Disease‑Modifying Trials in Parkinson’s Disease: Challenges, Lessons, and Future Directions

Parkinson’s disease (PD) is a progressive neurodegenerative disorder lacking approved therapies that slow or halt its underlying pathology. Despite decades of research, disease-modifying trials have faced persistent challenges, including patient heterogeneity, insensitive endpoints, and confounding symptomatic effects. Recent advances in biomarker science and adaptive trial frameworks offer strategies to overcome these limitations. Enrichment designs using α-synuclein seed amplification assays, dopamine transporter imaging, and genetic stratification for GBA1 or LRRK2 variants improve mechanistic alignment and statistical power in early-phase studies. Concurrently, platform trials and master protocols enable simultaneous evaluation of multiple interventions under a unified infrastructure, reducing resource waste compared to traditional sequential designs. However, gaps remain in defining sensitive outcomes, mitigating symptomatic confounders, and ensuring equitable access to biomarker-driven strategies. Future directions emphasize precision medicine approaches integrating multi-omics, digital biomarkers, and AI-driven prognostic models to optimize patient selection and endpoint sensitivity. Equity and diversity must be prioritized to address underrepresentation of racial and ethnic minorities, while ethical frameworks for genetic testing and biomarker disclosure are essential. Regulatory agencies increasingly support qualification of enrichment biomarkers, digital endpoints, and adaptive designs, alongside accelerated approval pathways. The aim of this review is to synthesize current challenges, lessons learned, and emerging strategies to guide the design of efficient, inclusive, and mechanistically aligned disease-modifying trials in PD.