Corporate Presentation - February 2021 Life-changing science - PYC Therapeutics
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Corporate
Life-changing
science Presentation
February 2021
Overview
PYC is an RNA therapeutics company with an initial focus on 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 solves this ‘delivery’ problem
PYC’s competitive advantage is getting more drug safely into the target cell
§ PYC is applying this advantage to develop drugs for eye disease: an area of unmet need
PYC’s lead program is the first disease-modifying therapy for Retinitis Pigmentosa type 11 - a USD1-
2B p.a. target market
§ PYC’s technology scales rapidly in the eye: same delivery tech for other RNA cargoes
PYC has two other defined drug programs, each with blockbuster potential, addressing Diabetic
Retinopathy and Autosomal Dominant Optic Atrophy
§ Building on its success in the eye, PYC is expanding the application of its technology
The Company’s initial focus outside the eye is on neurodegenerative diseases
2
Corporate Snapshot
(ASX: PYC)
Financial Information (29 January 2021, AUD) Share Price Performance (12 months)
ASX website
Share price $0.14
Number of shares 3,170M
Market Capitalisation $445M
Cash $57M
Debt Nil
Enterprise Value $388M
Board of Directors
Alan Tribe – Chairman
Sahm Nasseri– Chief Executive Officer (USA)
Dr Rohan Hockings – Chief Executive Officer (Australia)
Building out a US base to complement Australian discovery hub
Dr Bernard Hockings – Non-Executive Director
• Early discovery and candidate proof of concept development led by PYC Australia
Top Shareholders (29 January 2021) % • Pre-clinical, clinical development and regulatory engagement to be led by PYC US
Alan Tribe 30.11% • Corporate HQ shifting to US through 2021, in-line with corporate development activities
David Sietsma 8.96% • Broaden Board of Directors to include US membership
Dr Bernard Hockings 8.41%
Anthony Barton and Associates 6.10%
3
PYC’s growing Executive Leadership team built across the US and
Australia
PYC Australia Discovery and Early Development
PYC US Development and Corporate HQ Hub
Sahm Nasseri, Chief Executive Officer US Professor Sue Fletcher, Chief Scientific Officer
Extensive experience in commercial drug development Leading global expert and pioneer in RNA therapeutics. Co-
with Merck, incl. product leadership, investor relations and inventor of Exondys-51, Vyondys-53, and Casimersen,
business development. Consultant with McKinsey & Co commercialised by Sarepta. Prof. Fletcher leads PYC’s
prior to Merck. discovery team and is the co-inventor of VP-001
Dr Glenn Noronha, Chief Development Officer Dr Rohan Hockings, Chief Executive Officer Australia
Over 20 year experience leading drug development Experience across both clinical and commercial roles
programs, including six ophthalmology programs from including Private Equity, Commercial Law, and Strategy,
candidate nomination through clinical development and prior to joining PYC
approval. Previous C-suite and leadership roles at
Clearsite, Foresight, BridgeBio, and Alcon
Kaggen Ausma, Chief Business Officer
Previous roles in McKinsey & Co across Strategy,
Commercial, VC and PE, and public market finance with
CLSA Asia-Pacific
4
PYC combines World-class RNA therapy design + Revolutionary
delivery technology
World-class RNA drug design specialists, leveraging Delivery technology that enables RNA drugs to
Antisense Oligonucleotides reach their target inside the cell
§ Team led by Chief Scientific Officer- Prof. Sue Fletcher – co- § The single greatest challenge for RNA drugs is the ability to cross
inventor of two FDA approved RNA therapeutics with others in late- the cell membrane to reach their target
stage clinical development § PYC’s delivery technology is based on a unique library of Cell
§ RNA drugs are precision therapeutics that act on the inside of cells Penetrating Peptides, nature’s solution to safely access cells
§ They occupy a unique position in the pharmaceutical landscape due § Cell Penetrating Peptides safely deliver the RNA drug:
to their balance of durability and titratability § i) to the cell; and
§ PYC has the capability to identify highly valuable targets and § ii) across the cell membrane where it can engage its
design tailored RNA intervention strategies to match intended target in the cell nucleus
5
Delivery remains the rate limiting step for RNA drugs
PYC’s CPPs have a competitive edge in solving this problem
Delivery technology Companies Cargoes Tech dev. stage Technologies core mechanism of action
Naturally derived cell- PMO Pre-clinical § Utilise library of natural peptide to identify
penetrating peptides peptide sequence driven uptake for delivery of
cargoes into the cell
Chemically derived cell- PMO Phase 1/2 § Utilise chemically derived, highly charge dense
penetrating peptides and/or constrained peptides to enable delivery
of cargoes into the cell
Antibody conjugates ASO and Pre-clinical § Utilise an antibody to bind to a cell surface
siRNA receptor and transport to traffic cargoes into
the cell
Ligand conjugates ASO and Marketed § Utilise a ligand to bind to a cell surface receptor
siRNA and transport to traffic cargoes into the cell
Lipid conjugates siRNA Pre-clinical § Utilise a fatty acid to bind to a cell surface
receptor and transport to traffic cargoes into
the cell
Exosomes/LNP siRNA, ASO, Pre-clinical § Utilise exosomes to present or deliver ASOs
plasmid using the exosomes trafficking ability
Chemically modified ASO Marketed § Modify the ASO backbone chemistry to improve
backbone uptake and/or efficacy
6
PYC’s CPP-PMO technology offers several advantages over other
genetic therapy modalities
PYC CPP-PMO advantages Why it matters AAV gene ASO siRNA
therapies
• PMOs do not bind or sequester positively charged
Safe delivery of drug to
splicing factors as do negatively charged ASOs,
nucleus
hence cause lower toxicity
• PMOs have higher resistance to intracellular
Durability of drug within
degradation vs. other ASOs which provides potential
cell
for longer duration of effect
• CPP-PMO is distributed broadly across tissue—
Broad distribution within
critical for treating diseases affecting tissue
a target tissue
structure and for accessing hard to reach cells
• CPP-PMO has potential applicability to a range of
Effective delivery to a
target tissues and cell types vs. other delivery
range of target tissues
modalities (e.g., GalNAc and antibodies)
• Like other ASO approaches, CPP-PMO allows precise
Precise modulation of
intervention to modulate cellular pathways to treat
target gene multifactorial diseases
• Like other RNA therapies, CPP-PMOs avoid risk of over-
Retention of endogenous
expression of proteins which can cause additional
cellular control disease, esp. in diseases caused by haploinsufficiency
7
PYC is applying our technology to create life changing treatments,
with an initial focus on diseases of the eye
PYC is a multi-asset drug development company
Program overview Indication and stage of development Estimated market size
Organ Program Target Lead
Discovery IND-enabling Clinical Marketed
selection
Eye
VP-001 PRPF31 Retinitis pigmentosa type 11 US$1-2 billion p.a.
PYC-001 VEGF Diabetic retinopathy >US$5 billion p.a.
Autosomal dominant optic ~US$1 billion p.a.
VP-002 OPA1
atrophy
Multiple Undisclosed Discovery pipeline Multiples of programs
CNS
Multiple Undisclosed Discovery pipeline Multiples of programs
PYC has 100% ownership of PYC-001 and 90% ownership of VP-001 and VP-002 (10% ownership by Lions Eye Institute, Australia)
8
VP-001 has already demonstrated a strong preclinical efficacy
signal in vivo and in patient derived models
PYC has demonstrated delivery to the target cells, And shown upregulation of the target protein, PRPF31, in
Retinal Pigmented Epithelium (RPE), for 28 days in patient iPSC derived RPE pathogenic mutations in PRPF31
the mouse
100
%D7 RPE isolate (28 days) (each patients with a different mutation)
Exon 7 skipping in RPE1, Day 28 in the mouse eye post IVT PRPF31 protein levels2, RPE, 5µM treatment, (n=1 per patient)
80
2.5
Day 2 Day 5 Day 12 Untreated
Exon Skipping Smn (%)
60
60
Treated
Fold change over untreated
2.0
*
40
40 1.5
Anticipated disease
19.1 1.0
correction threshold
20
20 13.7
0.5
5.0
0.0
0 0.0
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Vehicle 1.6µg 3.2µg 6.4µg
l
e)
e)
e)
ro
ey
ey
ey
nt
Non-penetrant Penetrant
g/
g/
g/
co
Lead CPP-PMO
µ
µ
µ
.6
.2
.4
e
1 Day 28 post intravitreal injection in mice. A readout of drug delivery, Exon-skipping of Survival of Motor Neuron (Smn) in the mouse retina across 3 dose cohorts (n=12 for each dose cohort, n=4 for vehicle)
9
cl
(1
(3
(6
2 For anticipated disease correction threshold see ‘Venturini, G. CNOT3 Is a Modifier of PRPF31 Mutations in Retinitis Pigmentosa with Incomplete Penetrance. PLOS Genetics November 2012’
hi
See ASX Announcement 22 July 2020; 7 October 2020
1
1
1
The dose dependant response shows no increasing acute toxicity
in the mouse
Dose dependant increase in effect … … and no increase in toxicity markers
Exon 7 skipping, Day 7 in the mouse eye ddPCR
Gfap expression, for
Day 7 in theGFAP expression
mouse eye
in Neural Retina at D7 (n=12)
Neural Retina
0.025
Exon 7 Skipping Smn
Normalised to ave.
0.020
of HK genes
0.015
0.010
0.005
0.000
1.6µg
µg
µg
µg
Vehicle 3.2µg 6.4µg 1.6µg
l
Vehicle 3.2µg 6.4µg
ro
nt
6
2
4
1.
3.
6.
co
1
1
1
Lead CPP-ASO Lead CPP-ASO
N
N
N
l e
M
M
M
ic
S
S
S
eh
2-
2-
2-
Toxicity determined by treating mouse retinas with 1.6 micrograms of an Antisense Oligonucleotide (ASO) delivered by each peptide and then measuring retinal stress based on levels of Glial Fibrillary Acidic Protein (GFAP). GFAP levels
V
xt
xt
xt
have been measured after retinal harvesting from mice at day 7 post intravitreal injection and normalised to a pool of ‘house-keeping’ genes.
10
E
E
E
1-
1-
1-
See ASX Announcement 22 July 2020VP-001 has 2 fundamental advantages over AAV-gene therapies in
inherited retinal disease
Advantage of an RNA 1. RNA therapies achieve an even 2. RNA therapies retain endogenous
therapy approach cellular level distribution within the control of protein expression in the retina
retina
Comparison to AAV-gene AAV-gene therapy engenders a patchy AAV-gene therapy leads to a 4-5 fold increase in
therapy distribution in the target tissue due to PRPF31 expression
variable cellular uptake – the consequence is
a highly uneven drug distribution within the “In a highly specialized and organized tissue like
target tissue the retina, it is particularly important to
maintain endogenous gene regulation”2
Illustration in the “the rescue provided by AAV-derived PRPF31 PRPF31 gene therapy has the potential to
context of RP11 (PYC’s may be limited to certain RPE functions, induce a disease phenotype in remaining
lead program) while others like the barrier function cannot viable cells through overexpression of the
be rescued”1 target protein3
Implication for patients Only RNA therapies currently have There is a risk to the remaining viable
the ability to rescue the global cells in an RP11 patient’s eyes of the
function of the RPE monolayer – AAV-gene therapy that is avoided with
protecting patients from confounding an RNA based approach
macular oedema
11
1 Brydon. E. AAV-Mediated Gene Augmentation Therapy Restores Critical Functions in Mutant PRPF31+/− iPSC-Derived RPE Cells; 2 Bacchi. N. Splicing-Correcting Therapeutic Approaches for Retinal Dystrophies: Where
Endogenous Gene Regulation and Specificity Matter; 3 Farkas. M. RNA-seq guided gene therapy for vision lossPYC’s CPP-PMO has demonstrated potential outside the eye and a
clear delivery advantage
CPP-PMOs demonstrate strong uptake across high value CPP-PMOs show a clear advantage over naked
tissues include heart and diaphragm ASOs in delivery to ‘hard to reach’ tissues
Exon 7 skipping (%) in tissue 1, Single I.V. injection in mice, Exon 7 skipping (%) in RPE/Choroid, Single
day 2 IVT injection, day 5
Exon 7 Skipping Smn (%)
45
Exon 7 Skipping Smn (%)
40
35
31
30
25
20
15
10
5
0 0
0
PS ASO2 PMO CPP-PMO
10mcg/eye 1.6mcg/eye 1.6mcg/eye
1 Day 2 post intravenous injection in mice. A readout of drug delivery, Exon-skipping of Survival of Motor Neuron (Smn) in the mouse tissue across 3 dose cohorts (n=2 for each dose cohort)
2 PS: Phosphorothioate backbone antisense oligonucleotide;
12
See ASX Announcement 14 October 2019Major value catalysts in 2021 provide a strong foundation for
corporate development
• VP001- lead program
Multiple read-outs in 2021 across pipeline for additional Ocular programs and CNS programs (Retinitis Pigmentosa)
• PYC001 and VP002
additional ocular programs
• 1st CNS program expected
early 2021
• 4th and 5th ocular program
PYC001 and VP001 large PYC001 and
Key internal VP002 efficacy animal VP002 efficacy
expected in 2021
development Secured AUD data in patient (rabbit and data in animal VP001 IND
catalysts 40M capital derived models NHP) tox models submission
raise read-out (1H 2022)
4Q20 1Q21 2Q21 3Q21 4Q21 1Q22 2Q22
13PYC is focused on delivering clinical proof-of-concept in our lead
indication
PYC’s potential development pipeline in 2025 Milestones (2021 and 2022
highlighted in bold)
Lead IND-
Organ Program Discovery
selection enabling
Clinical Marketed
Ocular VP-001 Retinitis pigmentosa type 11
§ Large animal toxicity (Q1/2 2021)
§ IND (Q2 2022)
§ Human safety (H1 2023)
PYC-001 Diabetic retinopathy Revenue § Human efficacy (H1 2023 and 2024)
generating § NDA/revenue generation (H1/2 2025)
VP-002 Autosomal dominant optic atrophy
§ Efficacy in patient derived models (H1
Ocular program #4 2021)
§ Efficacy in animal models (H2 2021)
Ocular program #5 § IND toxicology/submission (H1/2 2023)
§ Human safety (2024)
Discovery pipeline
§ Efficacy in patient derived models (H1
2021)
CNS § Efficacy in animal models (H2 2021)
Neurodegenerative disease #1 § IND toxicology/submission (H1/2 2023)
§ Human safety/efficacy (2023/2024)
Neurodegenerative disease #2
§ Multiple read-outs across pipeline for:
Discovery pipeline § IP filing;
§ Efficacy milestones in animals and
patient derived models
§ Safety read-outs in animals
§ Progression into clinical
development
14PYC’s Therapeutic Approach
15PYC is in the right place at the right time
“In the long run, oligonucleotides are likely to become a major class of therapeutics, on
par with small molecules and biologics1”
Public RNA focused companies market capitalisation, USD B RNA therapy approvals
Drug RNA drug Approved
84
ASO2 1998
59 ASO 2013
43 ASO (PMO2) 2016
25 ASO 2016
11 ASO 2018
siRNA2 2018
2017 2018 2019 2020 Sep-20
ASO (PMO) 2019
Companies, # 7 8 11 12 12
siRNA 2019
Ave. valuation, USD B 1.6 3.2 3.9 4.9 7.0
1 Watts JK, Brown RH, Khvorova A. Nucleic Acid Therapeutics for Neurological Diseases. Neurotherapeutics. 2019;16(2):245-247
ASO (PMO) 2020
2 ASO: Antisense Oligonucleotide; PMO (phosphorodiamidate morpholino oligomer) are a chemical sub-class of antisense drugs; siRNA: small interfering RNA
16
Source: NASDAQ end of day quote 7 September 2020PYC’s drug design team know how to choose the right approach
for the target indication
Disease
state
Exons – code for Protein Isoform A
protein
mRNA
Pre-mRNA siRNA’s and ‘Gapmer’ ASOs
can mark mRNA for
ASOs can alter the exon selection
degradation to prevent
to change the protein. This can
Intron – translation. This reduces the
remove mutant sections or switch
non-coding, level of ‘unwanted’ protein
the protein’s function (from ‘bad’
regulatory
to ‘good’)
Healthy
DNA Pre-mRNA
state
Protein Isoform B
mRNA
Pre-mRNA
transcription splicing translation
DNA pre-mRNA mRNA Protein Function
The cell transcribes the full gene – The cell then ‘cuts’ or splices the mRNA is then translated
both protein coding and regulatory introns out to make mRNA by the cell into protein
sequences 17PYC’s drugs can access cells (and diseases) beyond the reach of
competitive RNA technologies
The challenge for most RNA drugs
The cell membrane has evolved over hundreds of PYC’s CPP-PMOs enable RNA therapeutics
millions of years to keep foreign substances out to target the previously unreachable
Exon skipping (%) in mouse Retinal Pigment Epithelium/
Choroid
Single IVT injection, day 5
50
40
31
30
20
10
0 0
0
PS ASO1 PMO CPP-PMO
10mcg/eye 1.6mcg/eye 1.6mcg/eye
PYC’s Cell Penetrating Peptides
PYC’s proprietary Cell Penetrating Peptides (CPPs) can deliver RNA
drugs, like PMOs, inside cells that are beyond the reach of competitive
technologies
1 PS: Phosphorothioate backbone antisense oligonucleotide;
18PYC’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
libraries leverage this pressure to screen for safe, highly effective delivery peptides
1 Genomes of microorganisms broken down 3 In vivo validation for each tissue and
and expressed as short peptides cargo type – with a focus on delivery
of ASOs
Smn exon skipping in mice, IV injection day
2 n=2
Screen and
validate
2 Peptides screened and
validated for cell-penetration
properties (effective delivery
Created with BioRender.com to the nucleus)
19
See ASX Announcement 14 October 2019PYC has deep (and evolving) IP protection supporting our platform
from discovery through to drug
Description Status Expiry
Libraries 2nd generation library construction and display Granted 2027
Screening Phenotypic screening of the peptide libraries Granted 2025
1st generation CPP Granted 2037
CPPs
2nd generation CPP (Ocular leads) PCT TBD
VP-001 program lead and associated molecules PCT TBD
ASOs
PYC-001 and VP-002 leads and associated molecules Provisional TBD
Growing protection through IP coverage of the conjugate
(CPP-ASO), new CPP’s for new targets, and new ASOs for
new indications
20Initial focus on eye disease applying CPP-PMO technology. CNS
diseases next area of development
PYC is a multi-asset drug development company
Program overview Indication and stage of development Estimated market size
Organ Program Target Lead
Discovery IND-enabling Clinical Marketed
selection
Eye
VP-001 PRPF31 Retinitis pigmentosa type 11 US$1-2 billion p.a.
PYC-001 VEGF Diabetic retinopathy >US$5 billion p.a.
Autosomal dominant optic ~US$1 billion p.a.
VP-002 OPA1
atrophy
Multiple Undisclosed Discovery pipeline Multiples of programs
CNS
Multiple Undisclosed Discovery pipeline Multiples of programs
PYC has 100% ownership of PYC-001 and 90% ownership of VP-001 and VP-002 (10% ownership by Lions Eye Institute, Australia)
21CPP platform has demonstrated applicability outside the eye, with
no systemic toxicity
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 All score 0 All score 0
Urea Normal Normal
Kidney Creatine Normal Normal
Pathology All score 0 All score 0
22
See ASX Announcement 14 October 2019PYC is exploring CPP-LNP conjugates to deliver other high value
cargoes to hard to reach tissues and cells
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 plasmids, Cas9 and others) in collaboration with the Peer Laboratory
of Precision NanoMedicine at Tel Aviv University
siRNA-induced cell death after treatment with LNP-CPP
conjugates
P Safety PLK-1 siRNA Efficacy Control siRNA
CP
CP P
Safety Efficacy Safety Efficacy
CPP
120
15nM 7.5nM
* *
120 120 120 120 ** 120 120 **
100 15nM 7.5nM15nM3.75nM
**15nM 7.5nM 7.5nM 1.87nM15nM 7.5nM 15nM 15nM
7.5nM
** 7.5nM
(normalized to untreated)
CPP **
3.75nM 3.75nM 3.75nM
1.87nM 1.87nM 1.87nM 3.75nM 1.87nM 3.75nM 3.75nM
1.87nM** 1.87n
100 100 100 100 100 100
(normalized to untreated)
(normalized to untreated)
(normalized to untreated)
(normalized to untreated)
(normalized to untreated)
(normalized to untreated)
% Cell viability
80
CP
P
100%
% Cell viability
80
% Cell viability
% Cell viability
% Cell viability
% Cell viability
80 80 % Cell viability 80 80 80
CPP
60
Lower values viability
60 60 60 60 demonstrate 60 60
indicates
CP P
40 better PYC’s CPP
40 40 40 40 efficacy 40 40
with the LNP
20 is not toxic
20 20 20 20 20 20
0
LNP
0 CPP-LNP LNP CPP-LNP
0 0 0 0 0
LNPwere treated
OVACAR8 cells CPP-LNP
for 72hrs with LNPs or CPP-LNPs LNP
at differentCPP-LNP
PLK1-siRNA doses. Cell viability was LNP CPP-LNP LNP CPP-LNP
measured by XTT assay
OVACAR8 cells were treated for 72hrs with LNPs or CPP-LNPs at different PLK1-siRNA doses. Cell viability was OVACAR8 cells were treated for 72hrs with LNPs or CPP-LNPs at different PLK1-siRNA doses.
OVACAR8 cells were treated for 72hrs with LNPs or CPP-LNPs at different PLK1-siRNA doses. Cell viability was measured by XTT assay
measured by XTT assay measured by XTT assay 23
See ASX Announcement 08 August 2020VP-001 for the treatment of Retinitis
pigmentosa type 11
24Executive Summary – VP-001 for Retinitis pigmentosa type 11
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 progressive cell death and blindness in
patients with RP11
§ PYC’s delivery technology can reach the target cell following intravitreal injection - conferring a
major competitive advantage over therapies requiring sub-retinal administration (in vivo model)
§ VP-001 engages its target and achieves the desired exon skipping effect (patient derived model)
§ VP-001 corrects the deficiency of the target protein once inside the cell (patient derived model)
§ The increase in the target protein rescues the downstream functional consequences of RP11
(patient derived models)
3. PYC’s Cell Penetrating Peptide – Antisense Oligonucleotide conjugates show no evidence of toxicity in
the retina (animal models)
4. VP-001 has an attractive path to market with small clinical trials and the potential for a single pivotal
study
25OVERVIEW
There are a large number of patients with Retinitis pigmentosa
type 11 who have no available treatment options
Retinitis pigmentosa is a genetic, blinding eye disease
§ VP-001 will treat Retinitis Pigmentosa Type 11 (RP11)
‒ Severe, progressive blinding eye disease
‒ Onset between the ages of 10 and 20
‒ Leads to blindness between 40-50 years of age
§ There is no treatment in market or in clinical development
RP11 represents a 1-2B USD p.a. treatment market
§ 4,000-8,000 patients in the western world
§ ~250,000 USD p.a. orphan drug pricing
§ 1-2B USD p.a. market
§ Straightforward and low cost sales and distribution channel
26OVERVIEW
VP-001 will serve a 1-2B USD p.a. market
Retinitis pigmentosa (RP) prevalence
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
in market or
Proportion of adRP that is RP11
8-10%1 in clinical
Patients is a disease causing mutation in PRPF31
development
Reimbursable RP11 patients
Number of patients in the US, EU, and Japan 4,000-8,000 patients1
Median Rare Disease drug price
Annual reimbursed cost for a rare disease drug US$250,000 p.a.2
Total addressable market
US$1-2bn p.a.
Margins assumed at 90% due to low COGs 3
1 Daiger et al. ‘Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa’ Cold Spring Harb. Perspect. Med. 5 (2014); Ellingford et al. ‘Molecular findings from 537 individuals with inherited retinal disease’ J Med Genet 53, 761-776
(2016); Sullivan LS, Bowne SJ, Birch DG, et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci. 2006;47(7):3052-3064.
2 Based on Luxturna pricing over 4 years (450k USD per eye). Luxturna is a gene therapy for treatment of a rare inherited retinal disease, approved in 2017, marketed by Spark Therapeutics. 27
3 Sarepta Therapeutics’ marketed Exondys 51 for a DMD subpopulation has margins which exceed 90% for a systemically delivered drug (much more product per dose)DEEP-DIVE
VP-001 targets a down-regulator of the gene underlying RP11
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-regulates the RP11 target gene
Our body uses these genes to ‘code’ This leads to insufficient healthy protein This increases the amount of protein
proteins in our cells being made by the cell from the healthy copy of the gene
(haploinsufficiency)
These proteins help our bodies function, The lack of protein means the retinal The additional healthy protein restores
including helping us to see cells in the eye don’t function correctly the eye’s ability to function properly and
and start to die – causing blindness prevents further degeneration
28DEEP-DIVE
Insufficient PRPF31 protein drives RP11 and CNOT3 expression
controls PRPF31 expression
PRPF31 expression levels determine if a patient suffers vision CNOT3 protein levels regulate PRPF31 expression
loss § CNOT3 is a negative regulator of PRPF31
§ RP11 patients have one healthy copy of PRPF31 and one mutated, § CNOT3 expression is higher in RP11 patients compared to
non-functional copy of PRPF31 ‘asymptomatic’ family members with the same PRPF31
§ For most patients this leads to insufficient PRPF31 protein for a mutations
healthy retina (~50% the PRPF31 protein of a healthy person)
§ However, some patients have only one healthy copy of PRPF31, but
late or no disease onset CNOT3 and PRPF31 expression in iPSC-derived
§ This is because their healthy gene produces ~1.2-1.4 fold more retinal pigment epithelium (RPE)1
protein than other patients
CNOT3 and PRPF31 expression in control patient
fibroblasts1
Relative mRNA expression
Patients
1 RT-qPCR analysis of PRPF31 and CNOT3 mRNA expression normalised with TATA-binding protein (TBP) expression in iPSCs-derived retinal pigment epithelium from RP11, asymptomatic and wild type (WT) individuals. Bar chart represent mean±standard
error of the mean (SEM) from three independent RT-qPCR. Expression of CNOT3 and PRPF31 transcripts in wild type was set to 1. *pDEEP-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
Without VP-001 With VP-001
PMO
Pre- Exon Intron Exon Intron
Exon C
Intron
Exon D
Exon Intron Exon Intron
Exon C
Intron
Exon D
A B A B
mRNA
Exon Exon Exon Exon
mRNA A B Exon C Exon D
A B Exon D
Full length protein Truncated protein
(non-functional)
Other domains (and
some functions) remain
Transcription Transcription
intact
Outcome PRPF31
PRPF31
VP-001 uses a PMO to remove in-frame exons encoding functional domains downregulating PRPF31
– the truncated CNOT3 isoform leads to an upregulation in PRPF31 expression levels 30DEEP-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
100
%D7 RPE isolate (28 days)
administration)1
Neural Retina(28 days)
Neural retina
%D7 Neural retina RPE/Choroid
RPE Isolate
100 80
80
Exon Skipping Smn
*
60
Exon Skipping Smn
*
60
*
40
40 28.2 19.1
26.0
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1 Day 28 post intravitreal injection in mice. A readout of drug delivery, Exon-skipping of Survival of Motor Neuron (Smn) in the mouse retina across 3 dose cohorts (n=12 for each dose cohort, n=4 for vehicle)
31
M
M
M
3'
3'
3'
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See ASX Announcement 22 July 2020
2-
2-
2-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 reach Breadth of delivery is also required to treat
the deepest cells at the back of the eye the entire eye
§ Cells degenerate across the entire retina causing
CPP-PMO PMO
it to ‘leak’ and the cells to die
§ An effective treatment must treat a majority of
the cells to prevent significant vision loss
CPP-ASO treatment area
(whole of the retina)
AAV
treatment
area
Target cell
31
PYC’s technology delivers the drug
where others cannot – the cells 0
where treatment is needed CPP- PMO1 Affected cells
PMO1
32
1 Exon 7 skipping of Smn at day 5 post 1.6mg Intravitreal administration in the mouse eye.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…
Exon skipping, retinal organoid Exon skipping, Retinal Pigment Epithelial
Day 14, 2 treatments (n=2) Day 5, single treatment
70
57
44
0 0
Untreated 5µM Untreated 2.5µM 5µM
PYC CPP-PMO PYC CPP-PMO
treatment treatment
Exon skipping in patient retinal organoid models (n=2 patients with RP11), with and without PYC’s drug treatment. Organoids (4-6 organoids combined) were treated with 5µM of drug administered twice over a 14 day time period. Due to
the successful delivery up to 71% of RNA molecules have been altered (skipped) by the PMO (n=1 sample per treatment)
Exon skipping in patient derived RPE model (n=1), with and without PYC’s drug treatment. (n=2 per treatment) 33
See ASX Announcement 1 April 2020DEEP-DIVE
This exon skipping translates into an upregulation of the deficient
protein at levels expected to rescue the disease
PRPF31 protein levels, RPE, 5µM treatment, (n=1 per patient)
2.5
Day 2 Day 5 Day 12 Untreated
Treated
Fold change over untreated
2.0
1.5
Anticipated disease
correction threshold
1.0
0.5
0.0
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Non-penetrant Penetrant
For anticipated disease correction threshold see ‘Giulia Venturini, Anna M. Rose, Amna Z. Shah, Shomi S. Bhattacharya, Carlo Rivolta. CNOT3 Is a Modifier of PRPF31 Mutations in Retinitis Pigmentosa with Incomplete Penetrance. PLOS
Genetics November 2012’
34
See ASX Announcement 7 October 2020DEEP-DIVE
VP-001 has demonstrated the ability to correct important
functional deficits associated with RP11
These results demonstrate VP-001’s ability to correct the structural deficiency in patient
derived retinal cells that is one of the key causes of vision loss in RP11 patients1
1 Buskin A. Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun. 2018 Oct 12;9(1):4234.
35
See ASX Announcement 16 December 2020DEEP-DIVE
Upregulation of the target protein rescues the functional deficits
associated with the disease
Structure of the Retina Impact of RP11
Restoration
Healthy RP11 Impact of RP11 with VP-001
§ Shorter ‘stunted’ connecting cilium in TBD
the photoreceptors
§ Lower ‘phagocytosis’ of outer
segments (lower ability of the RPE to
dispose of the toxin)
§ Shorter and less frequent cilium on
the RPE, showing poor RPE health
§ Short, less functional microvilli, which
are the ‘arms’ that collect the outer
segments during phagocytosis
§ RPE cells are not tightly joined and
become ‘leaky’, causing retinal TBD
degeneration
§ RPE loses polarity – or simply the cell TBD
becomes ‘disordered’
36DEEP-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 cells
of the eye (RPE) ‘clear away’ debris from the photoreceptors. If outer
segments are not phagocytosed, they build up and can
become toxic, impairing the ‘visual cycle’
Ganglion
cell layer
Inner
nuclear layer
Outer
nuclear layer
Photoreceptors
RPE
37DEEP-DIVE
VP-001 restores RPE functionality in patient derived models
Phagocytosis assay, 5µM 6hr timepoint
A) Green ‘specks’ are Phagocytosed outer-segments (more B) Intensity of phagocytosis per RPE cell
green = improved functionality)
pDEEP-DIVE
PYC’s lead drug is competitively differentiated in achieving this
functional correction without causing toxicity in the retina
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
PYC CPP-PMO – no thinning
indicates more toxicity
Higher expression
Control CPP-PMO – severe thinning
Toxicity determined by treating mouse retinas with 1.6 micrograms of an Antisense Oligonucleotide (ASO) delivered by each peptide and then measuring retinal stress based on levels of Glial Fibrillary Acidic Protein (GFAP). GFAP levels
have been measured after retinal harvesting from mice at day 5 post intravitreal injection and normalised to a pool of ‘house-keeping’ genes. Notes i) PepK – a third-party delivery peptide that serves as the current benchmark for
delivery peptides in clinical development (Red, n=6); ii) PYC’s delivery peptide (Green, n=2 ); and iii) a control group which received no treatment (Black, n=3). One-way ANOVA p values – PepK:naïve 0.1379; PYC CPP:naïve 0.9892 39
See ASX Announcement 8 April 2020DEEP-DIVE
The dose dependant response shows no increasing acute toxicity
in the mouse
Dose dependant increase in effect … … and no increase in toxicity markers
Exon-skipping, Day 7 in the mouse eye ddPCR
Gfap expression, for
Day 7 in theGFAP expression
mouse eye
in Neural Retina at D7 (n=12)
Neural Retina
0.025
Normalised to ave.
Exon Skipping Smn
0.020
of HK genes
0.015
0.010
0.005
0.000
1.6µg
µg
µg
µg
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2-
2-
2-
Toxicity determined by treating mouse retinas with 1.6 micrograms of an Antisense Oligonucleotide (ASO) delivered by each peptide and then measuring retinal stress based on levels of Glial Fibrillary Acidic Protein (GFAP). GFAP levels
V
xt
xt
xt
have been measured after retinal harvesting from mice at day 7 post intravitreal injection and normalised to a pool of ‘house-keeping’ genes.
40
E
E
E
1-
1-
1-
See ASX Announcement 22 July 2020OVERVIEW
The path to market for VP-001 has several major advantages over
conventional clinical development pathways
Stage IND-enabling Phase 1/2 Phase 2/3 Approval
Timeline 18 months 15 months 18 months 6 months
Higher Shorter time to Lower cost
probability of market
success
§ Orphan genetic drugs § Combined clinical trials § Lower patient numbers
have a ~45% chance of and single pivotal § 2 planned clinical trials
reaching market from § Favourable FDA § Favourable FDA
Phase 1 pathways and Orphan pathways
status
All numbers and timelines are estimates and are applicable to change and revision 41PYC-001 for the treatment of Diabetic
retinopathy
42PYC has the capability to rapidly scale its technology in the retina
Right Biology
Does the drug Do we
Does the drug progress to
alter the disease
Right Indication engage the IND-
in a functional
target safely? enabling
model?
studies?
Right Commercials
PYC’s ‘RNA hub’
~3 months ~6-12 months 3-6 months
43Advancing our lead program into the clinic will validate our drug
delivery platform for retinal disease
The Retina is a high value target Proven Delivery in the Eye Develop Further Applications
1.6ug IVT injection in mice
% Exon 7 Skipping Smn Diseases primarily affecting the
Photoreceptors
§ Glaucoma
57 § Usher Syndrome
§ Rhodopsin RP (most prevalent adRP in
the US)
§ >10 commercially viable Inherited
Retinal Diseases
0
Neural retina/
photoreceptors CPP-PMO PMO
60 Diseases primarily affecting the RPE
§ Diabetic retinopathy
§ Wet age-related macular degeneration
(wAMD)
§ Dry age-related macular degeneration
(dAMD)
0 § >5 commercial Inherited Retinal
Diseases
CPP-PMO PMO
RPE
(21 days post- (5 days post-IVT)
IVT)
44PYC-001 – PYC’s second drug development program
§ 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) therapies and the need for longer acting drugs
§ In addition, there is a growing body of evidence suggesting that prolonged VEGF inhibition is responsible
for the death of sensitive nerve cells in the retina
§ PYC has leveraged the unique advantages of its RNA therapeutics technology to create a modified VEGF
therapy that addresses these shortcomings – this drug promises to:
– Retain the ability of the current generation of drugs to stop blood vessels destroying the retina;
– Add a ‘pro-survival’ effect to help protect sensitive neurons from dying; and
– Significantly extend the dosing interval between treatments for patients
§ The drug leverages all of the intracellular delivery work undertaken for PYC’s lead program (a treatment
for a blinding disease of childhood called Retinitis Pigmenotsa) and, as a result, is expected to have a
rapid development pathway into the clinic
45Common eye diseases are linked through dysfunction of
blood vessels in the eye
46
Image: Mayoclinic.comInhibiting new blood vessel growth (VEGF-inhibition) has been a
major step forward in the management of these diseases
Global ocular anti-VEGF sales, USD B
10
9
8
7
6
5
4
3
2
1
0
2014 2015 2016 2017 2018 2019
47
Source: Roche, Regeneron annual reports and financial statementsBut… Inhibition of VEGF is known to cause retinal ganglion cells to
die and is also suspected of being linked to macular atrophy
“VEGF inhibition increased Retinal Ganglion Cells
apoptosis and neuronal damage in diabetic retinopathy”1
“A majority of patients show Macular Atrophy after
long-term anti-VEGF treatment” 2
“An association between anti-VEGF treatment and
atrophy development has been observed” 3
1 Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach. Int. J. Mol. Sci. 2020, 21, 2351; doi:10.3390/ijms21072351
2 Munk MR, Ceklic L, Ebneter A, Huf W, Wolf S, Zinkernagel MS. Macular atrophy in patients with long-term anti-VEGF treatment for neovascular age-related macular degeneration. Acta Ophthalmol. 2016 Dec;94(8):e757-e764. doi: 10.1111/aos.13157.
Epub 2016 Jul 15. PMID: 27417506.
48
3 SriniVas R. Sadda,Robyn Guymer,Jordi M. Monés,Adnan Tufail,Glenn J. Jaffe. Anti–Vascular Endothelial Growth Factor Use and Atrophy in Neovascular Age-Related Macular Degeneration Systematic Literature Review and Expert Opinion. Ophthalmology:
Journal of the American Academy of OphthalmologyDiabetic patients with higher VEGFA165a to VEGFA165b show
lower penetrance of Diabetic Retinopathy
Diabetes patients without retinopathy display proportionally more expression of the b
isoform
Distribution of growth factors (VEGF) among cases and controls, pg/ml
Mean and SEM
VEGFA165a VEGFA165b (VEGFA165a) – (VEGFA165b)
250 209
200 158
150 124
109
100 52 61
46 56
50 27
0
Control Diabetic Diabetic Control Diabetic Diabetic Control Diabetic Diabetic
control retinopathy control retinopathy control retinopathy
Paine SK, Mondal LK, Borah PK, Bhattacharya CK, Mahanta J. Pro- and antiangiogenic VEGF and its receptor status for the severity of diabetic retinopathy. Mol Vis. 2017 Jun 22;23:356-363 49There is an alternative method of inhibiting new blood vessel
growth without the negative effects of VEGF inhibition
PMO
VEGFA pre-mRNA Exon Exon Exon
Exon 7
7b 8a 8b
PYC’s drug ‘switches’ from
the 165a to the 165b
isoform of VEGF
VEGFA-165a mRNA VEGFA-165b mRNA
Exon Exon Exon Exon
Exon 1-5, 7 Exon 1-5, 7
7b 8a 7b 8b
Increase leaky new The current generation of VEGF inhibitors cause Decrease leaky new blood
blood vessel growth the loss of the ‘pro-survival’ signal that is likely vessel growth
the link between sustained exposure to these
drugs and retinal cell death – PYC’s drug
Pro-survival overcomes this issue Pro-survival
50A very subtle change in the ratio of protein regulated by this
‘switch’ is required to correct the disease process
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, Donaldson LF, Bainbridge JW, Bates DO. Vascular endothelial growth factor-A165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina. Clin Sci (Lond). 2017 Jun 1;131(12):1225-1243 51The therapeutic value of this approach has been recognised
“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 therapeutic development”
52
1 Kenneth P Mitton; Wendy A Dailey; Megan Moore; Alvaro E Guzman; Jennifer Felisky; Kaylee Moyer; Nahrain Putris; Peter Chen; Austen Knapp; Anju Thomas; Regan Miller; Brandon Metcalf. VEGFA Isoform Switching in Diabetic Retinopathy and ROP is a
Significant Factor in the Activation of Human Retinal Endothelial Cells. Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2669.The program is expected to progress into IND enabling studies in
2021
Evaluation in patient cells Evaluation in animal models
and/or patient derived models
Expected 4Q 2020 Expected 3Q 2021
IND-enabling decision in
2021 53VP-002 for the treatment of Autosomal
dominant optic atrophy (ADOA)
54Executive summary – PYC’s third drug development program
§ Autosomal dominant optic atrophy (ADOA) caused by mutations in the Optic Atrophy 1 (OPA1) gene
affects >8,000 patients in the Western World
§ ADOA is a ‘monogenic’ disease (a disease caused by a mutation in a single gene) where the mechanism of
disease is caused by haploinsufficiency (insufficient protein levels caused by a loss of function mutation in
one of the two copies of the OPA1 gene)
§ PYC has designed an oligonucleotide capable of correcting the OPA1 protein haploinsufficiency in cells
derived from ADOA patients (>100% protein upregulation in patient fibroblasts)
§ PYC has filed for intellectual property protection over this drug program
§ The Company will now create a drug through conjugation (joining) of this oligonucleotide to one of PYC’s
proprietary Cell Penetrating Peptides (CPP) and validate this drug in more sophisticated ADOA patient
disease models before deciding whether to progress the candidate into clinical development
§ This drug development program will benefit from a number of synergies with PYC’s lead drug program and
is expected to have a rapid development pathway
55Autosomal Dominant Optic Atrophy
ADOA is caused by the optic nerve cells (retinal
ganglion cells, RGCs) losing their ability to transmit
visual signals to the brain
§ This can cause severe vision loss in the patient
§ Vision loss often starts before the age of 10 Healthy
Healthy retina
Light
RGCs
Affects approximately 1 in 30,000 people
§ ~70% of all ADOA is caused by mutations in
mutation in one gene, OPA1
Signal to brain
§ ~75% of cases caused by OPA1 mutations are due to
low levels of the OPA1 protein
Dying Retina
Light RGCs with
optic
atrophy
Reduced signal to brain
Created with BioRender.com
56This increase has been replicated in ADOA patient fibroblasts
Change in OPA1 protein levels, 50µM PMO treatment, patient fibroblasts
For upregulation benchmark see poster ‘Antisense oligonucleotide mediated increase of OPA1 expression using TANGO technology for treatment of autosomal dominant optic atrophy’ Fig.6 at https://www.stoketherapeutics.com/wp- 57
content/uploads/ASGCT2020_final.pdfPYC’s path to validating a therapeutic for ADOA
Validate CPP-PMO conjugate in multiple human cell models
Validate leads in ADOA patient-derived target cell models for target engagement
Validate leads in ADOA patient-derived target cell models for functional readouts
Complete preliminary toxicology and QC studies
Determine if there is an appropriate in vivo efficacy model
58OPA1 upregulation may play a role in numerous mitochondrial-
driven diseases
Glaucoma ‘Overexpression of Optic Atrophy Type 1 Protects
Retinal Ganglion Cells and Upregulates Parkin
Expression in Experimental Glaucoma’1
‘Harnessing the protective role of OPA1 in diabetic
Cardiomyopathy
cardiomyopathy’2
‘OPA1 overexpression ameliorates mitochondrial
Neurodegeneration cristae remodelling, mitochondrial dysfunction, and
neuronal apoptosis in prion diseases’ 3
Hu X, Dai Y, Zhang R, Shang K, Sun X. Overexpression of Optic Atrophy Type 1 Protects Retinal Ganglion Cells and Upregulates Parkin Expression in Experimental Glaucoma. Front Mol Neurosci. 2018;11:350
Patten D, Harper ME, Boardman N. Harnessing the protective role of OPA1 in diabetic cardiomyopathy. Acta Physiol (Oxf). 2020 May;229(1) 59
Wu, W., Zhao, D., Shah, S.Z.A. et al. OPA1 overexpression ameliorates mitochondrial cristae remodeling, mitochondrial dysfunction, and neuronal apoptosis in prion diseases. Cell Death Dis 2019 10, 710Disclaimer
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. Accordingly,
these slides and the information they contain should be read in conjunction with past and future announcements made by Phylogica and
should not be relied upon as an independent source of information. Please contact PYC and/or refer to the Company's website for further
information.
The views expressed in this presentation contain information derived from publicly available sources that have not been independently
verified. No representation or warranty is made as to the accuracy, completeness or reliability of the information.
Any forward looking statements in this presentation have been prepared on the basis of a number of assumptions which may prove incorrect
and the current intentions, plans, expectations and beliefs about future events are subject to risks, uncertainties and other factors, many of
which are outside PYC’s control. Important factors that could cause actual results to differ materially from assumptions or expectations
expressed or implied in this presentation include known and unknown risks. Because actual results could differ materially to assumptions
made and PYC’s current intentions, plans, expectations and beliefs about the future, you are urged to view all forward looking statements
contained in this presentation with caution.
This presentation should not be relied on as a recommendation or forecast by PYC. Nothing in this presentation should be construed as either
an offer to sell or a solicitation of an offer to buy or sell shares in any jurisdiction.
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