Prasinezumab, a monoclonal antibody targeting aggregated α-synuclein, is being investigated as a potential disease-modifying therapy for early-stage Parkinson's disease (PD). Although the primary endpoint of the PASADENA phase 2 study was not met, prasinezumab-treated individuals showed slower motor sign progression compared to placebo-treated participants. This exploratory analysis assessed whether prasinezumab had greater benefits on motor sign progression in subgroups with faster motor progression. The analysis included four prespecified and six exploratory subpopulations, such as those using monoamine oxidase B inhibitors, Hoehn and Yahr stage, rapid eye movement sleep behavior disorder, data-driven subphenotypes, age, sex, disease duration, age at diagnosis, and motor subphenotypes. The results showed that prasinezumab had a greater effect on slowing motor sign progression in rapidly progressing subpopulations, particularly those with diffuse malignant phenotypes or using monoamine oxidase B inhibitors at baseline. These findings suggest that prasinezumab might reduce motor progression more effectively in individuals with more rapidly progressing PD. However, additional randomized clinical trials are needed to validate these findings.Prasinezumab, a monoclonal antibody targeting aggregated α-synuclein, is being investigated as a potential disease-modifying therapy for early-stage Parkinson's disease (PD). Although the primary endpoint of the PASADENA phase 2 study was not met, prasinezumab-treated individuals showed slower motor sign progression compared to placebo-treated participants. This exploratory analysis assessed whether prasinezumab had greater benefits on motor sign progression in subgroups with faster motor progression. The analysis included four prespecified and six exploratory subpopulations, such as those using monoamine oxidase B inhibitors, Hoehn and Yahr stage, rapid eye movement sleep behavior disorder, data-driven subphenotypes, age, sex, disease duration, age at diagnosis, and motor subphenotypes. The results showed that prasinezumab had a greater effect on slowing motor sign progression in rapidly progressing subpopulations, particularly those with diffuse malignant phenotypes or using monoamine oxidase B inhibitors at baseline. These findings suggest that prasinezumab might reduce motor progression more effectively in individuals with more rapidly progressing PD. However, additional randomized clinical trials are needed to validate these findings.