Path to Prevention Platform Trial in Early-Stage Neuronal Alpha-Synuclein Disease: Study Design

The development of biologically targeted therapeutics (BTTs) that slow Parkinson's disease progression has been hampered by a reliance on testing interventions in clinically defined populations with already advanced pathobiology. Publications on the biological definition and classification of neuronal a-synuclein disease (NSD), and the development of the NSD integrated staging system (NSD-ISS), have generated a framework for identifying individuals with NSD prior to the emergence of a clinically defined syndrome. Path to Prevention (P2P) is a phase 2A, randomized, double-blind, placebo-controlled platform trial designed to assess the safety and efficacy of interventions in an early-stage NSD population. The trial is embedded within the observational Parkinson's Precision Medicine Initiative (PPMI), a structure that enables recruitment of participants from the PPMI cohort, leverages existing operational infrastructure, and utilizes data from non-P2P enrolled PPMI participants in the Bayesian statistical modeling. P2P will enroll participants at least 60 years of age with NSD Stage 2B (abnormal ⍺-synuclein, dopaminergic dysfunction, and prodromal signs or symptoms without functional impairment) without a clinically defined diagnosis of PD or a related disorder. As a platform trial, P2P will enable the testing of multiple interventions under a Master Protocol at approximately 35 sites across North America and Europe. Interventions are selected from industry-submitted applications based on biological relevance of the targets, and on the adequacy of the safety data appropriate to the target population. Each treatment regimen will have 125 participants on active treatment and at least 125 shared placebo control participants. Participants will remain on treatment for a maximum of 144 weeks or until 96 weeks since the randomization of the last participant. P2P has two primary endpoints, 1) rate of change in mean putamen specific binding ratio from baseline through follow-up and, 2) rate of change in the MDS-UPDRS Part III motor examination from baseline through follow-up or initiation of dopaminergic treatment. A range of secondary and exploratory biomarker-focused endpoints will be assessed. The protocol was developed with input from multiple stakeholders, including people with early-stage NSD, biopharmaceutical industry leaders, and regulatory authorities. P2P is the first trial to test biologically targeted assets in biologically defined prodromal participants utilizing an efficient platform design, which will provide the field with tools to expand therapeutic development, and enable intervention at earlier stages of neurodegeneration. P2P is scheduled to begin enrollment in December 2026 and is committed to data sharing and broad dissemination of learnings from the study.