Background

UB-312 is an active vaccine to stimulate an immune response against α-synuclein. A 10-amino-acid fragment from the protein’s C-terminus is fused to a small peptide that activates T-helper cells, and combined with adjuvant for intramuscular injection. Vaxxinity is developing UB-312 for the α-synucleinopathies Parkinson’s disease and multiple system atrophy (MSA).

Antibodies to α-synuclein have been shown to prevent pathogenic α-synuclein spread and promote clearance of aggregates in animal models (Bae et al., 2012; Masliah et al., 2011). In guinea pigs, a 12-amino-acid predecessor of UB-312 elicited antibodies against toxic α-synuclein fibrils and oligomers, but not monomers. These antibodies bound synuclein inclusions in the substantia nigra and basal ganglia in postmortem brain tissue from people with PD, dementia with Lewy bodies, or MSA (Nimmo et al., 2020). In Line 61 transgenic mice that express human α-synuclein, UB-312 vaccination resulted in fewer α-synuclein oligomers in the cortex, hippocampus, and striatum three months later. Vaccinated mice did better at motor tests of walking on a beam and hanging from a wire. The vaccine also cleared α-synuclein from gut tissues (Nimmo et al., 2022).

Findings

In 2019, Phase 1 began with a dose-escalation study in 50 healthy people allocated to receive injections of 40 to 2,000 μg UB-312 or placebo at weeks 1, 5, and 13, in eight different dose groups. The vaccine caused a dose-dependent rise in blood and CSF α-synuclein antibodies, with three 300 μg doses generating a response in all volunteers. Higher dose cohorts were stopped after one participant developed severe flu-like symptoms. Doses up to 300 μg caused only minor side effects, including mild headache, cold-like complaints, fatigue, and pain or redness at the injection site. In CSF, the antibody concentration reached 0.2 percent of blood, on par with that reported for therapeutic monoclonal antibodies (Apr 2022 conference news; Yu et al., 2022).

The trial also enrolled 20 people ages 40 to 85 with early to mid-stage sporadic PD, who received three doses of 300 μg, or a 300/100/100 μg regimen of UB-312 or placebo on a 13-week schedule. Endpoints are safety, tolerability, and immunogenicity. Target engagement was measured by changes in total and free α-synuclein in the blood and CSF. An exploratory biomarker endpoint used protein misfolding cyclic amplification to measure pathogenic synuclein in the CSF before and after vaccination. In November 2022, the company reported that all patients had completed the injection series, and claimed the vaccine was well-tolerated, immunogenic, and generating detectable antibodies in CSF (press release). According to results presented at the March 2024 AD/PD conference, 12 of 13 vaccinated patients developed α-synuclein antibodies. The 300/100/100 μg regimen gave the highest titers in blood, and at that dose four of six patients had detectable antibodies in CSF. The elicited antibodies preferentially bound aggregated α-synuclein over monomeric species. After vaccination, seeded aggregation was reduced in CSF from vaccinated patients who had detectable CSF antibodies. These same patients had improvement in motor symptom scores on the MDS-Unified Parkinson’s Disease Rating Scale part II. Results were published after peer review (Eijsvogel et al., 2024).

In May 2023, investigators at New York University began a Phase 1b trial, whereby four patients with MSA and four with PD are receiving three priming and five booster injections of 300 μg UB-312 over two years. Outcomes are serum and CSF levels of anti-α-synuclein antibodies approximately six months after the last boost. The study is expected to run until April 2025.

For details on UB-312 trials, see clinicaltrials.gov.