Synonyms: RO7046015, RG7935, NEOD002
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Hoffmann-La Roche, Prothena
PRX002 is a humanized IgG1 monoclonal antibody directed against aggregated α-synuclein. Genetic and pathological evidence suggest that this protein plays a central role in the pathogenesis of Parkinson's disease (PD) and other α-synculeinopathies such as dementia with Lewy bodies (DLB). In mouse models of PD and DLB, the mouse version of PRX002, 9E4, has been reported to reduce a C-terminally truncated form of α-synculein that is considered neurotoxic, as well as α-synculein propagation from cell to cell, neuropathology, and behavioral endpoints (e.g., Games et al., 2013; Games et al., 2014; Masliah et al., 2011).
In March 2014, Prothena, in partnership with Roche, began a single-center study in 40 healthy adults younger than 66 to compare the safety and pharmacokinetics of a single infusion of 0.3, 1, 3, 10, or 30 mg/kg to placebo. This trial assessed peripheral target engagement (Mar 2015 news story, company press release). At the 2015 AD/PD conference, Prothena reported that the antibody was safe, well-tolerated, and dose-dependently reduced the concentration of free α-synuclein in the blood down to 4 percent; data were subsequently published (Schenk et al, 2017).
In June 2014, an 8-center, multiple-ascending-dose trial began comparing a six-month course of PRX002 to placebo in what was to be 64 people with idiopathic PD. The trial evaluated safety and pharmacokinetic parameters, included exploratory CSF, imaging, and clinical markers, and was completed in September 2016. At the 2017 AD/PD conference, the trial was reported to have enrolled 84 people with mild to moderate PD, and to have been safe, without anti-PRX002 antibodies, or serious adverse events. Side effects included gastrointestinal complaints, infusion site rash, headaches, peripheral edema. PRX002 half-life was 14 days, and the CSF/serum ratio was 0.3 percent for all dose groups at week 9. Unbound serum α-synuclein dropped by up to 97 percent at the highest dose, indicating peripheral target engagement. Antibody levels rose dose-dependently in CSF, but the amount of monomeric α-synuclein in CSF did not change. At the time, Prothena had no assay to measure the concentration of α-synuclein aggregates in CSF before and after treatment. There was no improvement on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS, see May 2017 conference news). These data were subsequently published, and the half-life estimate was revised to 10.2 days (Jankovic et al., 2018).
Notably, this trial explored the use of smartphone measures to monitor clinical changes, showing that they closely correlate with the MDS-UPDRS but may be more sensitive (May 2017 conference story).
In June 2017, Roche started PASADENA, a 2-year phase 2 study comparing the efficacy of two doses of intravenous PRX002 to placebo in 300 people with early PD. A 1-year placebo-controlled double-blind period will be followed by another year in which all participants receive the antibody but are blinded to dose. The primary outcome is change on the MDS-UPDRS; secondary outcomes include change in dopamine transporter imaging as per DaTscan, as well as a range of clinical, safety, and pharmacokinetic measures (for details, see April 2018 conference news). The trial is set to run until summer 2021.
For all clinical trials on PRX002, see clinicaltrials.gov.
Last Updated: 11 May 2018
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- Schenk DB, Koller M, Ness DK, Griffith SG, Grundman M, Zago W, Soto J, Atiee G, Ostrowitzki S, Kinney GG. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017 Feb;32(2):211-218. Epub 2016 Nov 25 PubMed.
- Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, Zago W, Ness DK, Griffith SG, Grundman M, Soto J, Ostrowitzki S, Boess FG, Martin-Facklam M, Quinn JF, Isaacson SH, Omidvar O, Ellenbogen A, Kinney GG. Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2018 Oct 1;75(10):1206-1214. PubMed.
- Games D, Seubert P, Rockenstein E, Patrick C, Trejo M, Ubhi K, Ettle B, Ghassemiam M, Barbour R, Schenk D, Nuber S, Masliah E. Axonopathy in an α-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated α-synuclein. Am J Pathol. 2013 Mar;182(3):940-53. PubMed.
- Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, Patrick C, Ubhi K, Nuber S, Sacayon P, Zago W, Seubert P, Barbour R, Schenk D, Masliah E. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci. 2014 Jul 9;34(28):9441-54. PubMed.
- Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, Patrick C, Trejo M, Ubhi K, Rohn TT, Mueller-Steiner S, Seubert P, Barbour R, McConlogue L, Buttini M, Games D, Schenk D. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338. PubMed.
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