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

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 immu...

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Published in:	Nature medicine Vol. 30; no. 9; pp. 2631 - 2640
Main Authors:	Eijsvogel, Pepijn, Misra, Pinaki, Concha-Marambio, Luis, Boyd, Justin D., Ding, Shuang, Fedor, Lauren, Hsieh, Yueh-Ting, Sun, Yu Shuang, Vroom, Madeline M., Farris, Carly M., Ma, Yihua, de Kam, Marieke L., Radanovic, Igor, Vissers, Maurits F. J. M., Mirski, Dario, Shareghi, Ghazal, Shahnawaz, Mohammad, Singer, Wolfgang, Kremer, Philip, Groeneveld, Geert Jan, Yu, Hui Jing, Dodart, Jean-Cosme
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-09-2024 Nature Publishing Group
Subjects:	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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/s41591-024-03101-8