UB-312 Meets Primary Objectives in Phase 1 Trial for Parkinson Disease

Geert Jan Groeneveld, MD, PhD

In recent news, Vaxxinity announced positive results from Part B of its phase 1 placebo-controlled, double-blind clinical trial (NCT04075318) of UB-312, an investigational vaccine for Parkinson disease (PD), demonstrating in the results that the vaccine met the primary objectives of the study. These findings suggest that UB-312 is a well-tolerated therapy and successfully induces anti-α-synuclein (α-Syn) antibody responses in patients with early PD.¹

Among 13 patients with PD who completed dosing with UB-312, 92% had developed anti-α-Syn antibodies, meeting the primary objective. Notably, antibodies were also observed in the cerebrospinal fluid (CSF) of patients and the therapy had an overall adverse event profile similar across the vaccine-treated and placebo-treated group.

“These positive phase 1 results demonstrate several important features necessary for an immunotherapy against PD and other synucleinopathies to be successful, and represent a further proof-of-principle for Vaxxinity’s platform in chronic disease,” Mei Mei Hu, JD, chief executive officer of Vaxxinity, said in a statement.¹ “UB-312 was observed to safely break immune tolerance, inducing antibodies against toxic aggregated forms of α-Syn. Importantly, these antibodies crossed the blood brain barrier, and the data also suggest potential target engagement in the periphery, where pathological α-Syn is known to be concentrated. Together these results support the further development of UB-312 in a phase 2 clinical trial. We continue to view UB-312 as a promising candidate for the prevention or disease modification of Parkinson disease globally.”

The phase 1 trial of UB-312, conducted at the Centre for Human Drug Research (CHDR) in the Netherlands, consisted of two parts. Following Part A, Part B explored the safety, tolerability and immunogenicity by using 2 doses of UB-312 compared with placebo in 20 age-matched patients with early PD for 20 weeks, followed observation for 24 weeks. This trial had exploratory measures of PD progression included such as parts 2 and 3 of the Unified Parkinson Disease Rating Scale (UPDRS), and the Montréal Cognitive Assessment. It was noted in a statement that these measurements were not designed or powered for detecting the differences between UB-312 and placebo.¹

"We are very pleased that UB-312 met the primary objectives of the trial. This is an important proof-of-principle for Vaxxinity's platform in chronic diseases and something we hope can one day benefit people with Parkinson disease around the world. Patients with Parkinson disease currently have limited options for treatment, most of which are designed only to ease symptoms, and with UB-312, we are trying to develop a therapy that can address some of the root causes to potentially treat or even prevent Parkinson disease," Jean-Cosme Dodart, PhD, senior vice president of research at Vaxxinity, told NeurologyLive®.

Although the 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 had previously demonstrated that UB-312 was highly immunogenic and generally well-tolerated in healthy volunteers, and we now confirm that UB-312 is also immunogenic and generally well-tolerated in individuals with early Parkinson disease. Overall, these results are very encouraging because we now have evidence that UB-312 can target toxic alpha-synuclein that is aggregating in peripheral tissues and in the brain," Dodart said. "These results support the continued clinical development of UB-312 for the prevention or disease modification of Parkinson's disease and we look forward to moving ahead with a phase 2 clinical trial."

Part A of the trial investigated the safety, tolerability, and immunogenicity of the UB-312 vaccine in healthy participants.² Among 50 healthy participants enrolled, 23 received all three 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 cerebrospinal fluid (CSF) (average CSF/serum ratio, 0.2%). For 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.¹

“A vaccine against alpha-synuclein is a revolutionary concept that can be of immense impact in treating neurodegenerative diseases such as Parkinson’s disease and synucleinopathies,” Geert Jan Groeneveld, MD, PhD, professor of clinical neuropharmacology at Leiden University Medical Center and principal investigator of the phase 1 trial said in a statement.¹

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

In other news, there is a 2-year project funded by The Michael J. Fox Foundation (MJFF) that will use the CSF collected from patients who participated in Part B of the trial that will be done through the collaboration of Vaxxinity, the Mayo Clinic, and the University of Texas Houston. This research will investigate the potential of protein misfolding cyclic amplification (PMCA), assessing target engagement and also will aim to identifiy the anti-aSyn antibodies created post administration of UB-312.¹

REFERENCES
1. Vaxxinity Announces UB-312 Successfully Met Primary Objectives of Phase 1 Clinical Trial in Parkinson’s Disease. News Release. Vaxxinity. Published June 22, 2023. Accessed June 22, 2023. https://www.globenewswire.com/en/news-release/2023/06/22/2692878/0/en/Vaxxinity-Announces-UB-312-Successfully-Met-Primary-Objectives-of-Phase-1-Clinical-Trial-in-Parkinson-s-Disease.html
2. Yu HJ, Thijssen E, van Brummelen E, et al. A Randomized First-in-Human Study With UB-312, a UBITh® α-Synuclein Peptide Vaccine. Mov Disord. 2022;37(7):1416-1424. doi:10.1002/mds.29016