Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial.
Level 2 - randomized trial
Individual randomized, double-blind, placebo-controlled clinical trial
PubMed 38902546 · doi:10.1038/s41591-024-03101-8
What was done
In a 44-week, double-blind, single-center phase 1 trial, 20 patients with Parkinson's disease were randomized (7:3 UB-312:placebo) into two intramuscular prime-boost dosing cohorts: 300/100/100 μg or 300/300/300 μg at weeks 1, 5, and 13. The primary outcomes evaluated safety, tolerability, and anti-α-synuclein (αSyn) antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes evaluated clinical rating scales and biomarker-based target engagement via αSyn seed amplification assays in CSF.
What was found
Safety profiles were similar across groups, with predominantly mild and transient adverse events; three serious adverse events occurred in two patients (one possibly treatment-related), all resolving without sequelae. Anti-αSyn antibodies developed in serum in 12 of 13 patients and in CSF in 5 of 13 patients who completed all three UB-312 doses. Mean serum log-dilution antibody titers increased from baseline by 1.398 (peaking at 2.520 at week 29) in the 300/100/100 μg group and by 1.354 (peaking at 2.133) in the 300/300/300 μg group. Mean CSF titers rose from 0 at baseline to 0.182 and 0.032 at week 21 in the respective groups. Exploratory clinical scales showed no statistically significant differences, but a significant reduction in CSF αSyn seeds was detected in a subset of UB-312-treated patients.
Why it matters
This trial demonstrates the feasibility and early target engagement of an active immunotherapeutic vaccine targeting pathological α-synuclein in Parkinson's disease, supporting progression to larger phase 2 trials.
Limits
The study had a very small sample size (n=20), was conducted at a single center, and was not powered to detect clinical efficacy or long-term disease modification. Target engagement on seed amplification assays was observed only in a subset of treated patients.
Cited by
- supports Vaxxinity has developed an alpha-synuclein targeting vaccine for Parkinson's disease that has completed Phase 1 and entered Phase 2 clinical trials.