Alterity Therapeutics Ltd. · ASX:ATH
Alterity Therapeutics — Prana Biotechnology — Investor Presentation (June 2018)
34 slides from Alterity Therapeutics's investor presentation, Jun 27, 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 ● Founded in Melbourne in 1997 ● Operations in both Melbourne, AUS and San Francisco, USA ● Listed on the ASX (PBT) in 2000 ● Listed on NASDAQ (PRAN) in 2002 ● Deep drug development experience and global network of world leading expertise – including Florey Institute and Harvar
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?
Highly experienced drug development team established in the US – ex - Teva Pharmaceuticals and AUSPEX Pharmaceuticals – responsible for two FDA approvals in 2017 Built on Experience Growing dossier of published research demonstrating strong activity of PBT434 in animals models of various Parkinsonia
Slide 5: US-based development team with strong drug development experience
US - based development team with strong drug development experience and FDA approvals David Stamler, MD Chief Medical Officer & Senior VP, Clinical Development Previously Senior Director, Teva Pharmaceuticals. At Teva, l ed non - clinical development of several neuroscience programs . As Executive D
Slide 6: Board of Directors
Board of Directors Executive Chairman, CEO Founded Prana in 1997 Extensive experience in investment and business development Overseen operations for the implementation of Prana’s strategic plan and technology commercialisation Mr. Geoffrey Kempler BEc LLB Grad. Dip. Comm. Law MBA Non - Executive Dir
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 - synuclein and tau, vital intracellular proteins that are implicated in neurodegenerative diseases such as Parkinson’s disease and atypical parkinso
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 improv
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
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 therapies . Several different therapeutic strategies designed to cle
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 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 15000
Slide 13: Alpha-synuclein Pathology and PBT434 Mechanism of Action
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 Fe Fe Fe Fe Alpha - synuclein Pathology and PBT434 Mechanism of Action Iron Chaperone, reducing α - s
Slide 14: Brain Iron Increased in Parkinson's Disease Patients
Brain Iron Increased in Parkinson’s Disease Patients Specialised MRI Technique (QSM) to Non - invasively Quantify Brain Iron (PD Patient) nmol iron/g of human brain nmol iron/g of human brain Dexter. Brain.1991;114 Langkammer. PLoS ONE 11(9): e0162460. 2016 14 And In Multiple System Atrophy Patients
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 S. nigra Brain Iron by MRI Motor Function – UPDRS III Devos et al. Antiox. and Redox Signaling. 2014; 21: 195 DF P PBO DF P PBO S. nigra Improvement Deferiprone • Indicated for Tre
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 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 Rev B
Slide 17: Initial Disease Targets: MSA and PSP
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 to available treatments.
Slide 18: Multiple System Atrophy and Progressive Supranuclear Palsy
Multiple System Atrophy (MSA) Halliday 2015, based on Brain 2015: 138; 2293 – 2309 Progressive Supranuclear Palsy (PSP) ● Progressive neurodegenerative disorder leading to severe disability and impairment in quality of life ● Sporadic, typically presents in 50s to 60s ● Orphan disease: Prevalence ~5
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 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 - Synuclein
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 Treatment: Randomly allocated, 4 months, ; 30 mg/kg/day or Vehicle (Veh) Data presented are for animals at 16 mo age Glial Cell Inclusions In Pons Veh PBT434 0 2 4 6 8 T i
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: Tau in disease
Tau in disease Structure and function of Tau ● Tau is an intracellular protein expressed in 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 synaptic vesicl
Slide 25: Progressive Supranuclear Palsy (PSP): A Tauopathy
Progressive Supranuclear Palsy (PSP): A Tauopathy Brain Iron increased compared to Healthy controls 25 Dexter et al. Brain. 1991;114:1953.
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 Treatment • Randomly allocated • Started at 10.5 months • 30 mg/kg/day x 1.5 mo Assessments done in blinded manner Performance in Y - maze 26 Vehicle PBT434
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 an
Slide 28: Building Momentum
x Phase I clinical trial of PBT434 x Prana presents at B. Riley FBR China Healthcare Investment and Partnering Symposium in Hangzhou, China x PBT434 poster presented at the 6th International Multiple System Atrophy Conference, New York x Prana presents at Biotech Showcase, San Francisco x Prana rece
Slide 29: Prana Biotechnology
___ PRANA BIOTECHNOLOGY 5
Slide 30: Scientific Appendices
Scientific Appendices
Slide 31: Link Between Iron and Severity of PD
Link Between Iron and Severity of PD 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 di
Slide 32: 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 parkinsonism ● Although α - synuclein is highly co
Slide 33: Frontotemporal Dementia – A Tauopathy
Frontotemporal Dementia – A Tauopathy Iron Content assessed by Brain MRI in FTD Patients 33 Evidence for increased Iron in the Frontal and Temporal lobes
Slide 34: PBT434 Prevents Tau Phosphorylation in Dose Dependent Manner
PBT434 Prevents Tau Phosphorylation in Dose Dependent Manner In vitro demonstration of anti - tau activity 12 107 106 93 80 50 1 0 20 40 60 80 100 120 Media only OA only OA+PBT434 1uM OA+PBT434 3uM OA+PBT434 10uM OA+PBT434 30uM PBT434 30uM Phosphorylated Tau level in PCC treated with OA pTau normali
Prana Biotechnology — Investor Presentation (June 2018) on 6ix