PROJECT SUMMARY / ABSTRACT Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease of aging that usually leads to death within 5-7 years of diagnosis. There are no effective treatments for PSP, but therapeutic approaches being tested in clinical trials for other neurodegenerative diseases, such as Alzheimer’s (AD) and amyotrophic lateral sclerosis may be even more promising for PSP. Despite excellent feasibility of large multicenter PSP clinical trials, there are few new studies, limiting options for patients to access experimental therapies and severely delaying the identification of effective treatments. New, efficient clinical PSP trial programs and focused efforts to identify PSP biomarkers are urgently needed. The overarching goal of the PSP Trial Platform (PTP) is to conduct a randomized, placebo-controlled, Phase 2 platform trial in mild-moderate PSP that will simultaneously test at least three different tau-related or neuroprotective therapies to determine safety, tolerability and clinical proof of concept based on a multimodal clinical rating scale, the modified PSP Rating Scale-15 (mPSPRS-15). Platform trials create economies of scale through generation of a common clinical trial protocol and the ability to share placebo group information to allow a greater number of therapies to be tested in a shorter amount of time and with less expense than multiple independent clinical trials. Three therapies will be compared for 12 months, in four parallel arms, with a 3:1 (drug:placebo) randomization ratio to encourage recruitment, followed by an optional, 12-month open-label extension. Key inclusion criteria will be a diagnosis of mild-moderate PSP, with symptoms < 5 years in duration, preserved ability to ambulate with minimal cognitive impairment (Mini Mental State Exam > 25). All individuals will be screened with a validated MRI diagnostic tool to rule out non-PSP etiologies. Using these criteria, we estimate that 110 participants per group (3 drug, 1 placebo) will be necessary to have 80% power to detect a 33% slowing in decline on the mPSPRS-15 over 12 months, accounting for 20% attrition. Key secondary endpoints will include including changes in the total PSPRS, activities of daily living (Schwab and England ADL), global status (Clinical Global Impression of disease severity), the PSP Quality of Life scale, a newly validated PSP Cognitive Composite, and volumetric MRI biomarkers including midbrain volume. Exploratory CSF biomarker discovery efforts will focus on changes in PSP-associated tau fragments, axon guidance network proteins, and lysosomal proteins and lipids over 12 months. Leveraging the experience and resources of the CurePSP Centers of Care, the Parkinson’s Study Group, the NIH-funded ALLFTD research network, and the NIH AD Clinical Trials Consortium (ACTC), we propose to enroll 440 participants at ~50 sites in North America over 24 months. Like other platform trials, additional therapeutic arms may be added after initial program launch. If successful, the PTP will provide key data for decision-making about which therapies to pursue in larger efficacy trials, create a new infrastructure to efficiently evaluate PSP therapies, and a new resource for longitudinal PSP clinical and biomarker data, and biosamples, to be shared with other researchers.

PROJECT NARRATIVE Progressive Supranuclear Palsy (PSP) is a severe brain disease of aging that is usually fatal within five to seven years after diagnosis. PSP has no cure, but because it shares a key biological feature with Alzheimer’s disease (AD), accumulation of tau protein in the brain, new treatments developed for AD and other neurodegenerative diseases might be equally or more effective to treat PSP. Building on recent advances in drug development and clinical trial methods, this project will test the ability of three new therapies to slow clinical disease progression and brain volume loss in PSP and will create a large amount of new data to share with other researchers to help develop new PSP diagnostic tests and therapies in the future.