Parkinson's disease (PD) lacks approved disease-modifying therapies. α-synuclein (αSyn) aggregation is a key pathological feature. Immunotherapies targeting αSyn, both passive (monoclonal antibodies) and active (vaccination), show promise in preclinical models. However, recent phase 2 trials of monoclonal antibodies failed, highlighting the need for improved trial design and biomarkers of target engagement. UB-312, a novel active immunotherapeutic, utilizes a synthetic T-helper peptide linked to target epitopes, aiming to induce a humoral antibody response without T cell-mediated cytotoxicity. Preclinical data demonstrate high immunogenicity and selective targeting of pathological αSyn forms. Part A of this phase 1 study, in healthy volunteers, demonstrated UB-312's safety and immunogenicity. Part B, detailed here, evaluated safety, tolerability, immunogenicity, and target engagement (using αSyn seed amplification assay; αSyn-SAA) in PD patients.

Extensive research points to the role of αSyn aggregation in PD pathogenesis. Mutations in αSyn are rare, but Lewy bodies (LBs), composed of αSyn aggregates, are a hallmark of the disease. Preformed αSyn fibrils can induce LB-like inclusions and cellular dysfunction. This strongly suggests that targeting pathological αSyn is a viable therapeutic strategy. Passive and active immunotherapies targeting αSyn have shown promise in preclinical models, leading to clinical development. However, the recent failure of two phase 2 clinical trials of monoclonal antibodies targeting αSyn highlights the importance of appropriate trial design, including patient selection, clinical scales, and biomarkers to assess target engagement. The success of amyloid PET imaging in Alzheimer's disease trials demonstrates the value of such biomarkers.

This phase 1, single-center, randomized, double-blind, placebo-controlled trial (Part B) enrolled 20 participants with PD (Hoehn and Yahr stage ≤III). Participants were randomized 7:3 to UB-312 (300/100/100 µg or 300/300/300 µg intramuscular prime-boost regimens) or placebo. Safety and tolerability were assessed through adverse event monitoring, physical and neurological examinations, ECGs, and blood and urine tests. Immunogenicity was evaluated by measuring anti-αSyn antibody titers in serum and CSF. Target engagement was assessed using the αSyn-SAA, an exploratory biomarker. Clinical efficacy was evaluated using the Montreal Cognitive Assessment (MoCA) and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Statistical analyses included descriptive statistics, seroconversion rates, and ANOVA for exploratory outcomes. Samples from a prior healthy volunteer study (Part A) were used for some biomarker analyses. Antibody purification techniques, including protein A purification and affinity purification, were employed.

UB-312 was generally safe and well-tolerated in PD patients. Adverse events were mostly mild and transient, comparable between UB-312 and placebo groups. Immunogenicity was confirmed by a time-dependent increase in anti-αSyn antibodies in serum and CSF of UB-312-treated patients. Seroconversion rates were high (12/13 participants receiving all three UB-312 doses). Serum antibody titers peaked at week 29 and remained elevated at week 45. CSF antibody titers were lower but detectable in several patients. Exploratory analyses using αSyn-SAA revealed a significant reduction in αSyn seeds in the CSF of a subset of UB-312-treated patients, particularly those with detectable CSF antibody titers. This reduction was associated with a significant improvement in MDS-UPDRS Part II scores in these patients. No significant differences were observed in MoCA or MDS-UPDRS Part III scores between groups.

This study demonstrates that UB-312 is safe, well-tolerated, and immunogenic in PD patients, inducing antibodies that cross the blood-brain barrier. The observation of reduced αSyn seeds in CSF and improvement in MDS-UPDRS Part II scores in patients with detectable CSF antibodies strongly suggests target engagement. While the study lacked power to detect differences between UB-312 dose regimens, findings suggest that a high prime dose followed by lower boost doses might be more immunogenic. The use of αSyn-SAA as a biomarker of target engagement provides a promising approach for future clinical trials. Differences in antibody levels between healthy volunteers and PD patients may be due to comorbidities, immune system compromise, or target-mediated clearance in the presence of aggregated αSyn.

This phase 1 trial shows that UB-312 is a safe and immunogenic active immunotherapeutic that engages its target in patients with PD. The observed reduction in αSyn seeds and improvement in a motor function subscale of the MDS-UPDRS in patients with detectable CSF antibody titers warrants further investigation in larger, longer-term trials focused on dose optimization and efficacy assessment. Future studies should explore various dosing regimens and the correlation between CSF antibody levels and clinical outcomes.

The small sample size limits the generalizability of findings and the statistical power to detect differences between dose groups or subtle clinical changes. The exploratory nature of the αSyn-SAA assessment and the lack of validated quantitative measures for this assay also limit the interpretation of the results. Differences in immune response and antibody clearance between healthy volunteers and PD patients requires further investigation.