Identification of cerebrospinal fluid pharmacodynamic biomarkers and molecular correlates of brain activity in a Phase 2 clinical trial of the Alzheimer's disease drug candidate CT1812

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-06-19 DOI:10.1002/trc2.70119

Valentina Di Caro, Eunah Cho, Hilary A. North, Jill Caldwell, Kiran Pandey, Duc Duong, Michael Grundman, Willem de Haan, Everard G. Vijverberg, Charlotte E. Teunissen, Anthony O. Caggiano, Nicholas T. Seyfried, Mary E. Hamby

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引用次数: 0

Abstract

INTRODUCTION

CT1812 (zervimesine) is an orally dosed modulator of the sigma-2 receptor (S2R) currently in clinical development for the treatment of Alzheimer's disease (AD). CT1812 has been shown in preclinical and early clinical trials to selectively prevent and displace binding of amyloid beta oligomers from their synaptic receptors and has improved cognitive function in animal models of AD.

METHODS

SEQUEL (NCT04735536) is a completed Phase 2, randomized, placebo-controlled 4-week crossover trial in adults with mild-to-moderate AD that investigated the effect of CT1812 on safety, synaptic function using quantitative electroencephalography (qEEG), and biomarkers. CT1812 improved established qEEG markers of spontaneous brain activity, suggesting improved neuronal and synaptic function. In the present study, cerebrospinal fluid (CSF)-based tandem mass tag mass spectrometry (TMT-MS) was performed on participant samples to investigate proteomic effects and identify potential biomarkers of CT1812.

RESULTS

Biomarkers found through proteomics analyses to be significantly differentially abundant in CT1812- versus placebo-treated participants supported pathway engagement and proof of mechanism for CT1812. Impacted proteins support a role for CT1812 at synapses, in vesicle trafficking, and in lipoprotein biology. Biomarkers correlated with the previously reported improvements in qEEG-based functional connectivity (inferred through alpha band Amplitude Envelope Correlations) with CT1812 treatment were also identified and may be potential early surrogate biomarkers of efficacy for CT1812. The processes and functions supported by biomarkers were congruent with those previously revealed in CSF proteomics analyses from phase 1 and 2 AD clinical trials with CT1812.

DISCUSSION

After 1 month of treatment, the identification of biomarkers supporting pathway engagement, the replication of biomarker findings from prior trials, and the discovery of molecular correlates of improved functional connectivity with CT1812 treatment bolster support for and expound upon the mechanism of action for CT1812 in displacing Aβ oligomers at neuronal synapses, as well as underscores the CT1812 relevance to AD.

Highlights

Exploratory proteomics identified candidate CSF biomarkers of CT1812 in SEQUEL.
Molecular correlates of functional brain connectivity (qEEG) were identified.
Proteins impacted by 1 month CT1812 treatment support target engagement.
Pharmacodynamic changes found in synapse, immune, vesicle, and lipoprotein biologies.
SEQUEL proteomics findings replicated previous trial findings with CT1812.

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阿尔茨海默病候选药物CT1812的2期临床试验中脑脊液药效学生物标志物和脑活动分子相关物的鉴定

CT1812 （zervimesine）是一种口服给药的sigma-2受体（S2R）调节剂，目前正处于临床开发阶段，用于治疗阿尔茨海默病（AD）。CT1812已在临床前和早期临床试验中被证明可以选择性地阻止和取代突触受体与β淀粉样蛋白寡聚物的结合，并改善阿尔茨海默病动物模型的认知功能。SEQUEL （NCT04735536）是一项已完成的2期、随机、安慰剂对照的4周交叉试验，在轻度至中度阿尔茨海默症成人患者中进行，研究CT1812对安全性、突触功能和生物标志物的影响。CT1812改善了已建立的自发性脑活动qEEG标记物，表明神经元和突触功能得到改善。本研究采用基于脑脊液（CSF）的串联质谱法（TMT-MS）对参与者样本进行蛋白质组学研究，并鉴定CT1812的潜在生物标志物。结果：通过蛋白质组学分析发现，CT1812治疗组与安慰剂治疗组的生物标志物显著差异丰富，这支持了CT1812的通路参与和机制证明。受影响的蛋白支持CT1812在突触、囊泡运输和脂蛋白生物学中的作用。与先前报道的基于qeeg的功能连接改善相关的生物标志物（通过α波段振幅包络相关性推断）与CT1812治疗也被确定，并且可能是CT1812疗效的潜在早期替代生物标志物。生物标志物支持的过程和功能与先前在CT1812的1期和2期AD临床试验的CSF蛋白质组学分析中显示的一致。治疗1个月后，支持通路参与的生物标志物的鉴定，先前试验中生物标志物发现的复制，以及CT1812治疗改善功能连接的分子相关性的发现，加强了对CT1812在神经元突触中取代Aβ低聚物的作用机制的支持和阐述。同时也强调了CT1812与AD的相关性。探索性蛋白质组学鉴定了SEQUEL中CT1812的候选CSF生物标志物。确定了功能性脑连接（qEEG）的分子相关性。受1个月CT1812治疗影响的蛋白质支持靶标接合。突触、免疫、囊泡和脂蛋白生物学的药效学变化。SEQUEL蛋白质组学研究结果与CT1812之前的试验结果一致。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.