Phase 1 Results Published in Nature Highlight Potential of Alpha-Synuclein-Targeted Therapy UB-312

Lou Reese

Recently, Vaxxinity published findings from its phase 1 study (NCT04075318) assessing UB-312, an active immunotherapeutic targeting pathological α-synuclein (αSyn) in patients with Parkinson disease (PD), the most common movement disorder worldwide. In Part B of the study, the agent met its primary prescpecified outcomes, with a time-dependent increase in anti-αSyn antibodies in both serum and cerebrospinal fluid (CSF) in treated participants.¹

In this randomized, double-blind, single-center study, 20 patients with PD were randomized 7:3 to placebo (n = 6), UB-312 300/100/100 ug (n = 7) or UB-312 300/300/300 ug (n = 7) treatment groups for a 44-week period. All told, UB-312 was deemed safe and well-tolerated with headache, local pain after lumbar puncture, and fatigue as the most common treatment-emergent adverse events (TEAEs). Most TEAEs were considered either mild or moderate after administration of the active therapy, comparable with placebo.

"The publication of this data in Nature Medicine immortalizes the profound impact of UB-312, leading the charge against the very core of Parkinson disease," Lou Reese, co-founder and executive chairman at Vaxxinity, said in a statement.¹ "It sparks a beacon of hope and anticipation for a future where Parkinson's no longer determines the trajectory of lives. This is more than just a scientific breakthrough; it's a battle cry for change, declaring that the status quo in Parkinson care is no longer acceptable."

Among UB-312-treated patients, only 1 in the 300/100/100 ug group met the definition for seroconversion. Epitope-specific anti-αSyn antibodies were also detectable in CSF, in a total of 5 of 13 participants who received all 3 doses; 4/6 in the 300/100/100 µg group and 1/7 in the 300/300/300 μg group. After peaking at week 21, CSF titers at week 45 were measurable in only 2 participants.

In the study, investigators reported 3 serious TEAEs, including a case of deep venous thrombosis on the left leg 50 days after the second administration of UB-312 300/100/100 ug. In this instance, the serious TEAE was considered possibly related to UB-312, mainly in part because of the timing of onset. In treated participants, there were no safety signals including electrocardiogram, vital signs, and blood and urine assessments.

On exploratory outcomes, investigators recorded stable scores on the Montreal Cognitive Assessment and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II and Part III, with no statistical differences between active and treated groups. Using postimmunization immunoglobulin fractions and affinity purified antibodies isolated from sera of healthy volunteers collected in Part A of the study, findings showed strong binding to aggregated αSyn and low binding to recombinant monomeric αSyn.

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After 45 weeks of treatment, longitudinal analyses showed a significant change in maximum fluorescence (F_max)(F = 6.622; CFB, 1.541-22.35; P = .009), with nonsignificant increases of 2.8% for placebo, significant 19.8% decrease (P <.05) for UB-312 (300/100/100 ug) and a nonsignificant 15.2% decrease for UB-312 (300/300/300 ug). Notably, there was 1 patient in the 300/300/300 ug group who was αSyn-SAA positive at baseline and end of treatment, but αSyn-SAA negative at the end of study.

A post-hoc analysis performed at week 21 revealed that reduction of F_max was more pronounced and statistically significant in those with detectable CSF antibody titers (n = 5) than those without (n = 13; time effect: F = 12.77; CFB, 1.73-26.82; P = .0002; treatment x time effect: F = 6.755; CFB, 2-31; P = .0037). Regardless of whether CSF antibodies were detectable, UB-312-treated patients showed significant differences from placebo in CSF levels of pS129-αSyn, further supporting the agent’s mechanism of action.

Despite no significant between-group changes in MDS-UPDRS-II and III, change from baseline on Part II of the scale indicated a statistically significant improvement in those with detectable CSF antibody titers compared with other patients (F = 12.94 (1.569–24.32), P = 0.0004; treatment × time effect: F = 4.739 (2–31), P = 0.016).

The study authors noted, "CSF antibodies could be detected using a titer assay; however, CSF antibody concentrations were all below the lower limit of quantification. A difference in processing or analysis method could potentially contribute to this discrepancy between the two assays. Either way, our results suggest that antibodies in CSF must reach detectable levels to have an effect on αSyn-SAA. Future dose optimization will be needed to achieve greater CSF antibody titer exposures and to confirm the effects of UB-312 on αSyn-SAA."²

REFERENCES
1. Vaxxinity UB-312 Parkinson’s trial results published in Nature Medicine. News release. Vaxxinity. June 20, 2024. Accessed July 8, 2024. https://www.globenewswire.com/news-release/2024/06/20/2901487/0/en/Vaxxinity-UB-312-Parkinson-s-Trial-Results-Published-in-Nature-Medicine.html
2. Eijsvogel P, Misra P, Concha-Marambio L, et al. Target engagement and immunogenicity of an active immunotherapeutic targeting pathological a-synuclein: a phase 1 placebo-controlled trial. Nature. Published online June 20, 2024. doi:10.1038/s41591-024-03101-8