New Approach to Parkinson s Disease: Synuclein Immunotherapy
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1 RB2014 Conference August 22, 2014 New Approach to Parkinson s Disease: Synuclein Immunotherapy Dale Schenk, PhD President and CEO Prothena Corporation plc
2 Primary Motor and Non-Motor Symptoms of Parkinson s Disease Motor Symptoms Bradykinesia (slow movements) Muscle Rigidity Postural Instability (poor balance) Tremor at Rest Non-Motor Symptoms Loss of olfaction REM Behavioral Sleep Disorder Autonomic nervous system (e.g., orthostatic hypotension) Constipation Cognitive changes 2
3 3 Neurotransmitter Basis for Motor Symptoms in Parkinson s Disease
4 Genes identified that are implicated in Parkinsonism 4
5 -Synuclein Abnormally Accumulates in Several Neurodegenerative Disorders Familial Parkinson s disease Alzheimer s disease -synuclein Trojanowski et al NBIA-1 Multiple system atrophy Masliah et al Lewy body disease Wakabayashi et al Galvin et al Takeda et al; Spillantini et al 5
6 Scientific evidence supporting the anti- synuclein immunotherapy for Parkinson s Disease -synuclein pathology strongly implicated in Parkinson s Disease Accumulation of -synuclein is a predominant neuropathological feature and it follows the topological progression of disease Genetic evidence favors a prominent role for -synuclein in disease: missense mutations, duplication/triplication of non-mutated (D/R) -synuclein as an extracellular target during pathogenesis Caudal-rostral staging suggests transynaptic spreading Host-to-graft transfer of -synuclein pathology in transplants Several intercellular -synuclein propagation models described Passive anti- -synuclein immunization is a viable disease-modifying therapy for PD -synuclein is not deposited extracellularly in PD and safety/dose-limiting concerns are not anticipated Preclinical efficacy in various in vivo -synucleinopathy models 6 6 8/19/2014
7 Hypothesis: -Synuclein Immunotherapy May Reduce Neuronal Toxicity and Prevent Cell-to-Cell Transfer Synaptic Loss and Pathogenic Spread Antibodies Reduce Pathogenic Spread and Decrease Synuclein Pathology 7
8 In Vitro Findings
9 PRX002 Immunoreacts with Lewy Pathology Tg mice brain (Line 61) Human brain (DLB) Lewy body PRX002 9E4 9E4 9 PRX002 PRX002 immunoreacts with Lewy bodies and Lewy neurites in brains of PD and DLB patients.
10 Murine Precursor of PRX002 Demonstrates Preferential Binding to Aggregates Over Monomeric -synuclein Competition of Monomeric Biotinylated Synuclein By Equal Mass of Monomeric or Aggregated (fibrillar) Synuclein Competition ELISA-Ability of equal mass of aggregated -synuclein versus monomeric -synuclein to displace biotinylated monomeric -synuclein 10
11 Antibodies Block Cell-to-Cell Transmission of - synuclein In Vitro in Concentration- and Epitope- Dependent Manner IgG1 g/ml g/ml 9E4 11 Games et al., 2014
12 C-terminal Cleaved -synuclein FL- -syn Syn105 Nucleus -C-terminally cleaved species of -synuclein are thought to contribute to increased -synuclein oligomerization and toxicity. -Prothena generated a novel antibody (SYN105) against the c- terminally truncated sequence (aa s ) of -synuclein. -Syn105 labels Lewy bodies/neurites and dystrophic neurites in brains of PD/DLB and -synuclein transgenic mice, but not brains of control subjects and wild-type mice. 12 Games et al., 2013
13 Blockade of Calpain-induced -synuclein Truncation by Antibodies is Epitope-specific monomer 13 Games et al., 2014
14 In Vivo Findings
15 Efficacy of Anti-synuclein Immunotherapy has been Reported in Various Models of Synucleinopathy Transgenic D-Line mice (PDGFβ promoter, Masliah et al.) -Moderate levels of human -syn (nonmutated). -Highest expression in neocortical and limbic system -Intracellular inclusions, motor deficits, dopamine loss Transgenic Line61 mice (mthy1 promoter, Masliah et al.) High and widespread human -syn (nonmutated) expression in CNS and PNS. Inclusions in cortex, hippocampus, basal ganglia, cerebellum. Mild nigrostriatal deficit at old age (>12mo). Non-motor deficits: olfactory, gastrointestinal, circadian, cognitive. Intracerebral injection of synthetic -synuclein fibrils (V.Lee et al.) Recruitment of endogenous -syn to form inclusions in cortex, hippocampus, basal ganglia, cerebellum. Temporal and spatial spread of -syn pathology Motoric deficits and loss of dopaminergic neurons in the substantia nigra. 15
16 Passive Immunization Promotes Clearance of -synuclein Aggregates, Protects Against Synaptic Loss, and Reduces Behavior Deficits in Line-D Transgenic Mice Line-D mice (6-month-old) received weekly IP injections (10 mg/kg) for 6 months with the carboxy terminus α-syn antibodies (9E4, 8A5) or amino terminus α-syn antibody (6H7) and IgG1 control (27-1). α-synuclein Loss of Synapses Behavior Deficit PSDs (EM) Insoluble Aggregates PSD95 (WB) 16 Masliah et al., 2011
17 Passive Immunization Promotes Clearance of -synuclein Aggregates, Protects Against Synaptic Loss, and Reduces Behavior Deficits in Line-61 Transgenic Mice Line-61 mice (3-month-old) received weekly IP injections (10 mg/kg) for 5 months with the carboxy terminus α-syn antibodies (9E4, 5C1, 5D12) or mid-region α-syn antibody (1H7) and IgG1 control (27-1). α-synuclein Pathology Loss of Synapses Behavior Deficit IgG1 9E4 Correct quadrant 25 IgG1 9E4 Time (sec) * 17 Games et al., 2014
18 Immunotherapy Blocks Uptake/Transmission of -synuclein Fibrils In Vivo Preservation of Neurons Blockade of Synuclein Uptake/Transmission Behavior Improvement Tran et al.,
19 Summary of Preclinical Efficacy Studies with Anti- -synuclein Antibodies Anti- -synuclein immunotherapy was demonstrated in various animal models of synucleinopathy to promote: Reduction of -syn aggregates and uptake/transmission by neurons Synaptic/Neuronal Loss and Pathological Spread Reduction of gliosis Preservation of synaptic integrity Amelioration of motor, cognitive, and sensorimotor behavioral deficits Antibodies neutralize and clear pathogenic synuclein The proposed MoA for antibodies are: 1) Neutralization and clearance of pathologenic -synuclein 2) Blockade of CT-cleavage by calpain 19
20 Efficacy of Immunotherapy in Models of Synucleinopathy IgG1 Blockade of cell-to-cell transmission IgG1 Lowering of -syn Pathology 9E4 9E4 mab g/ml) Improvement in Behavior (water maze) IgG1 Protection of Synapses 9E4 Proposed MoA s: -Neutralization -Clearance -Disaggregation -Blockade of calpain cleavage 9E4 20
21 Current Clinical Status of PRX002 Prothena and Roche entered into worldwide collaboration to co-develop and co-promote antibodies for treatment of Parkinson's disease. Ongoing double blind Single Ascending dose study in healthy volunteers Ongoing double blind Multiple ascending dose study in Parkinson s patients 21
22 Prothena Vision We target proteins in novel ways to resolve unmet clinical need in patients 22
23 Acknowledgements Dora Games Peter Seubert Robin Barbour Ronald Torres Lana Alexander Patricia Sacayon Wagner Zago Eliezer Masliah Edward Rockenstein Manuel Buttini Michael Mante Brian Spencer Anthony Adame Christina Patrick Elvira Valera Kiren Ubhi Silke Nuber Sarah Mueller-Steiner 23
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