Zenith Capital Corporation · OTC:ZHCLF
Zenith Capital — Zenith Epigenetics — EpiCongress July 2014
18 slides from Zenith Capital's conference presentation, July 2014
Slide 1: Developing Best in Class BET Inhibitors for Oncology & AI: from Discovery to the Clinic
Developing Best in Class BET Inhibitors for Oncology & AI: from Discovery to the Clinic Kevin G. McLure, PhD EpiCongress July 2014
Slide 2: Zenith Epigenetics Overview
Zenith Epigenetics Overview Formed from Resverlogix as an independent company to develop a novel epigenetic platform for oncology and autoimmune diseases • Developing small molecule inhibitors against BET Bromodomains (BET) Clinical studies initiating with ZEN-3365 in 2H 2014 for hematological malig
Slide 3: Phase I BET Inhibitor Oncology Clinical Trials
Phase I BET Inhibitor Oncology Clinical Trials Activity shown with OTX-015 Company Drug Indications Zenith Epigenetics ZEN-3365 AML, LPD Zenith Epigenetics ZEN-3365 Solid GlaxoSmithKline I-BET762 NUT midline carcinoma and other solid tumors GlaxoSmithKline I-BET762 Relapsed, Refractory Hematologic M
Slide 4: Zenith's broad platform has generated high potency BETi with desirable pharmaceutical properties
Zenith’s broad platform has generated high potency BETi with desirable pharmaceutical properties ZEN-3365 selected as Development Candidate from a panel of excellent compounds In Vivo FRET Brd4(1) FRET Brd4(12) c-MYC Proliferation PK Efficacy Compound ID IC50 (uM) IC50 (uM) IC50 (uM) IC50 (uM) (Rat)
Slide 5: ZEN-3365 selectively binds BET bromodomains
ZEN-3365 selectively binds BET bromodomains • 10 – 40 nM IC50 for BET bromodomains 1 74-185 345-457 632-710 801 BD1 BD2 ET • > 20-fold selectivity for BRD4(1) vs non-BET BRD2 bromodomains 1 34-145 307-419 562-640 726 • > 200-fold selectivity vs 68 cellular receptors BRD3 BD1 BD2 ET • 0/456 kinase do
Slide 6: ZEN-3365 selectively displaces BRD4 from a super-enhancer to repress gene expression
ZEN-3365 selectively displaces BRD4 from a super- enhancer to selectively repress gene expression • ZEN-3365 more potently represses super- enhancer driven MYC expression in MM.1S than regular enhancer/promoter driven BCL-2 in MM.1S or regular promoter-driven MYC in MV4-11 cells BRD4 Binding to Gene
Slide 7: ZEN-3365 inhibits expression of MYC and BCL-2 and induces apoptosis in AML and DLBCL
ZEN-3365 inhibits expression of MYC and BCL-2 and induces apoptosis in AML and DLBCL DMSO ZEN-3365, IC90 IC50 (nM) IC50 (nM) IC50 (nM) 1 uM AML (MV4-11) mRNA MV4-11 SUDHL-2 SUDHL-4 MYC 90 91 176 BCL-2 120 97 140 1.5 uM 21% 98% DLBCL (SUDHL-2) • ZEN-3365 reduces expression of MYC & BCL-2 mRNA and pro
Slide 8: MV4-11 xenograft model: ZEN-3365 causes durable tumor regression
MV4-11 xenograft model: ZEN-3365 causes durable tumor regression 8
Slide 9: ZEN-3365 potently inhibits proliferation of solid tumor cell lines
ZEN-3365 potently inhibits proliferation of solid tumor cell lines Cell Line Tumor Type IC50 (uM) MDA MB 231 Breast 0.37 HT-29 Colon 0.54 SCC-9 Head and Neck 0.32 DMS273 Lung 0.38 BPH1 Prostate 0.31 No. cell No. Tumor type lines IC50 < 2 uM CRC 23 15 CRPC 6 4 Medium sensitivity Higher sensitivity Br
Slide 10: ZEN-3365 inhibits MYC expression & CRC proliferation in vitro and inhibits xenograft growth
ZEN-3365 inhibits MYC expression & CRC proliferation in vitro and inhibits xenograft growth ZEN-3365: • ZEN-3365Tumor regression, inhibits complete and HT29 colorectal carcinoma cell proliferation (IC50 MYC expression response and sustained = 66 nM); effect up is well-tolerated tosee and 33 days 58
Slide 11: ZEN-3365 is a compelling molecule for clinical development
ZEN-3365 is a compelling molecule for clinical development Feature Comments Potency 50 nM BRD4 ; 90 nM MYC ; 160 nM MV4-11 proliferation Selectivity Highly selective for BET proteins Does not inhibit kinases No off-target binding to Panlabs 68 receptor panel PK/PD Orally bioavailable, level and dura
Slide 12: Phase 1 study of ZEN-3365: First patient in 3Q 2014
Phase 1 study of ZEN-3365: First patient in 3Q 2014 2014 2015 2016 2H 1H 2H 1H 2H IND Relapsed AML (Dose Escalation + Expansion Cohort) filing Expansion Cohort 1: TBD Dose Escalation Lymphoproliferative malignancies (LPM) Expansion Cohort 2: TBD Expansion Cohort 3: TBD Solid Tumors (Dose Escalation
Slide 13: BETi gene signature will be used to evaluate PD in clinic
BETi gene signature will be used to evaluate PD in clinic PD Marker mRNA in Human PBMCs (3 uM 6h) 2.0 Fold change mRNA 1.5 1.0 0.5 0.0 ZEN003365 ZEN003365 ZEN003365 ZEN003365 ZEN003365 DMSO DMSO DMSO DMSO DMSO MYC BCL-2 Gene A Gene B Gene C 13
Slide 14: Zenith's biology selectivity platform: developing next generation BD1 selective compounds
Zenith’s biology selectivity platform: developing next generation BD1 selective compounds Zenith’s compounds can uniquely dissect BD1 vs BD2 biology • Zenith has BD2 selective and pan-selective Compound BRD4(1) BRD4(2) MYC Proliferation compounds IC50 (uM) IC50 (uM) IC50 (uM) IC50 (uM) • BD1 [BRD4 (
Slide 15: Zenith's robust platform has generated promising BET inhibitors for auto-immune disorders
Zenith’s robust platform has generated promising BET inhibitors for auto-immune disorders FRET Brd4(1) FRET Brd4(12) IL6 IL17 PK In Vivo Compound ID IC50 (uM) IC50 (uM) IC50 (uM) IC50 (uM) (Rat) Efficacy Rat CIA ZEN-3118 0.07 0.07 0.23 0.19 +++ Mouse EAE ZEN-3309 0.05 0.05 0.23 0.36 +++ Rat CIA ZEN-
Slide 16: ZEN-3118 inhibits human autoimmune-related gene expression in vitro
ZEN-3118 inhibits human autoimmune-related gene expression in vitro • Zenith has demonstrated multiple cell systems where BETi inhibit drivers of autoimmune disease (antigen stimulation of T cells; macrophages; synovial fibroblasts) • IL-6, TNFa and IL-17 are implicated in rheumatoid arthritis • IL-
Slide 17: ZEN-3118 is efficacious in rat CIA & mouse EAE at well tolerated doses
ZEN-3118 is efficacious in rat CIA & mouse EAE at well tolerated doses • ZEN-3118 shows dose-dependent inhibition of disease progression in a therapeutic rat collagen- induced arthritis model of rheumatoid arthritis • Good efficacy in experimental autoimmune encephalomyelitis model of multiple scler
Slide 18: Summary
ZEN-3365 Summary BET bromodomains are a novel epigenetic target which regulate super-enhancer acquired oncogenic drivers such as c-MYC and BCL-2 • Significant MOA rationale and pre-clinical evidence for BET inhibition in leukemia/lymphomas and solid tumors Broad and differentiated chemistry platform