Early Promise for Vaccine in Parkinson’s and MSA

PHILADELPHIA — The experimental vaccine UB-312 shows early promise in Parkinson’s disease (PD) and multiple system atrophy (MSA), results of a phase 1b study suggest.
“UB-312 immunization in participants with multiple system atrophy and Parkinson’s disease has been safe, well-tolerated, and is able to produce antibodies detectable in serum and cerebrospinal fluid,” said study investigator Patricio Millar Vernetti, MD, research instructor in the Department of Neurology, NYU Grossman School of Medicine, New York City.
The findings were reported at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
Antibodies in Serum and CSF
Alpha-synuclein is a soluble protein abundantly expressed in the brain that, in certain diseases, forms oligomers and fibrils that aggregate, creating Lewy bodies and neurites in PD as well as cytoplasmic and neuroglial cell inclusions in MSA, Millar Vernetti explained. 
UB-312 is a peptide-based active immunotherapy designed to induce antibodies that preferentially bind to the oligomeric and fibrillar forms of alpha-synuclein. 
In a mouse model of PD, immunization with UB-312 prevented declines in motor function and significantly reduced oligomeric alpha-synuclein accumulation in the brain and gut.
A recently published phase 1 trial in 20 patients with PD showed that UB-312 generated anti–alpha-synuclein antibodies in serum and cerebrospinal fluid and was well tolerated. One serious adverse event, a case of deep venous thrombosis that occurred 50 days after the second dose, was deemed possibly related to study drug and resolved without sequalae. 
Millar Vernetti pointed out that “participants who produced antibodies in the cerebrospinal fluid had an increase in the signal in alpha-nucleic seed amplification assays, which was interpreted as a positive sign of target engagement.”
‘An Interesting New Approach’
The ongoing phase 1b trial enrolled 4 patients with MSA and three patients with PD, at different stages, and divided them into two groups. The treatment-first group received three priming doses of UB-312 (weeks 0, 4, and 12), a placebo injection at week 16, and three UB-312 booster doses (weeks 24, 36, and 48). 
The placebo-first group received two placebo injections (week 0 and 4), followed by three priming doses of UB-312 (weeks 12, 16, and 24), and two UB-312 booster doses (weeks 36 and 48). 
Participants with MSA received 300 μg of UB-312 per dose, whereas those with PD received 600 μg per dose. 
The MSA participants were aged 43-65 years. Two had MSA-cerebellar subtype and one had MSA-parkinsonian type; their Schwab and England Activities of Daily Living Scale scores were 40%-100%; and disease duration was 1-7 years.
Participants with PD were aged 62-66 years, had Schwab and England Activities of Daily Living Scale scores of 70%-100%, and disease duration of 1-9 years.
Six patients reported 15 adverse events. These included headache, diarrhea, post–lumbar puncture headache, generalized joint pain, injection-site pain, low-grade fever, nausea, and loss of appetite. All events were mild to moderate in intensity and resolved, Millar Vernetti said.
“In terms of immunogenicity, we saw that all participants that received priming doses had detectable anti–alpha-synuclein antibodies in serum, even as early as 8 weeks when they’d received their second dose. At each time they received a booster dose, every 12 weeks, they still had detectable antibodies,” he stated. 
Anti–alpha-synuclein antibodies were clearly detectable in cerebrospinal fluid in three of four patients with MSA and two of three patients with PD at week 29, Millar Vernetti noted. 
Additional immunogenicity and safety analyses are pending through week 72, he said. Clinical outcomes and biomarkers are also being assessed as secondary endpoints. 
Commenting for Medscape Medical News, Per Svenningsson, MD, PhD, professor of neurology, Karolinska Institutet, Stockholm, Sweden, said, “It’s another new vaccine, and it seems that they have an interesting way of generating antibodies that target the oligomeric forms of alpha-synuclein that we think are pathological.”
“So, it could be better than some of the antibodies that have been tried earlier, which are more of a passive vaccination. This is an active vaccination, where you activate the immune system.”
Svenningsson pointed out that it is early and more data is needed, particularly on how UB-312 acts in the brain and if inflammation is present in brain tissue. “He didn’t present on that, but I think it’s an interesting new antibody approach,” he added.
Millar Vernetti reported that the investigator-initiated study was performed in collaboration with Vaxxinity, which is developing UB-312. Svenningsson reported no relevant conflicts of interest.
 
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