Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model.

IF 13 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Drugs Pub Date : 2024-07-01 Epub Date: 2024-06-20 DOI:10.1007/s40265-024-02068-7
John A Hey, Jeremy Y Yu, Susan Abushakra, Jean F Schaefer, Aidan Power, Patrick Kesslak, Martin Tolar
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引用次数: 0

Abstract

Introduction: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.

Methods: The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ42/Aβ40) and tau pathology (p-tau181) were enrolled, with serial CSF and plasma levels of Aβ42 and Aβ40 measured over 104 weeks. Longitudinal changes of CSF Aβ42, plasma Aβ42/Aβ40 ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex.

Results: A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ42 level and plasma Aβ42/Aβ40 ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26).

Conclusions: In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification potential in AD.

Trial registry: https://clinicaltrials.gov/study/NCT04693520.

Abstract Image

利用定量系统药理学模型,分析口服 ALZ-801/Valiltramiprosate 的 APOE4 携带者早期阿尔茨海默病 2 年期试验中的脑脊液、血浆 β 淀粉样蛋白生物标志物和认知能力。
简介:ALZ-801/valiltramiprosate是一种口服小分子β-淀粉样蛋白(Aβ)聚集和寡聚体形成抑制剂,目前正处于作为早期阿尔茨海默病(AD)疾病调节疗法的后期开发阶段。本研究对淀粉样蛋白液体生物标志物进行了定量系统药理学(QSP)分析,并对APOE4携带者早期阿尔茨海默病患者进行的为期2年的ALZ-801 2期试验的认知结果进行了分析:这项单臂、开放标签的2期研究评估了ALZ-801每日2次(BID)、每次265毫克对早期AD APOE4携带者[迷你精神状态检查(MMSE)≥22]的脑脊液(CSF)和血浆淀粉样蛋白液体生物标志物的影响,为期104周。对淀粉样蛋白(Aβ42/Aβ40)和tau病理学(p-tau181)脑脊液生物标志物呈阳性的受试者进行登记,并在104周内连续测量脑脊液和血浆中Aβ42和Aβ40的水平。采用QSP方法将脑脊液Aβ42、血浆Aβ42/Aβ40比值和认知能力雷伊听觉言语学习测试(RAVLT)的纵向变化与已确定的AD自然疾病轨迹进行比较。淀粉样蛋白生物标志物和RAVLT的自然疾病轨迹数据分别从QSP模型和阿尔茨海默病神经影像倡议人群模型中提取。分析按疾病严重程度和性别进行分层:共有 84 名受试者参加了研究。除去一名在试验初期退出的受试者,83名受试者的数据被用于本次分析。ALZ-801治疗阻止了脑脊液Aβ42水平和血浆Aβ42/Aβ40比值的逐渐下降,并在104周内稳定了RAVLT。男女受试者对ALZ-801的反应相当,而轻度认知障碍(MCI)受试者(MMSE≥27)与晚期轻度AD受试者(MMSE 22-26)相比表现出更大的生物标志物反应:在这一基因定义和生物标志物丰富的早期AD人群中,QSP分析表明口服265毫克ALZ-801 BID可阻止CSF和血浆淀粉样蛋白生物标志物单体的自然下降,从而产生积极的治疗效果,这与104周内阻止其聚集成可溶性神经毒性低聚物并随后聚集成不溶性纤维和斑块的目标参与是一致的。伴随着淀粉样蛋白生物标志物的变化,ALZ-801 还稳定了 RAVLT 记忆测试的自然下降轨迹,这表明其临床益处与其作用机制是一致的。这种抑制疾病进展对生物标志物和认知能力下降的连续作用在有症状的早期 AD 阶段更为明显。QSP分析为ALZ-801提供了流体生物标志物和临床证据,证明它是第一类口服小分子抗Aβ寡聚体药物,具有改变AD疾病的潜力。试验登记:https://clinicaltrials.gov/study/NCT04693520。
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来源期刊
Drugs
Drugs 医学-毒理学
CiteScore
22.70
自引率
0.90%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Drugs is a journal that aims to enhance pharmacotherapy by publishing review and original research articles on key aspects of clinical pharmacology and therapeutics. The journal includes: Leading/current opinion articles providing an overview of contentious or emerging issues. Definitive reviews of drugs and drug classes, and their place in disease management. Therapy in Practice articles including recommendations for specific clinical situations. High-quality, well designed, original clinical research. Adis Drug Evaluations reviewing the properties and place in therapy of both newer and established drugs. AdisInsight Reports summarising development at first global approval. Moreover, the journal offers additional digital features such as animated abstracts, video abstracts, instructional videos, and podcasts to increase visibility and educational value. Plain language summaries accompany articles to assist readers with some knowledge of the field in understanding important medical advances.
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