Novel Therapy Shows Significant Promise Slowing Parkinson Disease Progression

Image Credit: Adobe Stock Images/Dr_Microbe

Approximately 90,000 people are diagnosed with Parkinson disease (PD) in the United States each year. While there are a number of treatments on the market to support patients with PD, there currently are no approved disease-modifying therapies. In a study published in Nature, a Phase I clinical trial investigating the safety, tolerability and immunogenicity of UB-312—a novel, active immunotherapeutic—found that patients experienced considerable improvements in motor function and overall cognitive health.^1,2

The investigators noted that treatments targeting a toxic species of α-Synuclein—a presynaptic neuronal protein that has been associated genetically and neuropathologically with PD—seek to inhibit disease progression.

“Passive and active immunotherapies targeting αSyn (that is, delivery of monoclonal antibodies or vaccination to raise an endogenous immune response, respectively) can ameliorate αSyn pathology and functional deficits in mouse models of PD, and both approaches are now in clinical development, the study authors wrote. “These approaches have exhibited promising results in Phase I clinical trials. Two Phase II clinical trials recently failed to demonstrate efficacy of monoclonal antibodies against αSyn, but as was experienced in Alzheimer’s disease, early failure to demonstrate clinical efficacy does not necessarily invalidate the therapeutic target or investigational drug.”

The 44-week, randomized, placebo-controlled, double-blind, single-center Phase I clinical trial was conducted at the Centre for Human Drug Research in the Netherlands following the Declaration of Helsinki and Good Clinical Practice guidelines. Twenty participants were recruited and then randomly assigned into different treatment groups, including placebo and UB-312 regimens of either 300 μg in week one, followed by 100 μg in weeks five and 13 or 300 μg in weeks one, five, and 13. After trial commencement, there were no important protocol changes put into place.

The primary endpoint of the study was to evaluate the safety, tolerability, and immunogenicity of UB-312 in patients with PD. Secondary endpoints included changes in clinical scales related to PD, biomarker-based target engagement assessments using the αSyn seed amplification assay (αSyn-SAA), and cognitive assessments.

Results found as follows:

• In the UB-312 300/100/100 μg group, seroconversion was reported in 83.3% (five out of six) patients. Epitope-specific anti-αSyn antibodies in cerebrospinal fluid (CSF) were found in four out of six patients.
• In the UB-312 300/300/300 μg group, all seven participants experienced seroconversion. Epitope-specific anti-αSyn antibodies in CSF was only found in one patient.
• In the placebo group, the data didn’t specify seroconversion or epitope-specific anti-αSyn antibodies in CSF.

Of all participants, 20 received the first two injections, with 19 receiving the third due to a participant in the 300/100/100 μg cohort experiencing a serious adverse event (AE). Common AEs included headache, local pain after lumbar puncture, and fatigue. Overall, two patients experienced severe AEs. All patients treated with UB-312 experienced at least one AE, while five of the six in the placebo group experienced at least one AE.

In terms of limitations, the authors suggested that future studies should employ a higher number of participants. Additionally, all patients were on stable PD medication before enrolling in the trial and demographics of each group were comparable. While there currently isn’t an immunotherapy targeting αSyn approved by a regulatory body, a number studies featuring clinical data have been published for active and passive immunotherapies.¹

“In conclusion, this first-in-patient trial of an active immunotherapeutic targeting aggregated αSyn in patients with PD met its primary outcomes of safety, tolerability and immunogenicity,” wrote the authors of the study. “UB-312 was observed to safely overcome immune tolerance, inducing antibodies specific against pathological forms of αSyn and importantly able to cross the blood–brain barrier. The results are consistent with conclusions from Part A of the Phase I study and with preclinical studies. Together, these data support continued development of UB-312 as a disease-modifying treatment for PD. Future trials should focus on optimizing dose and antibody exposure in CSF over longer treatment periods, and further assess the safety and efficacy of UB-312 in synucleinopathies.”

References

1. Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial. Nature. June 20, 2024. Accessed June 20, 2024. https://www.nature.com/articles/s41591-024-03101-8 

2. Statistics. Parkinson’s Foundation. Accessed June 20, 2024. https://www.parkinson.org/understanding-parkinsons/statistics#:~:text=A%202022%20Parkinson's%20Foundation%2Dbacked,in%20the%20U.S.%20each%20year.