First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers

Dale B Schenk, Martin Koller, Daniel K Ness, Sue G Griffith, Michael Grundman, Wagner Zago, Jay Soto, George Atiee, Susanne Ostrowitzki, Gene G Kinney, Dale B Schenk, Martin Koller, Daniel K Ness, Sue G Griffith, Michael Grundman, Wagner Zago, Jay Soto, George Atiee, Susanne Ostrowitzki, Gene G Kinney

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT02157714.

Keywords: Parkinson's disease; clinical trial; protein aggregation; protein misfolding; synucleinopathy.

© 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Figures

Figure 1
Figure 1
Pharmacokinetics of PRX002. Serum PRX002 concentration–time profiles after a single dose of PRX002.
Figure 2
Figure 2
Pharmacodynamics of PRX002. Change from baseline of serum‐free α‐synuclein after a single dose of PRX002.

References

    1. Lawson RA, Yarnall AJ, Duncan GW, et al. Severity of mild cognitive impairment in early Parkinson's disease contributes to poorer quality of life. Parkinsonism Relat Disord 2014;20:1071–1075.
    1. Stocchi F, Martinez‐Martin P, Reichmann H. Quality of life in Parkinson's disease–patient, clinical and research perspectives. . Accessed July 5, 2016.
    1. Sobell JM, Foley P, Toth D, et al. Effects of apremilast on pruritus and skin discomfort/pain correlate with improvements in quality of life in patients with moderate to severe plaque psoriasis. Acta Derm Venereol 2016;96:514–520.
    1. Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356–1364.
    1. Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A. The current and projected economic burden of Parkinson's disease in the United States. Mov Disord 2013;28:311–318.
    1. Cooney JW, Stacy M. Neuropsychiatric issues in Parkinson's disease. Curr Neurol Neurosci Rep 2016;16:49.
    1. Lee HM, Koh SB. Many faces of Parkinson's disease: non‐motor symptoms of Parkinson's disease. J Mov Disord 2015;8:92–97.
    1. Pedrosa DJ, Timmermann L. Review: management of Parkinson's disease. Neuropsychiatric Dis Treat 2013;9:321–340.
    1. Sprenger F, Poewe W. Management of motor and non‐motor symptoms in Parkinson's disease. CNS Drugs 2013;27:259–272.
    1. Breydo L, Wu JW, Uversky VN. Alpha‐synuclein misfolding and Parkinson's disease. Biochim Biophys Acta 2012;1822:261–285.
    1. Stefanis L. Alpha‐Synuclein in Parkinson's disease. Cold Spring Harb Perspect Med 2012;2:a009399.
    1. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha‐synuclein in Lewy bodies. Nature 1997;388:839–840.
    1. Kay DM, Factor SA, Samii A, et al. Genetic association between alpha‐synuclein and idiopathic Parkinson's disease. Am J Med Genet Neuropsychiatric Genet 2008;147B:1222–1230.
    1. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197–211.
    1. Games D, Valera E, Spencer B, et al. Reducing C‐terminal‐truncated alpha‐synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease‐like models. J Neurosci 2014;34:9441–9454.
    1. Masliah E, Rockenstein E, Adame A, et al. Effects of alpha‐synuclein immunization in a mouse model of Parkinson's disease. Neuron 2005;46:857–868.
    1. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha‐synuclein transgenic model of Lewy body disease. PLoS ONE 2011;6:e19338.
    1. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body‐like pathology in long‐term embryonic nigral transplants in Parkinson's disease. Nat Med 2008;14:504–506.
    1. Li JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host‐to‐graft disease propagation. Nat Med 2008;14:501–503.
    1. Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VM. Intracerebral inoculation of pathological alpha‐synuclein initiates a rapidly progressive neurodegenerative alpha‐synucleinopathy in mice. J Exp Med 2012;209:975–986.
    1. Forloni G, Artuso V, La Vitola P, Balducci C. Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases. Mov Disord 2016;31:77181.
    1. Hutter‐Saunders JA, Mosley RL, Gendelman HE. Pathways towards an effective immunotherapy for Parkinson's disease. Expert Rev Neurother 2011;11:1703–1715.
    1. Giugni JC, Okun MS. Treatment of advanced Parkinson's disease. Curr Opin Neurol 2014;27:450–460.
    1. McGeer PL, McGeer EG. Glial reactions in Parkinson's disease. Mov Disord 2008;23:474–483.
    1. McLean PJ, Kawamata H, Ribich S, Hyman BT. Membrane association and protein conformation of alpha‐synuclein in intact neurons: effect of Parkinson's disease‐linked mutations. J Biol Chem 2000;275:8812–8816.
    1. Mollenhauer B, Locascio JJ, Schulz‐Schaeffer W, Sixel‐Doring F, Trenkwalder C, Schlossmacher MG. Alpha‐Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 2011;10:230–240.
    1. Kang JH, Irwin DJ, Chen‐Plotkin AS, et al. Association of cerebrospinal fluid beta‐amyloid 1‐42, T‐tau, P‐tau181, and alpha‐synuclein levels with clinical features of drug‐naive patients with early Parkinson disease. JAMA Neurol 2013;70:1277–1287.
    1. Hong Z, Shi M, Chung KA, et al. DJ‐1 and alpha‐synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease. Brain 2010;133:713–726.
    1. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta‐peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916–919.
    1. Rinne JO, Brooks DJ, Rossor MN, et al. 11C‐PiB PET assessment of change in fibrillar amyloid‐beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double‐blind, placebo‐controlled, ascending‐dose study. Lancet Neurol 2010;9:363–372.
    1. Salloway S, Sperling R, Brashear HR. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer's disease. N Engl J Med 2014;370:1460.
    1. Liu S, Shi D, Wang HC, Yu YZ, Xu Q, Sun ZW. Co‐immunization with DNA and protein mixture: a safe and efficacious immunotherapeutic strategy for Alzheimer's disease in PDAPP mice. Sci Rep 2015;5:7771.
    1. Games D, Zago W, Valera E, et al. Passive immunotherapy against alpha‐synuclein reduces trans‐synaptic alpha‐synuclein propagation and axonal degeneration in a combined viral and trangenic model of synucleinopathy. Presented at: AD/PD 2015: Mechanisms, Clinical Strategies, and Promising Treatments of Neurodegenerative Diseases, March 18‐22, 2015; Nice, France.
    1. Anderson JP, Walker DE, Goldstein JM, et al. Phosphorylation of Ser‐129 is the dominant pathological modification of alpha‐synuclein in familial and sporadic Lewy body disease. J Biol Chem 2006;281:29739–29752.
    1. Tsigelny IF, Crews L, Desplats P, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS ONE 2008;3:e3135.
    1. Tran HT, Chung CH, Iba M, et al. Alpha‐synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha‐synuclein and neurodegeneration. Cell Rep 2014;7:2054–2065.
    1. Bae EJ, Lee HJ, Rockenstein E, et al. Antibody‐aided clearance of extracellular alpha‐synuclein prevents cell‐to‐cell aggregate transmission. J Neurosci 2012;32:13454–13469.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren