Regulatory endorsement for the application of α-synuclein seed amplification assay as a susceptibility and risk biomarker for clinical trials targeting synucleinopathies

Abstract

Transformation in the neurosciences in biomarkers is enabling novel therapeutic strategies targeting earlier stages of disease prior to onset of clinical symptoms. Emerging progress in the area of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) have significant implications for clinical trials. Misfolded α-synuclein aggregates (syn-seeds) propagate by templated misfolding of native α-synuclein, driving disease spread. The advent of the α-synuclein seed amplification assay (syn SAA) now enables highly sensitive and specific detection of syn-seeds in cerebrospinal fluid (CSF), allowing in vivo identification of underlying α-synuclein pathology, including in individuals prior to the onset of motor symptoms.To support regulatory alignment, the Critical Path Institute's Critical Path for Parkinson's (CPP) consortium compiled and evaluated the totality of scientific evidence in the area of syn SAA as an in vivo measure of misfolded alpha synuclein in CSF and submitted it to the U.S. Food and Drug Administration (FDA) in a request for a Biomarker Letter of Support (LoS). Within three months of submission, the FDA issued a LoS endorsing CSF syn SAA as a susceptibility and risk biomarker for use in clinical trials targeting α-synuclein-related neurodegenerative diseases, enabling enrichment of participants with underlying pathology and reducing trial risk. These data have enabled the development of biological classification frameworks for synucleinopathies that define disease based on molecular pathology rather than clinical symptoms alone.This review summarizes the regulatory-grade evidence supporting syn SAA and discusses its implications for biologically driven clinical trial design and early-intervention strategies.