SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 6-K
REPORT OF FOREIGN PRIVATE ISSUER PURSUANT TO RULE 13a-16 OR
15d-16 UNDER THE SECURITIES EXCHANGE ACT OF 1934
For the month of June 2018
Prana Biotechnology Limited
(Name of Registrant)
Level 3, 460 Bourke Street, Melbourne, VIC 3000, Australia.
(Address of Principal Executive Office)
Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F.
Form 20-F x Form 40-F ¨
Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(1): __
Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(7): __
Indicate by check mark whether by furnishing the information contained in this Form, the registrant is also thereby furnishing the information to the Commission pursuant to Rule 12g3-2(b) under the Securities Exchange Act of 1934.
Yes ¨ No x
If “Yes” is marked, indicate below the file number assigned to the registrant in connection with Rule 12g3-2(b): 82- _____
This Form 6-K is being incorporated by reference into the Registrant’s Registration Statements on Form F-3 (File No. 333-199783) and Form S-8 (File No. 333-153669).
PRANA BIOTECHNOLOGY LIMITED
| 6-K | Items |
| 1. | Investor Presentation – Treatment of Neurological Disorders |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.
| PRANA BIOTECHNOLOGY LIMITED | |||
| (Registrant) | |||
| By: | /s/ Geoffrey Kempler | ||
| Geoffrey Kempler, | |||
| Executive Chairman | |||
June 27, 2018
Treatment of Neurological Disorders David Stamler, MD Chief Medical Officer and SVP, Clinical Development June 2018
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 Harvard ● Focus on neurological disorders including Parkinsonian diseases ● Phase 1 clinical trial commenced ASX Code NASDAQ Code PBT PRAN Share Price A$0.043 US$1.96 (as of 25/06/2018) Shares on Issue ADR 1:60 533,891,470 Cash Position A$16.7m (as of 31/03/2018) Market Capitalisation A$22m 2
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
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 Parkinsonian diseases Published Research Development of PBT434 builds on the experience and science of earlier therapeutic programs in neurodegenerative disease and continues to draw on the work of global leaders in diseases of the brain Evolving Science • Chemistry – Bio21 identifying new drug candidates • Biology screening and translational – Florey Institute • Takeda Pharmaceuticals program focused on slowing or preventing neurodegeneration of the gastrointestinal system R&D Program Why Invest? 4
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 Director at Auspex Pharmaceuticals, led strategic planning and program management in Huntin g ton Disease - chorea from IND through NDA filing. Margaret Bradbury, Ph.D VP, Nonclinical Development 5 Previously Executive Direcgtor CMC Teva/Auspex Pharmaceuticals. Senior member of leadership team responsible for budget managme nt and operational direction of CMC team. Prior to Auspex, was Senior Director, CovX Operations at Pfizer WRD. James Kerr VP, Chemistry, Manufacturing and controls Former VP, Clinical Development and Therapeutic Head, Movement Disorders, Teva Pharmaceuticals and Chief Medical Officer, Auspex Phamarceuticals . Part of Teva’s US$3.5 billion acquisition of Auspex . Led development of AUSTEDO ( deutetrabenazine ), new drug for treatment of Huntington’s disease (approved by FDA - April 2017) and tardive dyskinesia, also in 2017.
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 Director Director since 2005 Director of Armadale Capital Principal of Henslow Non - Executive Director of Emefcy Group Previously Chairman of iSonea Ltd, formerly KarmelSonix Mr. Peter Marks B. Com., M Ec. Non - Executive Director 30 years experience in finance Previously Director Momentum Ventures Director of the Australian - Israel Chamber of Commerce Mr. Brian Meltzer B. Pharm, M.Sc., Ph.D. FAICD Non - Executive Director Extensive experience in the pharmaceutical industry Director of Waide Previously Executive Chairman and Founding Director of Synermedica, one of Australia’s leading consultant research organisations Dr. George Mihaly B.Sc. (Hons) Non - Executive Director Leading biotechnology investor and advisor Non - Executive Director of AusBiotech Former Biotechnology Analyst QIC, an investment fund with over $60 billion under management Previously Director of OncoSil Medical Mr Lawrence Gozlan Professor of Neurology, Pharmacology and Human Science Non - Executive Director Chairman of our Research and Development Advisory Board Has served as a member to several FDA advisory committees Professor Ira Shoulson 6
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 parkinsonism. ● PBT434 has been shown to reduce the abnormal accumulation of these proteins in animal models of disease by restoring normal iron balance in the brain. Amyloid beta Tau α - synuclein PBT434 (2nd generation) ● Targets intracellular proteins with established function: α - synuclein, tau ● Mechanism of action: Effluxes labile Fe ● Reduces α - synuclein accumulation in animal models of PD and MSA ● Reduces tau accumulation in animal model of tauopathy AD FTD CBD PSP MSA PD PDD DLB 7 Three proteins and associated diseases
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 function in animal models of synucleinopathy ● PBT434 also prevents tau accumulation and improves function in animal models of tauopathy ● Clear link between iron and the synucleinopathies and tauopathies ● Phase 2 data with a related compound supports proof of concept ● Clear development path for symptomatic therapy in atypical parkinsonism ● Current symptomatic therapy has limited benefit ● Potential path for disease modifying therapy for the synucleinopathies Conclusion: PBT434 is an excellent drug candidate to treat neurodegenerative diseases 8
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 ○ Non - toxic dose exceeds efficacious dose by >10 - fold based on allometric scaling 9
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 facilitating synaptic vesicle fusion to pre - synaptic membrane MAb to α - synuclein stains red 10
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 clear or prevent the formation of toxic forms of α - synuclein are currently being investigated in the laboratory, and clinical trials have already begun . ” AstraZeneca and Takeda establish collaboration to develop and commercialise MEDI 1341 for Parkinson’s disease - 29 August 2017 11
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 PBT434 ( ;M) F e r e l e a s e d ( C P M ) Iron efflux from cultured M17 cells *** *** α SN+Fe+PBT434 α SN+Fe 12
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 - synuclein accumulation, aggregation and preserving neurons Transferrin Normal Iron Trafficking Accumulation ↑H 2 O 2 ↑Fe Ineffective autophagy NH 2 HO HO Dopamine ↑ Oxidative Stress 13 N N O R R O R R Fe ↑ Ferroportin Fe Fe Fe Fe Cytoplasm Extracellular PBT434 exports Fe from cell
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
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 Treatment of Iron Overload • Black Box for neutropenia and agranucloctyosis • Iron Binding Affinity Kd=10 - 36 PBT434 • Iron Binding Affinity Kd=10 - 10 Reducing excess iron associated with improved motor function Worsening 15
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 Biochem 1980 49: 357 - 393 Aisen P, Leibman A, Zweier J. J Biol Chem. 1978; 253:1930 - 1937 Kline MA and Orvig C. Clin Chem (1992); 38: 562 - 565 16 Stronger binding
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. Patients with MSA have difficulty maintaining blood pressure along with bowel and bladder dysfunction whereas PSP patients have unsteady gait, frequent falls, visual difficulties and cognitive impairment . Initial Disease Targets 17
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 per 100,000 in the U.S. ● Characterised by a variable combination of ○ Parkinsonism, which responds poorly to Levodopa ○ Autonomic instability: Orthostatic hypotension, bladder dysfunction, erectile dysfunction, constipation ○ Cerebellar impairments ● MSA patients have neuron loss in multiple brain regions ● The hallmark of MSA is the accumulation of α - synuclein within neuronal cells and glial support cells ● Fatal and rapidly progressive neurodegenerative disease ● Typically presents in 50s ● Orphan disease: Prevalence ~5 per 100,000 in the U.S. ● Characterised by a variable combination of ○ Parkinsonism, which responds poorly to Levodopa ○ Loss of coordination, unsteady gait (walking pattern) ○ Vision difficulty ● Characterised by Parkinsonian movements with typical stiffness and lack of coordination, eye movement is also limited. An MRI may show a shrinking of the brainstem ● Aggregated tau is associated with PSP © Mayo Foundation for Education and Medical Research 18
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 assessing the safety and tolerability of PBT434 after single and multiple ascending dose administration. ● Secondary endpoints include a range of pharmacokinetics measures to understand how PBT434 is absorbed and metabolized by the body 19
Scientific evidence growing for PBT434 20
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 aggregation Treatment randomly allocated • 4 - 8 months of age • ; 30 mg/kg/day (via feed) Assessments done in blinded manner h A 5 3 T ; - s y n Vehicle PBT434 0 2 4 6 ** Foot Clasping % C l a s p i n g Vehicle PBT434 0 50 100 ** 21
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 m e ( s ) P=0.0489 Pole test (motor function) W/T Veh PBT434 2000 3000 4000 5000 6000 T o t a l N S N p c n e u r o n s P=0.001 Substantia nigra Neurons 22 Veh PBT434 0 5000 10000 15000 N G l i a l C e l l I n c l u s i o n s P=0.0007 Glial Cell Inclusions Substantia nigra Veh PBT434 0 5000 10000 15000 N G l i a l C e l l I n c l u s i o n s P=0.0012
Brain Iron is Increased in Synucleinopathies (PD, MSA) and also Tauopathies (PSP) 23
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 vesicles, and microtubule dynamics involved in memory formation ● Normal activity of tau is regulated by phosphorylation which is highly sensitive to iron levels ● In disease, hyperphosphorylation leads to disrupted cellular function/cell death ● Loss of tau function exacerbates iron dysregulation J. Cell Science 117, 5721 - 5729; 2004 Yamamoto, 2002; Ahmadi 2017 24 Tau in health
Progressive Supranuclear Palsy (PSP): A Tauopathy Brain Iron increased compared to Healthy controls 25 Dexter et al. Brain. 1991;114:1953.
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 0.00 0.05 0.10 0.15 0.20 0.25 S M I 5 1 p o s i t i v e / a r e a * Vehicle PBT434 20 25 30 35 40 T i m e ( % ) i n N o v e l a r m *
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 stabilization Genetic evidence for disease Yes (SNCA gene) Yes (MAPT gene) Iron dysregulation in associated disease Yes Yes Iron promotes phosphorylation and protein aggregation Yes Yes PBT434 effective in animal models Yes Yes Abnormal protein accumulates in disease Yes (Lewy body, Glial cell inclusions) Yes (Neurofibrillary tangles) Potential Target Diseases Multiple System Atrophy Parkinson’s Disease Progressive Supranuclear Palsy Frontotemporal Dementia 27
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 receives $3.02m cash refund under the Australian Government’s R&D x Prana expands with San Francisco office 28 Building Momentum
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Scientific Appendices
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 disease severity 31
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 conserved in vertebrates, only humans develop synucleinopathy ● Only human α - synuclein mRNA contains an Iron responsive element Lee and Trojanowski, 2006 ● The iron responsive element (IRE) of α - synuclein is a 5’ - untranslated region of mRNA predicted to form a single RNA stem loop ● The stem loop shows striking similarity to the 5’ - UTRs of mRNAs encoding ferritin and ferroportin Friedlich, Tanzi, et al. 2007 32
Frontotemporal Dementia – A Tauopathy Iron Content assessed by Brain MRI in FTD Patients 33 Evidence for increased Iron in the Frontal and Temporal lobes
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 normalised against GAPDH