Alterity Therapeutics Ltd. · ASX:ATH
Alterity Therapeutics — Prana Biotechnology — Investor Presentation (June 2018)
33 slides from Alterity Therapeutics's investor presentation, June 2018
Slide 1: Treatment of Neurological Disorders
Treatment of Neurological Disorders David Stamler, MD Chief Medical Officer and SVP, Clinical Development June 2018
Slide 2: Corporate Information
Corporate Information ASX Code PBT ● Founded in Melbourne in 1997 NASDAQ Code PRAN ● Operations in both Melbourne, AUS and San Francisco, USA Share Price A$0.043 ● Listed on the ASX (PBT) in 2000 US$1.96 (as of 25/06/2018) ● Listed on NASDAQ (PRAN) in 2002 Shares on Issue 533,891,470 ADR 1:60 ● Deep
Slide 3: Developing first-in-class therapies for orphan neurodegenerative diseases
Prana Biotechnology is developing first- in-class therapies to treat orphan neurodegenerative diseases Our lead drug candidate PBT434 is in Phase 1 clinical development with the potential to treat Parkinsonian diseases, many of which have limited or no treatment options 3
Slide 4: Why Invest?
Why Invest? Built on Experience Published Research Highly experienced drug development team Growing dossier of published research demonstrating established in the US – ex-Teva Pharmaceuticals strong activity of PBT434 in animals models of various and AUSPEX Pharmaceuticals – responsible for two Park
Slide 5: US-based development team with strong drug development experience and FDA approvals
US-based development team with strong drug development experience and FDA approvals David Stamler, MD James Kerr Margaret Bradbury, Ph.D VP, Chemistry, Manufacturing and Chief Medical Officer & Senior VP, Clinical VP, Nonclinical Development controls Development Former VP, Clinical Development and P
Slide 6: Board of Directors
Board of Directors Mr. Geoffrey Kempler Mr. Peter Marks Mr. Brian Meltzer Executive Chairman, CEO BEc LLB Grad. Dip. Comm. Law MBA B. Com., M Ec. Founded Prana in 1997 Non-Executive Director Non-Executive Director Extensive experience in investment and business Director since 2005 30 years experienc
Slide 7: Targeting proteins in neurodegenerative diseases
Targeting proteins in neurodegenerative diseases ● PBT434 is the first of a new generation of small molecules designed to inhibit the aggregation of α- Amyloid beta synuclein and tau, vital intracellular proteins that are implicated in neurodegenerative diseases such as AD Parkinson’s disease and at
Slide 8: Development Rationale
Development Rationale ● Alpha (α)-synuclein is an intracellular protein critical for neurotransmission ● Alpha-synulein accumulates and aggregates in many neurodegenerative diseases, implicated in pathology ● PBT434 blocks α-synuclein accumulation and aggregation, preserves neurons and improves func
Slide 9: 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 scale of GMP material ● Benign safety profile in GLP toxicology studies
Slide 10: Importance of α-Synuclein
Importance of α-Synuclein ● Essential for neurons to communicate ● α-Synuclein is an intracellular protein, abundantly expressed in the brain ● Soluble, in highest concentration at presynaptic nerve endings ● Key regulatory protein involved in neurotransmission ○ Enables neurotransmitter release by
Slide 11: α-Synuclein is an Established Disease Target
α-Synuclein is an Established Disease Target Strong genetic and pathological link to disease “Collectively these data strongly suggest that alpha synuclein is a potentially important and novel target of candidate neuroprotective AstraZeneca and Takeda establish collaboration to develop and therapies
Slide 12: PBT434 Inhibits α-Synuclein Aggregation by Restoring Intracellular Iron Balance
PBT434 Inhibits α-Synuclein Aggregation by Restoring Intracellular Iron Balance PBT434 blocks the aggregation of α-synuclein in vitro αSN+Fe PBT434 treatment preserves ferroportin levels in vivo αSN+Fe+PBT434 PBT434 Dose: 30 mg/kg 12
Slide 13: Alpha-synuclein Pathology and PBT434 Mechanism of Action
Alpha-synuclein Pathology and PBT434 Mechanism of Action Iron Chaperone, reducing α-synuclein accumulation, aggregation and preserving neurons Cell Death ↑ Oxidative Stress Fe Fe OH• Accumulation Fe Fe Fe Fe Fe Fe Fe Fe Fe H2O Fe Fe Fe Fe Fe PBT434 exports Fe Fe Fe Fe 2 Fe Fe Fe from cell Fe Fe Fe C
Slide 14: Brain Iron Increased in Parkinson's Disease Patients
Brain Iron Increased in Parkinson’s Disease Patients And In Multiple System Atrophy Patients nmol iron/g of human brain Specialised MRI Technique (QSM) to Non-invasively Quantify Brain Iron (PD Patient) nmol iron/g of human brain Dexter. Brain.1991;114 14 Langkammer. PLoS ONE 11(9): e0162460. 2016
Slide 15: 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 Brain Iron by MRI Motor Function – UPDRS III Deferiprone • Indicated for Treatment of Iron Overload Worsening • Black Box for neutropenia and agranucloctyosis • Iron Binding Affini
Slide 16: PBT434 has Optimal Iron Binding Affinity for Efficacy and Safety
PBT434 has Optimal Iron Binding Affinity for Efficacy and Safety Agent/Protein Kd for Fe3+ α-Synuclein 10-5 Stronger binding 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 R
Slide 17: Initial Disease Targets
Initial Disease Targets Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are two forms of atypical Parkinsonism with no approved therapies. Sufferers experience especially rapid deterioration compared to Parkinson’s disease and typically have motor symptoms that respond poorly
Slide 18: Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP)
Multiple System Atrophy (MSA) Progressive Supranuclear Palsy (PSP) ● Progressive neurodegenerative ● Fatal and rapidly progressive disorder leading to severe disability neurodegenerative disease and impairment in quality of life ● Typically presents in 50s ● Sporadic, typically presents in 50s to ●
Slide 19: Phase I Clinical trial of PBT434 commenced
Phase I Clinical trial of PBT434 commenced ● Ethics approval received for a clinical trial evaluating first in human dosing of PBT434 ● First cohort dosed ● Study conducted by the Nucleus Network in Melbourne ● The study will recruit healthy adult and elderly volunteers, with the primary goal of ass
Slide 20: Scientific evidence growing for PBT434
Scientific evidence growing for PBT434 20
Slide 21: 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 ↓ α-Synuclein aggregation Preserves neurons in S. nigra Foot Clasping ** 6 100 ** 4 50 2 0 0 Vehicle PBT434 Vehicle PBT434 Treatment randomly allocated • 4-8 months o
Slide 22: PBT434 Lowers Glial Cell Inclusions, Preserves Neurons and Improves Motor Function
PBT434 Lowers Glial Cell Inclusions, Preserves Neurons and Improves Motor Function Transgenic Mouse Model (PLP)-α-SYN of MSA Total N SNpc neurons Glial Cell Substantia Inclusions nigra Substantia Neurons nigra 8 P=0.0489 6 Glial Cell Pole test Inclusions (motor 4 In Pons function) 2 0 Veh PBT434 Tre
Slide 23: Brain Iron is Increased in Synucleinopathies and Tauopathies
Brain Iron is Increased in Synucleinopathies (PD, MSA) and also Tauopathies (PSP) 23
Slide 24: Structure and function of Tau
Structure and function of Tau ● Tau is an intracellular protein expressed in Tau in health Tau in disease neurons and glial support cells ● Natively unfolded, soluble protein ● Primary role is to regulate and stabilize microtubules inside cells ● Tau promotes neurite outgrowth, axonal transport of s
Slide 25: Progressive Supranuclear Palsy (PSP): A Tauopathy
Progressive Supranuclear Palsy (PSP): A Tauopathy Brain Iron increased compared to Healthy controls Dexter et al. Brain. 1991;114:1953. 25
Slide 26: PBT434 Prevents Tau Accumulation and Improves Cognitive Function
PBT434 Prevents Tau Accumulation and Improves Cognitive Function Transgenic Animal Model of Tauopathy (rTg4510) Tau accumulation in hippocampus Performance in Y-maze Time (%) in Novel arm Treatment • Randomly allocated • Started at 10.5 months • 30 mg/kg/day x 1.5 mo Assessments done in blinded mann
Slide 27: PBT434 has Potential for Wide Application in Neurodegenerative diseases
PBT434 has Potential for Wide Application in Neurodegenerative diseases α-Synuclein and Tau proteins share pathogenic features Parameter α-Synuclein Tau Localisation Intracellular Intracellular Native form Soluble Soluble Physiologic function Facilitates synaptic function Microtubule assembly and st
Slide 28: Building Momentum
Building Momentum Phase I clinical trial of PBT434 Prana presents at B. Riley FBR China Healthcare Investment and Partnering Symposium in Hangzhou, China PBT434 poster presented at the 6th International Multiple System Atrophy Conference, New York Prana presents at Biotech Showcase, San Fran
Slide 29: Scientific Appendices
PRANA Scientific Appendices
Slide 30: Link Between Iron and Severity of PD
Link Between Iron and Severity of PD Gotz et al. Ann N.Y. Acad Sci. 2004 Iron concentrations increase with disease severity Martin, et al. Neurology 2008;70:1411–1417 However, biochemical studies have reported increased iron content in the nigra in PD,2-4 with the changes most marked in severe disea
Slide 31: α-Synuclein as Target for PBT434
α-Synuclein as Target for PBT434 ● α-synuclein is unique in that it fibrillizes readily ● Factors regulating its production and conformation are relevant to disease pathogenesis and treatment ● Homeostasis of iron is disrupted in PD and atypical Friedlich, Tanzi, et al. 2007 parkinsonism ● Although
Slide 32: Frontotemporal Dementia – A Tauopathy
Frontotemporal Dementia – A Tauopathy Iron Content assessed by Brain MRI in FTD Patients Evidence for increased Iron in the Frontal and Temporal lobes 32
Slide 33: PBT434 Prevents Tau Phosphorylation in Dose Dependent Manner
PBT434 Prevents Tau Phosphorylation in Dose Dependent Manner In vitro demonstration of anti-tau activity Phosphorylated Tau level in PCC treated with OA pTau normalised against GAPDH 120 107 106 100 93 80 80 60 50 40 20 12 1 0
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