Alterity Therapeutics Ltd. · ASX:ATH
Alterity Therapeutics — Prana Biotechnology — Investor Presentation (January 2019)
25 slides from Alterity Therapeutics's investor presentation, Jan 7, 2019
Slide 1: Treatment of Neurological Disorders
1 January 2019 Treatment of Neurological Disorders David Stamler, MD Chief Medical Officer and SVP, Clinical Development
Slide 2: Targeting Proteins in Neurodegeneration
Targeting Proteins in Neurodegeneration 2 PBT2 (1 st generation) • Mechanism of action: Zn and Cu ionophore • Originally developed for neurological indications by targeting extracellular protein • Evaluating non - neurological indications for further development PBT434 (2 nd generation) • Targets in
Slide 3: Current Focus
Current Focus 3 Novel Drug Candidate PBT434 • Targets key proteins implicated in neurodegeneration of Parkinson’s disease and atypical parkinsonism • Distinct scaffold and biological profile compared to PBT2 Strong Research and Development • U.S. development team with proven track record • Innovativ
Slide 4: US-based development team with strong drug development experience and FDA approvals
US - based development team with strong drug development experience and FDA approvals Margaret Bradbury, Ph.D. VP, Nonclinical Development Previously Non - Clinical leadership at Auspex/ Teva. At Teva, l ed non - clinical development of several neuroscience programs . At Auspex Pharmaceuticals, led
Slide 5: Investment Thesis
Investment Thesis • Alpha ( α ) - synuclein is an intracellular protein critical for neurotransmission • α - synulein accumulates and aggregates in many neurodegenerative diseases and is implicated in pathology • PBT434 blocks α - synuclein accumulation and aggregation, preserves neurons and improve
Slide 6: PBT434: Promising Drug Profile
PBT434: Promising Drug Profile • Good CNS penetration based on low molecular weight and lipophilicity • Brain concentrations 2 to 3 fold higher than plasma • Straightforward synthetic process with demonstrated ability to make kg amounts of GMP material • Benign safety profile in GLP toxicology studi
Slide 7: Importance of α-Synuclein
Importance of α - Synuclein • α - Synuclein is an intracellular protein, abundantly expressed in the brain • Critical for normal function of neurons • Soluble, in highest concentration at presynaptic nerve endings • Key regulatory protein involved in neurotransmission • Enables neurotransmitter rele
Slide 8: α-Synuclein is an Important Disease Target
α - Synuclein is an Important Disease Target Strong genetic and pathological link to disease 8 “Collectively these data strongly suggest that alpha synuclein is a potentially important and novel target of candidate neuroprotective therapies. Several different therapeutic strategies designed to clear
Slide 9: α-Synuclein as Target for PBT434
α - Synuclein as Target for PBT434 • α - synuclein fibrillizes readily • Factors regulating its production and conformation are relevant to disease pathogenesis and treatment • Homeostasis of iron is disrupted in PD and atypical parkinsonism • α - synuclein is highly conserved in vertebrates but onl
Slide 10: PBT434 Inhibits α-Synuclein Aggregation by Restoring Intracellular Iron Balance
PBT434 Inhibits α - Synuclein Aggregation by Restoring Intracellular Iron Balance 10 PBT434 blocks the aggregation of α - synuclein in vitro PBT434 treatment preserves ferroportin levels in vivo F e r r o p o r t i n ( O D ) W/T Veh PBT434 0 2 4 6 * * PBT434 Dose: 30 mg/kg 0 1 10 20 0 5000 10000 150
Slide 11: Alpha-synuclein Pathology and PBT434 Mechanism of Action
11 Fe Fe Native, unfolded protein Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Aggregation of fibrillar protein Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe H 2 O 2 Fe OH • Cell Death N N O R R O R R Fe ↑ Ferroportin Fe Fe Fe Fe Fe Fe Fe Fe Alpha - synuclein Pathology and PBT434 Me
Slide 12: PBT434 Lowers α-Synuclein, Prevents Neuronal Death and Improves Motor Function
PBT434 Lowers α - Synuclein , Prevents Neuronal Death and Improves Motor Function Transgenic Animal Model ( hA53T) of Parkinson’s Disease 12 Preserves neurons in S. nigra T o t a l S N p c n e u r o n s W/T Vehicle PBT434 0 4000 8000 ** Finkelstein et al. Acta Neuropath Comm (2017) 5:53 ↓ α - Synucl
Slide 13: Strategy Supported by Proof of Concept with Deferiprone
Strategy Supported by Proof of Concept with Deferiprone 6 month placebo controlled data in Parkinson’s disease patients 13 S. nigra Brain Iron by MRI Motor Function – UPDRS III Devos et al. Antiox . and Redox Signaling. 2014; 21: 195 DFP PBO DFP PBO S. nigra Improvement Deferiprone • Indicated for T
Slide 14: PBT434 has Optimal Iron Binding Affinity for Efficacy and Safety
PBT434 has Optimal Iron Binding Affinity for Efficacy and Safety 14 Agent/Protein Kd for Fe 3+ α - Synuclein 10 - 5 PBT434 10 - 10 Ferritin 10 - 22 Transferrin 10 - 23 Deferiprone 10 - 36 Davies et al. PLoS ONE. 2011; 6; 1; e15814. doi.org/10.1371/journal.pone.0015814 Aisen P and Listowsky I. Ann Re
Slide 15: Link Between Iron and Severity of PD
Link Between Iron and Severity of PD 15 Gotz et al. Ann N.Y. Acad Sci. 2004 However, biochemical studies have reported increased iron content in the nigra in PD, 2 - 4 with the changes most marked in severe disease (PD) 5 Martin, et al. Neurology 2008;70:1411 – 1417 Iron concentrations increase with
Slide 16: Brain Iron Increased in Parkinson's Disease Patients
Brain Iron Increased in Parkinson’s Disease Patients 16 Substantia nigra (T) Substantia nigra (pc) Cerebellum n = 24 n = 13 nmol iron/g of human brain n = 9 n = 7 * n = 3 n = 8 * 0 10000 20000 30000 And in Multiple System Atrophy Patients Cerebral cortex Caudate nucleus Putamen (M) Putamen (L) Globu
Slide 17: Multiple System Atrophy
Multiple System Atrophy A form of Atypical Parkinsonism • Rapidly progressive neurodegenerative disorder leading to severe disability and impairment in quality of life • Sporadic, typically presents in 50s to 60s • Orphan Indication: Prevalence ~ 5 per 100,000 in the U.S. • Characterized by a variab
Slide 18: PBT434 reduces Alpha-synuclein and Lowers Glial Cell Inclusions
PBT434 reduces Alpha - synuclein and Lowers Glial Cell Inclusions Transgenic Mouse Model (PLP) - α - SYN of MSA 18 ↓ α - Synuclein Treatment: Randomly allocated, 4 months, 30 mg/kg/day or Vehicle ( Veh ) Data presented are for animals at 16 mo age Vehicle PBT434 0.0 0.1 0.2 0.3 0.4 R a t i o t o P
Slide 19: PBT434 Preserves Neurons and Improves Motor Function
PBT434 Preserves Neurons and Improves Motor Function Transgenic Mouse Model (PLP) - α - SYN of MSA 19 Treatment: Randomly allocated, 4 months, 30 mg/kg/day or Vehicle Vehicle PBT434 0 2 4 6 8 T i m e t o d e s c e n d t h e P o l e ( s ) * Pole Test after 4 months treatment 30 mg/kg at 16 months V
Slide 20: Brain Iron is also Increased in Tauopathies
Brain Iron is also Increased in Tauopathies 20
Slide 21: Progressive Supranuclear Palsy (PSP)
Progressive Supranuclear Palsy (PSP) A form of Atypical Parkinsonism 21 Cerebral cortex Caudate nucleus Putamen (T) Substantia nigra (T) Cerebellum n = 13 n = 11 n = 14 n = 11 n = 13 n = 11 n = 12 n = 7 nmol iron/g of human brain n = 8 n = 7 * 0 10000 20000 30000 * Healthy Patients Dexter et al . Br
Slide 22: PBT434 in an Animal Model of Acute Oxidative Stress
PBT434 in an Animal Model of Acute Oxidative Stress 22 Total SNpc neurons 0 1 3 10 30 80 C 0 3000 6000 T o t a l S N p c n e u r o n s PBT434 (mg/kg) *** *** * * Pole test 0 1 3 10 30 80 C 0 6 12 T i m e ( s e c s ) PBT434 (mg/kg) ** * For α - synuclein, lipid peroxidation: PBT434 dose 30 mg/kg/d †
Slide 23: Development Milestones
Development Milestones • Phase 1 Completion 1H ‘19 • Initiate LT toxicology 1H ‘19 • Initiate Phase 2 planning study 1H ‘19 • Initial Patient study start 2020 23
Slide 24: Preliminary Market Assessment (U.S. only)
Preliminary Market Assessment (U.S. only) $1 - 1.7B potential commercial opportunity for PBT434 in MSA and PSP* • Severely debilitating, fatal illnesses with no current treatments are ripe for new entrants targeting what may be the actual cause of the disease, even if only motor symptom endpoints Su
Slide 25: Summary
Summary • PBT434 is an excellent drug candidate to prevent alpha - synuclein aggregation and reduce oxidative stress by targeting intracellular reactive iron • Brain iron pathologically increased in Parkinson’s disease and atypical parkinsonism • PBT434 has demonstrated efficacy in various animal mo
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