NEJM:Prasinezumab治疗帕金森病再度失败,aSyn靶向免疫疗法前路茫茫

2022-08-05 MedSci原创 MedSci原创

帕金森病(PD)是一种慢性进行性神经变性疾病,其特征是黑质致密部(SNpc)多巴胺能神经元早期变性死亡,细胞内广泛存在aSyn聚集;PD患病率仅次于阿尔茨海默病,是常见的神经变性性疾病,发病率和患病率

帕金森病(PD)是一种慢性进行性神经变性疾病,其特征是黑质致密部(SNpc)多巴胺能神经元早期变性死亡,细胞内广泛存在aSyn聚集;PD患病率仅次于阿尔茨海默病,是常见的神经变性性疾病,发病率和患病率随年龄增长而增加,65 岁以上的人群患病率为2%~ 3%,患病典型症状为运动迟缓、肢体震颤、强直以及后期运动障碍等。聚集的 α-突触核蛋白在帕金森病的发病机制中起重要作用。目前,aSyn已成为帕金森研究中的一个热门靶标,除了阻止aSyn积累、促进aSyn降解外,研究发现其蛋白质错误折叠也与神经变性性疾病有关,解决其蛋白错误折叠方式也成为一种潜在治疗此类疾病的途径。因此,针对聚集的 α-突触核蛋白的单克隆抗体 prasinezumab 对帕金森病可能有效。

Prasinezumab是一种设计靶向作用于α-突触核蛋白的单克隆抗体。α-突触核蛋白是一种在神经元中发现的蛋白,可聚集并可以在细胞之间扩散。 这导致了神经元功能的障碍和丧失,最终导致帕金森氏病。

帕金森病候选药物Prasinezumab治疗帕金森病的2b期疗效试验,由罗氏制药公司(Roche)和Prothena生物技术公司共同推动。

2020年9月15日,2期研究PASADENA中发现,Prasinezumab未达到减缓运动和非运动症状进展的主要终点,但该药在次要和探索性指标上显示出具有疗效。研究表明,与安慰剂组相比,两个Prasinezumab治疗组的疾病进展都有所缓解。此外,使用运动障碍学会统一帕金森病评定量表(the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale,MDS-UPDRS)第III部分对患者进行评估,与安慰剂组相比,Prasinezumab治疗组的患者在接受治疗一年后其运动功能下降减少了35%。与安慰剂组相比,使用Prasinezumab治疗一年以上的患者发现其出现具有临床意义的运动进展恶化的时间显著延迟。

因此,开展了2b临床试验,主要针对MDS-UPDRS的改善作用。最新的两项2期研究结果发表在8月4日的《新格兰医学杂志》(NEJM)上。分别针对单克隆抗体 cinpanemab 和 prasinezumab,均发现对早期帕金森病几乎没有益处。见:NEJM:cinpanemab治疗早期帕金森病失败

在这项 2 期试验中,我们以 1:1:1 的比例将患有早期帕金森病的参与者随机分配接受静脉注射安慰剂或 prasinezumab,剂量为每 4 周 1500 mg 或 4500 mg,共 52 周。主要终点是运动障碍协会赞助的统一帕金森病评定量表修订版(MDS-UPDRS;范围,0 至 236 , 分数越高表示损伤越大)。次要终点包括半球壳核中的多巴胺转运蛋白水平,该水平与身体临床受影响较大的一侧同侧,通过 123I-碘氟烷单光子发射计算机断层扫描 (SPECT) 测量。

结果显示,共有316名参与者参加; 105 人被分配接受安慰剂,105 人接受 1500 mg prasinezumab,106 人接受 4500 mg prasinezumab。安慰剂组的基线平均 MDS-UPDRS 评分为 32.0,1500-mg 组为 31.5,4500-mg 组为 30.8,安慰剂组从基线到 52 周的平均 (±SE) 变化为 9.4±1.2组,1500-mg 组为 7.4±1.2(与安慰剂的差异,–2.0;80% 置信区间 [CI],–4.2 至 0.2;P=0.24),4500-mg 组为 8.8±1.2(差异与安慰剂相比,–0.6;80% CI,–2.8 至 1.6;P=0.72)。 SPECT 上的多巴胺转运蛋白水平在积极治疗组和安慰剂组之间没有显着差异。大多数临床次要终点的结果在积极治疗组和安慰剂组中相似。 1500 毫克组 6.7% 的参与者和 4500 毫克组 7.5% 的参与者发生严重不良事件;输液反应发生率分别为 19.0% 和 34.0%。

这项研究结果表明,与安慰剂相比,Prasinezumab 治疗对帕金森病进展的整体或影像学测量没有显著的临床意义的影响,并且会增加输液反应。

“除了有人认为低剂量 prasinezumab 治疗减缓了次要终点的进展外,两项试验均未显示对主要或次要终点的益处,”随附社论的作者写道。

aSyn已经成为帕金森病研究中的一个热门目标,但该靶点疗效的临床证据尚不充分。Biogen作为神经退行性疾病领域的领先者,在获得旗下Cinpanemab 2期数据后放弃了这款候选药,该文章也发表在同期的NEJM上。2022年4月,艾伯维宣布将终止与BioArctic的合作,停止帕金森病治疗药物α-突触核蛋白(aSyn)抗体ABBV-0805的后续临床开发。可见帕金森病aSyn靶向免疫疗法的开发前路漫漫。

原始出处:

Pagano G, Taylor KI, Anzures-Cabrera J, Marchesi M, Simuni T, Marek K, Postuma RB, Pavese N, Stocchi F, Azulay JP, Mollenhauer B, López-Manzanares L, Russell DS, Boyd JT, Nicholas AP, Luquin MR, Hauser RA, Gasser T, Poewe W, Ricci B, Boulay A, Vogt A, Boess FG, Dukart J, D'Urso G, Finch R, Zanigni S, Monnet A, Pross N, Hahn A, Svoboda H, Britschgi M, Lipsmeier F, Volkova-Volkmar E, Lindemann M, Dziadek S, Holiga Š, Rukina D, Kustermann T, Kerchner GA, Fontoura P, Umbricht D, Doody R, Nikolcheva T, Bonni A; PASADENA Investigators and Prasinezumab Study Group.Trial of Prasinezumab in Early-Stage Parkinson's Disease.N Engl J Med. 2022 Aug 4;387(5):421-432

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    2022-12-22 snf701207
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    2022-08-05 小元

    NEJM上果然牛,感谢梅斯更新及时

    0

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    2022-08-05 ms2000000635560722

    学习了

    0

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近日,一项发表在Neurology上的研究探讨了帕金森病(PD)患者脑储备基线结构测量与临床进展的关系,进一步提供 PD 脑储备结构测量的潜在机制。脑资源较多的 PD 患者有较大的代偿能力。

movement disorders:吸烟和基因相互作用,或促进帕金森发生

尽管这是PD研究中最有力的发现之一,但吸烟和PD之间的逆向关联的机制仍然未知

JNNP:不同帕金森病亚型具有不同的遗传决定因素

帕金森病(PD)是一种常见的进行性神经退行性疾病,具有广泛的运动和非运动特征。在表现和进展方面,这些特征具有相当大的异质性,这使得许多人相信该疾病有不同的临床相关亚型。数据驱动的方法已应用于许多帕金森

Annals Neurology-血浆MIA、CRP和白蛋白,预示着帕金森病的认知能力下降

基于血浆的预测因子可识别出有认知能力下降风险的PD患者

movement disorders: 早期帕金森患者,突触前结构变化和临床进展有何关系?

18 F-FE-PE2I PET在早期PD中显示出强有力的2年下降,但11 C-UCB-J PET没有

Cell:揭开帕金森病标志物的双面角色

Khurana及其同事的最初线索来自α-突触核蛋白毒性的酵母和果蝇模型,并通过对人类细胞,病人来源的神经元和人类遗传学的研究得到证实。