Parkinson Agent Prasinezumab Misses Primary End Point But Shows Positive Effects in Other Outcomes

Levi Garraway, MD, PhD

In newly announced data from the phase 2b PADOVA study (NCT04777331), treatment with investigational prasinezumab (Roche) did not meet its primary end point of time to confirmed motor progression in patients with Parkinson disease (PD); however, the treatment was safe, and showed positive trends on multiple secondary and exploratory end points. Full results from PADOVA are expected to be presented at an upcoming medical meeting.¹

Prasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein and inhibit the intercellular spread of pathogenic α-synuclein, thus protecting neurons and slowing PD progression. In PADOVA, prasinezumab failed to demonstrate statistical significance vs placebo on the primary end point of time to confirmed motor progression (HR, 0.84; 95% CI, 0.69-1.01) after 18 months; however, the effect of the agent was more pronounced among patients treated with levodopa (HR, 0.79; 95% CI, 0.63-0.99), which accounted for 75% of the participants included.

"Parkinson is complex and devastating with no disease modifying treatment options available for the millions of people impacted,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, said in a statement.¹ "We believe the consistent efficacy trends from the Phase IIb study of prasinezumab merit further exploration. We will continue our close collaboration with the Parkinson community as we further evaluate the data to determine next steps."

In PADOVA, a total of 575 patients with early-stage PD were randomly assigned to placebo or prasinezumab 1500 mg, dosed every 4 weeks for 18 months, followed by a 2-year open-label extension. Patients were between 50-85 years old, had idiopathic PD, Hoehn and Yahr stage 1 or 2, MDS-UPDRS Part IV score of 0, and on a stable dose of monoamine oxidase type B inhibitor or levodopa for at least 3 months prior to baseline. The study excluded those with a Parkinsonian syndrome other than idiopathic PD, a diagnosis of PD dementia, or if you were previously treated with dopamine agonists.

While prasinezumab did not meet its primary end point, it did show promising effects on other secondary and exploratory outcomes. In PADOVA, these included time to worsening of motor functioning, time to meaningful worsening on Clinical Global Impression of Change scales, change in MDS-UPDRS Part III, and change in Digital Health Tool-derived measures. Additionally, the study also looked at change in MDS-UPDRS Part II, Part IV, MDS-sponsored Nonmotor Symptoms Rating Scale, Montreal Cognitive Assessment, and Schwab and England Activities of Daily Living Scale.

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Prasinezumab is currently being assessed in ongoing open-label extensions of PADOVA, as well as another phase 2 study, PASADENA (NCT03100149). Results from an exploratory analysis of PASADENA recently published in Nature suggested that prasinezumab may slow motor progression in PD over a long-term period. In the analysis, investigators compared participants enrolled in the PASADENA open-label extension with those enrolled in an external comparator arm derived from the Parkinson’s Progression Markers Initiative observational study,

Results showed that the PASADENA delayed-start (n = 94) and early-start (n = 177) groups showed a slower decline in MDS-UPDRS Part III scores in the OFF state (delayed-start: –51%; early start: –65%), ON state (delayed-start: –94%; early-start: –118%), and MDS-UPDRS Part II (delayed-start: –48%; early-start: –40%) than did the PPMI external comparator (n = 303). After four years, the PASADENA study groups (delayed- and early-start) showed less progression in MDS-UPDRS Part I total scores compared to the PPMI cohort. The PASADENA groups had mean progressions of 6.28 and 6.39 points, respectively, versus 8.34 points in the PPMI cohort.

In the study, PASADENA early- and delayed-start groups demonstrated significantly lower sleep-related progression (items 7 and 8), with a 47% relative reduction in the delayed-start group and a 61% reduction in the early-start group. However, there was no significant difference in fatigue progression (item 13) between the PASADENA and PPMI groups. After four years, the delayed-start group had a mean difference of −0.11 points, while the early-start group had a mean difference of −0.06 points, both showing minimal change.

REFERENCES
1. Roche’s Phase IIb study of prasinezumab missed primary endpoint, but suggests possible benefit in early-stage Parkinson’s disease. News release. Roche. December 19, 2024. Accessed December 20, 2024. https://www.globenewswire.com/news-release/2024/12/19/2999515/0/en/Roche-s-Phase-IIb-study-of-prasinezumab-missed-primary-endpoint-but-suggests-possible-benefit-in-early-stage-Parkinson-s-disease.html
2. Pagano G, Monnet A, Reyes A, et al. Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial. Nature. 2024;30:3669-3675. doi:10.1038/s41591-024-03270-6