Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson's disease

Abstract

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings.

Fig. 1. Forest plot of prasinezumab effects on motor progression as measured by the MDS-UPDRS Part III (hypothetical strategy) across the primary prespecified subpopulations.

Adj., adjusted; MAO-B, monoamine oxidase B; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale; RBDSQ, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire. Error bars represent 80% confidence interval (CI).

Fig. 2. Prasinezumab effect on motor signs progression assessed using MDS-UPDRS Part III in participants taking MAO-B inhibitors at baseline and those who were treatment-naive at baseline.

a, Hypothetical strategy. b, Treatment policy in OFF state. c, Treatment policy in ON state. The MDS-UPDRS endpoints were analyzed using mixed models for repeated measures. Error bars represent s.e. MAO-B inhibitors at baseline: prasinezumab pooled n = 77; placebo n = 38; treatment-naive at baseline: prasinezumab pooled n = 134; placebo n = 67. MAO-B, monoamine oxidase B; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale.