Safety and Tolerability of Active Immunotherapy Targeting α-Synuclein with PD03A in Patients with Early Parkinson’s Disease: A Randomized, Placebo-Controlled, Phase 1 Study

Abstract

Background: Immunotherapies targeting α-synuclein aim to limit its extracellular spread in the brain and prevent progression of pathology in Parkinson’s disease (PD). PD03A is a specific active immunotherapy (SAIT) involving immunization with a short peptide formulation. Objective: This phase 1 study characterized the safety and tolerability of PD03A in patients with early PD. A key secondary objective was to evaluate immunological activity following immunization. Methods: This was a phase 1 study of two different doses of PD03A versus placebo in PD patients. Patients were randomized (1:1:1) to receive four priming plus one booster vaccination of PD03A 15μg, PD03A 75μg or placebo and were followed for 52 weeks. Results: Overall, 36 patients were randomized, of which 35 received five immunizations and completed the study. All patients experienced at least one adverse event. Transient local injection site reactions affected all but two patients; otherwise most AEs were considered unrelated to study treatment. A substantial IgG antibody response against PD03 was observed with a maximum titer achieved at Week-12. Differences in titers between both active groups versus placebo were statistically significant from the second immunization at Week-8 until Week-52. Conclusion: The safety profile and positive antibody response of PD03A supports the further development of active immunotherapeutic approaches for the treatment of PD.

Current experimental disease-modifying therapeutics for multiple system atrophy

“…However, the authors noticed that the antibody levels in the plasma were higher in individuals receiving PD01 than in patients receiving PD03 (Meissner et al 2020). In contrast, substantial levels of PD03induced antibodies were reported in PD patients (Poewe et al 2021). These differences in plasma antibody levels between PD and MSA patients receiving PD03 immunotherapy and the evidence of different α-Syn strains in PD and MSA (Schweighauser et al 2020;Shahnawaz et al 2020), led the researchers to speculate that vaccines may have different binding of the antibodies to disease-specific α-Syn conformations, which may result in the observed difference in plasma antibody levels reported in the clinical trials in PD and MSA.…”

α‐Synuclein Radiotracer Development and In Vivo Imaging: Recent Advancements and New Perspectives

“…There are currently no registered disease-modifying agents available for the treatment of α-synucleinopathies, current treatments are only acting on symptoms. 59 Several biological [60][61][62][63][64][65][66][67][68] and small molecule compounds [69][70][71] targeting αSyn aggregates are in clinical and pre-clinical development. However, currently there is no way to directly measure if or how much they lower the levels of aggregated αSyn in the brain.…”

Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

“…These peptides were further developed by Affiris as PD01A and PD03A (AFFITOPE) for active immunization clinical studies. Importantly, Phase I clinical trials using these antibodies in patients with PD were successfully completed in 2016, showing that both antibodies were locally and systemically well tolerated with no serious adverse effects, which resulted in their progress into Phase II clinical trials ( 148 – 150 ). In addition, a synthetic asyn peptide representing oligomeric and fibrillar asyn developed by United Neuroscience (UB312) is currently undergoing a Phase 1 clinical trial for PD (NCT04075318) ( 151 ).…”