Your partner for Medical Research and Development

Transcription

1 Your partner for Medical Research and Development

2 Overview

3 Integrated place for clinical research SERVICES AND RESOURCES DNA Sequencing Proteomics Imaging Histology Flow Cytometry Sample Processing Cryogenics Clinical Trials GMP Manufacture Software Solutions Genome Analytics

4 Commercial track record Commercialisation partnerships Immuno-Oncology IP licensing and R&D collaboration Adoptive Immunotherapy IP licensing and R&D collaboration Philanthropic partnerships Malaria challenge model, clinical collaboration Commercialisation Partners utilising QIMR Berghofer IP Contract/collaborative research Drug discovery collaboration

5 DMX8.1, Novel Cancer Therapeutic

6 DMX8.1 overview 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 6

7 DMX8.1 Mechanism of Action H3K9m e M e M e M e M e M e Cancer hypoxic tumour microenvironment Increase in G9a protein DNA M e Me Me M M M e ee e e Histones Gene expression repression Nucleosom e Gene repression expression Cancer Loss of cell tumour death pathways suppressor activated genes 7

8 DMX8.1 - chemistry 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 (10-6 cm/s) value of 1.2 (efflux ratio:35), LogD 7.4 of 2.54 and Mouse Live Microsomes half-life of 37.7 mins (male C57/BL6). 8

9 G9a MYC pathway targeted activity Adapted from Cancer Cell. 2018;34(4): G9a signature for patient selection DMX8.1 specifically enhances expression of genes repressed by MYC in cancer setting 9

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 10

11 T u m o r V o lu m e (m m 3 ) M o u s e w e ig h t (g ) DMX8.1 single agent efficacy in vivo T u m o u r V o lu m e M o u s e W e ig h t V e h ic le D M X V e h ic le D M X D a y s D a y s Reduced tumour growth of Triple Negative Breast Cancer AT32 syngeneic tumors were treated with DMX8.1 (ip 5mg/kg every 2 days). 11

12 DMX8.1 reverses endocrine therapy resistance Persistent activation of MYC target genes in tamoxifen resistant breast cancer (e.g. CCND1) DMX8.1 antagonises MYC actions. Re-sensitisation of tamoxifen resistant breast cancer MCF7TR treated with tamoxifen (ip 20mg/kg every two days), DMX8.1 (ip 5mg/kg every 2 days), or combination therapy. 12

13 DMX8.1 show improved PK by oral route IP administration every 2 nd 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 13

14 DMX8.1 Safety Profile 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 14

15 Intellectual Property 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 15

16 Invest or Partner 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 16

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 17

18 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 19

20 IN F - (p g /m l) % c e ll s u rv iv a l Gal9 axis stimulation Cytokine Release T cell Survival Ig G C tr l -G A L 9 Ig G C tr l -G A L 9 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. 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. 20

21 IF N - (p g /m l) T N F - (p g /m l) Blocking Gal9 blocks cytokine induction by DCs * * T c e ll D C + T c e ll -G a l9 + D C + T c e ll T c e ll D C + T c e ll -G a l9 + D C + T c e ll 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 21

22 T u m o r v o lu m e (m m 3 ) T u m o r v o lu m e (m m 3 ) T u m o r v o lu m e (m m 3 ) T u m o r v o lu m e (m m 3 ) Activating α-gal9 mabs Inhibit Tumors Melanoma B 1 6.F 0 Colon Cancer C T R a t Ig G - G a l R a t Ig G - G a l D a y s p o s t tra n s p la n t Prostate Cancer R a t Ig G - G a l R M D a y s p o s t tra n s p la n t Breast Cancer R a t Ig G - G a l S 2 W T P 3 p 2 6 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, D a y s p o s t tra n s p la n t D a y s p o s t tra n s p la n t 22

23 Human antibody discovery program CRO conducted human antibody discovery program Discovery screening against complete human IgG1 antibodies Counter screened against GAL4, closest Galectin family member 23

24 Fully Human Candidate mab diversity 24

25 Candidate mab characteristics Human IgG1 Monovalent K D s 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 25

26 M F I p g /m l Functional screen: cytokine induction IN F g T N F a 1, , , , N o P e p m ix P B S C tr l Ig G C tr l a n ti-p D 1 a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P N o P e p m ix P B S C tr l Ig G C tr l a n ti-p D 1 a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P a G 9 P A n t ib o d y C lo n e A n t ib o d y C lo n e 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) 26

27 T u m o r v o lu m e (m m 3 ) T u m o r v o lu m e (m m 3 ) α-gal9 mab inhibits tumour growth Colon Cancer Melanoma R a t Ig G P P R a t Ig G P P D a y s p o s t tra n s p la n t D a y s p o s t tra n s p la n t 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) 27

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 28