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Your partner for Medical Research and Development
Overview
SERVICES
AND
RESOURCES
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Sequencing
Proteomics
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Histology
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Manufacture
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Processing
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Solutions
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Trials
Integrated place for clinical research
Commercialisation
partnerships
Philanthropic
partnerships
Contract/collaborative
research
Immuno-Oncology IP
licensing and R&D
collaboration
Adoptive
Immunotherapy IP
licensing and R&D
collaboration
Drug discovery
collaboration
Malaria challenge
model, clinical
collaboration
Commercialisation Partners
utilising QIMR Berghofer IP
Commercial track record
DMX8.1, Novel Cancer Therapeutic
6
• Inhibitor of G9a, a histone methyltransferase over expressed in
many cancers
• Orally active, highly potent small molecule which modulates:• Dysregulated genes in cancer cells
• MYC and Wnt pathways
• Broad spectrum anti-cancer activity and activity against
endocrine and cisplatin resistant cancers
• High value lead indications:• Triple negative breast cancer
• ER+ endocrine resistant breast cancer
• Biomarkers for patient selection and clinical therapeutic activity
• Potential first-to-market in cancer
DMX8.1 overview
7
DMX8.1 Mechanism of Action
Me
Me
Me
Me
H3K9me
Histones
DNA
Nucleosome
Gene expression
MeMeMe
MeMeMe
Me
MeMe
Gene expression
Loss of tumour suppressor genes
Gene repression
Gene repression
Cancer cell death pathways activated
Cancerhypoxic tumour microenvironment
➔ Increase in G9a protein
8
• Novel series structurally dissimilar from published compounds
• BIX-01264,UNC0642, A366, none are suitable for in vivo conditions)
• Strong lead compound with backup options• Molecular and physical properties favourable for manufacturing
• Good oral bioavailability sufficient for oral dosing
• In vivo half-life sufficient for once daily dosing
• Highly selective for G9a
• No activity toward, SETD7, SMYD2, SETMAR, DOT1L and SET8)
• In-house X-ray crystal structures of G9a bound DMX8.1 inform
structure-based optimisation if required
• Favourable PK properties
• Pfizer CNS MPO score of 3.23, Papp Caco-2 (10-6cm/s) value of 1.2 (efflux ratio:35),
LogD7.4 of 2.54 and Mouse Live Microsomes half-life of 37.7 mins (male C57/BL6).
DMX8.1 - chemistry
9
G9a – MYC pathway targeted activity
Adapted from Cancer Cell. 2018;34(4):579-595.
DMX8.1 specifically enhances expression of genes repressed by
MYC in cancer setting
G9a signature for patient selection
10
DMX8.1 is a potent inducer of cell death
DMX8.1 reduces viability of breast cancer lines whilst having no
effect on non-cancerous (Normal) cell lines
11
1 5 2 0 2 5 3 0 3 5 4 0
2 1
2 2
2 3
2 4
M o u s e W e ig h t
D a y sM
ou
se
we
igh
t (g
)
V e h ic le
D M X 8 .1
1 5 2 0 2 5 3 0 3 5 4 0
0
2 5 0
5 0 0
7 5 0
1 0 0 0
T u m o u r V o lu m e
D a y s
Tu
mo
r V
olu
me
(m
m3
) V e h ic le
D M X 8 .1
DMX8.1 single agent efficacy in vivo
Reduced tumour growth of Triple Negative Breast CancerAT32 syngeneic tumors were treated with DMX8.1 (ip 5mg/kg every 2 days).
12
DMX8.1 reverses endocrine therapy
resistance
Re-sensitisation of tamoxifen resistant breast cancerMCF7TR treated with tamoxifen (ip 20mg/kg every two days), DMX8.1 (ip 5mg/kg every 2 days), or combination therapy.
• Persistent activation of MYC target
genes in tamoxifen resistant breast
cancer (e.g. CCND1)
• DMX8.1 antagonises MYC actions.
13
• IP administration every 2nd
day was efficacious in vivo in
spite of limited exposure
• Oral administration daily will
provide more consistent
exposure
• We predict even greater
efficacy by oral route
DMX8.1 show improved PK by oral route
14
• Specificity• 1.8 nM binding to G9a
• >3,000 lower binding to closest neighbour EZH2
• Screened for selectivity against a panel of 8 lysine methyltransferases
• Next step in specificity testing will be a CEREP SafetyScreen
• Toxicity• No adverse events in studies to date
• No weight loss in studies to date
• In vivo PK studies at 10x the current efficacious dose had no adverse events
• Next step will be ADME assay
• Safety• G9a is highly overexpressed in targeted cancer cells
• G9a affects multiple cancer specific targets such as Myc and Wnt
• Current data suggests a large therapeutic window
• Next steps will be hERG and cardiac profile studies
DMX8.1 Safety Profile
15
• Provisional and PCT patent applications• Companion prognostic/predictive tests and therapeutic activity
pharmacodynamic markers
• Novel IP space around chemistry• Domainex searches of on-line chemical databases indicate that our compounds
are novel, and that no similar structures have been disclosed as G9a inhibitors,
or patented for other purposes
• Composition of matter filing on chemistry delayed to date
to maximise patent life
• Shared IP by QIMR Berghofer and Domainex
Intellectual Property
16
• Investment into strategically formed start-up company
• Investment to deliver pre-clinical development through
IND enabling studies
• Funding required, $10 million
OR
• Partner with expertise in epigenetic modifiers, possibly
with other ‘synergistic’ compounds for combination studies
• License with collaborative research funding
Invest or Partner
17
Opportunity
High unmet medical need• TNBC
• No approved therapy; poor prognosis
• Not responsive to hormonal or targeted
therapies
• ER+ endocrine resistant BC• Chemotherapy is only therapy option
• Increasing rate of acquired chemotherapy
resistance
Commercial potential• Globally 2.3 million new cases 2018
• TNBC approximately 20% of BC• $1+ billion market in metastatic TNBC
• ER+ endocrine resistant BC
approximately 20% of BC• $1+ billion market in ER+ endocrine
resistant BC
Pre-clinical data• TNBC
• Efficacy in multiple cell lines
• Efficacy as monotherapy in vivo
• ER+ endocrine resistant BC• Efficacy in multiple cell lines
• Efficacy as a mono- and combination
therapy in vivo
Commercial exit• High return exit values at discovery or
Phase 1• Tensha Therapeutics acquired by Roche for
$115m upfront plus $420 in milestones.
Single asset BET inhibitor mid phase-1
• Triphase Accelerator licence to Celgene for
$40m upfront plus $940 in milestones.
Single asset WRD5 inhibitor pre-clinical
Novel I-O Axis mAbs targeting GAL9
19
Overview
• Novel I-O axis identified from native immune response
• Completed human mAb discovery campaign
• Lead candidate mAbs identified
• Potent in vivo efficacy
20
IgG
Ctr
l
-G
AL
9
0
2 0 0 0 0
4 0 0 0 0
6 0 0 0 0
8 0 0 0 0
1 0 0 0 0 0
INF
- (
pg
/ml)
IgG
Ctr
l
-G
AL
9
0
1 0
2 0
3 0
4 0
% c
ell
su
rv
iva
l
Human T cells were stimulated with
anti-CD3 (5ug/ml) and treated with
IgG or anti-Gal9 (ECA42; 20ug/ml).
INF-γ was measured after 72 hrs.
Cytokine Release T cell Survival
Gal9 axis stimulation
Mouse T cells were stimulated with
anti-CD3 (3ug/ml) and treated with
IgG or anti-Gal9 (RG9-1; 20ug/ml).
Survival was measured after 72 hrs.
21
Cells from malaria infected mice were stimulated by co-culture with dendritic cells, and treated
with a blocking α-Gal9 mAb (108A2; 20ug/ml). Cytokine production was measured after 36 hrs.
* p<0.05 to “DC + T cell”
Blocking Gal9 blocks cytokine induction by DCs
T c
ell
DC
+ T
cell
-G
al9
+ D
C +
T c
ell
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
IFN
- (
pg
/ml)
*
T c
ell
DC
+ T
cell
-G
al9
+ D
C +
T c
ell
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
TN
F-
(p
g/m
l)
*
22
Activating α-Gal9 mAbs Inhibit Tumors
Mice were implanted with various
tumours and treated with either
control IgG (BE0090; rat IgG2b)
or tool α-Gal9 antibody (RG9-1;
rat IgG2b): B16.F0 implanted
intradermally (ip, 200ug, days 3,
7, 11, 15); CT26 implanted
subcutaneously (ip, 200ug, days
7, 11, 15, 19); RM-1 implanted
subcutaneously (ip, 200ug, days
3, 7, 10, 13); and S2WTP2 p26
implanted into the mammary fat
pad (ip, 200ug, days 15, 17, 19,
21
0 5 1 0 1 5 2 0 2 5 3 0 3 5
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
1 2 0 0
C T 2 6
D a y s p o s t tra n s p la n t
Tu
mo
r v
olu
me
(m
m3
)
R a t Ig G
-G a l9
Colon Cancer
0 5 1 0 1 5 2 0 2 5
0
3 0 0
6 0 0
9 0 0
1 2 0 0
1 5 0 0
1 8 0 0
B 1 6 .F 0
D a y s p o s t tra n s p la n t
Tu
mo
r v
olu
me
(m
m3
)
R a t Ig G
-G a l9
Melanoma
0 5 1 0 1 5
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
R M -1
D a y s p o s t tra n s p la n t
Tu
mo
r v
olu
me
(m
m3
) R a t Ig G
-G a l9
Prostate Cancer
0 5 1 0 1 5 2 0 2 5 3 0 3 5
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
S 2 W T P 3 p 2 6
D a y s p o s t tra n s p la n t
Tu
mo
r v
olu
me
(m
m3
) R a t Ig G
-G a l9
Breast Cancer
23
• CRO conducted human antibody discovery program
• Discovery screening against complete human IgG1 antibodies
• Counter screened against GAL4, closest Galectin family member
Human antibody discovery program
24
Fully Human Candidate mAb diversity
25
Candidate mAb characteristics
• Human IgG1
• Monovalent KDs in low nM range
• No deamination sites
• No N-linked glycosylation sites
• No cysteines in CDRs
• Multiple epitope bins
• ~50% are cross-reactive with murine Gal9 protein• Cross-reactive mAbs used for in vivo studies were converted to murine IgG2a format
26
Functional screen: cytokine induction
No
Pep
mix
PB
S C
trl
IgG
Ctr
l
an
t i-P
D1
aG
9 P
9-1
5
aG
9 P
9-1
8
aG
9 P
9-2
1
aG
9 P
9-2
4
aG
9 P
9-2
5
aG
9 P
9-2
8
aG
9 P
9-2
9
aG
9 P
9-3
1
aG
9 P
9-3
8
aG
9 P
9-4
0
aG
9 P
9-4
1
aG
9 P
9-4
2
aG
9 P
9-5
0
aG
9 P
9-5
1
aG
9 P
9-5
2
aG
9 P
9-5
3
aG
9 P
9-5
4
aG
9 P
9-5
6
0
5 0 0
1 ,0 0 0
1 ,5 0 0
IN F g
A n t ib o d y C lo n e
MF
I
No
Pep
mix
PB
S C
trl
IgG
Ctr
l
an
t i-P
D1
aG
9 P
9-1
5
aG
9 P
9-1
8
aG
9 P
9-2
1
aG
9 P
9-2
4
aG
9 P
9-2
5
aG
9 P
9-2
8
aG
9 P
9-2
9
aG
9 P
9-3
1
aG
9 P
9-3
8
aG
9 P
9-4
0
aG
9 P
9-4
1
aG
9 P
9-4
2
aG
9 P
9-5
0
aG
9 P
9-5
1
aG
9 P
9-5
2
aG
9 P
9-5
3
aG
9 P
9-5
4
aG
9 P
9-5
6
0
5 0 0
1 ,0 0 0
1 ,5 0 0
T N F a
A n t ib o d y C lo n e
pg
/ml
Human PBMCs (3 donors) were placed in culture, stimulated with CMV peptide, and treated with controls
(PBS or human IgG1; green), anti-PD1 (Nivolumab; purple), or discovery program antibodies (human IgG1
format; black). Cytokine production was measured at 24 and 72 hrs post treatment by bead cytokine array.
(Representative data from 72hrs)
27
α-GAL9 mAb inhibits tumour growth
Colon Cancer
Mice were implanted with tumour lines and treated with either control IgG (BE0090; rat IgG2b) or program
α-GAL9 (P9-18; P9-21; human CDRs on murine IgG2a backbone): CT26 implanted subcutaneously (ip,
200ug, days 7, 11, 15, 19); B16.F10 implanted intradermally (ip, 200ug, days 3, 7, 11)
0 2 0 4 0 6 0 8 0 1 0 0
0
4 0 0
8 0 0
1 2 0 0
D a y s p o s t tra n s p la n t
Tu
mo
r v
olu
me
(m
m3
) R a t Ig G
P 9 -1 8
P 9 -2 1
0 5 1 0 1 5
0
4 0 0
8 0 0
1 2 0 0
D a y s p o s t tra n s p la n tT
um
or v
olu
me
(m
m3
)
P 9 -1 8
R a t Ig G
P 9 -2 1
Melanoma
28
Summary
• Targets novel I-O axis modulating native immune
response
• Lead candidate mAbs identified
• Potent in vivo efficacy
Partnering
• Partner with expertise in I-O or mAb clinical development
• Licence with collaborative research program