The monoclonal antibody prasinezumab promises to slow the rapid progression of Parkinson's disease

The monoclonal antibody prasinezumab promises to slow the rapid progression of Parkinson's disease

In a study recently published in the journalNatural medicine, a large international team of researchers conducted an exploratory analysis to evaluate whether the monoclonal antibody prasinezumab, previously observed to be effective in slowing the progression of motor symptoms of Parkinson's disease, actually shows benefits in subgroups of Parkinson's disease patients with rapidly progressive motor degeneration.

background

A hallmark of Parkinson's disease is the aggregation of α-synuclein, which is thought to spread between neurons and contribute to the pathogenesis of Parkinson's disease. One of the first therapeutic options targeting aggregated α-synuclein was the monoclonal antibody prasinezumab, which was evaluated in Phase II clinical trials in patients with early Parkinson's disease that were part of the PASADENA trial.

The primary endpoint of the phase II trials of the PASADENA trial was the Movement Disorder Society Unified Parkinson's Disease Rating Scale or MDS-UPDRS score. Although the monoclonal antibody was not found to be effective on all parameters of the MDS-UPDRS compared to those treated with placebo, those who received prasinezumab showed slower progression of motor degeneration. In addition, the team also believed that the MDS-UPDRS subscales were unlikely to show changes over short observation periods such as one year.

About the study

In the present study, the team examined the impact of prasinezumab on slowing the progression of motor degeneration in subgroups of Parkinson's patients suffering from the rapidly progressive form of the disease. Given that the MDS-UPDRS subscales may not show short-term changes associated with treatment, monitoring subgroups with the rapidly progressive form of Parkinson's disease could help improve the signal-to-noise ratio and reveal possible effects of monoclonal antibody treatment.

The PASADENA trial consisted of three treatments – placebo, 1,500 mg prasinezumab and 4,500 mg prasinezumab. Patients were randomly assigned to the three groups after stratification by age (over or under 60 years), gender, and use of monoamine oxidase B inhibitors. Patients who were taking other symptomatic Parkinson's medications such as dopamine agonists or levodopa at baseline were excluded. In cases where the use of these medications was considered mandatory, MDS-UPDRS scores were calculated before starting treatment.

The present study examined the effect of prasinezumab in patients who were receiving stable doses of monoamine oxidase B inhibitors at baseline and had other indicators of more rapid disease progression. The analyzes of the six primary prespecified subpopulations considered in phases I and II of the PASADENA study only included the results of four subpopulations.

Subpopulations were based on use of monoamine oxidase B inhibitors, stage 2 or Hoehn and Yahr versus stage 1 Parkinson's disease, those with and without REM sleep disorder or rapid eye movement disorder, and those with diffuse malignant phenotype versus nondiffuse malignant phenotype.

The analysis was also stratified into six exploratory subpopulations based on age, gender, disease duration, age at diagnosis, and motor subphenotypes such as tremor dominant versus akinetic rigid gait disorder or gait disorder with postural instability. Furthermore, since previous studies did not report a dose response, the two treatment groups consisting of 1,500 mg and 4,500 mg prasinezumab were combined for analysis.

Results

The results suggest that prasinezumab is more effective at slowing the progression of motor symptoms in Parkinson's patients with the rapidly progressive form of the disease. The subpopulation analyzes revealed that patients with diffuse malignant phenotypes or patients using monoamine oxidase B inhibitors at baseline, which are indicators of rapid disease progression, showed slower signs of motor degeneration than patients with phenotypes that did not indicate rapid disease progression of Parkinson's disease progression.

The MDS-UPDRS Part III score, which corresponds to physician-assessed motor signs, showed a slower increase or worsening of degeneration in prasinezumab-treated patients than in placebo-treated patients. Parts I and II of the MDS-UPDRS score correspond to patient-reported motor and non-motor signs, respectively.

The researchers believe that because the data indicated faster progression along MDS-UPDRS Part III compared to Parts I and II, Part III or physician-rated motor signs may precede the changes in Parts I and II. These results also suggest that longer observation periods are needed to accurately assess the potential effect of treatments such as prasinezumab.

Conclusions

Overall, the results suggest that the monoclonal antibody prasinezumab could potentially be used to slow the progression of motor degeneration in patients with the rapidly progressive form of Parkinson's disease. In addition, longer observation periods are required to observe the effect of prasinezumab treatment in patients with the slowly progressive form of the disease. Furthermore, additional randomized clinical trials need to further validate these results.

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