Nat Med:遗憾,Gantenerumab或Solanezumab对于显性遗传阿尔兹海默症无效

2021-06-22 haibei MedSci原创

52名携带突变的参与者被分配接受gantenerumab治疗,52名参与者接受solanezumab治疗,另外40名参与者接受安慰剂治疗。两种药物都涉及其Aβ靶点。

阿尔兹海默症(AD)是一种进行性的神经退行性疾病,在临床症状出现前几十年就会出现大脑的病理变化。据推测,淀粉样β(Aβ)斑块在大脑中的积累启动了一连串的破坏性机制,包括炎症和神经纤维缠结中tau蛋白的聚集。DIAD是一种罕见的疾病形式,估计占所有病例的<1%,在DIAD中,痴呆症在相对可预测的年龄发展,由特定的基因突变决定。

显性遗传性阿尔茨海默病网络(DIAN)于2008年启动了一项关于DIAD的观察性研究(DIAN-OBS)。通过跟踪临床、认知和生物标志物的测量,该研究发现生物标志物的变化,如淀粉样斑块的沉积和tau的变化,至少在临床症状发生前20年就开始了。

已有的专注于消除或中断散发性晚期AD中Aβ积累的药物试验没有包括DIAD患者,而且结果大多令人失望。过去负面结果的潜在原因包括在疾病过程中治疗太晚,剂量或目标参与不充分,目标不正确或试验人群中的痴呆不是由AD引起。

由于DIAD患者在可预测的年龄发生AD痴呆,在症状发生前多年就表现出疾病病理,并且不太可能有导致认知能力下降的合并症,因此这一人群为测试早期阶段的干预措施,以防止或减缓疾病进展提供了机会。

DIAN-Trials Unit(DIAN-TU)成立于2012年,是一个公私合作项目,用于测试DIAD各阶段的药物干预措施。DIAN-TU的平台设计能够以单一方案和共享安慰剂组同时测试多种治疗方法。

研究人员在2012年启动了第一个试验(DIAN-TU-001),作为一项为期两年的生物标志物研究,在DIAD的无症状和轻度症状阶段平行测试两种抗淀粉样蛋白单克隆抗体,即gantenerumab(一种抗纤维性Aβ抗体)和solanezumab(一种抗溶性Aβ抗体)2015年,该研究被过渡到一个为期四年的治疗试验,以认知为主要终点,研究药物减缓或防止认知衰退的潜力。

在该临床试验中,突变携带者被3:1分配到药物或安慰剂,并接受4-7年的治疗。主要结果是认知终点;次要结果包括临床、认知、成像和液体生物标志物措施。

52名携带突变的参与者被分配接受gantenerumab治疗,52名参与者接受solanezumab治疗,另外40名参与者接受安慰剂治疗。两种药物都涉及其Aβ靶点,但与对照组相比,都没有显示出对认知能力的有益影响

认知和临床结果

甚至,Solanezumab治疗组在某些指标上显示出更大的认知衰退,而在下游生物标志物上没有显示出好处。Gantenerumab明显减少了淀粉样斑块、脑脊液总tau和phospho-tau181,并削弱了神经丝轻链的增加。此外,gantenerumab组有19.2%的参与者(11人中有3人症状轻微)观察到淀粉样蛋白相关的影像学异常水肿,安慰剂组有2.5%,solanezumab组有0%。

因此,Gantenerumab和solanezumab并没有减缓有症状的DIAD的认知衰退。无症状组没有显示出认知能力的下降;有症状的参与者在达到目标剂量之前就已经下降了。

 

原始出处:

Stephen Salloway et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nature Medicine (2021). 

 

 

 

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style='color:#2F92EE;'>#Donanemab#</a>,在11月30日公布了与Aducanumab头对头的Ph3临床TRAILLAZER-ALZ 4试验结果。应该优于<a href='/topic/show?id=bf9120211d' target=_blank style='color:#2F92EE;'>#aducanumab#</a>,不过Aducanumab早被证明是失败的产品了。 不过,Anavex开发的口服小分子<a href='/topic/show?id=8b86105526d5' target=_blank style='color:#2F92EE;'>#Sigma-1R激动剂#</a><a href='/topic/show?id=c04910552ec9' target=_blank style='color:#2F92EE;'>#Blarcamesine#</a>,12月1日公布了Ph2b/3临床ANAVEX®2-73-AD-004试验初步结果。该试验共入组了509例早期AD患者,按1:1:1分别随机分配到高低两个用药剂量组和安慰剂组,给药48周后,进入96周的开放标签阶段。两个有效性主要临床终点是ADAS-Cog和<a href='/topic/show?id=fb741055289f' target=_blank style='color:#2F92EE;'>#ADCS-ADL#</a>,次要终点包括CDR-SB评分等。有效性方面,Blarcamesine用药组与安慰剂组相比, <a href='/topic/show?id=b4f51055297e' target=_blank style='color:#2F92EE;'>#ADAS-Cog评分#</a>从基线变化改善超过-0.50的比例高出84%(p=0.015),ADCS-ADL评分从基线变化改善超过3.5的比例高出167%(p=0.0255);此外,Blarcamesine用药组平均改善ADAS-Cog评分-4.03,相比安慰剂组差异为-1.85。在次要终点上,两个组的<a href='/topic/show?id=9edf10553038' target=_blank 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    2023-03-10 showtest 来自上海

    Solanezumab顺利进入临床阶段,在一期和二期都基本顺利,直到2012年#礼来#的两个代号为EXPEDITION-1和EXPEDITION-2的各1,000多例受试者的治疗轻中度AD的三期临床失败,唯一给研究者留下希望的就是Solanezumab对轻度AD患者亚组有更明显的认知及功能改善作用。 2013年礼来启动了基于以上这一亚组发现的EXPEDITION-3三期临床,专门入组了2,129例轻度AD患者,然而到2016年终于又宣布依然没有作出主要临床终点的显著性。 在Aβ假说被包括礼来在内一系列大药企的临床失败阴影笼罩下,该假说支持者的重要挽尊脑洞之一就是“治疗太晚”,即Aβ沉积大幅早于AD症状出现,在这一思路的驱使下,2013年礼来同步启动了这个代号为A4的三期临床,入组了超过1,100例有淀粉样板块沉积的PET影像、又无AD临床症状的受试者。 到2017年礼来内部组织架构变动,将A4临床交给AD研究所负责,并调整用药剂量(400mg->1,600mg),因此临床周期被延长了至少4.5年。 无论如何,Solanezumab几乎见证了Aβ假说从兴起至今的整个历程,又探索了从中度、轻度、到预防等几乎所有AD的疾病阶段,也证明AD治疗之难! 现在看来,#Lecanemab#有多么可贵!!是首个对#阿尔茨海默#有明显改善的药物。 另外,礼来还有一款另一款Aβ单抗#Donanemab#,在11月30日公布了与Aducanumab头对头的Ph3临床TRAILLAZER-ALZ 4试验结果。应该优于#aducanumab#,不过Aducanumab早被证明是失败的产品了。 不过,Anavex开发的口服小分子#Sigma-1R激动剂##Blarcamesine#,12月1日公布了Ph2b/3临床ANAVEX®2-73-AD-004试验初步结果。该试验共入组了509例早期AD患者,按1:1:1分别随机分配到高低两个用药剂量组和安慰剂组,给药48周后,进入96周的开放标签阶段。两个有效性主要临床终点是ADAS-Cog和#ADCS-ADL#,次要终点包括CDR-SB评分等。有效性方面,Blarcamesine用药组与安慰剂组相比, #ADAS-Cog评分#从基线变化改善超过-0.50的比例高出84%(p=0.015),ADCS-ADL评分从基线变化改善超过3.5的比例高出167%(p=0.0255);此外,Blarcamesine用药组平均改善ADAS-Cog评分-4.03,相比安慰剂组差异为-1.85。在次要终点上,两个组的#CDR-SB评分#差异为-0.42(这倒跟Lecanemab水平差异不大)。这是令人欣喜的!

    0

  2. 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replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97761, encryptionId=60ca9e761ce, topicName=阿尔兹海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=30bd35, createdName=一叶知秋, createdTime=Thu Jun 24 08:21:29 CST 2021, time=2021-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1611103, encodeId=2124161110323, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Thu Jun 24 08:21:29 CST 2021, time=2021-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=975955, encodeId=67369e5955a6, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210622/5a7c7235edec446382c43ae1d4ba07fc/b3f15ee0e56648a8b241ccf40b6d6fd3.jpg, createdBy=3db33254475, createdName=罗华鼎, createdTime=Tue Jun 22 22:28:32 CST 2021, time=2021-06-22, status=1, ipAttribution=)]
    2023-03-10 showtest 来自上海

    52名携带突变的参与者被分配接受#gantenerumab#治疗,52名参与者接受#Solanezumab#治疗,另外40名参与者接受安慰剂治疗。两种药物都涉及其Aβ靶点,但与对照组相比,都没有显示出对认知能力的有益影响。#阿尔兹海默症#,太难了,又倒下两个

    0

  3. 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style='color:#2F92EE;'>#Donanemab#</a>,在11月30日公布了与Aducanumab头对头的Ph3临床TRAILLAZER-ALZ 4试验结果。应该优于<a href='/topic/show?id=bf9120211d' target=_blank style='color:#2F92EE;'>#aducanumab#</a>,不过Aducanumab早被证明是失败的产品了。 不过,Anavex开发的口服小分子<a href='/topic/show?id=8b86105526d5' target=_blank style='color:#2F92EE;'>#Sigma-1R激动剂#</a><a href='/topic/show?id=c04910552ec9' target=_blank style='color:#2F92EE;'>#Blarcamesine#</a>,12月1日公布了Ph2b/3临床ANAVEX®2-73-AD-004试验初步结果。该试验共入组了509例早期AD患者,按1:1:1分别随机分配到高低两个用药剂量组和安慰剂组,给药48周后,进入96周的开放标签阶段。两个有效性主要临床终点是ADAS-Cog和<a href='/topic/show?id=fb741055289f' target=_blank style='color:#2F92EE;'>#ADCS-ADL#</a>,次要终点包括CDR-SB评分等。有效性方面,Blarcamesine用药组与安慰剂组相比, <a href='/topic/show?id=b4f51055297e' target=_blank style='color:#2F92EE;'>#ADAS-Cog评分#</a>从基线变化改善超过-0.50的比例高出84%(p=0.015),ADCS-ADL评分从基线变化改善超过3.5的比例高出167%(p=0.0255);此外,Blarcamesine用药组平均改善ADAS-Cog评分-4.03,相比安慰剂组差异为-1.85。在次要终点上,两个组的<a href='/topic/show?id=9edf10553038' target=_blank 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channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210622/5a7c7235edec446382c43ae1d4ba07fc/b3f15ee0e56648a8b241ccf40b6d6fd3.jpg, createdBy=3db33254475, createdName=罗华鼎, createdTime=Tue Jun 22 22:28:32 CST 2021, time=2021-06-22, status=1, ipAttribution=)]
    2022-06-05 liye789132251
  4. 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style='color:#2F92EE;'>#CDR-SB评分#</a>差异为-0.42(这倒跟Lecanemab水平差异不大)。这是令人欣喜的!, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73910, encryptionId=60bfe391059, topicName=礼来), TopicDto(id=104862, encryptionId=977a1048622c, topicName=Lecanemab), TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默), TopicDto(id=105525, encryptionId=76251055257b, topicName=Donanemab), TopicDto(id=2021, encryptionId=bf9120211d, topicName=aducanumab), TopicDto(id=105526, encryptionId=8b86105526d5, topicName=Sigma-1R激动剂), TopicDto(id=105527, encryptionId=c04910552ec9, topicName=Blarcamesine), TopicDto(id=105528, encryptionId=fb741055289f, topicName=ADCS-ADL), TopicDto(id=105529, encryptionId=b4f51055297e, topicName=ADAS-Cog评分), TopicDto(id=105530, encryptionId=9edf10553038, topicName=CDR-SB评分)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8f0715, createdName=showtest, createdTime=Fri 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replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97761, encryptionId=60ca9e761ce, topicName=阿尔兹海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=30bd35, createdName=一叶知秋, createdTime=Thu Jun 24 08:21:29 CST 2021, time=2021-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1611103, encodeId=2124161110323, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Thu Jun 24 08:21:29 CST 2021, time=2021-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=975955, encodeId=67369e5955a6, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210622/5a7c7235edec446382c43ae1d4ba07fc/b3f15ee0e56648a8b241ccf40b6d6fd3.jpg, createdBy=3db33254475, createdName=罗华鼎, createdTime=Tue Jun 22 22:28:32 CST 2021, time=2021-06-22, status=1, ipAttribution=)]
    2021-12-27 snf701207
  5. 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style='color:#2F92EE;'>#Donanemab#</a>,在11月30日公布了与Aducanumab头对头的Ph3临床TRAILLAZER-ALZ 4试验结果。应该优于<a href='/topic/show?id=bf9120211d' target=_blank style='color:#2F92EE;'>#aducanumab#</a>,不过Aducanumab早被证明是失败的产品了。 不过,Anavex开发的口服小分子<a href='/topic/show?id=8b86105526d5' target=_blank style='color:#2F92EE;'>#Sigma-1R激动剂#</a><a href='/topic/show?id=c04910552ec9' target=_blank style='color:#2F92EE;'>#Blarcamesine#</a>,12月1日公布了Ph2b/3临床ANAVEX®2-73-AD-004试验初步结果。该试验共入组了509例早期AD患者,按1:1:1分别随机分配到高低两个用药剂量组和安慰剂组,给药48周后,进入96周的开放标签阶段。两个有效性主要临床终点是ADAS-Cog和<a href='/topic/show?id=fb741055289f' target=_blank style='color:#2F92EE;'>#ADCS-ADL#</a>,次要终点包括CDR-SB评分等。有效性方面,Blarcamesine用药组与安慰剂组相比, <a href='/topic/show?id=b4f51055297e' target=_blank style='color:#2F92EE;'>#ADAS-Cog评分#</a>从基线变化改善超过-0.50的比例高出84%(p=0.015),ADCS-ADL评分从基线变化改善超过3.5的比例高出167%(p=0.0255);此外,Blarcamesine用药组平均改善ADAS-Cog评分-4.03,相比安慰剂组差异为-1.85。在次要终点上,两个组的<a href='/topic/show?id=9edf10553038' target=_blank 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  6. 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style='color:#2F92EE;'>#Donanemab#</a>,在11月30日公布了与Aducanumab头对头的Ph3临床TRAILLAZER-ALZ 4试验结果。应该优于<a href='/topic/show?id=bf9120211d' target=_blank style='color:#2F92EE;'>#aducanumab#</a>,不过Aducanumab早被证明是失败的产品了。 不过,Anavex开发的口服小分子<a href='/topic/show?id=8b86105526d5' target=_blank style='color:#2F92EE;'>#Sigma-1R激动剂#</a><a href='/topic/show?id=c04910552ec9' target=_blank style='color:#2F92EE;'>#Blarcamesine#</a>,12月1日公布了Ph2b/3临床ANAVEX®2-73-AD-004试验初步结果。该试验共入组了509例早期AD患者,按1:1:1分别随机分配到高低两个用药剂量组和安慰剂组,给药48周后,进入96周的开放标签阶段。两个有效性主要临床终点是ADAS-Cog和<a href='/topic/show?id=fb741055289f' target=_blank style='color:#2F92EE;'>#ADCS-ADL#</a>,次要终点包括CDR-SB评分等。有效性方面,Blarcamesine用药组与安慰剂组相比, <a href='/topic/show?id=b4f51055297e' target=_blank style='color:#2F92EE;'>#ADAS-Cog评分#</a>从基线变化改善超过-0.50的比例高出84%(p=0.015),ADCS-ADL评分从基线变化改善超过3.5的比例高出167%(p=0.0255);此外,Blarcamesine用药组平均改善ADAS-Cog评分-4.03,相比安慰剂组差异为-1.85。在次要终点上,两个组的<a href='/topic/show?id=9edf10553038' target=_blank 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  7. 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  8. [GetPortalCommentsPageByObjectIdResponse(id=2118655, encodeId=cba3211865588, content=Solanezumab顺利进入临床阶段,在一期和二期都基本顺利,直到2012年<a href='/topic/show?id=60bfe391059' target=_blank style='color:#2F92EE;'>#礼来#</a>的两个代号为EXPEDITION-1和EXPEDITION-2的各1,000多例受试者的治疗轻中度AD的三期临床失败,唯一给研究者留下希望的就是Solanezumab对轻度AD患者亚组有更明显的认知及功能改善作用。 2013年礼来启动了基于以上这一亚组发现的EXPEDITION-3三期临床,专门入组了2,129例轻度AD患者,然而到2016年终于又宣布依然没有作出主要临床终点的显著性。 在Aβ假说被包括礼来在内一系列大药企的临床失败阴影笼罩下,该假说支持者的重要挽尊脑洞之一就是“治疗太晚”,即Aβ沉积大幅早于AD症状出现,在这一思路的驱使下,2013年礼来同步启动了这个代号为A4的三期临床,入组了超过1,100例有淀粉样板块沉积的PET影像、又无AD临床症状的受试者。 到2017年礼来内部组织架构变动,将A4临床交给AD研究所负责,并调整用药剂量(400mg-&gt;1,600mg),因此临床周期被延长了至少4.5年。 无论如何,Solanezumab几乎见证了Aβ假说从兴起至今的整个历程,又探索了从中度、轻度、到预防等几乎所有AD的疾病阶段,也证明AD治疗之难! 现在看来,<a href='/topic/show?id=977a1048622c' target=_blank style='color:#2F92EE;'>#Lecanemab#</a>有多么可贵!!是首个对<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>有明显改善的药物。 另外,礼来还有一款另一款Aβ单抗<a href='/topic/show?id=76251055257b' target=_blank style='color:#2F92EE;'>#Donanemab#</a>,在11月30日公布了与Aducanumab头对头的Ph3临床TRAILLAZER-ALZ 4试验结果。应该优于<a href='/topic/show?id=bf9120211d' target=_blank style='color:#2F92EE;'>#aducanumab#</a>,不过Aducanumab早被证明是失败的产品了。 不过,Anavex开发的口服小分子<a href='/topic/show?id=8b86105526d5' target=_blank style='color:#2F92EE;'>#Sigma-1R激动剂#</a><a href='/topic/show?id=c04910552ec9' target=_blank style='color:#2F92EE;'>#Blarcamesine#</a>,12月1日公布了Ph2b/3临床ANAVEX®2-73-AD-004试验初步结果。该试验共入组了509例早期AD患者,按1:1:1分别随机分配到高低两个用药剂量组和安慰剂组,给药48周后,进入96周的开放标签阶段。两个有效性主要临床终点是ADAS-Cog和<a href='/topic/show?id=fb741055289f' target=_blank style='color:#2F92EE;'>#ADCS-ADL#</a>,次要终点包括CDR-SB评分等。有效性方面,Blarcamesine用药组与安慰剂组相比, <a href='/topic/show?id=b4f51055297e' target=_blank style='color:#2F92EE;'>#ADAS-Cog评分#</a>从基线变化改善超过-0.50的比例高出84%(p=0.015),ADCS-ADL评分从基线变化改善超过3.5的比例高出167%(p=0.0255);此外,Blarcamesine用药组平均改善ADAS-Cog评分-4.03,相比安慰剂组差异为-1.85。在次要终点上,两个组的<a href='/topic/show?id=9edf10553038' target=_blank style='color:#2F92EE;'>#CDR-SB评分#</a>差异为-0.42(这倒跟Lecanemab水平差异不大)。这是令人欣喜的!, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73910, encryptionId=60bfe391059, topicName=礼来), TopicDto(id=104862, encryptionId=977a1048622c, topicName=Lecanemab), TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默), TopicDto(id=105525, encryptionId=76251055257b, topicName=Donanemab), TopicDto(id=2021, encryptionId=bf9120211d, topicName=aducanumab), TopicDto(id=105526, encryptionId=8b86105526d5, topicName=Sigma-1R激动剂), TopicDto(id=105527, encryptionId=c04910552ec9, topicName=Blarcamesine), TopicDto(id=105528, encryptionId=fb741055289f, topicName=ADCS-ADL), TopicDto(id=105529, encryptionId=b4f51055297e, topicName=ADAS-Cog评分), TopicDto(id=105530, encryptionId=9edf10553038, topicName=CDR-SB评分)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8f0715, createdName=showtest, createdTime=Fri 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    2021-06-22 罗华鼎

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