Veri-T: A phase 1 Placebo-Controlled Trial of Verdiperstat in Semantic Variant Primary Progressive Aphasia Due to Underlying FTLD-TDP

Veri-T：Verdiperstat 治疗由潜在 FTLD-TDP 引起的语义变异原发性进行性失语症的 1 期安慰剂对照试验

• 批准号: 10280622
• 负责人: ADAM L. BOXER
• 金额: $ 67.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10280622
• 关键词: Address; Adverse event; Alzheimer' s Disease; Alzheimer' s disease diagnosis; American; Area; Attenuated; Autopsy; Binding Proteins; Biological; Biological Assay; Biological Availability; Biological Markers; Blinded; Blood; Characteristics; Chitinase; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical dementia rating scale; Conduct Clinical Trials; DNA; Diffusion; Disease; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Drug Targeting; Elements; Enrollment; Enzymes; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Funding; Future; Generations; Goals; Inflammatory; Infrastructure; International; Investigation; Laboratories; Light; Liquid substance; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measurement; Measures; Medical; Methodology; Modeling; Multi-Institutional Clinical Trial; Multicenter Trials; Nerve Degeneration; Neuronal Injury; Neuropsychological Tests; Neuropsychology; Oral; Oxidative Stress; Participant; Pathogenesis; Pathogenicity; Pathology; Patient Recruitments; Patients; Penetration; Pennsylvania; Peripheral; Peroxidases; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Plasma; Primary Progressive Aphasia; Proteins; Proteomics; Randomized; Reagent; Research; Role; Safety; Semantics; Severities; Site; Syndrome; Therapeutic Clinical Trial; Therapeutic Trials; United States National Institutes of Health; Universities; Variant; clinical Diagnosis; clinical efficacy; clinical research site; cohort; design; drug efficacy; effective therapy; efficacy trial; follow-up; glial activation; imaging biomarker; inhibitor/antagonist; limbic-predominant age-related TDP-43 encephalopathy; neurofilament; nonhuman primate; novel; pharmacodynamic biomarker; phase II trial; placebo controlled trial; pre-clinical; programs; protein TDP-43; proteomic signature; recruit; safety testing; targeted treatment; therapeutic candidate; therapeutic development; therapeutic target; therapy development

PROJECT SUMMARY/ABSTRACT The proposed multi-site clinical trial will fill a critical unmet need for therapeutic development in semantic variant primary progressive aphasia (svPPA), a syndrome that is over 85% predictive of frontotemporal lobar degeneration with mislocalization of TDP-43 on autopsy (FTLD-TDP). We will thereby address the larger critical unmet need for therapeutic development in the greater spectrum of TDP-43 pathology, which is present in up to 20% of suspected Alzheimer's disease and over half of frontotemporal dementia. We hypothesize that microglial myeloperoxidase (MPO), an enzyme responsible for generation of microglial oxidative species, is a key therapeutic target in the pathogenesis of FTLD with TDP-4 mislocalization. We will therefore conduct a phase 1 randomized, double-blind, placebo-controlled, sequential cohort, dose-ranging, tolerability, and preliminary pharmacodynamic study of two doses of Verdiperstat (BHV-3241), an orally administered MPO inhibitor, in patients with svPPA. As the first multi-site clinical trial focused on svPPA, this project will establish the crucial organizational infrastructure to conduct future multicenter trials in this cohort, while leveraging existing clinical expertise and patient recruitment infrastructure from the large NIH-funded ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) multisite clinical research consortium. In order to establish the appropriateness of follow-up phase 2 trials, we will determine the safety and tolerability (Aim 1) and the pharmacokinetics (in blood and CSF) (Aim 2) of 300mg (low dose) and 600mg (high dose) BHV-324, orally administered twice daily (BID) for 24 weeks in patients with svPPA due to underlying FTLD-TDP. N=55 Participants will be randomized overall to placebo (N=15), low dose (N=10), and high dose (N=30) BHV-3241 respectively. Given the lack of established pharmacodynamic measures of drug efficacy in FTLD, we will also explore the effects of BHV-3241 on peripheral MPO activity, fluid and imaging biomarkers of neurodegeneration, unbiased CSF proteomics, and clinical status in FTLD-TDP (Aim 3). Our proposed discovery and longitudinal characterization of candidate measures of svPPA biological and clinical severity will provide essential information, informing the design of future efficacy trials exploring BHV-3241 and other potential therapies in svPPA and the larger spectrum of FTLD-TDP.

项目摘要/摘要 拟议的多站点临床试验将满足语义上治疗发展的至关重要的需求 变体主要进行性失语症（SVPPA），一种超过85％的综合征，可预测额颞叶 TDP-43在尸检（FTLD-TDP）上的变性而变化。因此，我们将解决较大的 在更大的TDP-43病理学中，对治疗性发育的批判性未满足的需求， 多达20％的疑似阿尔茨海默氏病和超过一半的额颞痴呆症。我们假设这一点 小胶质细胞髓过氧化物酶（MPO）是一种负责生成小胶质氧化物种的酶，是一种 TDP-4错误定位的FTLD发病机理中的关键治疗靶标。因此，我们将进行 阶段1随机，双盲，安慰剂对照，顺序队列，剂量范围，耐受性和 两种剂量的Verdiperstat（BHV-3241）的初步药效学研究，一种口服的MPO 抑制剂，SVPPA患者。作为第一个针对SVPPA的多站点临床试验，该项目将建立 在该队列中进行未来多中心试验的至关重要的组织基础设施，同时 来自大型NIH资助的Artfl-Lefftds的现有临床专业知识和患者招聘基础设施 纵向额颞叶变性（AllFTD）多站点临床研究联盟。为了 确定随访第二阶段试验的适当性，我们将确定安全性和耐受性（AIM 1） 以及300mg（低剂量）和600mg（高剂量）BHV-324的药代动力学（在血液和CSF中）（AIM 2）， 由于基本的FTLD-TDP，SVPPA患者每天口服两次（BID）24周。 n = 55 参与者总体将随机分配到安慰剂（n = 15），低剂量（n = 10）和高剂量（n = 30）BHV-3241 分别。鉴于缺乏FTLD中药物疗效的既定药效学指标，我们还将 探索BHV-3241对外围MPO活性，流体和成像生物标志物的影响 神经变性，无偏的CSF蛋白质组学和FTLD-TDP中的临床状况（AIM 3）。我们提出的 SVPPA生物学和临床严重程度的候选措施的发现和纵向表征将 提供必要的信息，告知探索BHV-3241和其他的未来功效试验的设计 SVPPA和较大的FTLD-TDP频谱中的潜在疗法。