Monoclonal antibody Prasinezumab shows promise in slowing rapid Parkinson's progression

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In a recent study published in the journal Nature Medicine, a large, international team of researchers conducted an exploratory analysis to evaluate whether the monoclonal antibody prasinezumab, which had previously been observed to be effective in slowing the progression of motor-associated signs of Parkinson’s disease, did indeed show benefits in subgroups of Parkinson’s disease patients with faster progression of motor degeneration.

Study: Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Image Credit: Naeblys / ShutterstockStudy: Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Image Credit: Naeblys / Shutterstock

Background

A hallmark of Parkinson’s disease is the aggregation of α-synuclein, which is thought to propagate between neurons and contribute to the pathogenesis of Parkinson’s disease. One of the first therapeutic options to target the aggregated α-synuclein was the monoclonal antibody prasinezumab, which was investigated in phase II clinical trials among patients with early-stage Parkinson’s disease who were part of the PASADENA study.

The primary endpoint of the phase II trials of the PASADENA study 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 along all the parameters of the MDS-UPDRS, compared to individuals treated with placebo, those who received prasinezumab showed slower progression of motor-associated degeneration. Furthermore, the team also believed that the MDS-UPDRS subscales are unlikely to show changes over short observation periods such as a year.

About the study

In the present study, the team examined the impact of prasinezumab on slowing motor degeneration progression in subgroups of Parkinson’s patients who had the rapidly progressing form of the disease. Given that MDS-UPDRS subscales might not show short-term changes associated with treatment, observing subgroups with the rapidly progressing form of Parkinson’s disease could help in improving the signal-to-noise ratio and reveal potential effects of the monoclonal antibody treatment.

The PASADENA study consisted of three treatments — placebo, 1,500 mg prasinezumab, and 4,500 mg prasinezumab. The patients were randomly assigned to the three groups after being stratified by age (above or below 60), sex, and monoamine oxidase B inhibitor use. Patients using other symptomatic Parkinson’s disease medications, such as dopamine agonists or levodopa at baseline, were excluded. In cases where the use of these medications was considered imperative, the MDS-UPDRS scores were calculated before the initiation of treatment.

The present study examined the impact of prasinezumab among patients who were on stable doses of monoamine oxidase B inhibitors at baseline and who exhibited other indicators of faster disease progression. The analyses of the six primary prespecified subpopulations included in phases I and II of the PASADENA study only included the results of four subpopulations.

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

The analysis was also stratified along six exploratory subpopulations based on age, sex, duration of disease, age at diagnosis, and motor subphenotypes such as tremor dominant versus akinetic rigid or postural instability gait dysfunction. Furthermore, since previous studies reported no dose response, the two treatment groups consisting of 1,500 mg and 4,500 mg prasinezumab were pooled for the analysis.

Results

The findings suggested that prasinezumab was more effective in slowing the progression of motor signs in Parkinson’s disease patients with the rapidly progressing form of the disease. The subpopulation analyses revealed that patients with diffuse malignant phenotypes, or those who were using monoamine oxidase B inhibitors at baseline, which are indicators of rapid disease progression, showed slower signs of motor-associated degeneration compared to the patients with phenotypes that did not indicate rapid progression of Parkinson’s disease.

The MDS-UPDRS part III score, which corresponds to clinician-rated motor signs, showed a slower increase or worsening of degeneration in the patients treated with prasinezumab than in those treated with a placebo. Parts I and II of the MDS-UPDRS score correspond to patient-reported motor and nonmotor signs, respectively.

The researchers believe that since the data indicated a faster progression along MDS-UPDRS part III compared to parts I and II, part III or clinician-rated motor signs might precede parts I and II changes. These findings also indicate that more extended observation periods are required to assess the potential effect of treatments such as prasinezumab accurately.

Conclusions

Overall, the results suggested that the monoclonal antibody prasinezumab could potentially be used to slow the progression of motor-associated degeneration in patients with the rapidly progressing form of Parkinson’s disease. Furthermore, more extended observation periods are required to observe the impact of prasinezumab treatment in patients with the slowly progressing form of the disease. Moreover, additional randomized clinical trials need to validate these findings further.

Journal reference:
  • Pagano, G., Taylor, K. I., Cabrera, A., Simuni, T., Marek, K., Postuma, R. B., Pavese, N., Stocchi, F., Brockmann, K., Svoboda, H., Trundell, D., Monnet, A., Doody, R., Fontoura, P., Kerchner, G. A., Brundin, P., Nikolcheva, T., Bonni, A., PASADENA Investigators, & Prasinezumab Study Group. (2024). Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Nature Medicine. DOI: 10.1038/s4159102402886y, https://www.nature.com/articles/s41591-024-02886-y
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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