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The investigational monoclonal antibody prasinezumab (Roche; Prothena) fell short of achieving statistical significance for the primary endpoint of time to confirmed motor progression for early-stage Parkinson disease (PD) in the Phase IIb PADOVA trial (NCT04777331).1,2 However, investigators noted the drug showed potential efficacy by producing a numerical delay in motor progression, as well as positive trends across multiple secondary and exploratory endpoints.
“Parkinson’s is complex and devastating with no disease modifying treatment options available for the millions of people impacted,” Levi Garraway, MD, PhD, Roche chief medical officer and head of Global Product Development, said in a press release. “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’s community as we further evaluate the data to determine next steps.”1
Prasinezumab was developed to selectively bind aggregated α-syn and lower neuronal toxicity. Investigators have found that by targeting α-syn protein buildup in the brain, prasinezumab may be able to stop additional accumulation and spreading between cells to inhibit PD progression. The drug is currently under evaluation in open-label extensions (OLE) of the PADOVA trial and Phase II PASADENA trial.
An exploratory analysis of the PASADENA trial published in October 2024 in Nature Medicine found that patients with PD administered prasinezumab showed slower motor progression, as measured by the Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS–UPDRS) Part III in the OFF and ON medication states; as well as Part II across four years compared to an external comparator cohort taken from the Parkinson’s Progression Markers Initiative (PPMI) observational study and a mathematical model of PD progression.3
Approximately one million people in the United States are currently living with PD and 10 million people live with the disease worldwide, according to the Parkinson’s Foundation. Approximately 90,000 individuals in the United States are diagnosed with PD each year.4
Trial Design
The multicenter, randomized, double-blind PADOVA trial compared the efficacy and safety of prasinezumab vs. placebo in 586 patients with early-stage PD who were receiving stable doses of levodopa or monoamine oxidase-B inhibitor as monotherapy for more than three months at baseline. Patients were administered monthly intravenous doses of prasinezumab at a dose of 1500 mg or placebo every four weeks for at least 76 weeks, followed by a two-year ongoing OLE phase in which all patients are administered active treatment.
The primary endpoint is time to confirmed motor progression of PD measured by ≥5-point increase in MDS-UPDRS Part III score assessed in OFF medication state, with a five-point increase in MDS-UPDRS Part III representing a clinically meaningful motor progression event.
Trial Results
In a pre-specified analysis, investigators found that prasinezumab demonstrated potential clinical efficacy in the primary endpoint of time to confirmed motor progression with HR=0.84 [0.69-1.01] and p=0.0657, which fell short of statistical significance. They stated that the efficacy of prasinezumab was more prominent among patients who were treated with levodopa, representing 75% of participants, HR=0.79 [0.63-0.99].
Further, the study authors noted consistent positive trends across multiple secondary and exploratory endpoints. In terms of safety, prasinezumab was well tolerated, with no new safety signals reported.
Roche stated that both the PASADENA and PADOVA OLE trials will continue to analyze the observed effects across both studies, as they work with health authorities to determine next steps. Roche added that full results from the PADOVA trial will be presented at an upcoming medical meeting.
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 18, 2024. Accessed December 20, 2024. https://www.roche.com/media/releases/med-cor-2024-12-19
2. A Study to Evaluate the Efficacy and Safety of Intravenous Prasinezumab in Participants With Early Parkinson’s Disease (PADOVA). ClinicalTrials.gov. Updated October 22, 2024. Accessed December 20, 2024. https://clinicaltrials.gov/study/NCT04777331
3. 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. Nat Med 30, 3669–3675 (2024). https://doi.org/10.1038/s41591-024-03270-6
4. Statistics. Webpage. Parkinson’s Foundation. Accessed December 20, 2024. https://www.parkinson.org/understanding-parkinsons/statistics#:~:text=Nearly%2090%2C000%20people%20in%20the,are%20diagnosed%20before%20age%2050.