Citi 10 th Annual Biotech Conference! September 9, 2015!!

Transcription

1 Citi 10 th Annual Biotech Conference! September 9, 2015!!

2 Forward Looking Statements! Any statements in this presentation about future expectations, plans and prospects for Epizyme, Inc. and other statements containing the words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties inherent in the initiation of future clinical studies or expansion of ongoing clinical studies; availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial such as the results referred to in this presentation will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products; 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 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 Form 10-Q filed with the SEC on August 6, 2015, and in our other filings from time to time with the SEC. In addition, the forward-looking statements included in this presentation represent the Company's views as of the date hereof. The Company anticipates that subsequent events and developments will cause the Company's views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. These forwardlooking statements should not be relied upon as representing the Company's views as of any date subsequent to the date hereof.! 2!

3 Epizyme Highlights! 2013 Accomplishments! Leadership in HMT Inhibition Pioneers and leaders in HMT field; pipeline of novel HMT inhibitors! First-in-class Inhibitors Two first-in-class HMT inhibitors already in the clinic! Advancing Tazemetostat Demonstrated PRs and CRs in DLBCL, FL and an INI1-negative tumor;! Registration-supporting Phase II trials underway! Advancing Our Pipeline Proprietary efforts and partnerships with leading pharmaceutical companies to advance multiple new targets: Celgene, Eisai, GSK! IP Patented compositions of matter through at least 2032! 3! Financial Position Ended 2Q15 with $237 million in cash and equivalents: runway through at least the end of 2Q17!

4 Seasoned Management 2013 Accomplishments! Team with Deep Industry Expertise! Robert Gould, Ph.D.! President and CEO! 20 years at Merck in positions of increasing leadership, including VP of Licensing and External Research! Former Director of Novel Therapeutics at the Broad Institute of MIT and Harvard! B.A. from Spring Arbor College, Ph.D. from University of Iowa! Robert Copeland, Ph.D.! President of Research! and CSO! Former Vice President, Cancer Biology at GSK! Held scientific positions of increasing leadership at Merck and BMS! Held faculty position at University of Chicago Pritzker School of Medicine! B.S. from Seton Hall University, Ph.D. from Princeton University! Andrew Singer! Chief Financial Officer! Nearly 20 years of financial experience, with 15 years in life sciences field! Former Managing Director, Healthcare Investment Banking in Life Sciences Group at RBC Capital Markets! B.A. from Yale University, M.B.A. from Harvard Business School! Former Vice President of Oncology Development at J&J! Former Senior Vice President of Oncology at GSK! Former fellow at Dana- Farber, NCI and FDA! B.A. from Johns Hopkins, M.D. and Ph.D. from Yale Peter Ho, M.D., Ph.D.! University School of Chief Development Officer! Medicine! 4!

5 Incoming Chief Executive 2013 Accomplishments! Officer, Rob Bazemore (as of September 10, 2015)! Chief Operating Officer of Synageva through its acquisition in July 2015! President of Janssen Biotech, an immunology and oncology business with over $7 billion in revenues! Rob Bazemore, President and CEO Designate! Extensive experience leading J&J s largest franchise pipeline strategy, through:! New white space area strategy! NME identification & selection! Clinical development strategy! Product lifecycle management! Experience leading business development and partnership efforts to build a robust oncology portfolio, including:! Integration of Cougar Biotechnology, and launch of ZYTIGA! Development & commercial partnership with Pharmacyclics, and launch of IMBRUVICA! Led some of the most successful launches in immunology & oncology! 5!

6 Pioneers and Leaders in HMT Inhibitors! Lysine Methyl Transferases (KMTs)! Arginine Methyl Transferases (RMTs)! SMYD3: Breast, Liver, Colon, Gastric! SMYD2: Esophageal Squamous! EZH2: NHL, INI1,! Breast, Prostate, Colon, Gastric, Bladder, Liver, Melanoma! MLL4: Pancreatic, Glioblastoma! MLL: Leukemia! PRMT1: AML, Glioblastoma! PRMT7:! Breast! PRMT5:! Lymphoma! DOT1L: MLL-r! AML, ALL! SETD7! EZH1 PRMT8! SUV39H1:! Colon! PRMT3! PRMT6! CARM1: Breast,! Prostate! SETDB1:! Melanoma! EHMT1/2: Lung, Prostate, HCC! PRDM14: Breast! NSD1: AML! Published Epizyme proprietary inhibitors WHSC1L1: Lung, Breast! WHSC1: Multiple Myeloma! HMT with literature association with cancer NSUN2:! Breast! HMTs are part of a regulatory system that controls gene expression, called epigenetics! HMTs turn gene expression off and on by placing methyl marks on histones! HMTs can become oncogenic drivers due to misregulated gene expression! 96-member target class! 6! Source: Richon et al Chem. Biol. Drug Desi;,Copeland 2011 Drug Discov. Today Ther. Strat., Copeland 2013 Clinical Cancer Research!

7 Pipeline of First-In-Class 2013 Accomplishments! Epigenetic Therapeutics: Tazemetostat! Preclinical Development! Phase 1! Phase 2! Tazemetostat (EPZ-6438)! Phase 1 Dose Escalation and Dose Expansion:! NHL and Advanced Solid Tumors! Phase 2 NHL: 5-Arm Study in Relapsed/Refractory NHL! 1.! Wild type EZH2! Germinal Center DLBCL! 2.! Mutant EZH2! 3.! Wild type EZH2! Follicular Lymphoma! 4.! Mutant EZH2! 5! Non-Germinal Center DLBCL! Phase 2: Adult INI1-Deficient Tumors! Phase 1: Pediatric INI1-Deficient Tumors! n=38 fully enrolled! n=150 initiated June 2015! n=30! n=30! n=30! n=30! n=30! n=up to 90; planned! 4Q 2015! n=approx. 30; planned 4Q 2015! Clinical Pharmacology: Food Effect! Clinical Pharmacology: Drug-Drug Interaction! n=13 fully enrolled! n=12 planned September 2015! Initiated! 2015 Initiation Planned! 7!

8 Pipeline of First-In-Class 2013 Accomplishments! Epigenetic Therapeutics: Pinometostat & Additional Targets! Epizyme is a leader in HMT chemical biology, generating robust matter against eight novel targets and continuing work on proprietary pipeline against chromatin remodeling targets. Pinometostat (EPZ-5676)! Preclinical Development! Phase 1! Phase 2! Phase 1 Dose Escalation and Dose Expansion: Pediatric Acute Leukemias! Dose escalation: Under enrollment! GSK Targets! PRMT5 and two undisclosed targets! Celgene Targets! Three Undisclosed Targets! Novel HMT Targets! Solid Tumors and Hematologic Malignancies! Initiated! Preclinical Development! 8!

9 Multiple Genetic 2013 & Pharmacological Accomplishments! Factors May Sensitize B-Cell Lymphomas to EZH2 Inhibitors! Concurrent Treatment with Corticosteroids! EZH2! Hot Spot Muts! Wild- Type &! Mutant! EZH2! Concurrent Treatment with BCL2 & 6! Inhibitors! EZH2! ê! H3K27me3! MLL! LoF Muts! HAT! LoF Muts! Wild- Type! EZH2! Concurrent Treatment with! B-Cell! Signaling Inhibitors! PRC2 Subunit Amp/! Overexpression! Wild-Type! EZH2! KDM6A! LoF Muts! 9!

10 Tazemetostat 2013 Accomplishments! (EPZ-6438): Potent and Highly Selective EZH2 Inhibitor! Novel Structure, Potent Target Inhibition Selective for EZH2 PRMTs EPZ-6438: Ki <2.5 nm Selectivity >20,000-fold (100-fold for EZH1) Rodent oral bioavailability: 15-55% PKMTs In Vivo Efficacy with Oral Dosing mg/kg QD 10! Source: Knutson 2013, Knutson 2014

11 Tazemetostat First-in-human Phase 1 Trial Tazemetostat (EPZ-6438): oral dosing from 100 mg to 1600 mg BID! Population: relapsed or refractory B-cell lymphoma or solid tumors! Study design: 3+3 dose-escalation! Expansion cohorts at 800 mg (n=6 planned) and 1600 mg (n=6 planned)! Food effect sub-study at 400 mg (n=12 planned)! Primary endpoint: determination of RP2D/MTD! Secondary endpoints: safety, PK, PD and tumor response (every 8 wks)! Data cut-off: 8-Jun-2015! Dose Patients Solid tumors (mg BID)! (n=45)! (n=26)! B-cell NHL (n=19)! 100* Food Effect * 2 formulations 11!

12 Patient Tumor Types! Relapsed or refractory NHL n=19 * Diffuse large B-cell lymphoma (DLBCL) GCB 4 non-gcb 6 undetermined 3 Follicular lymphoma (FL) 5 Marginal zone lymphoma (MZL) 1 Relapsed or refractory solid tumor n=26 INI1-deficient tumor 10 GI malignancy 7 GU malignancy 5 Sarcoma 3 CNS tumor 1 * 14 NHL patients tested to date: 13 WT + 1 mutant by cobas EZH2 Mutation Test (in development, Roche Molecular Systems, Inc.) 12!

13 NHL Patient Demographics! Characteristic Patients (n=19) n (%) Median age, years (range) 61 (24-84) Sex (M / F) 14 (74) / 5 (26) # of prior therapeutic regimens 1 2 (10) 2 1 (5) 3 7 (37) 4 2 (10) >5 7 (37) Refractory to last prior regimen 7 (37) Prior autologous hematopoietic cell transplant 5 (26) 13!

14 Pharmacokinetics! D a y 1 5 E P Z p la s m a c o n c. (n g /m L ) T im e (h ) m g (s u s p ), n = m g (ta b ), n = m g, n = m g, n = m g, n = m g, n = 1 1 E P Z p la s m a c o n c. (n g /m L ) T ro u g h p la s m a c o n c. a t R P 2 D m g B ID D a y h D a y h D a y h D a y h Rapid absorption (t max = 1-2 h) with a mean terminal t 1/2 = 3-5 h Dose-proportional C max and AUC 0-12h at steady-state (day 15) through 1600 mg BID Decrease in systemic exposure between day 1 and day 15 with no further reduction afterwards 42% decrease in AUC 0-12h on day 15 vs. day 1 at 800 mg BID C trough levels reach steady-state by day 15 14!

15 PK-PD: EZH2 Inhibition in Surrogate Tissue Full Epithelium Full Epithelium H3K27Me3 Screening Week 4 Evidence of target inhibition in skin: Reduction of H3K27-Me3 IHC signal observed at week 4 at all doses Exposure-dependent reductions in H3K27- Me3 IHC signal Differential effects by epithelial layer Minimal changes to stratum basale Pronounced changes in stratum spinosum Full epithelium represents composite signal of stratum spinosum and basale Stratum Spinosum Stratum Basale Stratum Spinosum Stratum Basale Fractional change from baseline of % H3K27Me3 positive cells Full Epithelium Basale Spinosum mg 200 mg 400 mg 800 mg 1600 mg 15! Day 15 AUC 0-last (h*ng/ml)

16 Adverse Events! Patients with: DLT (thrombocytopenia) = 1 Dose reduction = 1 Drug discontinuation = 1 Dose interruption = 7 * >10% of patients all patients 16! n = 45! All Events! Treatment-Related! All Grades *! Grade >3! All Grades! Grade >3 Any patient with AE Asthenia Anorexia Anemia Dyspnea Nausea Constipation Vomiting Thrombocytopenia Dyspepsia Muscle spasm Hypertension Neutropenia Transaminase

17 Overall 2013 Best Accomplishments! Response: NHL 9/15 Evaluable Patients Have CR+PR! Evaluable Patients (n=15) DLBCL (n=9) FL (n=5) MZL (n=1) CR+PR * SD Remains on-study G N GCB non-gcb 17! 0 6 months * Cheson criteria / International Working Group

18 Target 2013 Lesion Accomplishments! Activity: NHL! Evolution of Response! * % change from baseline DLBCL FL MZL 18! weeks months * truncated

19 CR in Primary 2013 Accomplishments! Mediastinal B-Cell Lymphoma! Baseline 23 y.o. male 200 mg BID Week 40: CR EPZ-6438: ongoing response week ! PR PD PD PD Week 16: Week 40: 2014 PR 2015 CR

20 CR in Follicular Lymphoma (EZH2 wt )! Baseline 78 y.o. male 800 mg BID Week 60: CR EPZ-6438: ongoing response week 60 PR PD CR CR PD PD PD Week 8: Week 16: SD PR Week 32: CR !

21 Response in DLBCL (EZH2 Y646H )! Baseline Week 16: PR 53 y.o. female 800 mg BID Mutant by cobas EZH2 Mutation Test (in development). Confirmed Y646H by NGS. EPZ-6438: ongoing response week ! PR SD PD PR PD SD SD PD Week 16: PR

22 SWI/SNF & PRC Accomplishments! Effect Chromatin Remodeling in Opposing Manners! (A) Normal Cells: Balance between PRC2 & SWI/SNF Remodeling of Chromatin SAM& PRC2 AEBP2& SUZ12& RbAp48& EZH2&&&&& EED& SAH& SWI/SNF ARID1A/B INI1 SMARCA2/4 ATP ADP (B) INI1-Deficient Tumors: INI1 Loss Abrogates SWI/SNF Activity. Cells now addicted to PRC2 SAM& PRC2 AEBP2& SUZ12& RbAp48& EZH2&&&&& EED& SAH& 22! ARID1A/B SWI/SNF ATP X SMARCA2/4 X X INI1

23 CR in INI1-Negative Malignant Rhabdoid Tumor! 55 y.o. male 800 mg BID Baseline Week 8 Week 20 Baseline Week 4 Baseline Week mm: CR Diagnosis Surgery + XRT EPZ-6438: ongoing response week 58 23! 2013 CR PD Week 8: 2014 CR 2015

24 Study Conclusions! Tazemetostat has an acceptable safety profile! 800 mg BID dose confirmed as Recommended Phase 2 Dose! Supported by PK, PK/PD in surrogate tissue, safety, efficacy! Impressive efficacy, with 9 of 15 patients NHL patients demonstrating CR or PR! PR first observed as early as 2 months and as late 10 months! Evolution of objective response (SD PR, PR CR) seen in 7 patients! Relapsed DLBCL (both GCB and non-gcb) and FL! Responses in patients with EZH2 wild-type and mutant tumors! Phase 2 study for DLBCL (GCB and non-gcb) and FL now enrolling! Five parallel cohorts based on cell-of-origin and EZH2 mutation status! First patient enrolled on 10-June-2015; First patient dosed 9-July-2015! Continuing to add countries and study sites! 24!

25 Tazemetostat Phase Accomplishments! NHL Study Initiated; Phase 1 and 2 INI-Negative / Synovial Sarcoma Studies Planned! Phase 2 Study of Tazemetostat in Relapsed/Refractory (R/R) B-Cell Non- Hodgkin Lymphoma! n=150; 800 mg BID! Initiated: 2Q15 in Europe, Australia! Incidence: 155,000 patients*! Phase 2 Study of Tazemetostat in Adult INI1-Negative Tumors and Synovial Sarcoma! Expected initiation: 4Q15! Incidence: 1,700* R/R Germinal Center DLBCL! Wild-Type EZH2! n=30! Incidence: 24,000*! R/R Germinal Center DLBCL! Mutant EZH2! n=30! Incidence: 6,000*! R/R Follicular Lymphoma! Wild-Type EZH2! n=30! Incidence: 30,000*!! Phase 1 Study of Tazemetostat in Pediatric INI1-Negative Tumors and Synovial Sarcoma! Expected initiation: 4Q15! Incidence: 700*! 25! *Incidence figures for major markets! R/R Follicular Lymphoma! Mutant EZH2! n=30! Incidence: 6,000*! R/R Non-Germinal Center! DLBCL! n=30! Incidence: 89,000*!

26 Strong Synergy 2013 Between Accomplishments! Tazemetostat and Multiple Nodes of B-Cell Signal Transduction! Strong synergy with:! Corticosteroids! Inhibitors of kinases along B-cell signaling pathway! 26!

27 Tazemetostat Combination Studies! R-CHOP is standard of care front line therapy for DLBCL! R-CHOP components are rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone! Plan to initiate additional trials:! R-CHOP combination! Combination with a B-cell signaling agent or other emerging targeted therapy!! 27! Source: Knutson et al (2014) PLOS One!

28 Pinometostat (EPZ-5676) 2013 Accomplishments! First-in-Class Small Molecule Inhibitor of DOT1L! Mechanism of Action:! DOT1L inhibition (and target H3K79 methyl mark reduction) results in anti-leukemic effects in cancers with MLL genetic alterations! No effects in cancers without MLL alterations! Target indications: MLL-r AML and ALL! MLL-r primary indication genetically defined subset of AML and ALL, adult and pediatric! Orphan drug designation granted in US and EU! Phase 1 MLL-r pediatric patient trial initiated in May 2014! Enrolling patients between the ages of 3 months and 18 years to evaluate safety, PK, PD, with preliminary assessment of efficacy! PK modeling from study presented at ASH Annual Meeting 2014!!! 28!

29 Epizyme: A Rich Portfolio of HMT Inhibitors 96 HMTs identified Inhibitors for >13 targets Genetic ablation techniques Chemical biology Understanding the pathobiological roles of HMTs in cancer Impact of small molecule HMT inhibitors Proprietary collection of small molecule HMT inhibitors HMT enzymology and structural biology Pipeline of novel HMT inhibitors 29!

30 Pipeline: First-in-Class PRMT5 Inhibitor for MCL! Novel NCE! Unique Binding Mode! Potent and Selective for PRMT5! PD marker based on substrate methylation! 30! Penebre et al. Nature Chemical Biology, 2015! Robust tumor growth inhibition! With correlated PD!

31 Significant Strategic Partnering! $131 million to date, including equity! Worldwide option on two HMT targets and ex-us option on one HMT target! Up to $610 million in potential milestones for each selected option program! 31! $75 million developed-based license payments! $365 million regulatory-based milestone payments! $170 million sales-based milestone payments! Royalty to low double-digits! Global partnership on pinometostat (EPZ-5676)! Epizyme retains all US rights and funds Phase 1 studies! Celgene retains ex-us rights and pays royalties to mid-teens! $35 million remaining in potential clinical milestone payments! $100 million remaining in potential regulatory milestone payments! Epizyme has global development and commercialization rights ex-japan! Epizyme made $40 million upfront payment to Eisai! Epizyme pays up to $20 million in clinical milestones and up to $50 million in regulatory milestones! Epizyme pays a midteens royalty for sales ex- Japan! Eisai pays a mid-teens royalty for sales in Japan!! Partnership completed; $53 million to date! Epizyme delivered compounds against three targets, including first-in-class PRMT5 inhibitor! GSK has global development and commercialization rights! $620 million in remaining potential milestone payments for all three targets! $18 million in potential preclinical milestone payments! $109 million in potential clinical milestone payments! $275 in potential regulatory milestone payments! $218 in potential sales-based milestone payments! WW royalties up to low double digits!

32 Epizyme Financial Overview! Ended 2Q2015 with $237 million in cash and cash equivalents! No debt! Expected runway through at least the end of second quarter 2017! Shares outstanding as of June 30, 2015: 41.2 million! Fully diluted shares outstanding as of June 30, 2015: 44.5 million!! 32!

33 Multiple Catalysts Throughout 2015! ü ü Completed accrual of 14 patients in tazemetostat phase 1 dose expansion cohorts! ü Presented updated dose escalation data and initial dose expansion data June 20 at ICML! Present dose expansion data in INI1-negative solid tumors and synovial sarcoma at ESMO on September 26, 2015! Present additional phase 1 data in NHL before the end of 2015! Initiated tazemetostat phase 2 five-arm NHL studies! ü Prospective stratification of EZH2 mutant and wild type patients, germinal and non-germinal center, DLBCL and FL! Initial data expected mid-2016! Initiate INI1-negative and synovial sarcoma phase 2 adult study and phase 1 pediatric study in 4Q 2015! Interim read-outs from the phase 2 cohorts expected by year end 2016! Conducting clinical pharmacology studies of tazemetostat! ü Completed enrollment in food effect study! Initiating drug-drug interaction study in September 2015! ü Presented discovery research on HMT targets at AACR annual meeting: CARM1, SETDB1, SMYD3, PRMT6! Additional presentations at NCI-EORTC-AACR in November! Complete enrollment in pinometostat phase 1 pediatric study expected in 1H 2016! Present data in 2H 2016! 33!

34