Objective: To advance the regulatory maturity of drug development tools to support the newly proposed integrated staging of Neuronal Synuclein Disease (NSD-ISS) with focus on early intervention.

Background: Efficient data-driven advancement of biological staging of neuronal alpha-synuclein disease (NSD) relies on the ability to appropriately stage the disease process through the integration of biomarkers, genetics, clinical outcome assessment tools, and quantitative solutions across the continuum.

Method: Critical Path for Parkinson’s (CPP) is a public private international partnership consisting of multiple stakeholders including academic experts and industry, nonprofit organizations, people with lived experience, professional societies and government agencies.  A key aim of CPP is to provide regulatory endorsed tools that will enable a stepwise, data-driven analysis strategy grounded in biomarkers, genetics, and clinically meaningful measures. CPP has developed a unified clinical database consisting of patient level data from >13,000 participants from observational cohorts and clinical trials.

Results: The Neuronal Synuclein Disease integrated staging system NSD-ISS is linked to underlying biology of disease (Simuni et al., 2024). The core biologic features of NSD (S-synuclein, D-Dopamine Deficiency, G-genetics) are key elements of the evolving data focused strategy of CPP. CPP working groups leverage patient level item level clinical data in the CPP integrated database to advance the regulatory maturity of tools for clinical trials. Progress to date across CPP working groups has focused on carrying out comprehensive reviews as to the state of regulatory maturity of (1) neuroimaging biomarkers, with focus on DAT SPECT imaging; (2) biofluid biomarkers, with near term focus on alpha-synuclein seed amplification assay in CSF; (3) quantifying clinical progression as defined by MDS-UPDRS and (4) modeling disease progression of genetically defined individuals (LRKK2 carriers).

Conclusion: CPP is focused on aligning across research and clinical trials for evaluation and harmonization of biomarkers and models to inform clinical trials including those aimed at secondary prevention.  Regulatory engagement and alignment on efficient ways to collect and harmonize future biomarkers and clinical data will enhance the efficient application of biological staging in clinical trials.

Stephenson et al., MDS 2024

References: Simuni T et al., Lancet Neurol. 2024 Feb;23(2):178-190.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/advancing-regulatory-endorsed-drug-development-tools-in-alignment-with-emerging-biology-the-critical-path-for-parkinsons-consortium/