Phase 1 trial results investigating UB-312 revealed target engagement of aggregated alpha-synuclein in cerebrospinal fluid of patients with Parkinson disease, providing validation of the vaccine technology to selectively target aggregated, toxic forms of neurodegenerative proteins.
In recent news from the phase 1 trial (NCT04075318), findings showed that antibodies derived from UB-312 (Vaxxinity), an investigational immunotherapeutic for Parkinson disease (PD), slowed seeding of alpha-synuclein (α-Syn) in cerebrospinal fluid (CSF) of patients with the disease using multiple target engagement assays.1 These results suggest that UB-312 has created a clear target engagement, providing further validation of the vaccine technology to be an effective treatment in neurodegenerative diseases.
In PD, α-Syn is believed to play a key factor in the disease’s neuropathology and is a target considered for disease modification. UB-312, a synthetic α-Syn peptide conjugated to a T helper peptide, is designed to induce antibodies that against specifically oligomeric and fibrillar αSyn. Hence, the vaccine may be a potential immunotherapeutic for synucleopathies in diseases such as PD.2
“This is a major milestone for Vaxxinity in our quest to help patients with PD. Our candidate has shown target engagement of the toxic species of alpha-synuclein in patients, demonstrating not only proof of our technology platform, but also proof of the mechanism of our vaccine-derived antibodies specifically engaging with the toxic target in vivo,” Mei Mei Hu, JD, CEO of Vaxxinity, said in a statement.1 “Showing target engagement has always been a key challenge to overcome in neurodegeneration, and is of critical importance when demonstrated – a milestone worth celebrating. It is beyond our expectation to see this in our phase 1 trial. We are endlessly grateful to the patients who participated, and to The Michael J. Fox Foundation and our collaborators for their work on these cutting-edge assays that supported this breakthrough.”
Conducted at the Center for Human Drug Research (CHDR) in the Netherlands, the phase 1 trial of UB-312 consisted of 2 parts. Following Part A, Part B investigated the safety, tolerability and immunogenicity of 2 doses of UB-312 compared with placebo in 20 age-matched patients with early PD for 20 weeks, followed by an observation period for 24 weeks. The trial had exploratory measures of PD progression, including parts 2 and 3 of the Unified Parkinson Disease Rating Scale (UPDRS), and the Montréal Cognitive Assessment. In a statement, it was noted that these measurements were not designed or powered for detecting the differences between UB-312 and placebo.2
"This is a major milestone for Vaxxinity as we work to bring new treatment and preventive options to patients with Parkinson or other synucleinopathies. These results go beyond our expectations particularly for a phase 1 trial. The data are promising, as we have successfully shown that antibodies derived from our investigational vaccine UB-312 successfully target toxic aggregated alpha-synuclein," Jean-Cosme Dodart, PhD, senior author of the study and senior vice president of research at Vaxxinity, told NeurologyLive®. "This is truly exciting because the antibodies not only penetrate the blood-brain barrier but are also detectable in cerebrospinal fluid, which are important features for an immunotherapy for PD and other synucleinopathies to work. These findings support our UB-312 candidate for Parkinson and strengthen our confidence in our technology platform, which is also targeting other chronic diseases such as Alzheimer disease, hypercholesterolemia and migraine."
In Part A of the trial, researchers investigated the safety, tolerability, and immunogenicity of the UB-312 vaccine in healthy participants. Among 50 healthy participants enrolled, 23 received all 3 intramuscular doses of UB-312 at weeks 1, 5, and 13 (doses ranging between 40 and 2000 μg). In the participants receiving the 300/300/300 μg UB-312 dose regimen, antibodies were detectable in serum and CSF (average CSF/serum ratio, 0.2%). Upon further evaluation, the 100- and 300-μg doses were selected for participants with PD. These results, published in Movement Disorders, suggest that the vaccine is highly immunogenic, as all patients dosed with it showed detectable anti-α-Syn antibodies in both serum and CSF.3
In June 2023, UB-312 yielded positive results from Part B of the phase 1 placebo-controlled, double-blind clinical trial, with the vaccine meeting its primary objectives of the study. Among 13 patients with PD who completed dosing with UB-312, 92% had developed anti-α-Syn antibodies. Notably, antibodies were also observed in the CSF of patients and the therapy had an overall adverse event profile similar across the vaccine-treated and placebo-treated group. Although findings revealed that UB-312 was generally safe and well-tolerated, there were 2 patients with PD who experienced serious adverse events (SAEs). Additionally, there was only 1 adverse event that was considered possibly related to the trial, and all SAEs experienced by patients were resolved.
"We plan to continue analyzing the clinical data as part of the collaborative project funded by The Michael J. Fox Foundation (MJFF). This two-year project involves Vaxxinity, the Mayo Clinic, and UTHealth Houston. We have already gained valuable insights from this analysis, which shed light on the characteristics of anti-alpha synuclein antibodies induced by UB-312 during the phase 1 trial. Moving forward, we will conduct more analysis, including additional antibody characterization studies to explore binding kinetics and specificity. We will eventually want to confirm these promising results in an upcoming phase 2 trial for UB-312," Dodart told.