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Motor benefits for prasinezumab in rapidly progressing early-stage PD

By Lucy Piper, medwireNews Reporter

medwireNews: Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, has shown promise for slowing motor progression in patients with rapidly progressing Parkinson’s disease (PD) in a post-hoc analysis of the PASADENA phase 2 study.

The PASADENA study involved patients, aged 40–80 years, with idiopathic PD with bradykinesia and one other cardinal symptom. They were randomly assigned to receive prasinezumab, at a high dose of 4500 mg or a low dose of 1500 mg every 4 weeks, or placebo for 52 weeks.

Despite failing to meet its primary endpoint of a superior change from baseline in the sum of the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part I, II, and III scores with prasinezumab versus placebo, there was numerical evidence of a slowing in the progression of motor signs on the MDS–UPDRS Part III scale with prasinezumab.

Gennaro Pagano (University of Exeter Medical School, UK) and colleagues therefore carried out the current analysis to assess the effect of prasinezumab in patients from four primary and six exploratory subpopulations from the study who all had rapidly progressing disease, as measured on the MDS-UPDRS Part III, compared with their more slowly progressing counterparts.

The four primary subpopulations, which encompassed at least 20% of the modified intention-to-treat population, included: patients who were taking stable doses of monoamine oxidase (MAO)-B inhibitors at baseline versus those who were not; patients with Hoehn and Yahr stage 2 (bilateral involvement) versus 1 (unilateral); patients with versus without rapid eye movement (REM) sleep behaviour disorder (REM Behaviour Disorder Screening Questionnaire [RBDSQ] score ≥5 vs <5 points); and participants with diffuse malignant compared with nondiffuse malignant subphenotypes.

The mean MDS–UPDRS Part III score at baseline was 21.44 points among the pooled 211 patients given prasinezumab and 21.54 among the 105 given placebo.

Based on a hypothetical strategy assuming no changes in MAO-B inhibitor dose, the MDS-UPDRS Part III score at 52 weeks among patients taking MAO-B inhibitors at baseline worsened among the 38 patients given placebo, with an increase in score of 6.82 points from a mean 21.24 points at baseline.

This increase was significantly greater than the 4.15-points increase from 20.18 at baseline among the 77 patients given either dose of prasinezumab, giving a significant mean difference of 2.66 points and a 39% reduction in the risk of worsening with prasinezumab versus placebo. For the 67 placebo-treated and 134 prasinezumab-treated patients not taking MAO-B inhibitors, the mean difference was smaller at 0.87 points and a nonsignificant relative risk reduction of 17.3%.

For the 238 patients with Hoehn and Yahr stage 2, MDS-UPDRS Part III scores increased by a mean 3.76 points in those given prasinezumab and 6.34 points among those given placebo, giving a mean difference of 2.55 points and a significant 40.2% reduction in the risk for worsening. For the 78 patients with Hoen and Yahr stage 1, the opposite effect was seen, with prasinezumab associated with a significant 144.7% increase in relative risk, and mean increases in MDS-UPDRS Part III scores of 2.17 points with placebo versus 5.23 points with prasinezumab.

The relative risk reduction in worsening with prasinezumab compared with placebo was a nonsignificant 35.6% for the 85 patients who had REM sleep behaviour disorder and a nonsignificant 20.7% for the 230 who did not.

The biggest relative risk reduction with prasinezumab, of 64.0%, was seen for the 59 patients with the diffuse malignant subphenotype, with a 7.86-point difference compared with placebo, at mean increases of 12.29 points versus 4.39 points, respectively. For the 257 participants with the nondiffuse malignant subphenotype, the relative risk reduction with prasinezumab versus placebo was a nonsignificant 16.2%.

“These findings might suggest that prasinezumab slows the progression of motor signs in individuals with characteristics usually associated with more rapid progression within a 1-year timeframe,” the authors write in Nature Medicine.

The investigators note that the findings were similar when a treatment policy strategy was used, whereby the treatment effect on MDS-UPDRS Part III score was estimated irrespective of changes in MAO-B inhibitor treatment.

A greater effect with prasinezumab treatment than placebo was also seen in the six exploratory subpopulations, which compared rapid motor progressors with slow progressors according to age at baseline (≥60 years vs <60 years), disease duration (>12 months vs <12 months), age at diagnosis (≥60 years vs <60 years), and motor subphenotypes (akinetic–rigid and postural instability gait dysfunction vs tremor-dominant).

Overall, the subpopulations who progressed faster on MDS-UPDRS Part III with placebo than prasinezumab did not progress faster on MDS-UPDRS Parts I and II, observe Pagano et al.

“This may suggest that the progression of motor signs […] precedes notable changes in both motor and nonmotor symptoms,” say the investigators.

They suggest that “[m]uch longer studies may be required to test the effect of potential disease-modifying treatments, such as prasinezumab, on progression of patient-reported motor symptoms, functional activity of daily living and progression of nonmotor symptoms.”

Pagano and colleagues caution that their findings are exploratory and limited by the small sample sizes and the lack of correction for multiple comparisons, and therefore phase 2 randomized trials are needed.

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

This independent news story was supported by an educational grant from L’Institut Servier, Suresnes, France.

Nat Med 2024; 30: 1096–1103

Image credit: © Satjawat / stock.adobe.com

 

 

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