Prasinezumab is an investigational humanized monoclonal antibody designed to target aggregated α-synuclein, a protein centrally involved in the pathogenesis of Parkinson's disease (PD). By binding to these aggregates, prasinezumab may reduce neurotoxicity and potentially modify the course of the disease.

Mechanism of Action

Prasinezumab selectively binds to aggregated, pathogenic forms of α-synuclein. This binding is believed to inhibit the intercellular propagation of α-synuclein and facilitate its degradation via lysosomal pathways. Preclinical data suggest that such activity may attenuate neuronal damage and support cellular clearance mechanisms.

Clinical Development

Preclinical Studies:
In animal models of Parkinson's disease and dementia with Lewy bodies, the murine analog of prasinezumab (9E4) was shown to reduce levels of neurotoxic, C-terminally truncated α-synuclein. These studies demonstrated decreased pathological propagation and improvements in behavior and motor function.

Phase 1 Trials:
Early-phase human trials confirmed the safety of prasinezumab, its ability to cross the blood-brain barrier, and its pharmacodynamic effects, including a reduction in serum free α-synuclein levels in both healthy individuals and PD patients.

PASADENA Study (Phase 2):
A randomized, double-blind, placebo-controlled trial evaluated prasinezumab over 52 weeks in early-stage PD, followed by a blinded 52-week extension. Although the primary endpoint-change from baseline in the combined MDS-UPDRS I, II, and III scores-was not met, prasinezumab showed a trend toward slowing motor progression (Part III). Exploratory subgroup analyses indicated enhanced benefits in patients with faster disease progression.

PADOVA Study (Phase 2b):
This trial assessed prasinezumab in early-stage PD patients receiving stable symptomatic therapy. The primary endpoint-time to confirmed motor progression (≥5-point increase in MDS-UPDRS Part III in the OFF-medication state)-was not met. However, a numerical delay in progression was observed, particularly in patients also treated with levodopa.

Safety Profile

Across studies, prasinezumab has been generally well tolerated. Common adverse events include infusion-related reactions, skin irritation, nausea, chills, and fluctuations in blood pressure. No new safety signals have been identified in recent trials.

Clinical Implications

Although prasinezumab has not achieved primary endpoints in pivotal studies, emerging evidence points to potential disease-modifying effects, especially in patients with rapidly progressive PD or those on concurrent levodopa therapy. Ongoing open-label extensions of the PASADENA and PADOVA trials aim to further clarify its long-term efficacy and safety.

Conclusion

Prasinezumab offers a novel and targeted approach to Parkinson's disease by intervening in α-synuclein pathology. While definitive clinical efficacy remains under investigation, the therapeutic rationale and preliminary findings suggest it may have a meaningful role in modifying disease progression in selected patient populations.