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
TM
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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
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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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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
Robert BazemorePresident & CEO
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
Robert BazemorePresident & CEO
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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2000
1000
Tumo
r volu
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00TreatmentDay 0-28
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F PDXDay 19
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Day 92
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.
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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
150
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HRK
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EZH2 WT EZH2 mutant
BCL2L10BCL2BCL2A1BCL2L1MCL1BCL2L2BCL2L14 **BCL2L13BAK1BIK
BADBAXBIDPMAIP1BBC3 (PUMA)BCL2L11 (BIM)*
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Figure 1. Combination therapy with EZH2 and Bcl-2 inhibitors has in vitro antitumor activity in DLBCL model systems. (A) Cell viability, as measured by CellTiter-
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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EZH2 mutant, BCL2 translocated EZH2 WT, BCL2 translocated EZH2 WT, BCL2 WT
150
100
% vi
abilit
y rela
tive t
o veh
icle
50
0T V C T V C T V C T V C T V C T V C T V C T V C T V C T V C T V C T V C T V C T V C T V C
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Venetoclax Combination
DOCI-Ly1Vehicle Tazemetostat
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BAD 10PM
BAD 3PM
MS1 10PM
HRK 10PM
mutant, EZH2 translocated PDXBCL2
F210–1–2
Log FC(vs DMSO)
HRK
BCL2L12
EZH2 WT EZH2 mutant
BCL2L10BCL2BCL2A1BCL2L1MCL1BCL2L2BCL2L14 **BCL2L13BAK1BIK
BADBAXBIDPMAIP1BBC3 (PUMA)BCL2L11 (BIM)*
BMF *** Pro-
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Figure 1. Combination therapy with EZH2 and Bcl-2 inhibitors has in vitro antitumor activity in DLBCL model systems. (A) Cell viability, as measured by CellTiter-
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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Dr. Shefali AgarwalEVP, Chief Medical & Development Officer
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Dr. Shefali AgarwalEVP, Chief Medical & Development Officer
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
TM
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
37
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
Source: Management data
Tazemetostat + CD-19 Combination Opportunity in DLBCL
Source: Management data
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
Source: Management data
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
Source: Management data
• 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
- 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
Jeffery Kutok, M.D., Ph.D.Chief Scientific Officer
70
Jeffery Kutok, M.D., Ph.D.Chief Scientific Officer
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
HEL3 Solid Malignancies
HEL4 Solid Malignancies
HEL5 Solid Malignancies
HEL6 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
HEL1 Solid Malignancies
HEL2 Heme and Solid Malignancies
HEL3 Solid Malignancies
HEL4 Solid Malignancies
HEL5 Solid Malignancies
HEL6 Solid Malignancies
86
Realizing Epizyme’s Vision
87
Matt RosEVP, Chief Strategy & Business Officer
88
Matt RosEVP, Chief Strategy & Business Officer
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
Robert BazemorePresident & CEO
Dr. Shefali AgarwalEVP, Chief Medical and
Development Officer
Jeffery Kutok, M.D., Ph.D.Chief Scientific 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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