The Next EPIsode: Rewriting Oncology Treatment with Epigenetics NASDAQ: EPZM Robert Bazemore, President & CEO 1 Robert Bazemore President & CEO 2 Epizyme 2021 & Beyond: Strategic Priorities 3 FORWARD-LOOKING STATEMENTS Any statements in this presentation about future expectations, whether the company will receive regulatory approvals, including plans and prospects for Epizyme, Inc. and other statements accelerated approval, to conduct trials or to market products; the containing the words “anticipate," “believe,” “estimate,” impact of the COVID-19 pandemic on the company’s business, “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” results of operations and financial condition; whether the company's “potential,” “will,” “would,” “could,” “should,” “continue,” and cash resources will be sufficient to fund the company’s foreseeable similar expressions, constitute forward-looking statements within the and unforeseeable operating expenses and capital expenditure meaning of The Private Securities Litigation Reform Act of 1995. requirements; other matters that could affect the availability or Actual results may differ materially from those indicated by such commercial success of tazemetostat; and other factors discussed in forward-looking statements as a result of various important factors, the “Risk Factors” section of the company’s most recent Form 10-K including: whether commercial sales of TAZVERIK for epithelioid or Form 10-Q filed with the SEC and in the company's other filings sarcoma and follicular lymphoma in the approved indications will from time to time with the SEC. In addition, the forward-looking be successful; whether tazemetostat will receive marketing statements included in this presentation represent the company’s approval for epithelioid sarcoma or follicular lymphoma in other views as of the date hereof and should not be relied upon as jurisdictions, full approval in the United States or approval in any representing the company’s views as of any date subsequent to the other indication; whether results from preclinical studies or earlier date hereof. The company anticipates that subsequent events and clinical studies will be predictive of the results of future trials, such developments will cause the company’s views to change. However, as the ongoing confirmatory trials; whether results from clinical while the company may elect to update these forward-looking studies will warrant meetings with regulatory authorities, submissions statements at some point in the future, the company specifically for regulatory approval or review by governmental authorities disclaims any obligation to do so. under the accelerated approval process; 4 Epizyme: Who We Are Today TAZVERIK® 13 Ongoing >300 (tazemetostat) Clinical Trials Employees Approved in Heme & Solid Tumors by End 2021 4 ONE MISSION: Tazemetostat Epizyme-Invented REWRITE TREATMENT FOR CANCER Evaluated in Molecules in Clinical AND OTHER SERIOUS DISEASES THROUGH >1,100 Patients Development NOVEL EPIGENETIC MEDICINES 11 Preclinical A Number of Important “Firsts” in Both Programs Research & Development >300 Being Evaluated Issued Patents Held 5 The TAZVERIK Journey Marked by Consistent Execution TAZVERIK Approved in FL Corporate / Other NDA Acceptance & Priority Review for FL TAZVERIK (tazemetostat/EPZ-6438) 2 INDs Accepted TAZVERIK by FDA (DLBCL, Fast Track Approved in ES INI- Tumors & SS) Designations for FL & STS Unanimous ODAC First Patient Enrolled in Vote for ES Ph 1/2 Trial of EPZ-6438 First Patient Dosed in TAZ Incl. in NCCN Ph 2 Trial of EPZ-6438 NDA Acceptance Guidelines For R/R FL Abbott, Eisai & & Priority Review Roche Partnerships for ES TAZ Incl. in NCCN Orphan Drug Designation Guidelines For R/R ES Celgene Partnership for MRT GSK & Eisai Epizyme Partnerships Founded Boehringer Ingelheim EPZ-6438 Global Rights Collaboration Initial Public Offering Reacquired from Eisai Series B 2007 2011 2012 2013 2015 2016 2017 2018 2019 2020 Today 6 TAZVERIK Approvals and Launch Execution Accelerated approval granted in epithelioid sarcoma (ES) Jan 2020 TM Accelerated approval granted in follicular lymphoma (FL) June 2020 of Top Tier FL 100% accounts reached1 96% 50% of Top Tier FL Post-approval awareness Increase in new accounts 1 60-65% accounts prescribing among target physicians2 prescribing TAZVERIK in 4Q 203 NCCN GUIDELINES Lives covered in both indications1 Adapted to support TAZVERIK use in both ES and R/R FL >90% Not for promotional use. TAZVERIK approved for treatment of R/R FL on June 18, 2020; Full prescribing information is available at www.TAZVERIK.com. 1 Epizyme Internal Data. 2Epizyme Message Recall Study Fielded Oct-December 2020. N= 151. 3Ipsos US Oncology Monitor (October-December 7 2020), Participating doctors were primary treaters and saw a minimum number of patients per month.) Data © Ipsos 2020, all rights reserved Our Vision to Fuel Long-term Growth 1 2 BUILD ON TAVZERIK’S MAXIMIZE COMMERCIAL EFFECTIVENESS PIPELINE-IN-A-DRUG POTENTIAL 3 4 EXPAND PIPELINE & PORTFOLIO TO COLLABORATE TO EXPAND OVERCOME UNDRUGGABLE TARGETS PATIENT REACH & BUILD VALUE 8 Maximizing Commercial Effectiveness Continue to evolve our commercial model to ensure expanded adoption of 1 TAZVERIK during COVID-19 and beyond Further develop TAZVERIK to become the backbone therapy for follicular TM 2 lymphoma Pursue strategic partnerships and collaborations to bring 3 TAZVERIK to patients worldwide 9 Building on TAZVERIK’s Potential Promising Potential To Benefit A Significant Number Of Patients In Need EZH2 A KEY PLAYER IN MULTIPLE LEVERAGING INNOVATIVE COMBINATION OPPORTUNITIES WITH TUMOR TYPES TRIAL DESIGNS FOR EFFICIENCY SOC AND NOVEL TREATMENTS EZH2 POTENTIAL TO COMPLEMENT BASKET TRIALS TO IDENTIFY SIGNALS PROVIDE ROBUST FLOW OF NEW OTHER CANCER PATHWAYS ACROSS MULTIPLE CANCERS TAZEMETOSTAT DATA 10 Expand Pipeline to Bring Novel Epigenetic Therapeutics into Clinical Development First approved Leverage Advancing new Develop Advance 5 EZH2 inhibitor CRISPR and therapeutics programs with clinical-stage and significant other that hit single-agent programs over progress on advanced previously activity and the next 5 years multiple targets assays to undrugged ability to where Epizyme systematically targets to meet complement therapies could interrogate patient needs important be 1st in class potential targets cancer pathways to create powerful combinations 11 Working Collaboratively to Expand Patient Reach and Increase Shareholder Value PARTNER OF ACCESS NEW INNOVATIVE TRIAL COLLABORATE RESPONSIBLE CASH CHOICE MARKETS DESIGN EFFECTIVELY MANAGEMENT Become the leading Expand reach Novel clinical trial Pursue the right Carefully deploy our partner for assessing through strategic design to deals to maximize resources to become innovation in collaborations accelerate signal value for all cash flow positive oncology finding and data stakeholders 12 AGENDA Robert Bazemore EPIZYME 2021 & BEYOND: STRATEGIC PRIORITIES President & CEO Ari Melnick, M.D. EMERGING ROLE OF EPIGENETICS IN ONCOLOGY Weill Cornell Medicine Dr. Shefali Agarwal TAZVERIK DEVELOPMENT STRATEGY: THE NEXT CHAPTER EVP, Chief Medical & Development Officer Jeffery Kutok, M.D., Ph.D. THE FUTURE OF EPIZYME’S PIPELINE Chief Scientific Officer Matt Ros REALIZING EPIZYME’S VISION EVP, Chief Strategy & Business Officer Q&A SESSION Epizyme Speakers Robert Bazemore CLOSING REMARKS President & CEO 13 Emerging Role of Epigenetics in Oncology Ari Melnick, M.D. Weill Cornell Medicine 14 Ari Melnick, M.D. 15 How is it Possible for Single Cells to Develop into Complex Organisms? ? 16 The Epigenome Represents the Instructions and Blueprints that Explain All Cell Phenotypes Genome Epigenome Cell Blueprints 17 The Epigenome is Composed of Distinct Chemical Languages Controlled by Thousands of Proteins 18 Cancer Phenotypes are Universally Dependent on Epigenetic Instructions 19 All Cancers are Dependent on Epigenetic Mechanisms and Hence Susceptible to Epigenetic Therapies Epigenome Epigenetic Therapy 20 What is a Good Epigenetic Targeted Therapy? a. Hits a well-defined and specific epigenetic target b. Achieves full target engagement at clinically relevant doses, without off-target effects c. The target is mainly an epigenetic modifier in the cancer context EZH2 inhibitors d. The target drives a defined epigenetic dependency in FDA approved, strong specific cancers evidence that work via epigenetic actions, some bona fide biomarkers, clear e. Patients can be selected based on biomarker that indicates efficacy, limited toxicity, can dependency on a specific epigenetic mechanism be easily combined 21 EZH2 Inhibitor Mechanism of Action H3K4me3 H3K4me3 EZH2 H3K27me3 EZH2i Genes silenced Genes active EZH2i Tumor cells Tumor cells dying growing or differentiating EZH2i Immune System Immune System Suppressed Activated 22 Rationale for Combination of EZH2i with Immunotherapy & CAR-T Cells EZH2 mutation mediates Enhances T-cell response to antigen escape from T-cell surveillance Beguelin et al Cancer Cell 2020 1 1 V -1 -1 V - - Ezh2WT EZH2 mutant lymphomas are Ezh2i Ezh2i Ezh2i Ezh2i immune “cold” Einnishi et al Cancer Discovery 2019 Mut Ezh2 Enhances CAR T cell quality Car T-reg Central memory cells Taz induces recruitment of CD4 and CD8 cells into lymphomas in vivo Takata et al Under Review 2021 V EZH2i IST for CART + TAZ in process 23 AB 150 * * 106 *** **** 104 100 ** 2 ** 10 **** ** * 0 **** ** 10 2020 October 26 user on UN COL/CORNELL MED WEILL by http://ashpublications.org/bloodadvances/article-pdf/4/20/5226/1779441/advancesadv2020002580.pdf