the next episode: rewriting oncology treatment with

The Next EPIsode: Rewriting Oncology Treatment with Epigenetics

NASDAQ: EPZM

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Robert Bazemore, President & CEO

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Robert BazemorePresident & CEO

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Epizyme 2021 & Beyond: Strategic Priorities

FORWARD-LOOKING STATEMENTS

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whether the company will receive regulatory approvals, includingaccelerated approval, to conduct trials or to market products; theimpact of the COVID-19 pandemic on the company’s business,results of operations and financial condition; whether the company'scash resources will be sufficient to fund the company’s foreseeableand unforeseeable operating expenses and capital expenditurerequirements; other matters that could affect the availability orcommercial success of tazemetostat; and other factors discussed inthe “Risk Factors” section of the company’s most recent Form 10-Kor Form 10-Q filed with the SEC and in the company's other filingsfrom time to time with the SEC. In addition, the forward-lookingstatements included in this presentation represent the company’sviews as of the date hereof and should not be relied upon asrepresenting the company’s views as of any date subsequent to thedate hereof. The company anticipates that subsequent events anddevelopments will cause the company’s views to change. However,while the company may elect to update these forward-lookingstatements at some point in the future, the company specificallydisclaims any obligation to do so.

Any statements in this presentation about future expectations,plans and prospects for Epizyme, Inc. and other statementscontaining the words “anticipate," “believe,” “estimate,”“expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,”“potential,” “will,” “would,” “could,” “should,” “continue,” andsimilar expressions, constitute forward-looking statements within themeaning of The Private Securities Litigation Reform Act of 1995.Actual results may differ materially from those indicated by suchforward-looking statements as a result of various important factors,including: whether commercial sales of TAZVERIK for epithelioidsarcoma and follicular lymphoma in the approved indications willbe successful; whether tazemetostat will receive marketingapproval for epithelioid sarcoma or follicular lymphoma in otherjurisdictions, full approval in the United States or approval in anyother indication; whether results from preclinical studies or earlierclinical studies will be predictive of the results of future trials, suchas the ongoing confirmatory trials; whether results from clinicalstudies will warrant meetings with regulatory authorities, submissionsfor regulatory approval or review by governmental authoritiesunder the accelerated approval process;

Epizyme: Who We Are Today

TAZVERIK®(tazemetostat)

Approved in Heme & Solid Tumors

A Number of Important “Firsts” in Both Research & Development >300

Issued Patents Held

13 Ongoing Clinical Trialsby End 2021

>300Employees

Tazemetostat Evaluated in >1,100 Patients

11 Preclinical Programs Being Evaluated

ONE MISSION:REWRITE TREATMENT FOR CANCER

AND OTHER SERIOUS DISEASES THROUGH NOVEL EPIGENETIC MEDICINES

Epizyme-Invented Molecules in Clinical

Development

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The TAZVERIK Journey Marked by Consistent Execution

TAZVERIKApproved in ES

EpizymeFounded

TAZVERIK Approved in FL

TAZ Incl. in NCCN Guidelines For R/R ES

TAZ Incl. in NCCN Guidelines For R/R FL

TAZVERIK (tazemetostat/EPZ-6438)

Corporate / Other

Initial Public Offering

GSK & Eisai Partnerships

Celgene Partnership

Abbott, Eisai & Roche Partnerships

Series B

2007 2011 2012 2013 2015 2016 2017 2018 2019 2020 Today

First Patient Enrolled in Ph 1/2 Trial of EPZ-6438

EPZ-6438 Global Rights Reacquired from Eisai

First Patient Dosed in Ph 2 Trial of EPZ-6438

2 INDs Accepted by FDA (DLBCL, INI- Tumors & SS)

Orphan Drug Designation for MRT

Fast Track Designations for FL & STS

Boehringer Ingelheim Collaboration

NDA Acceptance & Priority Review for ES

NDA Acceptance & Priority Review for FL

Unanimous ODAC Vote for ES

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TAZVERIK Approvals and Launch Execution

Accelerated approval granted in epithelioid sarcoma (ES) Jan 2020

Accelerated approval granted in follicular lymphoma (FL) June 2020

Adapted to support TAZVERIK use in both ES and R/R FL

NCCN GUIDELINES

50%Increase in new accounts

prescribing TAZVERIK in 4Q 203

of Top Tier FLaccounts reached1100%of Top Tier FL accounts prescribing160-65% Post-approval awareness

among target physicians2

96%

Lives covered in both indications1>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 2020), Participating doctors were primary treaters and saw a minimum number of patients per month.) Data © Ipsos 2020, all rights reserved

http://www.tazverik.com/

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Our Vision to Fuel Long-term Growth

MAXIMIZE COMMERCIAL EFFECTIVENESS BUILD ON TAVZERIK’S PIPELINE-IN-A-DRUG POTENTIAL

EXPAND PIPELINE & PORTFOLIO TO OVERCOME UNDRUGGABLE TARGETS

COLLABORATE TO EXPAND PATIENT REACH & BUILD VALUE

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Maximizing Commercial Effectiveness

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Pursue strategic partnerships and collaborations to bring TAZVERIK to patients worldwide

Further develop TAZVERIK to become the backbone therapy for follicular lymphoma

Continue to evolve our commercial model to ensure expanded adoption of TAZVERIK during COVID-19 and beyond

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3

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LEVERAGING INNOVATIVE TRIAL DESIGNS FOR EFFICIENCY

BASKET TRIALS TO IDENTIFY SIGNALS ACROSS MULTIPLE CANCERS

COMBINATION OPPORTUNITIES WITH SOC AND NOVEL TREATMENTS

PROVIDE ROBUST FLOW OF NEW TAZEMETOSTAT DATA

EZH2 A KEY PLAYER IN MULTIPLE TUMOR TYPES

EZH2 POTENTIAL TO COMPLEMENT OTHER CANCER PATHWAYS

Building on TAZVERIK’s Potential

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Promising Potential To Benefit A Significant Number Of Patients In Need

Expand Pipeline to Bring Novel Epigenetic Therapeutics into Clinical Development

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First approved EZH2 inhibitor

and significant progress on

multiple targets where Epizyme therapies could

be 1st in class

Leverage CRISPR and

other advanced assays to

systematically interrogate

potential targets

Develop programs with single-agent activity and

ability to complement

important cancer

pathways to create powerful

combinations

Advancing new therapeutics

that hit previously

undrugged targets to meet patient needs

Advance 5 clinical-stage programs over

the next 5 years

Working Collaboratively to Expand Patient Reach and Increase Shareholder Value

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Expand reach through strategic

collaborations

ACCESS NEW MARKETS

Pursue the right deals to maximize

value for all stakeholders

COLLABORATE EFFECTIVELY

Carefully deploy our resources to become

cash flow positive

RESPONSIBLE CASH MANAGEMENT

Become the leading partner for assessing

innovation in oncology

PARTNER OF CHOICE

Novel clinical trial design to

accelerate signal finding and data

INNOVATIVE TRIAL DESIGN

EPIZYME 2021 & BEYOND: STRATEGIC PRIORITIES

TAZVERIK DEVELOPMENT STRATEGY: THE NEXT CHAPTER

EMERGING ROLE OF EPIGENETICS IN ONCOLOGY

REALIZING EPIZYME’S VISION

THE FUTURE OF EPIZYME’S PIPELINE

Q&A SESSION

CLOSING REMARKS

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AGENDA


Ari Melnick, M.D.Weill Cornell Medicine

Dr. Shefali AgarwalEVP, Chief Medical & Development Officer

Jeffery Kutok, M.D., Ph.D.Chief Scientific Officer

Matt RosEVP, Chief Strategy & Business Officer

Epizyme Speakers


Emerging Role of Epigenetics in Oncology

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Ari Melnick, M.D.Weill Cornell Medicine

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Ari Melnick, M.D.

How is it Possible for Single Cells to Develop into Complex Organisms?

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?

The Epigenome Represents the Instructions and Blueprints that Explain All Cell Phenotypes

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Genome Epigenome Cell Blueprints

The Epigenome is Composed of Distinct Chemical Languages Controlled by Thousands of Proteins

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Cancer Phenotypes are Universally Dependent on Epigenetic Instructions

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All Cancers are Dependent on Epigenetic Mechanisms and Hence Susceptible to Epigenetic Therapies

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Epigenome

Epigenetic Therapy

What is a Good Epigenetic Targeted Therapy?

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a. Hits a well-defined and specific epigenetic target

c. The target is mainly an epigenetic modifier in the cancercontext

d. The target drives a defined epigenetic dependency in specific cancers

e. Patients can be selected based on biomarker that indicates dependency on a specific epigenetic mechanism

b. Achieves full target engagement at clinically relevant doses, without off-target effects

EZH2 inhibitorsFDA approved, strong evidence that work via epigenetic actions, some bona fide biomarkers, clear efficacy, limited toxicity, can be easily combined

EZH2 Inhibitor Mechanism of Action

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H3K27me3

H3K4me3

H3K4me3

EZH2

EZH2i

Genes silenced Genes active

Tumor cells growing

Tumor cells dying or differentiating

Immune System Suppressed

Immune System Activated

EZH2i

EZH2i

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EZH2 mutation mediates escape from T-cell surveillanceBeguelin et al Cancer Cell 2020

EZH2 mutant lymphomas are immune “cold”Einnishi et al Cancer Discovery 2019

Ezh2

WT

Ezh2

Mut

Taz induces recruitment of CD4 and CD8 cells into lymphomas in vivoTakata et al Under Review 2021

Enhances CAR T cell quality

IST for CART + TAZ in process

Central memory cellsCar T-reg

EZH2iV

Enhances T-cell response to antigen

VEzh2i-1

Ezh2i-1 V

Ezh2i-1

Ezh2i-1

Rationale for Combination of EZH2i with Immunotherapy & CAR-T Cells

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Figure 2. Inhibition of EZH2 and Bcl-2 in combination results in tumor reduction and prolonged survival in vivo. (A,D,G) Tumor volume over time in SUDHL-6

xenografts and PDXs, as measured by calipers. Error bars represent standard error of the mean (SEM). Tumor growth in SUDHL-6 (B) and PDX (E) xeongrafts, as measured

by area under the curve (AUC), for the duration of treatment. Error bars represent SEM. (C,H) Kaplan-Meier curve for overall survival. P values represent comparison with

combination therapy for each cohort. Among PDX mice treated with combination therapy, 2 deaths occurred, both in mice without tumors. (F) MRI 3D renderings of PDX mice

taken at day 19 and at day 92. Images were obtained using a 1T M3 compact MRI system (Aspect Imaging Ltd.) with a T2-weighted scan without contrast. The tumor area of

interest, as determined by automatic thresholding settings, is shown in red. ***P , .001, ****P , .0001.

27 OCTOBER 2020 x VOLUME 4, NUMBER 20 COMBINED EZH2 AND BCL-2 INHIBITION IN DLBCL 5229

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Bcl2 translocation almost always present with EZH2 mutation or in FL in general

Beguelin et al Cancer Cell 2013Scholze et al Blood Advances 2020

EZH2-i reduce apoptotic threshold in DLBCL cells EZH2 mutant, BCL2 translocated EZH2 WT, BCL2 translocated EZH2 WT, BCL2 WT

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Glo, in a panel of DLBCL cell lines treated with vehicle, venetoclax alone (V), tazemetostat alone (T), or venetoclax and tazemetostat in combination (C). Drug dosing for each


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Glo, in a panel of DLBCL cell lines treated with vehicle, venetoclax alone (V), tazemetostat alone (T), or venetoclax and tazemetostat in combination (C). Drug dosing for each


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Synergistic effect on primary DLBCL organoids

Synergistic effect on primary human DLBCL in vivo

Rationale for Combination of EZH2i with Targeted Therapy and Chemo

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Role of Epigenetic Therapy in Cancer Treatment Regimens

Chemotherapy

Epigenetic Therapy Immunotherapy

“Precision” Therapy

Cancer Cell

TAZVERIK® (tazemetostat) Development Strategy: The Next Chapter

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ACTIVITY DEMONSTRATED

IN MULTIPLE CANCERS

BROAD THERAPEUTIC POTENTIAL

IN SOLID TUMORS AND HEME MALIGNANCIES

Not for promotional use

TM

GENERALY WELL-TOLERATED;

LOW DISCONTINUATION RATES

COMBINATION OPPORTUNITIES

WITH SOC TREATMENTS

NOVEL MECHANISM

OF ACTION

POTENTIAL FOR EXTENDED

TREATMENT DURATION

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Executing a Multi-year Vision to Bring the Benefits of TAZVERIK to Patients in Need

The Next EPIsode: Rewriting Oncology Treatment with Epigenetics

Approval of tazemetostat to treat patients with ES and FL

Bring tazemetostat benefits to earlier lines of ES and FL therapy

Bring tazemetostat to patients beyond ES and FL as monotherapy and in combination

TM

Not for promotional use

• Disruption of pro-survival signaling

• Restoration of cell cycle control

• Disruption of DNA damage repair

• Suppression of immune evasion

• Modulation of microenvironment

• Reprogramming of cellular metabolism

Chemotherapy

Radiotherapy

Immunotherapy

Targeted Therapies

Hormone therapy

Therapy Class Rationale for Epigenetic Sensitization*

Epigenetic Therapies Have Demonstrated the Potential to Enhance Activity of Standard-of-Care Cancer Therapies Across Heme and Solid Tumors

• Facilitate access to DNA, re-express tumor suppressors and increase ROS (DNMTi, HDACi, EZH2i)

• Differentiate cancer stem cells (DNMTi, EZH2i and LSD1i)

• Decrease DDR capabilities (BETi and PRMTi)• Facilitate access to DNA (DNMTi and HDACi)

• Increase antigen presentation and chemokine / IFN expression (DNMTi, HDACi and EZH2i)

• Anti-inflammatory (BETi)

• Revert EMT (DNMTi and HDACi)• Promote HIF1αdegradation and reduce oncoprotein stability (HDACi)• Prevent oncogene transcription (BETi) or re-express tumor

suppressors (EZH2i)

• Reverse endocrine resistance (HDACi, HATi, BETi, EZH2i)

Epigenetic Drug-induced Sensitization Mechanisms

Combating cancer resistance and enhancing activity of

standard-of-care therapiesNote: * Not an exhaustive list; ^ Based on ongoing ISTs and company-sponsored programs and does not include future basket trials; † Includes rituximab, which is I/O; † † Dabrafenib and trametinibSource: Frontiers in Oncology: The Role of Epigenetic Modifications in Cancer Progression; MDPI; Nature: Signal Transduction and Targeted Therapy; Management data; L.E.K. research

Tazemetostat Trials^

• Doxorubicin in ES• R-CHOP † in DLBCL and FL• BR † in FL

• Rituximab, R2 in FL• Pembro in solid tumors • Axi-cel in DLBCL• Other combinations

• Abiraterone / Prednisone or Enzalutamide in mCRPC

• Venetoclax in FL and DLBCL• PI3K in FL• D/T † † in melanoma• Other combinations

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Expansive Tazemetostat Development Program into Potential New Indications and Combinations

TAZEMETOSTAT AREAS OF INTEREST

THERAPEUTIC AREA TREATMENT APPROACH

Lymphomas & B-Cell Malignancies- DLBCL- MCL- MM- Other B-cell malignancies

Inhibit tumor proliferation governed by EZH2 expression

I/O Sensitive Tumors- Colorectal cancer- Bladder cancer- Soft tissue sarcomas- Non-small cell & small cell lung cancer

Re-sensitize tumors to immuno-oncology therapies

Chemo/Treatment-Resistant Tumors- Small cell lung cancer- Ovarian cancer- Mesothelioma- Castration-resistant prostate cancer

Re-sensitize tumors to chemo and other therapies (e.g., PARP)

Mutationally Defined Solid Tumors - Chordoma- Melanoma- Tumors with SWI/SNF alteration

Inhibit abnormal EZH2 function, restoring cells to natural state

INDICATIONS OF INTEREST

Internal and collaboration combination development efforts will prioritize both standard-of-care (SoC) therapies and new mechanism-of-action (MOAs) to solidify placement of TAZVERIK in the treatment paradigm

The basket design optimizes shorter clinical development timelines anticipated to broaden TAZVERIK label and expand available patient populations for TAZVERIK

Basket trials for heme and solid tumors offer an efficient signal finding mechanism while producing a wide and consistent flow of new data

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Broad Development Approach for TAZVERIK: Initiating Basket Studies in Heme and Solid Tumors to Maximize Signal Finding Efficiency Across Multiple Tumors

Maximize signal-finding potential

Combo with SoC and

novel therapies

Accelerate clinical timelines

Ongoing Heme Studies

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Broad Label in Relapsed/Refractory FL

Adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies

Adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options

LABEL ENABLES PHYSICIAN DISCRETION TO PRESCRIBE TAZVERIK REGARDLESS OF EZH2 MUTATIONAL STATUS OR LINE OF R/R TREATMENT

ü Relapsed/refractory 2L+ patients who have unsatisfactory treatment options

ü Physician discretion whether to test for EZH2 mutation status; if desired, option to use any FDA-approved test

ü Post-marketing activities underway to support full approval and potential label expansion

• Global, randomized adaptive confirmatory trial combing TAZVERIK with R2 in 2L+ FL patients (PFS as primary endpoint)

• Expanded Phase 2 cohort of wild-type EZH2 patients with 2L+ FL

NCCN Guidelines® recommend TAZVERIK as category 2A treatment for FL

Not for promotional useR2 = Revlimid® in combination with a rituxmab product is indicated for the treatment of adult patients with previously treated follicular lymphoma

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Current Label

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Developing TAZVERIK® to Become the Backbone of Therapy for Patients with Follicular Lymphoma

TM

R2 = Revlimid® in combination with a rituxmab product is indicated for the treatment of adult patients with previously treated follicular lymphoma1 Freedman et al. American Journal of Hematology; Volume 87, Issue 10.

~11,000

~6,000

~5,000

2021 Follicular Lymphoma Epidemiology~13,700 Patients Diagnosed Annually

TAZVERIK + R-CHOPHigh-risk FL Patients

IST EnrollingTAZVERIK + BRIST Approved

TAZVERIK + R2

Confirmatory Phase 1b/3 trial (EZH-302)Safety run-in complete Efficacy portion initiated

TAZVERIK + RituximabPhase 2 (EZH-1401) Enrolling

1st Line

2nd Line

3L+ 2L+ Supported by Current LabelTAZVERIK +

Other CombinationsMultiple ISTs Ongoing

Source: internal drug-treated estimates.

Patients with relapsed / rituximab refractory FL who have been treated with at least one prior systemic therapy.

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EZH-302 Phase 1b/3 Tazemetostat in Combination with R2 in Patients with R/R FL

Population

Key ObjectivesPhase 3 (efficacy)Primary: PFS as determined by Investigator; interim analyses for futilitySecondary: PFS by IRC, response rate, duration of response, OS, QOL, safety

Placebo + Rituximab + Lenalidomide(N=250, mPFS 25 mos)

Taz + Rituximab + Lenalidomide(N=250, mPFS 36 mos)

Stratification for randomized portion by EZH2 mutation status: treatment sensitive vs refractory to prior rituximab containing

regimen, patients treated with 1 prior vs ≥ 2 prior systemic therapies.

EZH2 MUT / WT Enrichment Based on cobas® EZH2 Mutation Test All-comers

Safety Run-in Phase 3 Randomization (12 Months)

Taz + Rituximab + Lenalidomide

(N=3-18)

Maintenance (24 Months)

Placebo (N=250)

Tazverik Monotherapy(N=250)

Phase 1b (safety run-in)Safety, pharmacokinetics, anti-tumor activity

EZH302: Study of Tazemetostat + R2 in 2nd Line+ Follicular LymphomaRationale for Success in Phase 3 Confirmatory Study

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üPre-clinical evidence suggesting synergy between tazemetostat + lenalidomide and tazemetostat + rituximab, the two components of the R2 regimen

üPreliminary clinical activity with rituximab in Phase 1b study of R-CHOP + tazemetostat previously presented

üUnique clinical trial design for EZH-302• Inclusion of patients who initially failed rituximab (real world population)• Inclusion of tazemetostat maintenance treatment period to extend treatment benefit• Adaptive study design allows adjustment of Phase 3 trial based on 2 interim assessments

üTAZVERIK safety characteristics allows for extended treatment with high treatment compliance

38

Tazemetostat + Lenalidomide Has Shown Enhanced Antiproliferative Activity Upon Treatment in KMS-11 Cell Line When Compared to Single Agents Alone

Protocol details: • KMS-11 cells were treated for 14 days (split and redose on D7) with combinations Lenalidomide and Tazemetostat • The concentrations were chosen from the 14-day LTP assays for each of the agents tested• Antiproliferative activity measured via ATP detection in cultures

0 2 4 6 8 10 12 14 16103

104

105

106

107

Time (Days)

Cel

l Cou

nts

(RLU

)

Taz/Len

DMSO

LenTaz

****

P values derived from one-way ANOVA with Tukey’s Multiple Comparisons of treatment compared to each of the dual combinations.

**** p< 0.0001

Compound Concentration (nM)

-

100

1000

100/1000

0 2 4 6 8 10 12 14 16103

104

105

106

107

Time (Days)

Cel

l Cou

nts

(RLU

)

Taz/Len

DMSO

LenTaz

Tazemetostat + Lenalidomide Demonstrated Enhanced Combination Activity in vitro

39

Epizyme Observed Synergistic Antiproliferative Activity in Mutant EZH2 DLBCL Cell Lines with the Combination of Tazemetostat And Rituximab

Synergistic antiproliferative activity of tazemetostat + rituximab observed when tested in

DLBCL cell lines in vitro

Source: Management data

EZH2 inhibition may play key role in enhancing multiple aspects of anti-tumor immunity which can

supplement anti-CD20 activity

Synergy in SU-DHL-6 (Mutant EZH2 GCB)

% in

hibi

tion

1 10 100 10000

20

40

60

80

100

[Tazemetostat], nM

% Inhibition

200ug/mL20ug/mL2ug/mL0.2ug/mL0

Rituximab

JAGLOWSKI et al BLOOD, 11 NOVEMBER 2010,VOLUME 116, NUMBER 19

NO DLTs reported for patients evaluated during first cycle

Only 4 patients had treatment-related AEs that were Grade 3 or 4

Only 1 patient had at least 1 treatment-related emergent SAE

NO patients discontinued study treatment due to an AE

NO special interest adverse events were reported

EZH-302 Safety Summary

40

Safety of tazemetostat (400, 600, 800 mg BID) + rituximab (375 mg/m2)

+ lenalidomide (10, 20 mg) evaluated in 13 patients

Tazemetostat well tolerated up to 800 mg BID in combination with R2

In-line with highest dose level for tazemetostat approved as monotherapy

41

Seven of 13 Patients Treated with Tazemetostat + R2 to Date Were Evaluable for Response; All Seven Patients Responded to Treatment

TAZEMETOSTAT + R2 Treatment Duration and Patient Response to Investigator Assessment (iTT Population)

TAZEMETOSTAT + Lenalidomide/Rituximab

Best Overall Tumor ResponseEvaluable Population*

Complete Response (CR) 3 (43%)

Partial Response (PR) 4 (57%)

Stable Disease (SD) 0

Progressive Disease (PD) 0

Objective Response Rate (ORR) 7 (100%)

All but one patient remain on therapy

*Six patients not yet evaluable due to no post-baseline scan data yet*Data cut mid-February 2021

0 1 2 3 4 5 6Treatment Duration (Months)

400 mg

600 mg800 mg

CR

PRPD

42

Patient Background:Female in 50s with follicular lymphoma, predom grade 1-2 (80%) with focal grade 3A (20%), stage IVA (subcutaneous nodules, extensive left axillary / subpectoral adenopathy, and diffuse LA). Markedly FDG-avid bulky axillary LA concerning for transformation, bx confirmed FL grade 1-2 (no e/o transformation).

Genetics: EZH2 unknown

Tx #1: R-CHOP x 6, CR in 2015, s/p rituximab maintenance completed 2017. Relapse 2018 (<12 mo from last Rituximab dose). - Multiple PET and lymph node biopsy confirm FL grade 1-2, disease

focal area with FL3A

Tx #2: Single-agent Rituximab x 4, completed 2020 with PR. Continued progression summer 2020

CR in Rituximab Refractory Patient with Extensive Extranodal Disease (600 mg Cohort)

Before After 1st Restaging

Case courtesy of Dr. Connie Batlevi

Tx #3: Tazemetostat 600mg BID + R2, initiated tx on 9/8/20, CR to treatment

42

43

Tx #2: Tazemetostat 800mg BID +R2, initiated tx on 11/12/20 in CR

Patient Background:Male in 80s with stage IV FL grade 2, diagnosed with multiple extranodal sites in gallbladder, bone and >4 nodal sites. EZH2 WT

Tx#1: R-Bendamustine x 6 completed on 2019 complicated by cytopenias, CR at end of treatment

- Relapse <12 months from end of treatment

CR in Elderly Patient with Early POD24 (800 mg Cohort)

Before After 1st Restaging

Case courtesy of Dr. Connie Batlevi43

44

EZH-302 Phase 1b Safety Run-in Summary

Safety profile observed with tazemetostat (800mg BID) + R2 is consistent with that described in the respective reference safety information documents

- No patients discontinued study treatment due to an AE

Seven of seven evaluable patients responded to treatment with tazemetostat + R2

- 3 complete responses and 4 partial responses

All but one patient remain on therapy

Preparing to Advance to Phase 3 Randomized Portion of EZH-302 Trial

Ongoing Solid Tumor Studies

45

46

FDA-Approved For Epithelioid Sarcoma

INDICATION: Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection

NCCN Guidelines® recommend TAZVERIK as category 2A treatment for ES

ü First FDA-approved treatment specifically indicated for ES

ü Safe and generally well-tolerated

ü Prolonged disease stabilization

ü Efficacy portion of global confirmatory trial (EZH-301) assessing the combination of TAZVERIK plus doxorubicin compared with doxorubicin plus placebo ongoing

ACCELERATED APPROVAL SUPPORTED BY PHASE 2 DATA (n=62)• 15% overall response rate• 16.4 months median DOR

• 6 month+ duration of response in 67% of patients (3.7, 24.5+)• 21% disease control rate

• Tumor reduction observed in 68% of patients• Many patients experienced prolonged disease stabilization

TM

Gounder M. et al. The Lancet Oncology. 6 Oct. 2020.

EZH2 in metastatic CRPC

47

Targeting EZH2 in mCRPC with Tazemetostat: Clinical Hypotheses

Varambally et al. 2002 Nature. 419:624

a, b: EZH2 protein expression correlates with advancing disease progressionc. Moderate to high EZH2 expression associated with worse failure-free survival

EZH2 cooperates with the androgen receptor during oncogenic transformation, leading to epigenetic silencing of many tumor suppressors and regulators of differentiation

In combination experiments, EZH2 inhibition resensitizes both mCRPCcultured cells and xenograft tumor models to androgen signaling inhibitor (ASI) therapy

a

b c

All 8 cohorts (5 enzalutamide, 3 abiraterone/prednisone) dosed without DLTs

48

EZH-1101 Phase 1b Prostate Cancer Safety Overview

Patients With a TEAE, n (%) TAZ+A/P(n=7)

TAZ+E(n=14)

Total(N=21)

Any TEAE 7 (100) 12 (85.7) 19 (90.5)

Grade 3 or 4 TEAE 2 (28.6) 5 (35.7) 7 (33.3)

TEAE leading to dose reduction 1 (14.3) 1 (7.1) 2 (9.5)

TEAE leading to study drug interruption 2 (28.6) 3 (21.4) 5 (23.8)

TEAE leading to study drug discontinuation 0 1 (7.1) 1 (4.8)

TEAE leading to study withdrawal 0 0 0

• Low rate of Grade ≥3 AEs

• Low rate of dose interruptions / modifications

• No new safety signals

PSA reduction of ≥50% in 7/21 patients treated, across all cohorts• 6 patients receiving taz/enza PSA50• 1 on taz/abi/pred PSA50• 10 patients remain on therapy with potential to

exhibit response• 1 additional patient with PSA decrease of ≥35%

All responses were in ARV7- patients• 85 to 90% of prostate cancer patients are ARV7-• Only one ARV7+ patient enrolled in safety run-in

portion of the study

47% disease control rate to date• Longest patient continuation since January 2020

*Data cut mid-February 2021

49

To Date, We’ve Already Observed PSA50 Responses Across Dosing Cohorts

EZH-1101: Maximum PSA Reduction To Date

Tazemetostat + Abiraterone/Prednisone (n=1) Tazemetostat + Enzalutamide (n=6)

-100.00%

-90.00%

-80.00%

-70.00%

-60.00%

-50.00%

-40.00%

-30.00%

-20.00%

-10.00%

0.00%

1010-1005(1600mg)

1001-1004(600mg)

1001-1003(400mg)

1010-1002(800mg)

1010-1001(600mg)

1010-1006(1600mg)

1010-1004(1200mg)

50

Signs of Early Response to Treatment with Tazemetostat + Enzalutamide in Prostate Cancer Patient

Baseline (May 2020)

RECIST response

C3 JUL2020 -24%

C5 SEP2020 -32%

C7 Nov2020 -36%

Before After Four Cycles(Taz + Enza )

Baseline Scan - May 2020 C7 Scan – Nov. 2020

Note: scan is performed at the end of a cycle and before the start of the next cycle, e.g., at C3D1 scan the patient has received 2 cycles of treatment

• 77-year-old male with mCRPC progressing on Lupron and Zytiga/prednisone

• Lesions at left apex and mid gland of the prostate

• Patient treated with tazemetostat 600mg BID and enzalutamide 160mg DAILY

After 2 Cycles: 24% reduction in diameter of the

target lesion

After 3 Cycles: 32% reduction (PR)

36% Lesion ReductionAfter Four Cycles

5151

Randomized Portion of Phase 2 EZH-1101 Trial Ongoing

Tazemetostat (1200 mg BID)+

Enzalutamide (160 mg QD)N=40

Primary Endpoint: Radiographic Progression-Free Survival (rPFS)

Enzalutamide (160 mg QD)N=40

vs

Randomization

Tazemetostat RP2D for Enzalutamide combination(1200mg BID)

Secondary Endpoints:• PSA50, TTPP, time to first SRE, ORR and

BOR, DCR, time to new treatment• Safety, PK• FACT-P, FWB and PCS subscales and TDD

Intensive Biomarker Program

Safety Run-in Complete10 of 21 Patients Remain on Therapy

Randomized Efficacy Portion Ongoing

RP2D: tazemetostat 1200mg BID plus enzalutamide 160mg DAILY

PLANNED ACTIVTIES

MCL

53

Tazemetostat Potential in Heme Indications will be Evaluated Through Seven Combos Across Four Indications

HEME BASKET TRIAL DESIGN FL DLBCL MM

Note: * Contingent upon FDA agreement that single arm study design is appropriateSource: Management discussions

Tazemetostat + Bispecific Ab

Tazemetostat + CD-19+Len

Tazemetostat + Gem/Ox

Tazemetostat + Lenalidomide

Tazemetostat + BTKi

Tazemetostat +Dex + Pom

• U.S. based trials• Intended to Further

validate tazemetostat as a safe, broadly applicable heme asset

• Targets 2L+ for all indications

• Assumes SoC comparator arm may or may not be needed

• Supported by preclinical data validating synergistic effects of combinations

• Epizyme found synergistic activity between tazemetostat and rituximab in EZH2 mutant DLBCL model in vitro; additionally, EZH2 inhibition is expected to enhance anti-CD3 activity

• Epizyme preclinical studies show that EZH2 inhibition strongly synergizes with Dex + Pom in multiple MM cell lines and xenograft models

• Tazemetostat demonstrated combinatorial activity with BTK inhibitors in a panel of MCL cell lines as well as in vivo murine xenograft model in preclinical studies performed by Epizyme. Tazemetostat inhibited in vitro cell line growth in BTKi-resistant cell lines

• Epizyme RNAseq studies found increased expression of CD19 in GCB DLBCL cell lines, especially in those with EZH2 mutations, indicating potential synergy of tazemetostat and CD19

• In vitro work performed by Epizyme found combination effects of tazemetostat and lenalidomide in a subset of DLBCL cell lines; independent studies by external collaborator confirmed the findings

• Combination with DNA damaging agents may enhance induction of cell death; internal data show enhancement of cytotoxic cell killing by GemOx with tazemetostat in DLBCL cell lines

MCL

FL

DLBCL

MM

54

Epizyme’s Preclinical Efforts Establish In Vitro and In Vivo Scientific Rationale to Support the Design of the Heme Basket

Bispecific Ab

Len+ CD-19

Gem/Ox

Lenalidomide

Dex + Pom

BTKi

TRIAL COHORT SCIENTIFIC RATIONALE


Tazemetostat + CD-19 Combination Opportunity in DLBCL


CD19 Expression Increased in Various Sub-Types of DLBCL

Cell Lines in Presence of Tazemetostat, Particularly in

GCB EZH2 Mutant

↑ CD19 increase > 2-fold

55

56

Tazemetostat + Dex + Pom Combination Opportunities in MM


Combination Benefit of EZH2i with Pom/Dex in

MM.1S Xenograft Model

DLBCL

R/R DLBCL (N =20)

Basket trial provides an efficient signal finding

mechanism while producing a wide and consistent set of

new data

Adaptive study design leveraging Bayesian

continuous monitoring based on predictive probability

Objective response (CR or PR) and Biomarker PD will determine go/no-go

R/R DLBCL (N =20)

R/R DLBCL (N =20)

57

A Phase 1/2 Open-Label Bayesian Basket Trial of Tazemetostat with Multiple Combinations in Hematological Malignancies

Phase 2 ExpansionSafety Run-in

Tazemetostat + Gem+Ox (N = 6)

Tazemetostat + Len (N = 6)

Plan to Initiate Cohorts in Heme Basket Study 2H 2021

MCL

FL

MM

R/R FL (N = 20)Tazemetostat + Bispecific (N = 6)

Tazemetostat + Len+ CD19 (N = 6)

R/R MCL (N =20)Tazemetostat + BTKi (N = 6)

R/R MM (N =20)Tazemetostat + Pom+Dex (N = 6)

Partial List of Active Studies & Approved IST Concepts for Tazemetostat in Hematologic Malignancies

1L FL +BR

r/r FL +venetoclax

r/r NHL +venetoclax

r/r FL/PTCL +belinostat

1L DLBCL +R-CHOP

3L GCB-DLBCL +axi-cel

DH/TH DLBCL+DA-EPOCH-R

TKI-resistant CML +TKI

R/R FL + ubi/umbra

Protocol ApprovedActive Stage Concept StageProtocol Pending 58

59

Tazemetostat’s Potential in Solid Tumors will be Evaluated in a Basket Trial of 4 Cohorts Across 3 Tumor Types

SOLID TUMOR BASKET TRIAL DESIGN Ovarian

cancerSCLC Prostate

cancer

Tazemetostat + PARP Inhibitor

Tazemetostat + Checkpoint Inhibitor


• U.S. based trial • Intended to build the TAZVERIK

opportunity in solid tumors as well as larger indications with higher unmet need

• Supported by preclinical models validating synergistic effects of combinations

• Indications selected based on where Epizyme has the highest degree of confidence in PARP activity; if successful, several other indications could be pursued

• Assumes potential for approval based on single-arm study design allowing for shorter timelines

DNA Damage

60

EZH2 Inhibition and Response to DNA Damage:Hypothesis for Synergy Between EZH2 and PARP Inhibitors

PARP1

PAR polymers

EZH2 activity

Gene silencingH3K27me3

CELL SURVIVAL

EZH2 activity

Gene activationActive histone marksPRC2 Complex

EZH2Activated

PARP1

PARP activityEZH2 activity

CELL DEATH

PARPi

PARPi

1Yamaguchi Oncogene 20182Caruso Oncotarget 2018 3 Martin Mol and Cell Biology 2015

Dissociated PRC2 Complex

Schematic adaptation from Tempera lab(http://www.temperalab.org/research/)

No Inhibitors

PARP1 Inhibition

Combined PARP1 and EZH2 Inhibition

EZH2

PARPi-induced stabilization of PRC2 complex may lead to resistance

PARP1PRC2 Complex

EZH2

PRC2 Complex

EZH2

EZH2 inhibition may sensitize cell to PARP inhibitor treatment

PRC2 Complex

EZH2

EZH2i

PARP1

http://www.temperalab.org/research/

- Consistent tumor reduction observed in all mice with combination of niraparib and tazemetostat -- Tolerability did not allow for higher doses of niraparib (limitation in this model) -

61

0 10 20 30 400

500

1000

1500

2000

Time (Days)

Tum

or V

olum

e (m

m3 )

Vehicle--; po; bid to end

Tazemetostat 125 mg/kg; po; bid to endNiraparib 12.5 mg/kg; po; qd to end

Tazemetostat + Niraparib

28%

46%

P = 0.011

11%

Moderate Combinatorial Activity Observed of Tazemetostat with SOC in Chemo-Refractory OVCAR8 Murine Xenograft

0

1000

2000

3000

Tum

or V

olum

e (m

m3 ) *P = 0.0108

Individual tumor volumes (day 35)

Vehicle

Taz 1

25 m

g/kg

Niraparib

12.5

mg/kg

Combination

0

50

100

150

200

Percent of Control

H3K27me3 (PD Biomarker) Decreases with Tazemetostat Treatment

Dosing

Tazemetostat + Niraparib

62

Rationale for Combination of Tazemetostat with Cancer Immunotherapy

Wang et al. 2018 Vcell Reports. 23:3262

The Cancer Immunity Cycle: EZH2 Plays a Role in Multiple Processes

Targeting EZH2 Reprograms IntratumoralT-regs to Enhance Cancer Immunity

Trafficking of T cells to tumors (CTLs)4

Infiltration of T cells into tumors (CTLs, enodothelial cells)

5

Recognition of cancer cells by T cells (CTLs, cancer cells)

6

Killing of cancer cells (Immune and cancer cells)7

Priming and activation

(APCs & T cells)3

Cancer antigen

presentation (dendritic

cells/APCs)

2

Release of cancer cell antigens (cancer cell death) 1

63

Rationale for Combination of Tazemetostat with Cancer Immunotherapy

Wang et al. 2018 Vcell Reports. 23:3262

EZH2 inhibition suppresses MC38 tumor growth and enhances number CD8+ T cells

Study evaluating patients previously treated with a

PARP inhibitor or chemotherapy ineligible

Adaptive study design leveraging Bayesian

continuous monitoring based on predictive probability

Objective response (CR or PR) and Biomarker PD will determine go/no-go

PARPi resistant Prostate Cancer (N=20)

PARPi resistant Ovarian Cancer(N=20)

Chemo resistant SCLC(N=20)

64

A Phase 2 Open-Label Bayesian Basket Trial of Tazemetostat with a PARP inhibitor or IO in Patients with Solid Tumors

Tazemetostat + PARP inhibitor(N=6)

Advanced stage, metastatic cancer, progressed on PARPi

Tazemetostat + CP inhibitor(N=6)

Advanced stage, metastatic SCLC chemotherapy resistant

Chemo ineligible front-line SCLC (N=20)

Plan to Initiate Cohorts in Solid Tumor Basket Study 2H 2021

Phase 2 ExpansionSafety Run-in

Partial List of Active Studies & Approved IST Concepts for Tazemetostat in Solid Tumors

Urothelial +pembro

Pediatric MATCH OvarianCAIRE

+durvalumab

IO res SCCHN +pembro

IO resistant Lung +pembro

ATRT +nivo/ipi

1L Meso +cis/pem

BRAF-m Melanoma +DT

mCRPC+talazoparib

SCLC/NSCLCTopo+pembro

Solid Tumors with EZH2 Mutation

MPNST ARID1AMT in Solid Tumors

Advanced Triple Negative BC

+atezo

INI 1 loss Sarcoma+doxo/ifosfamide

SCCHN+ nivo

Protocol ApprovedActive Stage Protocol Pending 65

Summary

66

Plan

ned

Stud

ies

Ong

oing

Stu

dies

67

Robust Tazemetostat Development Program Will Produce a Stream of New Data Over the Next 5 Years

PARP Inhibitor

Checkpoint Inhibitor

PARPi resistant Prostate Cancer

PARPi resistant Ovarian Cancer

Chemo Resistant SCLC

Chemo Ineligible Front-Line SCLC

Solid Tumor Basket Study

Heme Basket Study

R/R FL

R/R DLBCL

R/R DLBCL

R/R MCL

R/R DLBCL

R/R MM

Bi-Specific Antibody

R-CHOP

Gem+Ox

BTK Inhibitor

Lenalidomide

Pom + DexInitiating Heme & Solid Tumor Basket

Study Cohorts 2H 2021

Follicular Lymphoma

Epithelioid Sarcoma

Len + CD19

BR

EZH-302: R2

EZH-1401: Rituximab

High-Risk Front-Line FL

Front-Line FL

Second-Line FL; Confirmatory Trial

Multiple ISTs Ongoing

Third-Line+Phase 2

Third-Line+

EZH-301: Doxorubicin Front-Line FL; Confirmatory Trial

Prostate Cancer EZH-1101: Abi / Enza R/R Prostate Cancer;

Phase 1b/2

Enrollment in safety run-in complete; Ph3 trial in process of initiation

Ph2 trial ongoing

Enrollment in safety run-in complete; Ph3 trial in process of initiation

Investigator Initiated Studies

Enrollment in safety run-in complete; Ph2 trial enrollment initiated

Broad expansion plan for TAZVERIK in multiple indications of interest, supported by preclinical data and biological rationale

Several ongoing clinical trials evaluating TAZVERIK combinations advancing; steady stream of data expected over next five years

Objective Responses demonstrated in EZH-302 Phase 1b safety run-in study of TAZ+R2 with no new safety signals; advancing to Phase 3 randomization trial

68

TMKey Takeaways

PSA50 and Objective Response demonstrated in EZH-1101 Phase 1 safety run-in study in combination with Abiraterone or Enzalutamide in mCRPC; advancing to Phase 2 portion in combination with Enzalutamide

Heme basket trial evaluating 7 combinations across 4 indications & solid tumor basket trial evaluating 4 combinations across 3 indications on track to initiate 2H21

Over 30 active or approved IST concepts across heme and solid tumors, supporting broad interest in TAZVERIK combinations

The Future of Epizyme’s Pipeline

69


70


71

Epizyme EpigeneticExperience

Epizyme Proprietary Platform

Pipeline of Novel Drug Candidates Across Multiple Classes of Epigenetic Targets

72

Differentiated Research Platform to Create Next Generation of Targeted Epigenetic Medicines

ASSESS POOL OF EPIGENETIC GENE

FAMILIES

APPLY CRISPR SCREENING TECHNOLOGY AND

FUNCTIONAL GENOMICS APPROACH

ANALYZE TARGET CREDENTIALS

IDENTIFY PRIORITY TARGETS

APPLY EPIGENETIC DRUG

DISCOVERY ENGINE & COMPOUND LIBRARY

SMALL MOLECULE DRUG DEVELOPMENT USING MULTI-DISCIPLINARY

APPROACH

• VIABLE CLINICAL PATH• FILLS UNMET NEED• VALIDATED DISEASE

BIOLOGY• DRUG-ABILITY

Robust Discovery Pipeline Across 3 Important Epigenetic Target Families

73

PROGRAM POTENTIAL INDICATIONS TARGET VALIDATION LEAD DISCOVERY LEAD

OPTIMIZATIONDEVELOPMENT CANDIDATE IND-ENABLING

HMT INHIBITORS

SETD2 Heme Malignancies

HMT2 Heme & Solid Malignancies

HMT3 Heme Malignancies

HAT INHIBITORS

HAT1 Heme & Solid Malignancies

HAT2 Solid Malignancies

HELICASE INHIBITORS

HEL1 Solid Malignancies

HEL2 Heme and Solid Malignancies





SETD2 is a Histone Methyltransferase That Plays Important Roles in Cellular Homeostasis

74

SETD2

• Recruitment of H3K36me3 “readers” and DNA methylators to prevent mistaken initiation of transcription within genes

• Recruitment of DNA repair response proteins to sense and repair DNA damage (homologous recombination and mismatch repair)

• Recruitment of splicing machinery and selection of splice sites

Histone H3K36 trimethylation

• Interaction with TP53 and modulation of specific TP53 downstream targets

• STAT1 methylation and Interferon response• Tubulin methylation: mitotic spindle integrity• Other transcription factors for regulation of specific gene sets

Non-Histone Functions

Mar BG Blood 2017; Licht JD Blood 2017; Li J Oncotarget 2016;

Chen R. J Cancer 2020

75

Preclinical Data Support Rationale for Investigating SETD2 Inhibitor

Targeted therapy for mutation-specific multiple myeloma

Broader activity in non-mutant multiple myeloma

Potential beyond multiple myeloma in other B-cell malignancies

Combination activity with standard of care and tazemetostat

in multiple myeloma

Multiple myeloma is a heterogenous disease characterized by an abnormal proliferation of plasma cells in the bone marrow usually accompanied by excessive production of monoclonal antibodies.• 2nd most common heme malignancy

• Accounts for 2% of all cancer-related deaths.• Treatment usually includes mono or combination therapy

with chemotherapy, immuno-modulating agents, proteasome inhibitors or monoclonal antibodies with results varying depending on the subtype of MM

Multiple Myeloma (MM): Clinical Overview

76

Mehta et al, Cjasn, 2006

MM: Bone Marrow Plasmacytosis

Despite recent drug launches and evolution of combination therapy, still considerable unmet needs, especially for high-risk disease, including MM with the

(4;14) chromosomal translocation

77

The (4;14) translocation occurs in 15-20% of multiple myeloma (MM) patients

• Associated with high risk disease and poorer prognosis (mSMART3.0)

• Bortezomib combined with iMIDSor stem cell transplant plus bortezomib have improved outcomes in t(4;14) MM patients, but unmet need persists

t(4;14) Myeloma is a High-Risk Subset of Multiple Myeloma with Poor Prognosis

Source: Perrot JCO 2019; Decision Resources (2019); ASCO Ed Book 2018; Nemec Leuk Lymph 2012

Overall Survival

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 10 20 30 40 50 60 months

No complex karyotype* & No t(4;14)Complex karyotype & No t(4;14)No complex karyotype* & t(4;14)Complex karyotype & t(4;14)

• t(4;14) juxtaposes IgH control elements with multiple myeloma SET domain (MMSET) gene leading to its overexpression• MMSET scientifically confirmed as driver in t(4;14) pathogenesis (Mirabella et al Blood Canc J 2013), but MMSET

remains undruggable• Over-expression of MMSET results in ubiquitous H3K36me2 in t(4;14) MM, which is the substrate for HMT SETD2

SETD2 is a Therapeutic Target, Particularly in MM with (4;14) Translocation

78

t(4;14) drives high levels of MMSET and, therefore, H3K36me2

Does the overexpression of

MMSET and subsequent increase

in H3K36me2 in t(4;14) MM lead to a

dependency on SETD2 for MM cell growth

and survival ?

MMSET MMSET SETD2

CH3 CH3 CH3 CH3 CH3

CH3

Histone 3 Lysine 36 (K36)

Histone 3 K36

Histone 3 K36

Histone 3 K36

Cell Death

79

Epizyme has Discovered a Potent and Selective, Oral Inhibitor of SETD2

MOLECULE TARGETING SETD2 was discovered from Epizyme’s large internal library of compounds and significant structure activity relationship analysis

SELECTIVE - >11,000-fold selectivity over other HMTs

POTENT – low nanomolar inhibitor of enzymatic activity

EXCELLENT DRUG-LIKE PROPERTIES – potential for oral administration

78

SETD2 Inhibition Impaired Growth of a t(4;14) Multiple Myeloma Cell Line

H3K36me2 (1:1K)

Total H3 (1:20K)

DM

SO

5000

nM

1000

nM

200n

M

40nM

8nM

1.6n

M

0.32

nM

H3K36me3 (1:1K)

Total H3 (1:20K)

t(4;14) MM cell line, had a cytotoxic response to SETD2 inhibitor with an 80nM proliferation IC50 in a 14-day long term proliferation assay

H3K36 trimethylation was inhibited with SETD2 inhibitor while H3K36 dimethylation

was unaffected

10000

100000

1000000

10000000

0 2 4 6 8 10 12 14 16

Cel

l Cou

nt (R

LU)

Time (Days)

10

3.3

1.1

0.37

0.12

0.04

0.014

0.005

0.0015

0.0005

0.2% DMSO

Media

t(4;14) MM cell lineSETD2 Inhibitor

conc. (uM)

SETD2 Inhibitor Concentration

Thomenius et al ASH Annual Meeting 2018

SETD2 Inhibition Elicited Robust Tumor Inhibition/Regressions in a t(4;14) and Non-t(4;14) Multiple Myeloma Xenograft Models

81

t(4;14) MM model Non-t(4;14) MM model

0

500

1000

1500

2000

2500

3000

3500

4000

0 5 10 15 20 25 30

Mea

n Tu

mor

Vol

ume

(mm

3 )

Days Post Treatment

Vehicle_BID

31.25mpk_BID

62.5mpk_BID

Start of dosing 76%

100%0

500

1000

1500

2000

2500

3000

0 5 10 15 20 25

Mea

n Tu

mor

Vol

ume

(mm

3 )

Days Post Treatment

Vehicle_BID

15.625mpk_BID

31.25mpk_BID

62.5mpk_BID29%

46%

85%

SETD2 Inhibitor Exhibited Synergy With Existing Myeloma Therapeutic Agents in Both t(4;14) and Non-t(4;14) MM Cell Lines

82

Additivity Synergy No effect Pending

Combination Effect Summary (7 Day Co-treatment)

Drug t(4;14) t(4;14) t(4;14) non-t(4;14) non-t(4;14) non-t(4;14)Dexamethasone

Pomalidomide

Lenalidomide

Bortezomib

Selinexor

Panobinostat

Venetoclax

CC-122

1000

10000

100000

1000000

10000000

0 2 4 6 8 10 12 14 16

Cel

l Cou

nts

(RLU

)

Time (Days)

DMSO

SETD2inhibitorTaz

Taz+SETD2inhibitor

Enhanced Anti-Proliferative Activity With Combination of SETD2 Inhibitor and Tazemetostat in t(4;14) Myeloma Cell Line Compared to Single Agents

83

**** p< 0.0001****

P values derived from one-way ANOVA with Tukey’s Multiple Comparisons of treatment compared to each of the dual combinations.

0

500

1000

1500

2000

2500

0 5 10 15 20 25 30

Mea

n Tu

mor

Vol

ume

(mm3 )

Days Post Treatment

Vehicle_BID 60mpk_BID

0

200

400

600

800

1000

1200

1400

1600

1800

2000

0 5 10 15 20 25 30

Mea

n Tu

mor

Vol

ume

(mm3 )

Days Post Treatment

Vehicle_BID 60mpk_BID

84

SETD2 Inhibitor Elicited Robust Tumor Inhibition in DLBCL In Vivo Models

84%

Germinal Center Cell type DLBCL

87%

Activated B Cell type DLBCL

85

SETD2 Inhibitor Summary and Milestones

Preclinical data to support rationale for investigating SETD2 in:

t(4;14) MM and non – t(4;14) MM as a single agent

t(4;14) MM and non – t(4;14) MM Synergy with existing MM therapies

B-cell malignanciesas a single agent

t(4;14) MMSynergy with tazemetostat

Key Milestone for SETD2 inhibitor in 2021• IND filing planned mid-year

Robust Discovery Pipeline Across 3 Important Epigenetic Target Families PROGRAM POTENTIAL INDICATIONS TARGET

VALIDATION LEAD DISCOVERY LEAD OPTIMIZATION

DEVELOPMENT CANDIDATE IND-ENABLING

HMT INHIBITORS

SETD2 Heme Malignancies

HMT2 Heme & Solid Malignancies

HMT3 Heme Malignancies

HAT INHIBITORS

HAT1 Heme & Solid Malignancies

HAT2 Solid Malignancies

HELICASE INHIBITORS


HEL2 Heme and Solid Malignancies





86

Realizing Epizyme’s Vision

87


88


89

Continuing Momentum Over Next 5 Years

R&D and commercial

capabilities to build a thriving oncology

company

Pipeline in solid & heme indications via basket trials to bring

additional value-generating

milestones and inflection points

across each basket cohort

Well funded to execute; ~$370M of cash provide financial runway

into 2023

Ability to deliver 5 clinical stage

programs over the next 5-year horizon

Preferred partner of choice for accessing innovation in epigenetics

Access markets ex-U.S.

Leverage research collaborations to interrogate multiple assets

Clinical Trial collaborations with other compounds where TAZVERIK combination makes sense

Business Development Strategic Imperatives

Opportunistically evaluate in-licensing opportunities to complement existing portfolio

90

Realizing Our Vision – 2021 Milestones

Continue to expand the commercial adoption of TAZVERIK® (tazemetostat) in FL and ES

Advance to the efficacy stages of our ES, FL, and prostate cancer clinical programs and presenting updated data from the safety run-in portions of these trials

Initiate our novel basket trials in both hematological malignancies and solid tumors

Advance SETD2 into the clinic

91

92

Q&A


Dr. Shefali AgarwalEVP, Chief Medical and

Development Officer


Matt RosEVP, Chief Strategy &

Business Officer

EPIZYME OVER THE NEXT 5 YEARS

93

TAZVERIK approved in additional heme and solid tumor indications

Robust flow of data read-outs

TAZVERIK partnered to reach ex-US markets

Multiple clinical and scientific collaborations

Five new clinical-stage programs

Evolving oncology portfolio company

TAZVERIK adopted as backbone therapy for FL

TAZVERIK utilized in multiple combination regimensMAXIMIZE COMMERCIAL EFFECTIVENESS

BUILD ON TAVZERIK’S PIPELINE-IN-A-DRUG POTENTIAL

EXPAND PIPELINE & PORTFOLIO TO OVERCOME UNDRUGGABLE TARGETS

COLLABORATE TO EXPAND PATIENT REACH & BUILD VALUE

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2

3

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the next episode: rewriting oncology treatment with

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