Details Behind Potential Phase 2 Trial With UB-312 Alpha Synuclein Vaccine for Parkinson Disease

Jean-Cosme Dodart, PhD

In Parkinson disease (PD), α-synuclein (α-Syn) is believed to play a central role in the disease’s neuropathology and is a target considered for disease modification. UB-312 (Vaxxinity) is a synthetic α-Syn peptide conjugated to a T helper peptide. The vaccine is designed to induce antibodies that against specifically oligomeric and fibrillar αSyn. Therefore, UB-312 may be a potential immunotherapeutic for synucleopathies in diseases such as PD.¹

A previous randomized, placebo-controlled, double-blind study published in Movement Disorders investigated the safety, tolerability, and immunogenicity of the UB-312 vaccine in healthy participants (NCT04075318).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.

Jean-Cosme Dodart, PhD, senior author of the study and senior vice president of research at Vaxxinity, sat down with NeurologyLive® to talk about the results of UB-312 from the phase 1 trial. Dodart has been overseeing research at Vaxxinity for almost 5 years and with experience in the industry for more than 20 years working with various companies involved in mostly Alzheimer disease (AD) and PD. In his research, he has expanded across multiple types of central nervous disorders and is focused on neuroscience drug discovery.

NeurologyLive®: What are the key findings and significance of the phase 1 clinical trial for the alpha synuclein vaccine, UB-312, in healthy volunteers?

Jean-Cosme Dodart, PhD: We're excited about this approach to potentially help patients with PD and other patients with other synucleinopathies, like multiple system atrophy or dementia with Lewy bodies. We initiated a phase 1 clinical trial just before the pandemic, and got a bit delayed because of the pandemic. We managed to complete Part A of the clinical trial in healthy volunteers. Despite everything during the pandemic, we published the data in Movement Disorders last year, and we're excited about the results.

It was a trial very focused on the safety profile of our vaccine technology and the immunogenicity of UB-312. We were encouraged by the data, as you know α-synuclein is an endogenous protein. We had to induce while stimulating the immune system to produce antibodies against α-synuclein in a safe way, and we demonstrated that. The technology proved to be 100 % efficacious, at least in this patient population, breaking immune turnarounds in only individuals given 300 mcg. We did see high antibody titers in all those individuals. We've started to characterize the antibodies that have been produced by healthy volunteers. I think it's fantastic that the preclinical data that we produced are translated into clinical practice. The antibodies that were produced by humans were very comparable to the antibodies that were produced by preclinical species. They were recognizing mostly pathological α-synuclein and normal α-synuclein, which was encouraging.

What collaborations are you working on for utilizing these tools in clinical trials to assess target engagement?

At the moment, we are collaborating with the Michael J. Fox Foundation to address whether the α-synuclein seed amplification assay, which is a recently validated method that can detect pathological of forms of α-synuclein in biological fluids, could be applied to clinical trials to assess target engagement. Amprion, Michael J. Fox Foundation and other collaborators published a paper just last week in Lancet Neurology showing that it's an effective method to diagnose individuals with α-synucleinopathies. But it's not yet proven that we can address target engagement using this method. This is some work that we are working on in collaboration with Michael J. Fox Foundation, UT Health, a Houston, Mayo Clinic and Amprion. We are trying to tweak the assay to get more sensitivity and perhaps a clear quantitative assessment of pathological α-synuclein in biological fluids.

Once the pandemic was almost over and we got the green light to reinitiate the clinical trial, our focus was to try a couple of doses where the results obtained came from healthy volunteers and translate into PD. Again, it was mostly focused on addressing safety and immunogenicity in patients with PD. Recently, Vaxxinity has completed dosing patients with PD in Part B of the phase 1 trial of UB-312 and anticipates a data readout in summer 2023. But it's fair to say that we didn't have any complaints and no patient dropped out during the clinical trial.

What did the preliminary results from the trial with UB-312 indicate and what implications does the data have for future research and treatment options?

The preliminary data that we generated halfway through the clinical trial indicated that we do see immunogenicity in patients with PD as well. We're very encouraged with the results that we've generated so far and are planning a phase 2 clinical trial in patients with Parkinson disease. We would love to collaborate with potential partners to address a significant patient population and make sure that we give this vaccine the best chance of success and hopefully, the best choice for treatment in patients with PD. It’s not an easy task to design a phase 2 clinical trial and as we know, we have the same situation happening with our research in an AD vaccine.

We know that those individuals with neurodegenerative disorders start losing their neurons way earlier on, and the earliest that we can intervene and the best it is for the patients. At the moment, clinical trials have the most difficult task in identifying individuals at the very early stages of those disorders, although there's been a lot of effort across the field to better address this. Also, photomultiplier tubes are bringing to the table an amazing tool to better identify patients that might be in the prodromal stages of the disease and perhaps could already participate in clinical trials. As I was mentioning, the earlier we intervene, the better chance for the patients to live a higher quality of life.

Transcript edited for clarity.

REFERENCES
1. 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
2. Vaxxinity Reports Fourth Quarter and Full-Year 2022 Financial Results and Provides Corporate Updates. News Release. Vaxxinity. Published March 27, 2023. Accessed May 11, 2023. https://ir.vaxxinity.com/news-releases/news-release-details/vaxxinity-reports-fourth-quarter-and-full-year-2022-financial