title: First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers.
abstract: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice.
  
  
  
  This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.3, 1, 3, 10, or 30 mg/kg; n = 6/cohort) or placebo (n = 2/cohort).
  
  
  
  PRX002 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity. No serious adverse events, discontinuations as a result of adverse events, or dose-limiting toxicities were reported. Serum PRX002 exposure was dose proportional; the average terminal half-life across all doses was 18.2 days. A significant dose-dependent reduction in free serum α-synuclein (unbound to PRX002) was apparent within 1 hour after PRX002 administration, whereas total α-synuclein (free plus bound) increased dose-dependently, presumably because of the expected change in kinetics following antibody binding.
  
  
  
  This study demonstrates that serum α-synuclein can be safely modulated in a dose-dependent manner after single intravenous infusions of an anti-α-synuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson's disease. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
authors.affiliation: Prothena Biosciences Inc, South San Francisco, California, USA.
authors.forename: Dale B
authors.initials: DB
authors.lastname: Schenk
authors.affiliation: Prothena Biosciences Inc, South San Francisco, California, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Koller
authors.affiliation: Prothena Biosciences Inc, South San Francisco, California, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Ness
authors.affiliation: ClinPharma Resources, San Diego, California, USA.
authors.forename: Sue G
authors.initials: SG
authors.lastname: Griffith
authors.affiliation: Global R&D Partners, LLC, San Diego, California, USA.|University of California, San Diego, San Diego, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Grundman
authors.affiliation: Prothena Biosciences Inc, South San Francisco, California, USA.
authors.forename: Wagner
authors.initials: W
authors.lastname: Zago
authors.affiliation: Prothena Biosciences Inc, South San Francisco, California, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Soto
authors.affiliation: Worldwide Clinical Trials, Inc, San Antonio, Texas, USA.
authors.forename: George
authors.initials: G
authors.lastname: Atiee
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ostrowitzki
authors.affiliation: Prothena Biosciences Inc, South San Francisco, California, USA.
authors.forename: Gene G
authors.initials: GG
authors.lastname: Kinney
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D051844:alpha-Synuclein / Q000097:blood* / Q000187:drug effects* / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Parkinson's disease; clinical trial; protein aggregation; protein misfolding; synucleinopathy