Prasinezumab is an investigative therapy for neurological conditions, developed through a partnership between Prothena Corporation and Roche. It is a monoclonal antibody, an engineered protein designed to interact with specific targets in the body.
Understanding Alpha-Synuclein in Parkinson’s
Parkinson’s disease is a progressive neurodegenerative disorder characterized by the loss of dopamine-producing neurons, primarily in a brain region called the substantia nigra. This neuronal degeneration links to the abnormal accumulation of alpha-synuclein. Normally, alpha-synuclein is a flexible protein in the brain, involved in synaptic vesicle transport and neurotransmitter release.
In Parkinson’s disease, however, alpha-synuclein misfolds and aggregates into insoluble clumps. These aggregates form Lewy bodies and Lewy neurites, hallmark pathological features observed in the brains of individuals with Parkinson’s disease. Their formation and spread contribute to progressive neuronal damage and death, causing motor and non-motor symptoms of the disease.
How Prasinezumab Interacts with Alpha-Synuclein
Prasinezumab is a humanized monoclonal antibody designed to target aggregated alpha-synuclein. Unlike existing symptomatic treatments for Parkinson’s, prasinezumab aims to address the underlying biological processes driving the disease. It selectively binds to pathological aggregates like insoluble fibrils and Lewy bodies, largely sparing the normal, monomeric form.
By binding to these aggregates, prasinezumab reduces their toxicity to neurons. This interaction prevents further accumulation and limits the spread of harmful protein clumps between brain cells. This targeted approach aims to slow or halt neuronal damage progression, impacting the disease course rather than just managing symptoms.
Results from Clinical Trials
Prasinezumab has been evaluated in Phase 2 clinical trials, including PASADENA and PADOVA, to assess its efficacy and safety. The PASADENA study was a multicenter, randomized, double-blind, placebo-controlled trial involving 316 participants with early-stage Parkinson’s disease, who received monthly intravenous doses of prasinezumab or placebo for 52 weeks. While PASADENA did not meet its primary endpoint (change in MDS-UPDRS total score at 52 weeks), exploratory analyses indicated promising signals. Participants treated with prasinezumab showed a slower progression of motor signs, as measured by MDS-UPDRS Part III. This effect appeared more pronounced in individuals with rapidly progressing disease phenotypes.
The Phase 2b PADOVA study investigated prasinezumab in 586 individuals with early-stage Parkinson’s disease, treated for at least 18 months while on stable symptomatic treatment. This study also did not achieve statistical significance for its primary endpoint (time to confirmed motor progression). However, PADOVA showed numerical delays in motor progression and consistent positive trends across multiple secondary and exploratory endpoints. A pre-specified analysis revealed that the effect of prasinezumab was more noticeable in the 75% of participants who were also being treated with levodopa. Across both studies, prasinezumab was well tolerated, with no new safety signals observed in the safety database, which includes data from over 900 participants, with more than 500 treated for 1.5 to 5 years.
Ongoing Development and Next Steps
Based on Phase 2 trial findings, including PASADENA, PADOVA, and their open-label extensions, Roche will advance prasinezumab into Phase 3 clinical development. This is a significant step in evaluating prasinezumab as a potential disease-modifying treatment for early-stage Parkinson’s disease. Phase 3 trials involve testing the drug in a larger number of people, often thousands, to further assess its effectiveness, safety, and side effects.
Ongoing open-label extension studies of PASADENA and PADOVA continue to gather long-term safety and efficacy data from over 750 participants. Roche will announce further details regarding the Phase 3 trial design and scope in the coming months. If successful, the results from these trials could potentially lead to regulatory approval, making prasinezumab one of the first medications to slow the progression of Parkinson’s disease.