Slide 1: Technical Presentation October 2020
For personal use only Technical Presentation October 2020
Slide 2: Key investment highlights
Key investment highlights For personal use only PYC is an RNA therapeutics company specialising in diseases of the eye RNA therapeutics have come of age But their ongoing success is impeded by inefficient or toxic delivery inside cells PYC’s cell-penetrating peptide (CPP) delivery platform solve
Slide 3: Corporate overview
For personal use only Corporate overview 3
Slide 4: PYC Corporate Snapshot
PYC Corporate Snapshot (ASX: PYC) For personal use only Financial Information (5 October 2020, AUD) Share Price Performance (12 months) Share price $0.17 Number of shares 2,930M Market Capitalisation $498M Cash (30-Jun-20) $25M Debt (30-Jun-20) Nil Enterprise Value $473M Board of Director Alan Tribe
Slide 5: Leadership team
Leadership team For personal use only Executive management Dr Rohan Hockings Professor Sue Fletcher Kaggen Ausma MBBS (Hons), JD GDLP PhD, BSc LLB, Becons (Hons) Chief Executive Officer Chief Scientific Officer Chief Business Officer Experience across both clinical Leading global expert and pioneer
Slide 6: PYC trades at a substantial discount to its US peers
PYC trades at a substantial discount to its US peers For personal use only Market Cap. USD M1 Cash, USD M2 Stage IND date Platform Lead target 330 18 Pre-clinical 1H 22 RNA delivery Rare Ocular 1,250 345 Pre-clinical 2H 21 RNA delivery Rare Muscle 1,040 375 Pre-clinical 1H 22 RNA delivery Rare Muscl
Slide 7: PYC's Therapeutic Approach
For personal use only PYC’s Therapeutic Approach 7
Slide 8: PYC combines RNA drug design expertise with RNA drug delivery technology
PYC combines RNA drug design expertise with RNA drug delivery technology to create powerful precision therapies World-class RNA drug design specialists Delivery technology that enables RNA drugs to For personal use only reach their target inside the cell Team led by Prof. Sue Fletcher – co-invento
Slide 9: PYC is in the right place at the right time
PYC is in the right place at the right time – An RNA specialist in the era of precision medicine “In the long run, oligonucleotides are likely to become a major class of For personal use only therapeutics, on par with small molecules and biologics1” Public RNA focused companies market capitalisation
Slide 10: PYC's drug design team know how to choose the right approach
PYC’s drug design team know how to choose the right approach for the target indication For personal use only Disease state Exons – code for Protein Isoform A protein mRNA Pre-mRNA siRNA’s and ‘Gapmer’ ASOs can alter the exon ASOs can mark mRNA for selection to change the protein. degradation to prev
Slide 11: PYC's drugs can access cells beyond the reach of competitive RNA technologies
PYC’s drugs can access cells (and diseases) beyond the reach of competitive RNA technologies For personal use only The challenge for most RNA drugs The cell membrane has evolved over hundreds of PYC’s CPP-PMOs enable RNA therapeutics to millions of years to keep foreign substances out target the pre
Slide 12: PYC's proprietary delivery platform is unique
PYC’s proprietary delivery platform is unique - leveraging nature’s solution to identify distinctive delivery vehicles Microorganisms have evolved over millions of years to safely interact with the human body – PYC’s For personal use only libraries leverage this pressure to screen for safe, highly e
Slide 13: PYC's drug development pipeline
PYC’s drug development pipeline For personal use only PYC is a multi-asset drug development company Program overview Indication and stage of development Estimated market size Lead Organ Program Target Discovery IND-enabling Clinical Marketed selection Eye VP-001 PRPF31 Retinitis Pigmentosa Type 11 U
Slide 14: Upcoming milestones
Upcoming milestones For personal use only 2H20 1H21 2H21 1H22 Orphan drug DRF studies in Rabbit Large animal long Submission of IND and VP-001 designation for VP-001 and NHP term toxicity data CTN for RP11 for RP11 Large animal PK data Assessment of pro- Assessment of anti- PYC-001 sur
Slide 15: PYC has deep (and evolving) IP protection
PYC has deep (and evolving) IP protection supporting our platform from discovery through to drug For personal use only Description Status Expiry Libraries 2nd generation library construction and display Granted 2027 Screening Phenotypic screening of the peptide libraries Granted 2025 1st generation
Slide 16: VP-001 for the treatment of RP11
For personal use only VP-001 for the treatment of RP11
Slide 17: Executive Summary – VP-001 for Retinitis Pigmentosa type 11
Executive Summary – VP-001 for Retinitis Pigmentosa type 11 For personal use only 1. Retinitis Pigmentosa type 11 (RP11) is a large target market with no disease-modifying therapies available for patients (nor in clinical development) 2. PYC’s lead drug program (VP-001) holds the promise of rescuing
Slide 18: RP11 is a large target market with no disease-modifying therapies
For personal use only 1. RP11 is a large target market with no disease-modifying therapies available for patients (nor in clinical development)
Slide 19: Large number of patients with RP11 have no treatment options
OVERVIEW There are a large number of patients with Retinitis Pigmentosa type 11 who have no available treatment options For personal use only Retinitis Pigmentosa is a genetic, blinding eye disease VP-001 will treat Retinitis Pigmentosa Type 11 (RP11) ‒ Severe, progressive blinding eye disease ‒ O
Slide 20: VP-001 will serve a 1-2B USD p.a. market
OVERVIEW VP-001 will serve a 1-2B USD p.a. market Retinitis Pigmentosa (RP) prevalence For personal use only 1 in 2,500-4,0001 proportion of people in the population with RP Proportion of RP that is autosomal dominant (adRP) 30-40%1 Inherited in a dominant pattern No competitors Proportion of adRP t
Slide 21: VP-001 targets a down-regulator of the gene underlying RP11
DEEP-DIVE VP-001 targets a down-regulator of the gene underlying RP11 For personal use only Healthy eye Eye with RP11 PYC’s lead drug We all have two copies of each gene in People with RP11 have only one healthy Our drug knocks down a protein that our chromosomes gene (and one mutated gene) down-reg
Slide 22: Insufficient PRPF31 protein drives RP11; CNOT3 controls PRPF31 expression
DEEP-DIVE Insufficient PRPF31 protein drives RP11 and CNOT3 expression controls PRPF31 expression PRPF31 expression levels determine if a patient suffers vision loss CNOT3 protein levels regulate PRPF31 expression For personal use only RP11 patients have one healthy copy of PRPF31 and one CNOT3
Slide 23: VP-001 uses an antisense oligo with a morpholino backbone
DEEP-DIVE VP-001 uses an antisense oligo with a morpholino (PMO) backbone to reduce the functional effect of CNOT3 on PRPF31 expression Schematic strategy of PMO-mediated CNOT3 exon skipping For personal use only Without VP-001 With VP-001 PMO Pre- Exon Intron Exon Intron Exon C Intron Exon D Exon I
Slide 24: VP-001 holds the promise of rescuing progressive cell death
For personal use only 2. VP-001 holds the promise of rescuing progressive cell death and blindness in patients with RP11
Slide 25: Delivery of an RNA therapeutic into the nucleus of the RPE in mice
DEEP-DIVE PYC’s drug delivery technology can successfully deliver an RNA therapeutic into the nucleus of the target cell (the RPE) in mice Delivery dose response (lead CPP with ‘reporter ASO’ targeting Smn gene after IVT administration)1 For personal use only Neural Retina RPE/Choroid Exon Skipping
Slide 26: VP-001 is the only disease modifying therapy treating the entire retina
DEEP-DIVE VP-001 is the only disease modifying therapy in development that treats the entire retina Treating the disease requires a delivery technology to Breadth of delivery is also required to For personal use only reach the deepest cells at the back of the eye treat the entire eye Cells degener
Slide 27: VP-001 achieves desired exon skipping in patient derived models
DEEP-DIVE VP-001 achieves the desired exon skipping effect at the anticipated clinical concentration in patient derived models We have proven that our drug modulates target gene expression in multiple patient derived models… For personal use only Exon skipping, retinal organoid Exon skipping, Retina
Slide 28: Exon skipping translates into upregulation of the deficient protein
DEEP-DIVE This exon skipping translates into an upregulation of the deficient protein at levels expected to rescue the disease For personal use only PRPF31 protein levels, RPE, 5µM treatment, (n=1 per patient) 2.5 Day 2 Day 5 Day 12 Untreated Fold change over untreated Treated 2.0 1.5 Anticipated di
Slide 29: Upregulation of target protein rescues functional deficits
DEEP-DIVE Upregulation of the target protein rescues the functional deficits associated with the disease Structure of the Retina Impact of RP11 For personal use only Restoration Healthy RP11 Impact of RP11 with VP-001 Shorter ‘stunted’ connecting cilium in TBD the photoreceptors Lower ‘phagocyto
Slide 30: RP11 patients experience lost functionality of RPE cells
DEEP-DIVE RP11 patients experience lost functionality of Retinal Pigment Epithelial cells (RPE) Structure of the Retina – target cells in the back Phagocytosis – the ‘self-repair’ process where RPE For personal use only of the eye (RPE) cells ‘clear away’ debris from the photoreceptors. If outer seg
Slide 31: VP-001 restores RPE functionality in patient derived models
DEEP-DIVE VP-001 restores RPE functionality in patient derived models Phagocytosis assay, 5µM 6hr timepoint For personal use only A) Green ‘specks’ are Phagocytosed outer-segments B) Intensity of phagocytosis per RPE cell (more green = improved functionality) p<0.01 Untreated PYC CPP-PMO Un- PYC CPP
Slide 32: PYC's CPP delivery technology is both safe and effective
For personal use only 3. PYC’s CPP delivery technology used in VP-001 is both safe and effective 32
Slide 33: Functional correction without causing toxicity in the retina
DEEP-DIVE PYC’s lead drug is competitively differentiated in achieving this functional correction without causing toxicity in the retina For personal use only Retinal stress marker expression in mice Retinal thinning in mice Day 5 post single 1.6µg IVT injection Day 21 post IVT injection OCT imaging
Slide 34: Dose dependent response shows no increasing acute toxicity
DEEP-DIVE The dose dependant response shows no increasing acute toxicity in the mouse Dose dependant increase in effect … … and no increase in toxicity markers For personal use only Exon-skipping, Day 7 in the mouse eye Gfap expression, Day 7 in the mouse eye Neural Retina 0.025 Normalised to ave. 0
Slide 35: VP-001 has an attractive path to market
For personal use only 4. VP-001 has an attractive path to market with small clinical trials and the potential for a single pivotal study 35
Slide 36: The path to market for VP-001 has several major advantages
OVERVIEW The path to market for VP-001 has several major advantages over conventional clinical development pathways For personal use only Stage IND-enabling Phase 1/2 Phase 2/3 Approval Timeline 18 months 15 months 18 months 6 months Higher probability Shorter time to Lower cost of success market
Slide 37: VP-001 is on track for clinical development starting in 2022
OVERVIEW VP-001 is on track for Clinical development starting in 2022 For personal use only 2H 2020 1H 2021 2H 2021 1H 2022 Pre-clinical Dose Range finding studies (Rabbit, NHP) Long term GLP toxicology studies (Rabbit and NHP) Pharmacokinetics (Rabbits) Regulatory ODD IND submission submission CTN
Slide 38: Ocular pipeline
For personal use only Ocular pipeline 38
Slide 39: PYC has the capability to rapidly scale its technology in the retina
PYC has the capability to rapidly scale its technology in the retina For personal use only Right Biology Does the drug Do we Does the drug progress to alter the disease in Right Indication engage the IND-enabling a functional target safely? studies? model? Right Commercials PYC’s ‘RNA hub’ ~3 months
Slide 40: Advancing our lead program will validate our platform for retinal disease
Advancing our lead program into the clinic will validate our drug delivery platform for retinal disease For personal use only The Retina is a high value target Proven Delivery in the Eye Develop Further Applications 1.6ug IVT injection in mice % truncated SMN1 transcript Diseases primarily affecting
Slide 41: PYC-001 – PYC's second drug development program
PYC-001 – PYC’s second drug development program For personal use only Diabetic Retinopathy (DR) is the leading cause of vision loss in adults aged 20–74 years Current treatment options for DR are limited due to a lack of response to first line anti-Vascular Endothelial Growth Factor (VEGF) thera
Slide 42: Common eye diseases are linked through dysfunction of blood vessels
Common eye diseases are linked through dysfunction of blood vessels in the eye For personal use only 42 Image: Mayoclinic.com
Slide 43: Inhibiting new blood vessel growth has been a major step forward
Inhibiting new blood vessel growth (VEGF-inhibition) has been a major step forward in the management of these diseases For personal use only Global ocular anti-VEGF sales, USD B 10 9 8 7 6 5 4 3 2 1 0 2014 2015 2016 2017 2018 2019 43 Source: Roche, Regeneron annual reports and financial statements
Slide 44: Inhibition of VEGF is known to cause retinal ganglion cells to die
But… Inhibition of VEGF is known to cause retinal ganglion cells to die and is also suspected of being linked to macular atrophy For personal use only “VEGF inhibition increased Retinal Ganglion Cells apoptosis and neuronal damage in diabetic retinopathy” (1) “A majority of patients show Macular Atr
Slide 45: Alternative method of inhibiting blood vessel growth without negative effects
There is an alternative method of inhibiting new blood vessel growth without the negative effects of VEGF inhibition For personal use only VEGFA pre-mRNA Exon 7 Exon 7b Exon 8a Exon 8b PYC’s drug ‘switches’ from the 165a to the 165b isoform of VEGF VEGFA-165a mRNA VEGFA-165b mRNA Exon 1-5, 7 Exon 7b
Slide 46: A subtle change in ratio of protein regulated by this switch
A very subtle change in the ratio of protein regulated by this ‘switch’ is required to correct the disease process For personal use only VEGF-A165a causes RPE tight junction breakdown VEGF-A165b prevents VEGF-A165a -induced changes in tight junctions Worse outcome Ved N, Hulse RP, Bestall SM, Donald
Slide 47: The therapeutic value of this approach has been recognised
The therapeutic value of this approach has been recognised For personal use only “This switch changes what would be otherwise mild effects from activation by VEGFA165b, to stronger activation of retinal endothelial cells. Isoform switching from VEGFA165a to VEGFA165b would be an excellent target for
Slide 48: Program expected to progress into IND enabling studies in 2021
The program is expected to progress into Investigational New Drug enabling studies in 2021 For personal use only Evaluation in patient cells Evaluation in animal models and/or patient derived models Expected 4Q 2020 Expected 3Q 2021 IND-enabling decision in 2021 48
Slide 49: Leveraging the platform beyond the eye
For personal use only Leveraging the platform beyond the eye 49
Slide 50: PYC has multiple CPPs with demonstrated capability outside the eye
PYC has multiple CPPs with demonstrated capability outside the eye For personal use only Intravenous administration of CPP-PMO(Smn) into mice Systemic toxicity markers, 48hr post 32mg/kg n=2/dose injection in mice Lead CPP – PMO Linker 1 Linker 2 ALT Normal Normal Liver AST Normal Normal Pathology A
Slide 51: PYC is exploring CPP-LNP conjugates to deliver other high value cargoes
PYC is exploring CPP-LNP conjugates to deliver other high value cargoes to hard to reach tissues and cells For personal use only PYC is currently in ‘proof of concept’ studies for a CPP-LNP conjugate delivery system to enable the effective and safe delivery of negative charged molecules (siRNA, DNA
Slide 52: Disclaimer
Disclaimer For personal use only The purpose of this presentation is to provide an update of the business of PYC Therapeutics Limited (ASX:PYC) [‘PYC’]. These slides have been prepared as a presentation aid only and the information they contain may require further explanation and/or clarification. A