Disease‑Modifying Therapies for Parkinson’s Disease: Biological Mechanisms, Pharmacological Strategies, and Clinical Pipeline

Parkinson’s disease (PD) is a biologically heterogeneous neurodegenerative disorder characterized by progressive motor and non-motor symptoms. Despite decades of research, no pharmacologic intervention has conclusively demonstrated disease-modifying efficacy in late-phase randomized controlled trials. Current strategies primarily target pathogenic mechanisms such as α-synuclein aggregation, mitochondrial dysfunction, impaired autophagy, and neuroinflammation, alongside genetic contributors including LRRK2 and GBA variants. Therapeutic approaches under investigation encompass monoclonal antibodies, small molecules, gene therapy, and metabolic modulators; however, pivotal trials of agents such as isradipine, cinpanemab, prasinezumab, exenatide, and inosine have failed to alter long-term progression, underscoring limitations in trial design, biomarker validation, and patient stratification. Repurposing of approved drugs—representing approximately one-third of disease-modifying therapy trials—offers a cost-efficient strategy, with candidates including GLP-1 receptor agonists, α1-adrenergic antagonists, and lysosomal enhancers such as ambroxol. Emerging paradigms emphasize biomarker-driven and genotype-enriched designs to improve internal validity and enable precision medicine, particularly for GBA- and LRRK2-associated PD. Despite these advances, major unmet needs persist, including validated progression biomarkers, robust adaptive trial frameworks, and strategies for early or prodromal intervention. This review synthesizes biological mechanisms, pharmacological strategies, and clinical pipeline trends, highlighting lessons from past failures and opportunities for translational innovation. Accelerating progress will require global platform trials, integration of molecular staging, and harmonization of regulatory pathways to bridge mechanistic insights with clinically meaningful outcomes.