Personalized Therapeutics The Power of Epigenetics. Company Overview. June 2014

Transcription

1 Personalized Therapeutics The Power of Epigenetics Company Overview June 2014

2 2013 Accomplishments Forward Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, prospects, plans and objectives of management, are forwardlooking statements. The words anticipate, believe, estimate, expect, intend, may, plan, predict, project, target, potential, will, would, could, should, continue, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results may differ materially from those indicated by such forwardlooking statements as a result of various important factors, including: uncertainties inherent in the initiation of future clinical studies, expectations of expanding ongoing clinical studies, availability and timing of data from ongoing clinical studies, whether interim results from a clinical trial will be predictive of the final results of the trial or results of early clinical studies will be indicative of the results of future studies, expectations for regulatory approvals, development progress of the Company s companion diagnostics, availability of funding sufficient for the Company s foreseeable and unforeseeable operating expenses and capital expenditure requirements, other matters that could affect the financial performance of the Company, other matters that could affect the availability or commercial potential of the Company s therapeutic candidates or companion diagnostics and other factors discussed in the "Risk Factors" section of the Company s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 14,

3 Company Overview 2013 Accomplishments Biopharmaceutical company creating personalized therapeutics for patients with genetically defined cancers n diagnostics First-in-class small molecule inhibitors targeting histone methyltransferases (HMTs), a 96-member class of epigenetic enzymes that drive many cancers and other diseases Clinical programs for genetically defined cancers EPZ-5676 DOT1L inhibitor (demonstrated objective responses in adult Phase 1 dose escalation) EPZ-6438 EZH2 inhibitor (Phase 1/2 ongoing) Product platform generating pipeline of novel personalized therapeutic programs Intellectual property with earliest composition of matter expected expirations in 2032 Rx collaborations with Celgene, Eisai, and GSK CDx collaborations with Abbott and Roche 3

4 HMTome Target 2013 Class Accomplishments Oncogenic HMT Disease Misregulated gene expression HMTs are part of regulatory system that controls gene expression, called epigenetics HMTs regulate gene expression by placing methyl marks on histones Genetic alterations can alter HMT activity making them oncogenic due to misregulated gene expression 96-member target class, 20 prioritized based on oncogenic mechanism 4

5 Pipeline of First-In-Class 2013 Accomplishments Personalized Therapeutics Preclinical Development Clinical Development EPZ-5676 DOT1L GSK3 EPZ-6438 EZH2 Acute leukemias NHL and INI1-deficient tumors GSK Target 1 GSK Target 2 GSK Target 3 Solid tumor programs Hematological malignancy programs <200 nm <50 nm <600 nm Development candidate milestone 2013 Lead candidate milestone in 2014 Lead candidate milestone in 2014 Novel HMT targets in Epizyme s product platform 5

6 2014 Clinical Milestones 2013 Accomplishments 5 Planned POC Programs HMT Indication Annual Incidence 2014 Objectives Partner DOT1L 1. MLL-r adult 3,600 patients 2. MLL-r peds 1,300 patients 3. MLL-PTD 2,300 patients Phase 1 dose escalation and MLL-r expansion stage POC data* Phase 1b POC initiated Phase 1 POC expansion stage enrollment Epizyme 100% US rights Celgene EZH2 4. Non-Hodgkin lymphoma 12,100 patients Phase 1 dose escalation data* Phase 2 POC initiation** Epizyme 50% US rights Eisai 5. Synovial sarcoma/ini- 1 1,700 patients Phase 2 POC initiation** 6 *Data disclosure in 2H14 **Gated to Phase 1 dose escalation data

7 EZH2 Inhibition 2013 for Genetically Accomplishments Defined Cancers SWI/SNF COMPLEX INI1 PRC2 COMPLEX Change of function mutation Non-Hodgkin lymphoma Loss of function due to INI1 deficiency Synovial sarcoma, MRT, others Methylation Demethylation K27 K27(me) 3 At least 3 distinct genetically defined cancers, growing list Non-Hodgkin lymphoma, germinal center (EZH2 point mutations) Synovial sarcoma (SSX-SS18 fusion) MRT (INI1-deletion) 7

8 EPZ-6438 EZH Inhibitor Accomplishments Clinical Candidate Potent against intended target in WT and mutant form 2.5 nm biochemical assay Highly selective vs. HMTs and other targets Biochemical >20,000-fold by K i Cellular only inhibits target associated methyl mark Orally bioavailable Target methyl mark inhibition that leads to specific killing of genetically defined cancer cells in vitro Combinations with glucocorticoid receptor agonists or signaling pathway modulators extends activity to all germinal center derived NHL cells Profound and sustained in vivo efficacy in animal models following inhibition of target methyl mark EPZ-6438 (mm) 0 1 H3K27Me1 H3K27Me2 H3K27Me3 H3K4Me3 H3K9Me3 H3K36Me2 H3K79Me2 H3K27Ac H3 EZH2 Products 8

9 EPZ-6438 Selective 2013 Accomplishments Killing of EZH2-Mutant Cells Target methyl mark inhibition leads to specific killing of genetically defined cancer cells as function of dose and time EZH2 Mutant Cells EZH2 Non-Mutant Cells µm E7438 Day Day µm E7438 H3K27me3 H3 Methylation IC50 = µm Methylation IC50 = µm Knutson et al., Nature Chemical Biology (2012) 9

10 EPZ-6438 Pre-Clinical 2013 Accomplishments NHL Tumor Regressions Potent and durable therapeutic effect of targeting oncogenes in pre-clinical studies EPZ-6438 in Nude Mouse Xenograft (28-day BID) Durable in vivo efficacy in animal models Dose-, exposure- and timedependent effects Sustained tumor regressions seen at well-tolerated dose Keilhack et al., Blood (2012) 10

11 EPZ-6438 Synovial 2013 Accomplishments Sarcoma Synovial sarcoma is a soft tissue sarcoma, affecting primarily adolescents and young adults, and represents 7-10% of soft tissue malignancies Clinical course characterized by frequent and late local or metastatic recurrence; no specific or effective treatments after failure of ifosfamide-based therapy 1 Characterized by t(x;18) (SSX-SS18), which inactivates SWI/SNF via displacement and degradation of INI1 2 EPZ-6438 selectively kills mutant SSX-SS18 cells in vitro SSX-SS18 fusion negative SSX-SS18 fusion positive 1 Rosen, Cancer (1994) 2 Kadoch, Cell (2013) Knutson et al. (unpublished data) 11

12 EPZ-6438 Malignant 2013 Accomplishments Rhabdoid Tumor (MRT) MRT is a deadly childhood cancer caused by a gene alteration that misregulates EZH2 activity Typical presentation in kidney or brain in children less than 2 years of age with event-free survival rates less than 20% Current therapy is intensive chemotherapy and radiation with significant treatment-related morbidity EPZ-6438 selectively kills mutant MRT cells in vitro Selective Killing of Mutant MRT Cells in vitro Complete and Sustained Regression of Mutant MRT Xenografts Knutson, et al., PNAS (2013) 12

13 EPZ-6438 Clinical 2013 Development Accomplishments Plan Phase 1 dose escalation ongoing advanced solid tumors and B-cell lymphomas Initiated in June 2013 Expected 2014 completion and 2H14 data disclosure Phase 2 POC programs planned for 2014 gated to data from dose escalation EZH2-mutated Germinal Center NHL In design of current Phase 1/2 study Relapsed/refractory EZH2-mutant GC DLBCL and Grade 3 FL Multinational site participation Synovial Sarcoma Initiation in parallel with NHL Phase 2 13

14 DOT1L MLL-r 2013 Oncogenic Accomplishments Mechanism Chromosomal Translocation Creates MLL-Fusion Protein Aberrant DOT1L Recruitment by MLL- Fusion Site-Specific Hyper-Methylation Disease Phenotypic Changes Transcriptional Changes 14

15 EPZ-5676 Acute 2013 Leukemias Accomplishments with MLL Alterations MLL-r Genetic Alteration Reciprocal chromosomal translocations involving 11q23 Disease 5-10% AML and ALL In adults and pediatrics 4,900 annual incidence in major markets Diagnostic Test Cytogenetics, FISH Standard test in all patients diagnosed with acute leukemia Abbott partnership Prognostic Implications Poor DFS and OS compared with non-mll-r leukemias MLL-PTD Partial tandem duplication of MLL gene 5-8% of AML in adults 2,300 annual incidence in major markets PCR Research test in selected patients Associated with short initial remission duration with poor response to subsequent therapy 1 Overall survival by cytogenetic risk groups in adult AML Patients Event free survival by genetic abnormality in pediatric ALL patients 1 Doehner K et al., J Clin Oncol 2002 Graphs: Byrd J C et al., Blood 2002; Pui et al., N Engl J Med

16 V ia b le C e lls /m L Total Cells EPZ-5676 Selective 2013 Accomplishments Killing of MLL-r Cells Target methyl mark inhibition leads to specific killing of genetically defined cancer cells as function of dose and time MLL-Rearranged Cells Increasing dose H3K79me2 Total H3 Non-MLL-Rearranged Cells Increasing dose H3K79me2 Total H Time D a(days) y s E P Z mm V e h ic le Time (Days) Untreated & Treated Jurkat + Jurkat - Daigle et al., Blood (2013) and unpublished data 16

17 EPZ-5676 Pre-Clinical 2013 Accomplishments Tumor Regressions Durable therapeutic effect of targeting DOT1L in pre-clinical studies is dose- and time-dependent Nude Rat MLL-r Xenograft Model Durable in vivo efficacy in animal models Dose-, exposure- and timedependent effects Sustained tumor regressions seen at well-tolerated doses Daigle et al., Blood (2013) 17

18 m R N A P e r c e n t C o n t r o l A n n e x i n +, A A D - EPZ-5676 Pre-Clinical 2013 Accomplishments Mechanism of Action Both differentiation and apoptosis are observed in MLL-r pre-clinical models Inhibition of H3K79 methylation EPZ-5676 Increasing dose CD14 upregulation Differentiation Morphologic evidence of maturation H3K79me2 Total H3 Vehicle EPZ-5676 Reduction in MLL-r target genes H O X A 9 M E I S 1 Apoptosis (Annexin staining) T i m e ( D a y s ) 0 V e h i c l e Increasing dose EPZ Daigle et al., Blood (2013) and unpublished data 18

19 EPZ-5676 Phase Adult Accomplishments Program Dose Escalation Enrollment completed 2013 Patients with advanced hematologic malignancies (including MLL-r patients) Expansion Currently enrolling MLL-r patients (also permits MLL- PTD) 21-day on/7-day off administration with dose escalation - Uninterrupted administration as IRB-approved exception 6 sites Uninterrupted administration with possible dose escalation Up to 12 sites (US + Europe) Outcome measures Safety and tolerability PK (dose and exposure) PD (methyl mark inhibition) Outcome measures Safety and tolerability Assessment of efficacy in MLL-r and MLL-PTD patients 19

20 EPZ-5676 Phase Adult Accomplishments Status as of December 2013 Favorable safety profile and anti-leukemic activity Dose escalation stage (advanced hematologic malignancies, including MLL-r) 21 day on/ 7 day off schedule evaluated, doses of 12 mg/m2/day-80 mg/m2/day Heavily pre-treated population No DLTs, drug-related treatment discontinuations, or dose-toxicity relationship Dose-proportional exposure Dose- and time-dependent methyl mark reduction Objective responses observed in 2 cohort 4 (54 mg/m2/day) patients (switched to uninterrupted administration) Cohort 5 enrolled 80 mg/m2/day Expansion cohort stage (restricted to MLL-r and MLL-PTD patients) Initiated December 2013, currently enrolling Starting dose 90 mg/m2/day, uninterrupted continuous IV infusion Dose escalation permitted 20

21 EPZ-5676 Phase Pediatric Accomplishments Program Dose Escalation Expansion Initiated in May 2014 Pediatric patients between 3 months and 18 years of age with MLL-r leukemia (AML/ALL) MLL-r patients at recommended Phase 2 dose CIV infusion for 28 days of a 28-day cycle Uninterrupted administration with possible dose escalation Outcome measures Safety and tolerability Preliminary assessment of efficacy Outcome measures Further assessment of safety and tolerability Continued preliminary assessment of efficacy 21

22 Intellectual Property 2013 Accomplishments Composition of matter claims for therapeutic candidates EPZ-5676 issued 2013, expected to expire in 2032 EPZ-6438 issued 2013, expires in 2032 In 2014, complementary claims were issued covering the diagnosis of patients with EZH2 mutations and their subsequent treatment with an EZH2 inhibitor, with expected expiration date in 2031 Broad IP position covering platform and therapeutic candidates Composition of matter all created in-house Methods of use including treatment, combination therapy and biomarkers Formulations, polymorphs and methods of manufacture Research and screening methods 22

23 Collaborations as 2013 Business Accomplishments Drivers $178 million non-equity funding with significant retained US rights ex-us Rights April 2012 Epizyme retains all DOT1L US rights $117M to date (includes equity) Ex-US option for other programs for 3 years Global co-development and funding $135M remaining DOT1L milestones $160M in potential milestones for each non-dot1l target selected Ex-US royalties to mid teens 50% US Rights April 2011 EZH2 only, Epizyme US option $35M to date Eisai funds 100% through POC Epizyme option for US profit share and cocommercialization $195M in additional milestones Ex-US royalties Platform Expansion January targets $48M to date Research funding $620M in potential milestones WW royalties 23

24 2014 Clinical Studies 2013 Accomplishments and Data Disclosures Ongoing Phase 1 clinical study expansion stage of EPZ-5676 in MLL-r adult patients and MLL-PTD adult patients - planned clinical data disclosure of the dose escalation and expansion stage results at a medical conference in the second half of 2014 Initiated Phase 1b clinical study of EPZ-5676 in MLL-r pediatric patients in May 2014 Ongoing Phase 1 dose escalation study of EPZ-6438 in patients with advanced solid tumors or B cell lymphoma - planned clinical data disclosure of dose escalation stage in the second half of 2014 Planned Phase 2 POC clinical study of EPZ-6438 in non-hodgkin lymphoma patients with EZH2 point mutations, pending Phase 1 results Planned Phase 2 POC clinical study of EPZ-6438 in INI1-deficient tumors, such as synovial sarcoma, pending Phase 1 results 24

25 Accomplishments 2013 in 2013 Accomplishments and 2014 to Date Advanced EPZ-5676 DOT1L inhibitor program $25 million proof of concept milestone with Celgene Initiated Phase 1 study expansion stage for adult MLL-r and MLL-PTD patients Initiated Phase 1b study in pediatric MLL-r patients Initiated ongoing EPZ-6438 EZH2 inhibitor Phase 1 dose escalation study $6 million study initiation milestone with Eisai Achieved three pre-clinical milestones with GlaxoSmithKline $4 million development candidate milestone for 1 st target in December 2013 $2 million lead candidate milestone for 2 nd target in February 2014 $4 million lead candidate milestone and license payment for 3 rd target in March-April 2014 Advanced intellectual property position with U.S. patents issued, including composition claims for EPZ-5676 and EPZ-6438 expected to expire in 2032 and Rx and Dx claims expected to expire in EOY 2014 more than $170 million cash guidance Cash runway through at least mid-2016 prior to any additional milestones

26 2013 Accomplishments 26