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

项目摘要/摘要 拟议的多点临床试验将填补语义治疗开发方面尚未满足的关键需求 变异型原发性进行性失语(SvPPA)--一种85%以上可预测额颞叶的综合征 尸检发现TDP-43变性错位(FTLD-TDP)。因此，我们将解决更大的 在TDP-43病理的更大范围内的治疗开发的关键未得到满足的需求，这是存在的 高达20%的疑似阿尔茨海默病患者和超过一半的额颞部痴呆患者。我们假设 小胶质细胞髓过氧化物酶(MPO)是一种负责产生小胶质细胞氧化物种的酶。 TDP-4错位致病机制中的关键治疗靶点。因此，我们将进行一项 第1阶段随机、双盲、安慰剂对照、序贯队列、剂量范围、耐受性和 口服MPO两种剂量Verdiperstat(BHV-3241)的初步药效学研究 SvPPA患者应用抑制剂。作为首个专注于svPPA的多点临床试验，该项目将建立 在这个队列中进行未来多中心试验的关键组织基础设施，同时利用 NIH资助的大型ARTFL-LEFFTDS现有的临床专业知识和患者招募基础设施 纵向额颞叶变性(ALLFTD)多点临床研究联盟。为了 确定后续第2阶段试验的适当性，我们将确定安全性和耐受性(目标1) 和300 mg(低剂量)和600 mg(高剂量)BHV-324在血液和脑脊液中的药代动力学(目标2)， SvPPA患者由于潜在的FTLD-TDP，每天口服两次(BID)，为期24周。N=55 参与者将被随机分为安慰剂(N=15)、低剂量(N=10)和高剂量(N=30)BHV-3241 分别进行了分析。鉴于FTLD缺乏既定的药效药效学衡量标准，我们还将 探讨BHV-3241对外周MPO活性、体液及影像标志物的影响 FTLD-TDP中的神经退行性变、无偏倚脑脊液蛋白质组学和临床状态(AIM 3)。我们的建议 SvPPA生物学和临床严重度的候选指标的发现和纵向表征 提供基本信息，为未来探索BHV-3241和其他药物的疗效试验的设计提供信息 SvPPA的潜在治疗方法和FTLD-TDP的更大范围。

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.