合物1的有效量可为每天10mg至20mg、每天20mg至30mg、每天30mg至40mg、每天40mg至50mg或每天50mg至60mg。在一些实施方案中，化合物1的药学上可接受的盐的有效量可为等效于每天10mg至20mg、每天20mg至30mg、每天30mg至40mg、每天40mg至50mg或每天50mg至60mg的化合物1的量。
如本文所用，当表示值范围时，其包括两个端点。例如，10mg至60mg的量包括10mg和60mg。类似地，介于10mg与20mg之间的量包括10mg和20mg。
“受试者”和“患者”可互换使用，并且意指需要治疗的哺乳动物，例如伴侣动物(例如狗、猫等)、农场动物(例如牛、猪、马、绵羊、山羊等)和实验室动物(例如大鼠、小鼠、豚鼠等)。通常，受试者是需要治疗的人。
所公开的方法可用于MS的所有阶段，包括复发型多发性硬化(或多发性硬化的复发形式)、复发缓解型多发性硬化、原发进展型多发性硬化、继发进展型多发性硬化和临床孤立综合征(下文为“CIS”)。
复发型多发性硬化(或多发性硬化的复发形式)包括临床孤立综合征、复发缓解型多发性硬化和活动性继发进展型多发性硬化。
复发缓解型多发性硬化是MS的一个阶段，其特征为不可预测的复发，接着是数月至数年的相对平静(缓解)期，无新的疾病活动迹象。发作期间出现的缺陷可能解决或留下问题，后者占约40％的发作并且个人患病时间越长就越常见。这描述80％多发性硬化个体的初始病程。
继发进展型多发性硬化发生在大约65％的初始复发缓解型多发性硬化患者中，这些患者最终在急性发作之间具有进行性神经功能衰退，而无任何明确的缓解期。可能出现偶尔的复发和轻微的缓解。疾病发作与从复发缓解型转为继发进展型多发性硬化之间的最常见时间长度为19年。
原发进展型多发性硬化的特征为与继发进展型多发性硬化相同的症状，即急性发作之间的进行性神经功能衰退，而无任何明确的缓解期，也无先前的复发-缓解阶段。
EDSS是一种捕捉神经系统检查和长距离行走的变化的次序MS失能量表。时间25英尺步行测试(Time 25 Foot Walk Test，T25FW)是短距离行走能力的定量量度，并且因此对失能患者来说很敏感，以根据步行能力来检测临床进展。9孔钉测试(9 Hole Peg Test，9HPT)是一种上肢功能的定量量度，其已证明在MS群体中因各种失能而恶化。在一个实施方案中，所公开的方法在治疗之前EDSS评分为2.0至6.0的患者的EDSS、T25FW或9HPT测试中的一项或多项中提供在12周治疗中的统计学显著改善。在另一个实施方案中，所公开的方法在治疗之前EDSS评分为2.0至6.0的患者的EDSS、T25FW或9HPT测试中的一项或多项中提供在12周治疗中至少5％、10％、15％或20％的改善。
在另一个实施方案中，所公开的方法提供在42周治疗内总基线非增强T2病灶中归一化磁化转移比和扩散张量成像径向扩散率的统计学显著变化。在另一个实施方案中，所公开的方法提供在48周治疗内总基线非增强T2病灶中归一化T1强度和T1低强度体积的统计学显著变化。
化合物1的合成制剂和化合物1的合适配制物描述于美国专利第9,340,527号中，其全部教导内容通过引用并入本文。
化合物1中环己基上的两个取代基相对于彼此呈顺式构型。当按名称或结构提及化合物1时，其立体化学纯度是按重量计至少90％、至少95％、至少98％或至少99％。立体化学纯度是顺式构型化合物占顺式和反式构型化合物总和的重量比。
本发明通过以下实施例进行说明，所述实施例并不旨在以任何方式进行限制。
范例
实施例1-化合物1抑制DHCR7活性，如由7-DHC的积累所证明
42名健康志愿者接受化合物1QD持续28天(或提前停药前)，其中每个群组6名个体参与者在第1天和第2天接受1mg(群组1)、3mg(群组2)、10mg(群组3)、30mg(群组4)、60mg负荷剂量与10mg维持剂量(群组5)化合物1、60mg(群组6)或90mg负荷剂量，以及30mg维持剂量(群组7)。研究中也有14名参与者接受安慰剂；群组4中的1名参与者在第19天服用错误剂量并且似乎已接受至少一次30mg剂量的化合物1。群组1至5中的参与者报告以下方案偏差：他们随意接受预先给与的水(不限于给药前1小时和给药后1小时)并且给药后30分钟(并非给药后4小时)进餐。共49名参与者完成治疗，包括37名接受积极治疗的参与者。
参与者在第1天接受第一剂量的研究治疗(化合物1或安慰剂)，并且继续接受每日一次的研究治疗直至第28天。参与者在整个给药期间留在诊所。参与者在完成所有评估后于第29天出院。
定期从每名志愿者抽取血液并立即储存在-80℃。为测量人类血清中的代谢物浓度，将样品离心并且将所得上清液用于进一步分析。
使用Biocrates Kit过滤板，用甲醇从样品中提取游离氧甾醇。预先将内标混合物装入板中。使用带电喷雾电离(ESI)的SCIEX API5500
(AB SCIEX,Darmstadt,German)仪器，通过UHPLC-MS/MS与多反应监测(MRM)以正模式测定代谢物浓度。使用适当质谱软件对数据进行定量并导入Biocrates Met/DQTM软件以进行进一步分析。
图1显示了健康志愿者中的循环平均总胆固醇水平，其表明总循环胆固醇的逐渐、时间和剂量依赖性降低。
基于这些观测结果，使用Monolix开发群体PK/PD模型以将循环胆固醇浓度描述为化合物1的血浆浓度和暴露的函数。所述模型是根据来自上述研究(研究1)以及在健康志愿者中进行的两项额外临床研究(研究2和研究3)的胆固醇数据开发。在研究2中，30名健康志愿者接受单次口服剂量的化合物1，每个群组6名个体参与者接受3mg(群组1)、10mg(群组2)、30mg(群组3)、60mg(群组4)、100mg(群组5)。也有9名参与者在研究中接受安慰剂。在研究3中，8名健康成年志愿者接受单剂量的30mg化合物1。
这个模型中循环胆固醇的浓度在高于10mg的所有日剂量下都降低。尽管数据可变性影响预测效果，但所述模型显示循环胆固醇浓度呈剂量依赖性降低的明确证据。这种降低的EC50为约3μg/mL，其接近化合物1在60mg日剂量下的稳态浓度。
在研究1中接受60mg剂量的健康志愿者的总胆固醇平均降低高达约20％，目前认为其对低密度脂蛋白部分的影响程度大于对高密度脂蛋白部分的影响程度。所述模型预测，在60mg QD的剂量水平下，循环胆固醇可降低约35％。更高剂量的化合物1可导致循环胆固醇水平的更大降低，但也可能导致中性粒细胞减少。循环胆固醇的减少预计会在与血浆中化合物1稳态浓度增加相称的时间范围内发生(大约15天)，之后循环胆固醇水平预计在给药持续时间内稳定。所述模型预测，在化合物1治疗停止后，循环胆固醇将在大约30天内恢复至基线水平。所述模型也预测，循环胆固醇水平的降低和恢复速率均受血浆中化合物1的积累和清除速率的限制。在临床研究中使用的剂量范围内用化合物1治疗期间循环胆固醇的预测稳态浓度如图2所示。
实施例2–化合物1导致大鼠OPC中7-DHC的积累、链甾醇的减少和胆固醇的无变化
来自雌性Sprague Dawley出生后第2天(P2)大鼠的少突神经胶质细胞富集群体在培养物中生长。简言之，将前脑解剖并置于汉克缓冲盐溶液(HBSS)(Life technologies)中。将组织切成1mm片段并且在37℃下于0.01％胰蛋白酶和10μg/ml DNA酶中温育15分钟。将解离的细胞接种在聚D-赖氨酸(PDL)包被的T75组织培养瓶上，并且在含20％胎牛血清(Life technologies)的杜贝卡氏改良依格培养基(Dulbecco's Modified Eagle Medium，DMEM)中在37℃下生长10天。少突神经胶质细胞前体(A2B5+)通过在37℃下以200rpm摇动烧瓶过夜来收集，产生95％纯的群体。培养物维持在含10ng/ml成纤维细胞生长因子/血小板衍生生长因子(FGF/PDGF)(Peprotech)的限定生长培养基(高葡萄糖DMEM、0.1％ BSA、50ug/ml Apo-转铁蛋白、5ug/ml胰岛素、30nM亚硒酸钠、10nM生物素和氢化可的松)中2-3天。为评估化合物1促进大鼠A2B5+祖细胞分化为成熟髓鞘碱性蛋白阳性(MBP+)髓鞘化少突神经胶质细胞的能力，将A2B5+细胞接种至10-cm PDL包被的培养板中补充有10ng/ml CNTF和15nM T3的不含FGF/PDGF的生长培养基中，并且立即用化合物1处理。在培养24小时和72小时时收集细胞团块并储存在-80℃。随后将细胞团块运送至Metabolon(Morrisville,NC,USA)，并且在运输和储存期间维持在-80℃直至加工。细胞团块样品用甲醇在剧烈摇动下提取2分钟(Glen Mills GenoGrinder 2000)以沉淀蛋白质并且解离与蛋白质结合或捕获于沉淀蛋白质基质中的小分子，接着离心以回收化学上多样化的代谢物。接着将所得提取物等分并且在Metabolon的HD4平台上进行分析。若干类型的质量控制样品，包括在提取之前添加的回收标准，来自每个实验样品、过程和溶剂空白组合而成的池的技术重复物，以及掺料的QC标准混合液，在样品制备和分析期间应用于质量评估和过滤失败样品。
Metabolon数据揭示，与相同时间点的媒介物对照相比，化合物1处理导致培养物中DHCR7底物7-DHC积累增加，并且DHCR7产物、链甾醇和胆固醇的积累减少或趋向减少。在24小时时，经化合物1处理的OPC培养物显示8.3倍的7-DHC(p＝2.5e-5，q＝0.005)、0.44倍的链甾醇(p＝0.002，q＝0.15)和0.64倍的胆固醇(p＝0.018，q＝0.15)。至72小时时，经化合物1处理的OPC培养物显示出12.86倍的7-DHC(p＝8.1e-8，q＝2.6e-5)、0.4倍的链甾醇(p＝0.001，q＝0.022)，并且胆固醇无显著变化。参见图3。
数据表明，尽管化合物1显示可降低人类中的外周胆固醇水平，但其未降低大鼠OPC中的胆固醇水平。
实施例3-化合物1在溶血磷脂酰胆碱诱导的脊髓和胼胝体脱髓鞘和铜腙脱髓鞘动物模型中增强髓鞘再生
溶血磷脂酰胆碱(下文为“LPC”)诱导的脊髓和胼胝体脱髓鞘模型是用于研究髓鞘再生的简单体内系统。在第0天将LPC注射至9周龄成年雌性SD大鼠的背柱或胼胝体中。在第3天开始每天通过口服给药施用化合物1。在第9天处死动物，并且将包含病灶的脊髓区域切除并切片。通过对来自1-μm薄切片的甲苯胺蓝染色的有髓鞘纤维进行量化来确定髓鞘再生轴突。对来自每只动物10个显微镜视野和每组3只动物的有髓鞘轴突的数量进行计数。
来自对照处理动物的组织切片显示出具有广泛脱髓鞘区域的大病灶，如根据病灶区域中不存在染色的髓鞘再生轴突所显而易见。相反，化合物1以剂量依赖性方式增强髓鞘再生。最小有效剂量是0.3mg/kg，并且90％最大观测生物效应的剂量(ED90)是3mg/kg，这是通过对病灶中髓鞘再生轴突纤维计数而确定的。通过脱髓鞘脊髓背柱的甲苯胺蓝染色观察髓鞘再生。结果如图5所示。***p<0.001。误差条表示平均值的标准误差。
在铜腙喂食引起的脱髓鞘后，化合物1诱导胼胝体的髓鞘再生。在这个模型中，在铜腙喂食4周后，通常可在小鼠胼胝体中检测到病灶。
九周龄C57/BL6小鼠被喂食含有0.3％铜腙(Harlan)的饲料颗粒，并且经腹膜内注射雷帕霉素持续6周(10mg/kg，5天/周)。在铜腙/雷帕霉素治疗的最后2周中，每天通过口服灌胃用化合物1治疗动物。在最后一次治疗结束时处死动物并解剖大脑以确定化合物1对胼胝体(白质)和大脑皮层区域中髓鞘再生的影响。穿过胼胝体的冠状切片(纹状体中隔切片，1mm厚度)被切割，然后在中矢状平面上切割并包埋在环氧树脂(epon)中，定向以观察胼胝体中矢状体的整个横截面。通过甲苯胺蓝染色量化胼胝体病灶中的有髓鞘轴突。**p<0.01，***p<0.001。结果如图6所示。化合物1显示髓鞘再生的剂量依赖性增强。误差条表示平均值的标准误差。对于研究，N＝39。
实施例4–化合物1在大鼠背根(DRG)/少突神经胶质细胞测定中增强髓鞘表达
将从胚胎第14天(E14)至第17天(E17)Sprague Dawley大鼠解剖的胚胎背根神经节(DRG)接种在聚L-赖氨酸(100μg/ml)包被的盖玻片上2周并且在补充有B27(Lifetechnologies)的Neurobasal培养基中生长。为了去除增殖的神经胶质细胞，在第2-6天和第8-10天用氟脱氧尿苷(20μM)脉冲培养物两次。然后在37℃和5％ CO2下在存在或不存在化合物的情况下将大鼠A2B5+少突神经胶质细胞添加至DRG神经元悬滴培养中持续13天。每周两次更换具有新鲜化合物的培养基(补充有B27和100ng/ml神经生长因子(NGF)的Neurobasal培养基)。通过蛋白质印迹确定髓鞘形成以量化MBP水平。在OPC/DRG共培养测定中，化合物1以剂量依赖性方式促进髓鞘形成(参见图7)。
实施例5–化合物1增强人类iPSC衍生的少突神经胶质细胞祖细胞分化和髓鞘形成
人类诱导多能干细胞(iPSC)衍生的OPC维持在由补充有N2、B27、Glutamax、5mg/mL肝素(Sigma)、1μM嘌吗啡胺(Merck)、20ng/ml FGF/PDGFa(Peprotech)、10ng/ml IGF(Peprotech)和60ng/ml T3(Sigma)的高级DMEM-F12组成的增殖培养基中。为允许OPC分化，从培养基中去除嘌吗啡胺和FGF/PDGF。将化合物1(0.02和0.2μM)与人类iPSC衍生的OPC在分化培养基中培养40天。
将从胚胎第14天(E14)至第17天(E17)Sprague Dawley大鼠解剖的胚胎背根神经节(DRG)接种在聚L-赖氨酸(100μg/ml)包被的盖玻片上2周并且在补充有B27(LifeTechnologies)的Neurobasal培养基中生长。为去除增殖的神经胶质细胞，在第2-6天和第8-10天用氟脱氧尿苷(20μM)脉冲培养物两次。然后将如上所述制备的人类OPC添加至DRG神经元悬滴培养中。大鼠OPC-DRG共培养物的培养基是补充有B27和100ng/ml NGF的Neurobasal培养基，每周两次更换新鲜化合物。人类OPC-大鼠DRG共培养物的培养基是不含嘌吗啡胺和FGF/PDGF的人类OPC的增殖培养基。化合物1(0.02、0.2或2μM)或DMSO对照处理在OPC加入DRG培养物后1天开始。为观察髓鞘形成，培养物用4％多聚甲醛(PFA)固定并用抗髓鞘碱性蛋白(MBP)抗体标记，以通过ICC鉴定髓鞘形成的变化。
结果如图8所示。从图8可见，相对于对照，化合物1增加MBP+细胞的数量和MBP+有髓鞘轴突簇的数量。
实施例6-S1P4在神经细胞大鼠OPC中表达，但在来自MS组织的人类CNS细胞中不表达
S1P4在大鼠神经细胞中的表达通过对从大鼠神经细胞获得的RNA合成的第一链互补DNA进行定量PCR分析来评价。大鼠肌动蛋白信使RNA(mRNA)被扩增作为内部对照。结果如图9所示，特别是在大鼠CNS和周围神经系统细胞中，包括在OPC中存在显著的S1P4信使核糖核酸(mRNA)水平。呈现1-磷酸鞘氨醇受体4(S1P4)mRNA相对于A2B5+少突神经胶质细胞祖细胞(OPC)中的归一化量[级别为1]的丰度。DRG＝背根神经节。
根据标准方案对活体诊断为多发性硬化的供体受试者进行尸体剖检和神经病理学评价。简言之，根据组织库网格系统解剖包含通过尸体剖检组织的大体检查以及正常出现的白质鉴定的活动性或慢性活动性病灶的区域。活动性和慢性活动性病灶被定义为具有弥漫性(活动性)或多灶性(慢性活动性)油红O阳性载脂巨噬细胞/小神经胶质细胞浸润的白质或灰质的脱髓鞘(在选择的组织块上使用抗MOG免疫组织化学(IHC))区域。组织在10％NBF中固定3周，浸入30％蔗糖培养基中2周，然后在干冰上冷却的异戊烷中速冻，之后在-80℃长期储存。诊断为继发进展型MS并且具有含有活动性、慢性活动性和看似正常的白质(NAWM)的大脑或脊髓块的供体被选择用于使用原位杂交(ISH)评价S1PR4表达。
将固定的冷冻组织解冻，然后浸入10％ NBF中并在室温下固定过夜，然后加工和包埋在石蜡中。块以5um切片。对NAWM块进行PPIB(亲环蛋白B)的ISH，以确定是否可显示足够的信号。检查载玻片的PPIB信号。有多病灶扩散信号，在灰质中最为稳健。在一些标本中，大区域的PPIB信号缺失。这些区域有时与活动性或慢性活动性的脱髓鞘区域的存在相关。对于S1PR4 ISH选择具有足够且相对均匀的PPIB信号的NAWM块的供体，如下表所详述。
S1PR4 ISH是在Leica Biosystems的BOND RX平台上使用自动化RNAscope测定来进行的。其根据制造商的说明进行。使用下表中的以下探针/试剂进行S1PR4 mRNA表达和对照的ISH。研究中使用的探针和ISH试剂获自Advanced Cell Diagnostics,Inc(ACD)。研究样品的组织质量通过阳性对照探针-PPIB(亲环蛋白B)进行检查，并且探针的特异性分别通过阴性对照探针-dapB(细菌基因)进行评估。使用Panoramic全载玻片成像仪扫描S1PR4反应的ISH载玻片。数字图像由经委员会认证的兽医病理学家检查，以确定在各种细胞类型和解剖区域中是否存在信号。例如，在脑膜浸润、血管袖套和CNS实质内描述了S1PR4 ISH信号的检测。
以下对照实验在来自上述MS供体的组织块子集(n＝6)上操作。RNA酶处理：根据ACD的说明进行测定。简言之，在
蛋白酶消化后，将组织用RNA酶(RNA酶-Qiagen目录#19101)在40℃处理30分钟，然后进行探针杂交和剩余的RNAscope程序。S1PR4有义探针：由ACD科学家定制设计，以精确补充用于上述反义探针的S1PR4序列。S1PR4基因由单个外显子组成。这使得反义探针更有可能与基因组DNA杂交。
S1PR4反义、有义、RNA酶处理的组织和组织块子集(n＝6)上的PDGFRa的图像分析：整个组织中并且对细胞核和核周区域具特异性的S1PR4 ISH信号检测：使用深度学习和常规图像分析特征的组合在Visiopharm软件中利用定制算法检测ISH点。通过经由苏木精复染将核区域分割为单独的ROI，对细胞核和核周区域特异的ISH信号进行量化。
在血管周围袖套和脑膜中观测到弱至中等的S1P4信号，其被解释为源自被认为是B淋巴细胞的浸润淋巴细胞。使用针对血小板衍生的生长因子受体的探针的阳性对照染色表明在OPC中的丰富表达。
S1P4受体在人类中的表达仅限于造血来源的细胞，在中性粒细胞和单核细胞中表达最高。
实施例7–化合物1对中性粒细胞计数的影响
实施例1中描述的研究中的56名参与者中有2名患上CTCAE 3级中性粒细胞减少(<1.0至0.5×109个中性粒细胞/L)。在这2名参与者中，中性粒细胞减少被报告为AE，导致研究药物中断：
·群组6中的1名参与者(化合物1 60mg)
·群组7中的1名参与者(化合物1)90mg负荷剂量，接着是30mg维持剂量)
除了这2名参与者的中性粒细胞减少外，在接受剂量≥30mg的研究中其他22名参与者的实验室数据中，观测到绝对中性粒细胞计数相比于基线的剂量依赖性下降：
·群组4中的6名参与者(化合物1 30mg)
·群组5中的6名参与者(化合物1 60mg负荷剂量，接着是10mg维持剂量)
·群组6中的5名参与者
·群组7中的5名参与者
本研究中在低化合物1剂量(<30mg，即群组1、2和3)下中性粒细胞计数下降的程度与安慰剂对照无法区分，表明在这些浓度下化合物1对中性粒细胞的影响最小。除了因CTCAE 3级中性粒细胞减少而中断治疗的患者外，60mg QD剂量的所有样品在整个研究过程中都保持在绝对单核细胞计数的正常范围内。
Claims (36)
1.一种治疗患有多发性硬化(MS)的人类受试者的方法，所述方法包括向所述受试者施用每天10mg至60mg的化合物1：
或等效于每天10mg至60mg的化合物1的量的其药学上可接受的盐。
2.如权利要求1所述的方法，其中所述受试者被施用每天10至60mg的化合物1。
3.如权利要求1或2所述的方法，其中所述MS处于复发缓解阶段。
4.如权利要求1或2所述的方法，其中所述MS处于继发进展阶段。
5.如权利要求1-4中任一项所述的方法，所述方法还包括向所述人类受试者施用有效量的可有效治疗MS的额外药剂的步骤。
6.如权利要求5所述的方法，其中所述可用于治疗MS的额外药剂是干扰素-β1或醋酸格拉替雷。
7.如权利要求2-6中任一项所述的方法，所述方法包括向所述受试者施用每天10mg的化合物1。
8.如权利要求2-6中任一项所述的方法，所述方法包括向所述受试者施用每天30mg的化合物1。
9.如权利要求2-6中任一项所述的方法，所述方法包括向所述受试者施用每天60mg的所述化合物1。
10.一种治疗患有多发性硬化(MS)的人类受试者的方法，所述方法包括在不存在降胆固醇药物的情况下向所述受试者施用有效量的化合物1：
或其药学上可接受的盐。
11.如权利要求10所述的方法，其中所述受试者正在用降胆固醇药物进行治疗，并且在开始用化合物1或其药学上可接受的盐治疗之前终止用所述降胆固醇药物进行的治疗。
12.如权利要求10或11所述的方法，其中在开始用化合物1或其药学上可接受的盐治疗之前至少6天终止用所述降胆固醇药物进行的治疗。
13.如权利要求10-12中任一项所述的方法，其中所述降胆固醇药物是他汀类药物、PCSK9抑制剂、选择性胆固醇吸收抑制剂、胆酸螯合剂、贝特类药物或降脂质疗法。
14.如权利要求10-13中任一项所述的方法，其中所述受试者被施用每天10mg至60mg的化合物1或等效于每天10mg至60mg化合物1的量的其药学上可接受的盐。
15.如权利要求10-13中任一项所述的方法，其中所述受试者被施用每天10mg至60mg的化合物1。
16.如权利要求10-13中任一项所述的方法，其中所述受试者被施用每天10mg的化合物1。
17.如权利要求10-13中任一项所述的方法，其中所述受试者被施用每天30mg的化合物1。
18.如权利要求10-13中任一项所述的方法，其中所述受试者被施用每天60mg的化合物1。
19.如权利要求10-18中任一项所述的方法，其中所述MS处于复发缓解阶段。
20.如权利要求10-18中任一项所述的方法，其中所述MS处于继发进展阶段。
21.如权利要求10-20中任一项所述的方法，所述方法还包括向所述人类受试者施用有效量的可有效治疗MS的额外药剂的步骤。
22.如权利要求21所述的方法，其中所述可用于治疗MS的额外药剂是干扰素-β1或醋酸格拉替雷。
23.一种治疗患有多发性硬化(MS)的人类受试者的方法，其中所述受试者正在用有效量的降胆固醇药物进行治疗，所述方法包括以下步骤：
i)向所述受试者施用有效量的化合物1：
或其药学上可接受的盐；
ii)评估所述受试者的血浆胆固醇水平；
iii)如果所述受试者的血浆胆固醇水平在目标范围之外，则调整向所述受试者施用的降胆固醇药物的量以使所述受试者的血浆胆固醇水平在所述目标范围内。
24.如权利要求23所述的方法，其中重复步骤ii)和iii)直至所述受试者的血浆胆固醇水平在所述目标范围内。
25.如权利要求23或24所述的方法，其中所述目标范围介于100mg/dL与200mg/dL之间。
26.如权利要求23或24所述的方法，其中所述目标范围介于125mg/dL与200mg/dL之间。
27.如权利要求23至26中任一项所述的方法，其中所述降胆固醇药物是他汀类药物、PCSK9抑制剂、选择性胆固醇吸收抑制剂、胆酸螯合剂、贝特类药物或降脂质疗法。
28.如权利要求23-27中任一项所述的方法，其中所述受试者被施用每天10mg至60mg化合物1或等效于每天10mg至60mg化合物1的量的其药学上可接受的盐。
29.如权利要求23-27中任一项所述的方法，其中所述受试者被施用每天10mg至60mg的化合物1。
30.如权利要求23-27中任一项所述的方法，其中所述受试者被施用每天10mg的化合物1。
31.如权利要求23-27中任一项所述的方法，其中所述受试者被施用每天30mg的化合物1。
32.如权利要求23-27中任一项所述的方法，其中所述受试者被施用每天60mg的化合物1。
33.如权利要求23-32中任一项所述的方法，其中所述MS处于复发缓解阶段。
34.如权利要求23-32中任一项所述的方法，其中所述MS处于继发进展阶段。
35.如权利要求23-34中任一项所述的方法，所述方法还包括向所述人类受试者施用有效量的可有效治疗MS的额外药剂的步骤。
36.如权利要求35所述的方法，其中所述可用于治疗MS的额外药剂是干扰素-β1或醋酸格拉替雷。
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- 2021-08-19 WO PCT/US2021/046589 patent/WO2022040369A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW202227069A (zh) | 2022-07-16 |
| EP4199927A1 (en) | 2023-06-28 |
| WO2022040369A8 (en) | 2022-04-14 |
| WO2022040369A1 (en) | 2022-02-24 |
| JP2023538065A (ja) | 2023-09-06 |
| US20230390270A1 (en) | 2023-12-07 |
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