Target engagement rarely aligns with clinical benefit in synuclein-related disorder trials

A PRISMA-compliant review in Brain examined whether biomarker evidence of target engagement corresponded to clinical benefit in disease-modifying trials for Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies. The review included 26 phase II and III trials conducted during 2020–2025, involving 2,195 participants. All included at least one fluid or imaging biomarker intended to assess target engagement.

Target engagement was reported in 14 of 19 Parkinson’s disease trials, one of four multiple system atrophy trials and two of three dementia with Lewy bodies trials. Eight of 26 trials demonstrated both target engagement and statistically significant clinical benefit: seven phase II trials and one phase III trial. Only two of these, both phase II, were rigorously controlled with low or moderate risk of bias. Nine trials showed target engagement without clinical benefit, while two reported clinical improvement without measurable target engagement.

Baseline biomarker-guided patient selection was uncommon and rarely aligned with the intervention’s mechanism of action. Patient-reported outcomes were widely used but rarely improved. These findings caution against interpreting target-engagement biomarkers as evidence of clinical efficacy and support closer biological alignment between trial populations and experimental treatments. This assessment is based on the abstract; individual interventions, effect sizes and detailed review methods were not available.