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

项目总结/摘要 拟议的多中心临床试验将填补语义治疗开发的关键未满足需求 变异型原发性进行性失语症（svPPA），一种超过85%预测额颞叶 尸检时TDP-43的变性和错误定位（FTLD-TDP）。因此，我们将解决更大的问题， 在TDP-43病理学的更大范围内，治疗开发的关键未满足需求， 在20%的疑似阿尔茨海默病和超过一半的额颞叶痴呆症中。我们假设 小胶质细胞髓过氧化物酶（MPO），一种负责产生小胶质细胞氧化物质的酶，是一种 TDP-4错误定位的FTLD发病机制中的关键治疗靶点。因此，我们将进行 I期随机化、双盲、安慰剂对照、序贯队列、剂量范围、耐受性和 两种剂量Verdiperstat（BHV-3241）的初步药效学研究，口服MPO 抑制剂，在svPPA患者。作为首个针对svPPA的多中心临床试验，该项目将建立 在该队列中进行未来多中心试验的关键组织基础设施， 来自NIH资助的大型ARTFL-LEFFTDS的现有临床专业知识和患者招募基础设施 纵向额颞叶变性（ALLFTD）多中心临床研究联盟。为了 确定随访II期试验的适当性，我们将确定安全性和耐受性（目标1） 以及300 mg（低剂量）和600 mg（高剂量）BHV-324的药代动力学（血液和CSF中）（目的2）， 每日两次（BID）口服给药，持续24周。N=55 受试者将总体随机分配至安慰剂组（N=15）、低剂量组（N=10）和高剂量组（N=30）BHV-3241 分别鉴于FTLD中缺乏确定的药物疗效药效学指标，我们还将 探索BHV-3241对外周MPO活性、体液和影像学生物标志物的影响， 神经变性、无偏倚CSF蛋白质组学和FTLD-TDP的临床状态（目的3）。我们提出的 svPPA生物学和临床严重性的候选量度的发现和纵向表征将 提供基本信息，为探索BHV-3241和其他药物的未来疗效试验的设计提供信息 svPPA和更大范围的FTLD-TDP的潜在疗法。

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.