Target Engagement of UB-312 in Parkinson’s Disease Patients: Insights from CSF Analysis

• UB-312 represents a promising avenue in Parkinson’s disease (PD) treatment by focusing on pathological forms of alpha-synuclein (aSyn), a key protein associated with the progression of synucleinopathies. Unlike conventional approaches, UB-312 aims to elicit antibodies that specifically recognize and neutralize these harmful forms of aSyn, potentially halting or slowing the neurodegenerative processes underlying PD
• The Phase I trial revealed that UB-312 was immunogenic in both healthy volunteers and Parkinson’s disease patients. This suggests that the investigational active immunotherapy has the ability to stimulate the immune system to produce an antibody response against pathological forms of alpha-synuclein (aSyn), laying the groundwork for its potential efficacy in treating and preventing synucleinopathies

Vaxxinity, Inc. presented compelling findings at the 2024 American Academy of Neurology conference regarding the investigational active immunotherapy UB-312. The study aimed to investigate target engagement in cerebrospinal fluid (CSF) samples of PD patients using the Amprion R&D aSyn seed amplification assay (aSyn-SAA).

In this Phase I study, 20 PD patients with unknown aSyn-SAA status were enrolled and randomly assigned to receive either placebo or UB-312. Treatment was administered intramuscularly on weeks 1, 5, and 13, with patients followed up until week 45. CSF samples were collected at baseline, week 21, and week 45 and analyzed using the aSyn-SAA over 24 hours. The kinetics of aSyn amplification, including maximum fluorescence (Fmax), were assessed.

Of the 20 patients, 19 tested positive for aSyn seeds at baseline and week 21. Interestingly, one patient no longer met the criteria for aSyn seed positivity at week 45 after receiving UB-312 treatment. Longitudinal analysis revealed a significant change in mean Fmax from baseline, with placebo showing a 2.8% increase, while patients treated with UB-312 exhibited decreases of 19.8% (300/100/100μg dose) and 15.2% (300/300/300μg dose) at week 45. Posthoc analyses further demonstrated a significant decrease in Fmax by week 45 in patients with detectable UB-312 antibodies in CSF at week 21 compared to those without detectable CSF antibodies.

Conclusion

The data presented by Vaxxinity, Inc. suggest successful target engagement of UB-312 in the CSF of several treated PD patients. These promising results support further development of UB-312 as a potential therapeutic option for synucleinopathies. Dosing optimization and trials involving a larger patient population will be essential to confirm and expand upon these findings, paving the way for potential disease-modifying treatments for PD and related disorders.