Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial.
Pepijn EijsvogelPinaki MisraLuis Concha-MarambioJustin D BoydShuang DingLauren FedorYueh-Ting HsiehYu Shuang SunMadeline M VroomCarly M FarrisYihua MaMarieke L de KamIgor RadanovicMaurits F J M VissersDario MirskiGhazal ShareghiMohammad ShahnawazWolfgang SingerPhilip H C KremerGeert Jan GroeneveldHui Jing YuJean-Cosme DodartPublished in: Nature medicine (2024)
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 .
Keyphrases
- placebo controlled
- double blind
- end stage renal disease
- phase ii
- clinical trial
- ejection fraction
- phase iii
- newly diagnosed
- open label
- cerebrospinal fluid
- prognostic factors
- chronic kidney disease
- emergency department
- metabolic syndrome
- machine learning
- adipose tissue
- squamous cell carcinoma
- high throughput
- social media
- weight loss
- cancer therapy
- liquid chromatography tandem mass spectrometry
- single cell
- mass spectrometry
- drug induced
- genetic diversity