Target engagement and efficacy in disease-modifying trials of synuclein-related disorders

Disease-modifying trials in Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) increasingly incorporate fluid and imaging biomarkers to demonstrate target engagement, de-risk subsequent phases of drug development and provide mechanistic evidence of biological activity. Whether biomarker modulation predicts clinical benefit remains unclear. We conducted a PRISMA-compliant review of phase II and III disease-modifying trials (2020-2025) that included at least one biomarker intended to assess target engagement. Twenty-six trials met inclusion criteria (PD=19, MSA=4, DLB=3; n=2,195 participants). Target engagement was reported in 14 of 19 PD trials (12 phase II/2 phase III), 1 of 4 MSA trials, and 2 of 3 DLB trials (all phase II). Concordance between target engagement and clinical improvement was uncommon, as only 8/26 studies (7 phase II/1 phase III) demonstrated both target engagement and statistically significant clinical benefit, and just two of these (both phase II, one in PD and one in MSA) were rigorously controlled with low or moderate risk of bias. Nine trials showed target engagement without clinical benefit, whereas two reported clinical improvement without measurable target engagement. Baseline biomarker-guided patient selection was uncommon and rarely aligned with the compound's mechanism of action. Patient-reported outcomes were widely used but rarely improved. Across recent disease-modifying trials in PD, DLB, and MSA, target engagement was frequently demonstrated, yet clinical benefit rarely followed. These findings question the predictive value of currently used target-engagement biomarkers and highlight the need to biologically align trial populations with the mechanisms targeted by experimental molecular interventions.