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: 10677747
• 负责人: ADAM L. BOXER
• 金额: $ 63.89万
• 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/10677747
• 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; CHI3L1 gene; Characteristics; 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; Oral Administration; Oxidative Stress; Participant; Pathogenesis; Pathogenicity; Pathology; Patient Recruitments; Patients; Penetration; Pennsylvania; Peripheral; Peroxidases; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebo Control; Placebos; Plasma; Primary Progressive Aphasia; Proteins; Proteomics; Randomized; Reagent; Research; Rodent; Role; Safety; Semantics; Severities; Site; Syndrome; Tars; 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; 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.

项目总结/文摘