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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