Summary: Prasinezumab, a monoclonal antibody targeting alpha-synuclein aggregation, shows promise in slowing motor deterioration in rapidly progressing Parkinson’s disease (PD), according to an exploratory analysis from the phase 2 PASADENA clinical trial.
While there are currently no disease-modifying treatments for PD, prasinezumab offers a potential breakthrough by specifically binding to aggregated alpha-synuclein, a key driver of PD pathology. In the trial, prasinezumab significantly reduced motor symptom worsening in patients with rapidly progressing disease at the one-year mark, compared to those on placebo.
This finding highlights the need for further research to confirm prasinezumab’s efficacy in broader PD populations and those with slower disease progression.
Key Facts:
- Prasinezumab is designed to target and degrade aggregated alpha-synuclein, implicated in the progression of Parkinson’s disease.
- In the PASADENA trial, prasinezumab effectively slowed the worsening of motor symptoms in PD patients identified as having rapidly progressing disease after one year of treatment.
- The trial used the Movement Disorder Society Unified PD Rating Scale Part III to assess motor symptoms, revealing significant benefits in rapid progressors but not in slow progressors.
Source: Nature
Prasinezumab, a monoclonal antibody, is shown to reduce signs of motor deterioration in individuals with Parkinson’s disease (PD) who have rapidly progressing disease, as reported in an exploratory analysis of data from a large phase 2 clinical trial published in Nature Medicine.
There are currently no disease-modifying treatments for PD, a neurodegenerative disorder characterized by worsening of both motor and non-motor symptoms over time.
Aggregation of alpha-synuclein in the brain is a hallmark of PD, and several preclinical studies have suggested that this pathology is a key driver of disease progression.
Prasinezumab is the first experimental therapeutic monoclonal antibody designed to bind aggregated alpha-synuclein, allowing it to be degraded.
The antibody was recently investigated in 316 patients with early-stage PD in the phase 2 PASADENA clinical trial, but was found to have no meaningful effect on disease progression in this cohort. However, participants in the trial had highly variable disease progression.
Gennaro Pagano and colleagues analyzed the potential effects of prasinezumab on motor progression in four pre-specified subpopulations who had rapidly progressing motor symptoms in the phase 2 PASADENA trial.
These rapidly progressing subgroups were defined by the use of monoamine oxidase B (MAO-B) inhibitors at baseline, the staging of their disease on the Hoehn and Yahr scale, the presence of rapid eye movement sleep behavior disorder, or the presence of diffuse malignant phenotypes.
Researchers found that prasinezumab treatment reduced motor symptom worsening in all rapidly progressing subpopulations after 52 weeks, compared with the motor symptoms of those treated with a placebo.
This effect was not seen in treated subpopulations characterized as slow progressors. Assessment of motor symptoms was done using part III of the Movement Disorder Society Unified PD rating scale (MDS-UPDRS), which is the standard clinical assessment tool for quantifying motor symptoms in PD.
These findings suggest that the clinical efficacy of prasinezumab is seen only at one year in treated patients with rapidly progressing PD. Further research is needed to determine if prasinezumab may be effective in patients with slower progression of disease after longer treatment duration periods; this is being explored in an extended open-label phase of the PASEDENA trial.
Further trials are also needed to confirm these effects in patients with rapidly progressing PD, and this is currently being investigated in a large phase 2 trial (the PADOVA study).
About this Parkinson’s disease and neuropharmacology research news
Author: Gennaro Pagano
Source: Nature
Contact: Gennaro Pagano – Nature
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease” by Gennaro Pagano et al. Nature Medicine
Abstract
Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease
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.
