The road for developing new pharmacological therapies for Parkinson's disease: Current trends and targets in clinical trials

Background Despite substantial research efforts, advances in Parkinson's disease therapeutics remain largely confined to the management of motor symptoms, with comparatively limited progress in addressing non-motor features, and with no proven success in disease-modifying therapies to date. Objectives To describe recent trends in Parkinson's disease therapeutic trials and to characterize the experimental compounds and targets investigated in drug development programs. Methods We conducted a cross-sectional analysis of Parkinson's disease therapeutic clinical trials registered in ClinicalTrials.gov, EUCTR, and CTIS since 2013. For the subset of commercially sponsored medicinal product trials, we further described therapeutic objectives and pharmacological targets. Results We identified 1855 trials, of which 29% were ongoing. Commercial trials predominantly investigated drugs and devices, whereas non-commercial trials more often focused on non-pharmacological interventions. Among 294 commercial medicinal product trials, 166 distinct products representing 146 active compounds were identified, mapped to 52 pharmacological targets, with additional compounds acting through multiple or unclear mechanisms. Dopaminergic approaches dominated (dopamine receptor agents, 18%; dopamine replacement, 15%), followed by aSyn-targeted strategies (10%). Advanced therapies, including cell and gene therapies, were investigated in 8%. Motor symptoms, particularly motor fluctuations, were the most frequent objectives (45%), whereas non-motor symptoms were rarely addressed (8%). Conclusions The landscape of Parkinson's disease trials has expanded over the past decade, but progress has largely been limited to incremental improvements in dopaminergic therapies. The continued lack of effective treatments for non-motor symptoms and disease modification suggests a need to rethink current approaches to drug development in Parkinson's disease.