A Randomized First‐in‐Human Study With UB‐312, a UBITh® α‐Synuclein Peptide Vaccine

Abstract

A BS TRACT: Background: α-Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB-312 a potential immunotherapeutic for synucleopathies. Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study. Methods: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, doubleblind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 μg). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-αSyn antibody concentrations. Results: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose-and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 μg UB-312 dose regimen. The average CSF/serum ratio was 0.2%. Conclusions: UB-312 was generally safe, well tolerated, and induced anti-αSyn antibodies in serum and CSF of healthy participants. The 100 and 300 μg doses are selected for further evaluation in participants with PD.

The safety and effectiveness of α-synuclein immunotherapy vs. placebo for the treatment of Parkinson’s disease: a systematic review and meta-analysis

“…Titles and abstracts were checked before 83 articles were screened out. Finally, a total of 6 RCTs were included after a full-text review (19,20,(22)(23)(24)(25). Figure 1 depicts the literature screening process.…”

Alpha-synuclein Immunization Strategies for Synucleinopathies in Clinical Studies: A Biological Perspective

“…Very recently, the results of a safety and tolerability phase I trial 50 eligible healthy individuals were published. UB-312 was generally safe and well-tolerated and showed a positive seroconversion of 91.3% in all participants, which was highest in the high-dose recipients, and in CSF titers [ 102 ]. A phase Ib study in PD patients is currently planned.…”

“…NCT04075318 (completed) Phase I Part A in healthy individuals, PART B in PD patients (H&Y ≤ III). NCT04075318 (Active, not recruiting) Heterologous T-helper cell epitope linked directly or through a heterologous spacer to a B-cell epitope; epitope: C-terminal region of α-syn within aa G 111–D 135 (suggested by preclinical data) [ 99 , 100 , 101 , 102 ] …”

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases

“…Similarly, peptide-based vaccines employing specific epitopes or peptides that mimic the structure of epitopes (mimotopes) are currently being developed to prevent and/or treat NDDs by harnessing the activity of the immune system (active immunization) [ 35 , 36 , 37 ]. As an example, in recent years a variety of vaccine designs for NDDs have been described, including MultiTEP-based vaccines, virus-like particle (VLP)-based vaccines, DNA-based vaccines, modified vaccinia virus Ankara (MVA) poxvirus-based vaccines, and synthetic peptide vaccines [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”