Journal Article

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial

de Kam, Marieke L., Vissers, Maurits F. J. M., Mirski, Dario, Hsieh, Yueh-Ting, Eijsvogel, Pepijn, Ding, Shuang, Radanovic, Igor, Singer, Wolfgang, Groeneveld, Geert Jan, Ma, Yihua, Sun, Yu Shuang, Kremer, Philip, Concha-Marambio, Luis, Shahnawaz, Mohammad, Dodart, Jean-Cosme, Boyd, Justin D., Vroom, Madeline M., Misra, Pinaki, Yu, Hui Jing, Fedor, Lauren, Shareghi, Ghazal, Farris, Carly M.

2024

Overview

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson’s disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 μg and 300/300/300 μg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov: NCT04075318 . A first-in-patient trial of UB-312, an active immunotherapeutic for Parkinson’s disease, was well tolerated and elicited antibodies that engage misfolded α-synuclein.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/308/153 / 692/617/375/1718 / Adverse events / Aged / alpha-Synuclein - immunology / Antibodies / Biomarkers / Biomarkers - blood / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cerebrospinal fluid / Clinical trials / Dilution / Disease control / Double-Blind Method / Drug dosages / Drug withdrawal / Female / Humans / Immunogenicity / Immunotherapy / Immunotherapy, Active - methods / Infectious Diseases / Male / Medicine / Metabolic Diseases / Middle Aged / Molecular Medicine / Monoclonal antibodies / Movement disorders / Mutation / Neurodegenerative diseases / Neurosciences / Parkinson Disease - drug therapy / Parkinson Disease - immunology / Parkinson Disease - therapy / Parkinson's disease / Patients / Placebos / Statistical analysis / Synuclein / Toxic diseases