The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial.
The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial.
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DOI：
10.1093/brain/awab167
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发表时间：
2021-10-22
期刊：
影响因子：
--
通讯作者：
Lauria G
中科院分区：
文献类型：
--
作者：
Dalla Bella E;Bersano E;Antonini G;Borghero G;Capasso M;Caponnetto C;Chiò A;Corbo M;Filosto M;Giannini F;Spataro R;Lunetta C;Mandrioli J;Messina S;Monsurrò MR;Mora G;Riva N;Rizzi R;Siciliano G;Silani V;Simone I;Sorarù G;Tugnoli V;Verriello L;Volanti P;Furlan R;Nolan JM;Abgueguen E;Tramacere I;Lauria G
强有力的证据表明，内质网应激通过改变蛋白质稳态调节在肌萎缩侧索硬化症（ALS）的发病机制中发挥着关键作用。可靠的临床前研究结果表明，在体外和体内模型中，guanabenz 选择性抑制内质网应激诱导的 eIF2α-磷酸酶，从而清除错误折叠的蛋白，减少神经元死亡并延长存活时间。然而，其对 ALS 患者的安全性和有效性尚不清楚。为了解决这些问题，我们进行了一项无效设计的多中心、随机、双盲试验。过去 18 个月内出现症状的 ALS 患者以 1:1:1:1 的比例随机分配，每天接受 64 mg、32 mg 或 16 mg 胍那苯或安慰剂，作为利鲁唑的附加治疗，持续 6 个月。安慰剂组盲法的目的是确定安全性而非有效性。主要结果是使用 ALS 米兰-都灵分期系统测量的 6 个月内进展至更高疾病阶段的患者比例，与包含 200 名 ALS 患者的历史队列进行比较。次要结局是修订后的 ALS 功能评定量表总分的下降率、缓慢的肺活量变化、死亡时间、气管切开术或永久通气以及 6 个月时的血清轻神经丝水平。使用意向治疗分析进行初步疗效评估。使用64毫克和32毫克胍那苯的治疗组，无论是单独使用还是联合使用，均达到了无效的主要假设，6个月时进展至疾病更高阶段的患者比例显着低于无效假设下的预期，并且总修订后的ALS功能评定量表评分的中位变化率差异显着较低。这种效应是由延髓发病的患者驱动的，与接受 16 mg 胍那苯治疗的患者 (4/8; 50%)、单独历史队列 (21/49; 43%; P==0.001) 或加安慰剂 (25/60; 42%; P = 0.001）。任何胍那苯组中经历至少一种不良事件的患者比例均高于安慰剂组，较高剂量组的药物相关副作用比例显着较高，而 64mg 组的退出率显着较高。胍那苯组和安慰剂组之间严重不良事件的数量没有显着差异。我们的研究结果表明，有必要对一种针对未折叠蛋白反应途径的分子进行更大规模的试验，且不产生胍那苯的 α-2 肾上腺素能相关副作用。内质网应激通过改变蛋白质稳态调节在 ALS 发病机制中发挥关键作用。在 2 期无效试验中，Dalla Bella 等人。研究表明，与历史对照相比，α-2 肾上腺素受体激动剂 guanabenz 降低了 6 个月时进展至疾病更高阶段的患者比例。
Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted. ER stress plays a key role in ALS pathogenesis through altered regulation of proteostasis. In a phase 2 futility trial, Dalla Bella et al. show that the alpha-2 adrenergic receptor agonist guanabenz reduces the proportion of patients progressing to higher stages of disease at 6 months compared to historical controls.
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DOI：
10.1126/science.aaa4484
发表时间：
2015-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Das I;Krzyzosiak A;Schneider K;Wrabetz L;D'Antonio M;Barry N;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A
影响因子：
5.3
作者：
Goutman SA;Brown MB;Glass JD;Boulis NM;Johe K;Hazel T;Cudkowicz M;Atassi N;Borges L;Patil PG;Sakowski SA;Feldman EL
通讯作者：
Feldman EL
影响因子：
11.1
作者：
Barbezier, Nicolas;Chartier, Aymeric;Bidet, Yannick;Buttstedt, Anja;Voisset, Cecile;Galons, Herve;Blondel, Marc;Schwarz, Elisabeth;Simonelig, Martine
通讯作者：
Simonelig, Martine
影响因子：
9.9
作者：
Atassi, Nazem;Berry, James;Leitner, Melanie
通讯作者：
Leitner, Melanie
影响因子：
11
作者：
Chio, Adriano;Hammond, Edward R.;Filippini, Graziella
通讯作者：
Filippini, Graziella