Target engagement without clinical benefit: a systematic review, mechanism-concordant meta-analysis, and research agenda for Parkinson’s disease immunotherapy

Background Immune-based and inflammation-targeted therapies have strong biological rationale in Parkinson’s disease (PD). We re-examined this translational gap using a tiered evidence framework and mechanism-concordant quantitative synthesis.Methods The prespecified search logic for records published between 1 January 2010 and 28 February 2026 was completed on 23 July 2026 across PubMed/MEDLINE, ClinicalTrials.gov, Embase via Ovid, and the Cochrane Central Register of Controlled Trials via Ovid. Phase II/III randomized trials were separated from early-phase biomarker trials, registry records, conference reports, press releases, and post-cut-off updates. Risk of bias was assessed with cochrane risk-of-bias 2 tools. “Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD420261333324.”Results Four phase II trials contributed quantitative efficacy data (n = 960). In the primary mechanism-concordant analysis of prasinezumab and cinpanemab (k = 2; n = 673), antibodies used as passive immunotherapy showed no benefit (mean difference −0.047, 95% CI − 0.202 to 0.108; I2 = 13%). An extended cross-mechanism synthesis adding azathioprine and venglustat remained null (k = 4; n = 960; standardised mean difference (SMD) 0.038, 95% CI − 0.123 to 0.198; I2 = 30%; 95% prediction interval −0.486 to 0.560).Conclusion Randomized evidence does not currently support disease modification by immune-based or inflammation-targeted therapy in PD. This translational paradox reflects incomplete central engagement due to risk or engagement without clinical benefit.