The Next EPIsode: Rewriting Oncology Treatment with Epigenetics
NASDAQ: EPZM Robert Bazemore, President & CEO
1 Robert Bazemore President & CEO
2 Epizyme 2021 & Beyond: Strategic Priorities
3 FORWARD-LOOKING STATEMENTS
Any statements in this presentation about future expectations, whether the company will receive regulatory approvals, including plans and prospects for Epizyme, Inc. and other statements accelerated approval, to conduct trials or to market products; the containing the words “anticipate," “believe,” “estimate,” impact of the COVID-19 pandemic on the company’s business, “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” results of operations and financial condition; whether the company's “potential,” “will,” “would,” “could,” “should,” “continue,” and cash resources will be sufficient to fund the company’s foreseeable similar expressions, constitute forward-looking statements within the and unforeseeable operating expenses and capital expenditure meaning of The Private Securities Litigation Reform Act of 1995. requirements; other matters that could affect the availability or Actual results may differ materially from those indicated by such commercial success of tazemetostat; and other factors discussed in forward-looking statements as a result of various important factors, the “Risk Factors” section of the company’s most recent Form 10-K including: whether commercial sales of TAZVERIK for epithelioid or Form 10-Q filed with the SEC and in the company's other filings sarcoma and follicular lymphoma in the approved indications will from time to time with the SEC. In addition, the forward-looking be successful; whether tazemetostat will receive marketing statements included in this presentation represent the company’s approval for epithelioid sarcoma or follicular lymphoma in other views as of the date hereof and should not be relied upon as jurisdictions, full approval in the United States or approval in any representing the company’s views as of any date subsequent to the other indication; whether results from preclinical studies or earlier date hereof. The company anticipates that subsequent events and clinical studies will be predictive of the results of future trials, such developments will cause the company’s views to change. However, as the ongoing confirmatory trials; whether results from clinical while the company may elect to update these forward-looking studies will warrant meetings with regulatory authorities, submissions statements at some point in the future, the company specifically for regulatory approval or review by governmental authorities disclaims any obligation to do so. under the accelerated approval process;
4 Epizyme: Who We Are Today
TAZVERIK® 13 Ongoing >300 (tazemetostat) Clinical Trials Employees Approved in Heme & Solid Tumors by End 2021
4 ONE MISSION: Tazemetostat Epizyme-Invented REWRITE TREATMENT FOR CANCER Evaluated in Molecules in Clinical AND OTHER SERIOUS DISEASES THROUGH >1,100 Patients Development NOVEL EPIGENETIC MEDICINES
11 Preclinical A Number of Important “Firsts” in Both Programs Research & Development >300 Being Evaluated Issued Patents Held
5 The TAZVERIK Journey Marked by Consistent Execution TAZVERIK Approved in FL
Corporate / Other NDA Acceptance & Priority Review for FL TAZVERIK (tazemetostat/EPZ-6438) 2 INDs Accepted TAZVERIK by FDA (DLBCL, Fast Track Approved in ES INI- Tumors & SS) Designations for FL & STS Unanimous ODAC First Patient Enrolled in Vote for ES Ph 1/2 Trial of EPZ-6438 First Patient Dosed in TAZ Incl. in NCCN Ph 2 Trial of EPZ-6438 NDA Acceptance Guidelines For R/R FL Abbott, Eisai & & Priority Review Roche Partnerships for ES TAZ Incl. in NCCN Orphan Drug Designation Guidelines For R/R ES Celgene Partnership for MRT GSK & Eisai Epizyme Partnerships Founded Boehringer Ingelheim EPZ-6438 Global Rights Collaboration Initial Public Offering Reacquired from Eisai Series B
2007 2011 2012 2013 2015 2016 2017 2018 2019 2020 Today
6 TAZVERIK Approvals and Launch Execution
Accelerated approval granted in epithelioid sarcoma (ES) Jan 2020
TM Accelerated approval granted in follicular lymphoma (FL) June 2020
of Top Tier FL 100% accounts reached1 96% 50% of Top Tier FL Post-approval awareness Increase in new accounts 1 60-65% accounts prescribing among target physicians2 prescribing TAZVERIK in 4Q 203
NCCN GUIDELINES Lives covered in both indications1 Adapted to support TAZVERIK use in both ES and R/R FL >90%
Not for promotional use. TAZVERIK approved for treatment of R/R FL on June 18, 2020; Full prescribing information is available at www.TAZVERIK.com. 1 Epizyme Internal Data. 2Epizyme Message Recall Study Fielded Oct-December 2020. N= 151. 3Ipsos US Oncology Monitor (October-December 7 2020), Participating doctors were primary treaters and saw a minimum number of patients per month.) Data © Ipsos 2020, all rights reserved Our Vision to Fuel Long-term Growth
1 2 BUILD ON TAVZERIK’S MAXIMIZE COMMERCIAL EFFECTIVENESS PIPELINE-IN-A-DRUG POTENTIAL
3 4 EXPAND PIPELINE & PORTFOLIO TO COLLABORATE TO EXPAND OVERCOME UNDRUGGABLE TARGETS PATIENT REACH & BUILD VALUE
8 Maximizing Commercial Effectiveness
Continue to evolve our commercial model to ensure expanded adoption of 1 TAZVERIK during COVID-19 and beyond
Further develop TAZVERIK to become the backbone therapy for follicular TM 2 lymphoma
Pursue strategic partnerships and collaborations to bring 3 TAZVERIK to patients worldwide
9 Building on TAZVERIK’s Potential
Promising Potential To Benefit A Significant Number Of Patients In Need
EZH2 A KEY PLAYER IN MULTIPLE LEVERAGING INNOVATIVE COMBINATION OPPORTUNITIES WITH TUMOR TYPES TRIAL DESIGNS FOR EFFICIENCY SOC AND NOVEL TREATMENTS
EZH2 POTENTIAL TO COMPLEMENT BASKET TRIALS TO IDENTIFY SIGNALS PROVIDE ROBUST FLOW OF NEW OTHER CANCER PATHWAYS ACROSS MULTIPLE CANCERS TAZEMETOSTAT DATA
10 Expand Pipeline to Bring Novel Epigenetic Therapeutics into Clinical Development
First approved Leverage Advancing new Develop Advance 5 EZH2 inhibitor CRISPR and therapeutics programs with clinical-stage and significant other that hit single-agent programs over progress on advanced previously activity and the next 5 years multiple targets assays to undrugged ability to where Epizyme systematically targets to meet complement therapies could interrogate patient needs important be 1st in class potential targets cancer pathways to create powerful combinations
11 Working Collaboratively to Expand Patient Reach and Increase Shareholder Value
PARTNER OF ACCESS NEW INNOVATIVE TRIAL COLLABORATE RESPONSIBLE CASH CHOICE MARKETS DESIGN EFFECTIVELY MANAGEMENT
Become the leading Expand reach Novel clinical trial Pursue the right Carefully deploy our partner for assessing through strategic design to deals to maximize resources to become innovation in collaborations accelerate signal value for all cash flow positive oncology finding and data stakeholders
12 AGENDA
Robert Bazemore EPIZYME 2021 & BEYOND: STRATEGIC PRIORITIES President & CEO Ari Melnick, M.D. EMERGING ROLE OF EPIGENETICS IN ONCOLOGY Weill Cornell Medicine Dr. Shefali Agarwal TAZVERIK DEVELOPMENT STRATEGY: THE NEXT CHAPTER EVP, Chief Medical & Development Officer Jeffery Kutok, M.D., Ph.D. THE FUTURE OF EPIZYME’S PIPELINE Chief Scientific Officer Matt Ros REALIZING EPIZYME’S VISION EVP, Chief Strategy & Business Officer
Q&A SESSION Epizyme Speakers
Robert Bazemore CLOSING REMARKS President & CEO
13 Emerging Role of Epigenetics in Oncology
Ari Melnick, M.D. Weill Cornell Medicine
14 Ari Melnick, M.D.
15 How is it Possible for Single Cells to Develop into Complex Organisms?
?
16 The Epigenome Represents the Instructions and Blueprints that Explain All Cell Phenotypes
Genome Epigenome Cell Blueprints
17 The Epigenome is Composed of Distinct Chemical Languages Controlled by Thousands of Proteins
18 Cancer Phenotypes are Universally Dependent on Epigenetic Instructions
19 All Cancers are Dependent on Epigenetic Mechanisms and Hence Susceptible to Epigenetic Therapies
Epigenome
Epigenetic Therapy
20 What is a Good Epigenetic Targeted Therapy?
a. Hits a well-defined and specific epigenetic target
b. Achieves full target engagement at clinically relevant doses, without off-target effects
c. The target is mainly an epigenetic modifier in the cancer context
EZH2 inhibitors d. The target drives a defined epigenetic dependency in FDA approved, strong specific cancers evidence that work via epigenetic actions, some bona fide biomarkers, clear e. Patients can be selected based on biomarker that indicates efficacy, limited toxicity, can dependency on a specific epigenetic mechanism be easily combined
21 EZH2 Inhibitor Mechanism of Action
H3K4me3 H3K4me3
EZH2 H3K27me3 EZH2i
Genes silenced Genes active
EZH2i Tumor cells Tumor cells dying growing or differentiating
EZH2i Immune System Immune System Suppressed Activated
22 Rationale for Combination of EZH2i with Immunotherapy & CAR-T Cells
EZH2 mutation mediates Enhances T-cell response to antigen escape from T-cell surveillance Beguelin et al Cancer Cell 2020
1 1 V -1 -1 V - - Ezh2WT EZH2 mutant lymphomas are Ezh2i Ezh2i Ezh2i Ezh2i immune “cold” Einnishi et al Cancer Discovery 2019 Mut Ezh2 Enhances CAR T cell quality
Car T-reg Central memory cells
Taz induces recruitment of CD4 and CD8 cells into lymphomas in vivo Takata et al Under Review 2021 V EZH2i IST for CART + TAZ in process
23 AB 150 * *
106 *** **** 104
100 ** 2 ** 10 **** ** * 0 **** ** 10 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/20/5226/1779441/advancesadv2020002580.pdf by WEILL MED COL/CORNELL UN user on 26 October 2020 1 ** *
CI value (log) **** ** ** A SUDHL-6 BC **** 50 * Vehicle SUDHL-6 *** 0.1 Venetoclax ** % viability relative to vehicle Tazemetostat *** Vehicle 2000 synergistic antagonistic Combination 20000 100 Venetoclax
) Tazemetostat 3 0.01 Combination
0 DB HT AUC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC Toledo Farage 10000 OCI-Ly1 DOHH2 OCI-Ly8OCI-Ly7 50 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/20/5226/1779441/advancesadv2020002580.pdf by WEILL MED COL/CORNELL UN user on 26 October 2020 OCI-Ly19 SUDHL-6 Karpas422SUDHL-4 SUDHL-5SUDHL-8 1000 % survival DB HT Toledo Farage WSU-DCLC2 SUDHL-6 OCI-Ly1 SUDHL-4 DOHH2OCI-Ly19 OCI-Ly8 OCI-Ly7SUDHL-5SUDHL-8
Karpas422 volume (mm Tumor WSU-DCLC2 p=0.0017 p=0.0027 p=0.0018 EZH2 mutant, BCL2 translocated EZH2 WT, BCL2 translocated EZH2 WT, BCL2 WT 0 0 01020 30 40 50 60 70 0 OCI-Ly1 PDX Vehicle Treatment Day C D AB0 10 20 30 Venetoclax Day 0-28 Vehicle Tazemetostat Vehicle 150 Tazemetostat * TazemetostatCombination * Treatment Day Day 0-28 106 *** **** 104 D PDX E F PDX **** Day 19 Day 92 100 ** 2 Vehicle 15000 ** 10 Venetoclax Rationale**** for Combination** of EZH2i with TargetedTazemetostat Therapy and**** Chemo * 0 1000 **** ** 10 Combination Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/20/5226/1779441/advancesadv2020002580.pdf by WEILL MED COL/CORNELL UN user on 26 October 2020 1
* ) ** 3 10000 ** ** CI value (log) 50 * *** Tazemetostat 0.1 AUC Venetoclax Combination Venetoclax Combination ** % viability relative to vehicle
Bcl2 translocation almost always present with500 EZH2synergistic mutation antagonistic or5000 in FL in general 0.01 Tumor volume (mm Tumor
0 HT DB 0 TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC TVC Toledo Farage OCI-Ly1 DOHH2 OCI-Ly8OCI-Ly7 Combination OCI-Ly19 SUDHL-6 Karpas422SUDHL-4 SUDHL-5SUDHL-8 DB HT Toledo WSU-DCLC2 0 OCI-Ly1 DOHH2 OCI-Ly8 FarageOCI-Ly7 SUDHL-6 EZH2Karpas422-i reduceSUDHL-4 apoptoticOCI-Ly19 SynergisticSUDHL-5SUDHL-8 effect on primary 0 Synergistic5 10 effect15 20on primaryVehicle human DLBCL in WSU-DCLC2 Venetoclax TazemetostatCombination threshold in DLBCLEZH2 mutant, BCL2 cells translocated EZH2 WT, BCL2DLBCL translocated organoidsEZH2 WT, BCL2 WT Treatment Day vivo Day 0-21 C OCI-Ly1 D PDX EGF Vehicle Tazemetostat Vehicle Tazemetostat G H OCI-Ly1 HRK **** PDX PDX 2 Veh 100 BCL2L11 (BIM) 70 3000 Vehicle **** 1 * BBC3 (PUMA) Taz Venetoclax 0 100 PMAIP1 60 Tazemetostat 80 **** –1 BID Combination –2 BAX 50 ) 3 60 Log FC BAD 2000 (vs DMSO) BMF *** Pro-apoptotic 40 50
BIK **** % survival
% live cells 40 BAK1 Venetoclax Combination Venetoclax Combination 70 **** BCL2L13 ****
BCL2L14 volume (mm Tumor 1000 20 ** % cytochrome release 20 BCL2L2 * Vehicle p=0.0522 p=0.0442 p=0.0339 0 MCL1 ns Venetoclax 10 0 50 100 150 200 0 BCL2L1 Tazemetostat Combination Veh Taz Ven Com BCL2A1 Treatment Day BCL2 0 0 Day 0-21 0 50 100 150 200 BCL2L10 Anti-apoptotic M M M M BCL2L12 Treatment Day BIM 1 A3 A4 RL HT
SR BAD 3 DB Ri-1 PUMA 1 BADM 10 M MS1 10 HRK 10 Day 0-21 TMD8 Toledo Farage RC-K8 Pfeiffer U2932 MC116 OCI-Ly3 OCI-Ly7 OCI-Ly1 DOHH2 OCI-Ly19 SUDHL-2 SUDHL-5 SUDHL-4 SUDHL-6 Karpas422
SUDHL-10 EZH2 mutant, BCL2 translocated PDX
WSU-DLCL2 EGF Figure 2. Inhibition of EZH2 and Bcl-2 in combination resultsBeguelin in tumor reductionet al andCancer prolonged Cell survival 2013 in vivo. (A,D,G) Tumor volume over time in SUDHL-6 OCI-Ly1 HRK **** 2 xenografts and PDXs, as measuredVeh by calipers. Error bars represent standard error of the mean (SEM). Tumor growth in SUDHL-6 (B) and PDX (E) xeongrafts,asmeasured EZH2 WT EZH2 mutant 100 BCL2L11 (BIM)* 70 Scholze et al Blood Advances 2020 **** 1 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 BBC3 (PUMA) Taz 0 PMAIP1 60 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 Figure 1. Combination therapy with EZH2 and Bcl-2 inhibitors has in vitro antitumor activity in DLBCL80 model systems. (A) Cell viability, as measured by CellTiter- **** –1 BID 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 Glo, in a panel of DLBCL cell lines treated with vehicle, venetoclax alone (V), tazemetostat alone (T), or venetoclax and tazemetostat in combination–2(C). Drug dosing for each BAX 50 interest, as determined by automatic thresholding settings, is shown in red. ***P , .001, ****P , .0001. 60 Log FC BAD 24 (vs DMSO) BMF *** Pro-apoptotic 40 27 OCTOBER 2020 x VOLUME 4, NUMBER 20 COMBINED EZH2 AND BCL-2 INHIBITION IN DLBCL 5229 BIK ****
% live cells 40 BAK1 27 OCTOBER 2020 x VOLUME 4, NUMBER 20 COMBINED EZH2 AND BCL-2 INHIBITION IN DLBCL 5227 70 **** BCL2L13 **** BCL2L14 20 ** % cytochrome release 20 BCL2L2 * MCL1 ns 10 0 BCL2L1 Veh Taz Ven Com BCL2A1 BCL2 0
BCL2L10 Anti-apoptotic M M M M BCL2L12 BIM 1 A3 A4 RL HT
SR BAD 3 DB Ri-1 PUMA 1 BADM 10 M MS1 10 HRK 10 TMD8 Toledo RC-K8 Farage Pfeiffer U2932 MC116 OCI-Ly3 OCI-Ly7 OCI-Ly1 DOHH2 OCI-Ly19 SUDHL-2 SUDHL-5 SUDHL-4 SUDHL-6 Karpas422
SUDHL-10 EZH2 mutant, BCL2 translocated PDX WSU-DLCL2
EZH2 WT EZH2 mutant
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
27 OCTOBER 2020 x VOLUME 4, NUMBER 20 COMBINED EZH2 AND BCL-2 INHIBITION IN DLBCL 5227 Role of Epigenetic Therapy in Cancer Treatment Regimens
Epigenetic Therapy Immunotherapy
Chemotherapy “Precision” Therapy
Cancer Cell
25 TAZVERIK® (tazemetostat) Development Strategy: The Next Chapter Dr. Shefali Agarwal EVP, Chief Medical & Development Officer
26 Dr. Shefali Agarwal EVP, Chief Medical & Development Officer
27 TM
NOVEL MECHANISM ACTIVITY DEMONSTRATED GENERALY WELL-TOLERATED; OF ACTION IN MULTIPLE CANCERS LOW DISCONTINUATION RATES
BROAD THERAPEUTIC POTENTIAL POTENTIAL FOR EXTENDED COMBINATION OPPORTUNITIES IN SOLID TUMORS AND TREATMENT DURATION WITH SOC TREATMENTS HEME MALIGNANCIES
Not for promotional use 28 The Next EPIsode: Rewriting Oncology Treatment with Epigenetics
TM Approval of tazemetostat to treat patients with ES and FL
Bring tazemetostat benefits to earlier Executing a lines of ES and FL therapy Multi-year Vision to Bring the Benefits of TAZVERIK Bring tazemetostat to patients beyond ES and FL as monotherapy and in to Patients in Need combination
Not for promotional use 29 Epigenetic Therapies Have Demonstrated the Potential to Enhance Activity of Standard-of-Care Cancer Therapies Across Heme and Solid Tumors
Therapy Class Rationale for Epigenetic Sensitization* Tazemetostat Trials^ Epigenetic Drug-induced Sensitization Mechanisms • Facilitate access to DNA, re-express tumor suppressors and • Doxorubicin in ES Chemotherapy increase ROS (DNMTi, HDACi, EZH2i) • R-CHOP † in DLBCL and FL • Disruption of pro-survival • Differentiate cancer stem cells (DNMTi, EZH2i and LSD1i) • BR † in FL signaling
• Restoration of cell cycle control • Decrease DDR capabilities (BETi and PRMTi) Radiotherapy • Facilitate access to DNA (DNMTi and HDACi) • Disruption of DNA damage repair • Rituximab, R2 in FL • Increase antigen presentation and chemokine / IFN expression • Pembro in solid tumors • Suppression of immune evasion Immunotherapy (DNMTi, HDACi and EZH2i) • Axi-cel in DLBCL • Anti-inflammatory (BETi) • Modulation of • Other combinations microenvironment • Revert EMT (DNMTi and HDACi) • Venetoclax in FL and DLBCL Targeted • Promote HIF1α degradation and reduce oncoprotein stability (HDACi) • PI3K in FL • Reprogramming of cellular Therapies • Prevent oncogene transcription (BETi) or re-express tumor • D/T † † in melanoma metabolism suppressors (EZH2i) • Other combinations
Combating cancer resistance • Abiraterone / Prednisone or • Reverse endocrine resistance (HDACi, HATi, BETi, EZH2i) and enhancing activity of Hormone therapy Enzalutamide in mCRPC standard-of-care therapies
Note: * 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 trametinib Source: Frontiers in Oncology: The Role of Epigenetic Modifications in Cancer Progression; MDPI; Nature: Signal Transduction and Targeted Therapy; Management data; L.E.K. research
30 Expansive Tazemetostat Development Program into Potential New Indications and Combinations
THERAPEUTIC AREA TREATMENT APPROACH INDICATIONS OF INTEREST
- DLBCL Inhibit tumor proliferation - MCL Lymphomas & B-Cell Malignancies governed by EZH2 expression - MM - Other B-cell malignancies
Inhibit abnormal EZH2 function, - Chordoma Mutationally Defined Solid Tumors - Melanoma restoring cells to natural state TAZEMETOSTAT - Tumors with SWI/SNF alteration AREAS OF INTEREST - Small cell lung cancer Re-sensitize tumors to chemo Chemo/Treatment-Resistant Tumors - Ovarian cancer and other therapies (e.g., PARP) - Mesothelioma - Castration-resistant prostate cancer
- Colorectal cancer Re-sensitize tumors to - Bladder cancer I/O Sensitive Tumors immuno-oncology therapies - Soft tissue sarcomas - Non-small cell & small cell lung cancer
31 Broad Development Approach for TAZVERIK: Initiating Basket Studies in Heme and Solid Tumors to Maximize Signal Finding Efficiency Across Multiple Tumors
Maximize signal- Basket trials for heme and solid tumors offer an efficient signal finding finding potential mechanism while producing a wide and consistent flow of new data
Combo with Internal and collaboration combination development efforts will prioritize SoC and both standard-of-care (SoC) therapies and new mechanism-of-action novel therapies (MOAs) to solidify placement of TAZVERIK in the treatment paradigm
The basket design optimizes shorter clinical development timelines Accelerate anticipated to broaden TAZVERIK label and expand available patient clinical timelines populations for TAZVERIK
32 Ongoing Heme Studies
33 TM Broad Label in Relapsed/Refractory FL
Current Label LABEL ENABLES PHYSICIAN DISCRETION TO PRESCRIBE TAZVERIK REGARDLESS OF EZH2 MUTATIONAL STATUS OR LINE OF R/R TREATMENT Adult patients with ü Relapsed/refractory 2L+ patients who have unsatisfactory treatment options relapsed or refractory follicular lymphoma whose tumors are positive ü Physician discretion whether to test for EZH2 mutation status; if desired, for an EZH2 mutation as option to use any FDA-approved test detected by an FDA- approved test and who have received at least 2 ü Post-marketing activities underway to support full approval and prior systemic therapies potential label expansion • Global, randomized adaptive confirmatory trial combing TAZVERIK with R2 in 2L+ FL patients (PFS as primary endpoint) Adult patients with • Expanded Phase 2 cohort of wild-type EZH2 patients with 2L+ FL relapsed or refractory follicular lymphoma who have no satisfactory NCCN Guidelines® recommend TAZVERIK alternative treatment options as category 2A treatment for FL
Not for promotional use 34 R2 = Revlimid® in combination with a rituxmab product is indicated for the treatment of adult patients with previously treated follicular lymphoma Developing TAZVERIK® to Become the Backbone of Therapy for Patients with Follicular Lymphoma
2021 Follicular Lymphoma Epidemiology ~13,700 Patients Diagnosed Annually
TAZVERIK + R-CHOP 1st Line High-risk FL Patients TAZVERIK + BR IST Enrolling IST Approved ~11,000
TAZVERIK + R2 2nd Line Confirmatory Phase 1b/3 trial (EZH-302) TM Safety run-in complete Efficacy portion initiated ~6,000 2L+ Supported TAZVERIK + 3L+ TAZVERIK + Rituximab by Current Label Phase 2 (EZH-1401) Enrolling Other Combinations ~5,000 Multiple ISTs Ongoing
Source: internal drug-treated estimates. R2 = Revlimid® in combination with a rituxmab product is indicated for the treatment of adult patients with previously treated follicular lymphoma 1 Freedman et al. American Journal of Hematology; Volume 87, Issue 10.
35 EZH-302 Phase 1b/3 Tazemetostat in Combination with R2 in Patients with R/R FL
Patients with relapsed / rituximab refractory FL who have been treated with at least one Population prior systemic therapy.
Phase 1b (safety run-in) Phase 3 (efficacy) Key Objectives Safety, pharmacokinetics, Primary: PFS as determined by Investigator; interim analyses for futility anti-tumor activity Secondary: PFS by IRC, response rate, duration of response, OS, QOL, safety
Safety Run-in Phase 3 Randomization (12 Months) Maintenance (24 Months)
All-comers EZH2 MUT / WT Enrichment Based on cobas® EZH2 Mutation Test
Taz + Rituximab + Lenalidomide Tazverik Monotherapy Taz + Rituximab + (N=250, mPFS 36 mos) (N=250) Lenalidomide (N=3-18) Placebo + Rituximab + Lenalidomide Placebo (N=250, mPFS 25 mos) (N=250)
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.
36 EZH302: Study of Tazemetostat + R2 in 2nd Line+ Follicular Lymphoma Rationale for Success in Phase 3 Confirmatory Study
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
37 Tazemetostat + Lenalidomide Has Shown Enhanced Antiproliferative Activity Upon Treatment in KMS-11 Cell Line When Compared to Single Agents Alone
Tazemetostat + Lenalidomide Demonstrated Enhanced Combination Activity in vitro
DMSO 107 CompoundTaz Concentration (nM)
) Len U 6 - L DMSO 170 1R 0
( Taz/Len Taz 100 s
t **** ) n 5 Len 1000 U u 160 L
1o 0 R ( C Taz/Len 100/1000
l s
t 4
e 10 n 5 C
u 10 P values derived from one-way ANOVA with Tukey’s Multiple Comparisons of treatment compared to each of o the dual combinations.
C 3 10 l 4 **** p< 0.0001 e 10 0 2 4 6 8 10 12 14 16 C Time (Days)
Protocol103 details: • KMS-11 cells were treated for 14 days (split and redose on D7) with combinations Lenalidomide and Tazemetostat • The concentrations0 2 were4 chosen6 from8 the10 14-day12 LTP assays14 for16 each of the agents tested • Antiproliferative activity measuredTime ( Dviaa ATPys )detection in cultures
38 Epizyme Observed Synergistic Antiproliferative Activity in Mutant EZH2 DLBCL Cell Lines with the Combination of Tazemetostat And Rituximab
EZH2 inhibition may play key role in enhancing Synergistic antiproliferative activity of multiple aspects of anti-tumor immunity which can tazemetostat + rituximab observed when tested in supplement anti-CD20 activity DLBCL cell lines in vitro
Synergy in SU-DHL-6 (Mutant EZH2 GCB)
Rituximab 100 200ug/mL 80 20ug/mL 2ug/mL 60 % Inhibition 0.2ug/mL 40 0 % inhibition 20
0 1 10 100 1000 [Tazemetostat], nM
JAGLOWSKI et al BLOOD, 11 NOVEMBER 2010,VOLUME 116, NUMBER 19
39 Source: Management data EZH-302 Safety Summary
Safety of tazemetostat (400, 600, 800 mg BID) + rituximab (375 mg/m2) + lenalidomide (10, 20 mg) evaluated in 13 patients
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
Tazemetostat well tolerated up to 800 mg BID in combination with R2 In-line with highest dose level for tazemetostat approved as monotherapy
40 Seven of 13 Patients Treated with Tazemetostat + R2 to Date Were Evaluable for Response; All Seven Patients Responded to Treatment
TAZEMETOSTAT + TAZEMETOSTAT + R2 Treatment Duration and Patient Lenalidomide/Rituximab Response to Investigator Assessment (iTT Population)
Best Overall Tumor Response Evaluable Population*
Complete Response (CR) 3 (43%)
Partial Response (PR) 4 (57%) CR Stable Disease (SD) 0 PR PD Progressive Disease (PD) 0 400 mg 600 mg Objective Response Rate 7 (100%) 800 mg (ORR) *Six patients not yet evaluable due to no post- 0 1 2 3 4 5 6 baseline scan data yet *Data cut mid-February 2021 Treatment Duration (Months) All but one patient remain on therapy
41 CR in Rituximab Refractory Patient with Extensive Extranodal Disease (600 mg Cohort)
Before After Patient Background: 1st Restaging 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
Tx #3: Tazemetostat 600mg BID + R2, initiated tx on 9/8/20, CR to treatment
Case courtesy of Dr. Connie Batlevi 42 CR in Elderly Patient with Early POD24 (800 mg Cohort)
Before After Patient Background: 1st Restaging 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
Tx #2: Tazemetostat 800mg BID +R2, initiated tx on 11/12/20 in CR
Case courtesy of Dr. Connie Batlevi 43 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
44 Ongoing Solid Tumor Studies
45 TM FDA-Approved For Epithelioid Sarcoma
INDICATION: Adults and pediatric patients aged 16 years and older ü First FDA-approved treatment with metastatic or locally advanced epithelioid sarcoma not eligible specifically indicated for ES for complete resection ü Safe and generally well-tolerated ACCELERATED APPROVAL SUPPORTED BY PHASE 2 DATA (n=62) ü Prolonged disease stabilization • 15% overall response rate • 16.4 months median DOR ü Efficacy portion of global • 6 month+ duration of response in 67% of patients (3.7, 24.5+) confirmatory trial (EZH-301) • 21% disease control rate assessing the combination of TAZVERIK plus doxorubicin • Tumor reduction observed in 68% of patients compared with doxorubicin plus • Many patients experienced prolonged disease stabilization placebo ongoing
NCCN Guidelines® recommend TAZVERIK as category 2A treatment for ES
Gounder M. et al. The Lancet Oncology. 6 Oct. 2020. 46 Targeting EZH2 in mCRPC with Tazemetostat: Clinical Hypotheses
EZH2 in metastatic CRPC EZH2 cooperates with the androgen receptor during oncogenic a transformation, leading to epigenetic silencing of many tumor suppressors and regulators of differentiation
In combination experiments, EZH2 b c inhibition resensitizes both mCRPC cultured cells and xenograft tumor models to androgen signaling inhibitor (ASI) therapy
a, b: EZH2 protein expression correlates with advancing disease progression c. Moderate to high EZH2 expression associated with worse failure-free survival
Varambally et al. 2002 Nature. 419:624 47 EZH-1101 Phase 1b Prostate Cancer Safety Overview
All 8 cohorts (5 enzalutamide, 3 abiraterone/prednisone) dosed without DLTs
TAZ+A/P TAZ+E Total Patients With a TEAE, n (%) (n=7) (n=14) (N=21)
Any TEAE 7 (100) 12 (85.7) 19 (90.5) • Low rate of Grade ≥3 AEs Grade 3 or 4 TEAE 2 (28.6) 5 (35.7) 7 (33.3) TEAE leading to dose • Low rate of dose interruptions / 1 (14.3) 1 (7.1) 2 (9.5) reduction modifications TEAE leading to study drug 2 (28.6) 3 (21.4) 5 (23.8) • No new safety signals interruption TEAE leading to study drug 0 1 (7.1) 1 (4.8) discontinuation TEAE leading to study 0 0 0 withdrawal
48 To Date, We’ve Already Observed PSA50 Responses Across Dosing Cohorts
PSA reduction of ≥50% in 7/21 patients EZH-1101: Maximum PSA Reduction To Date treated, across all cohorts 0.00% • 6 patients receiving taz/enza PSA50 -10.00% • 1 on taz/abi/pred PSA50 -20.00% • 10 patients remain on therapy with potential to exhibit response -30.00%
• 1 additional patient with PSA decrease of ≥35% -40.00%
-50.00% All responses were in ARV7- patients • 85 to 90% of prostate cancer patients are ARV7- -60.00% • Only one ARV7+ patient enrolled in safety run-in -70.00% portion of the study -80.00%
47% disease control rate to date -90.00% -100.00% • Longest patient continuation since January 2020 1010-1005 1001-1004 1001-1003 1010-1002 1010-1001 1010-1006 1010-1004 (1600mg) (600mg) (400mg) (800mg) (600mg) (1600mg) (1200mg) *Data cut mid-February 2021 Tazemetostat + Abiraterone/Prednisone (n=1) Tazemetostat + Enzalutamide (n=6)
49 Signs of Early Response to Treatment with Tazemetostat + Enzalutamide in Prostate Cancer Patient
• 77-year-old male with mCRPC progressing on Before After Four Cycles Lupron and Zytiga/prednisone (Taz + Enza ) • Lesions at left apex and mid gland of the prostate • Patient treated with tazemetostat 600mg BID and enzalutamide 160mg DAILY
After 2 Cycles: Baseline RECIST 24% reduction in (May 2020) response diameter of the C3 JUL2020 -24% 36% Lesion Reduction target lesion After Four Cycles C5 SEP2020 -32% After 3 Cycles: Baseline Scan - May 2020 C7 Scan – Nov. 2020 32% reduction (PR) C7 Nov2020 -36%
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
50 Randomized Portion of Phase 2 EZH-1101 Trial Ongoing
Primary Endpoint: Secondary Endpoints: Radiographic Progression- • PSA50, TTPP, time to first SRE, ORR and Intensive Biomarker Free Survival (rPFS) BOR, DCR, time to new treatment Program • Safety, PK • FACT-P, FWB and PCS subscales and TDD
RP2D: tazemetostat 1200mg BID plus enzalutamide 160mg DAILY
Tazemetostat (1200 mg BID) + Safety Run-in Complete Enzalutamide (160 mg QD) 10 of 21 Patients Remain on Therapy Tazemetostat RP2D for N=40 Enzalutamide Randomized Efficacy combination vs Portion Ongoing (1200mg BID) Randomization Enzalutamide (160 mg QD) N=40
51 51 PLANNED ACTIVTIES Tazemetostat Potential in Heme Indications will be Evaluated Through Seven Combos Across Four Indications
HEME BASKET TRIAL DESIGN FL DLBCL MCL MM • U.S. based trials • Intended to Further validate tazemetostat Tazemetostat + Bispecific Ab as a safe, broadly applicable heme Tazemetostat + CD-19+Len asset • Targets 2L+ for all Tazemetostat + Gem/Ox indications Tazemetostat + Lenalidomide • Assumes SoC comparator arm may Tazemetostat + BTKi or may not be needed • Supported by Tazemetostat +Dex + Pom preclinical data validating synergistic effects of combinations
Note: * Contingent upon FDA agreement that single arm study design is appropriate 53 Source: Management discussions Epizyme’s Preclinical Efforts Establish In Vitro and In Vivo Scientific Rationale to Support the Design of the Heme Basket
TRIAL COHORT SCIENTIFIC RATIONALE
FL • Epizyme found synergistic activity between tazemetostat and rituximab in EZH2 mutant DLBCL model in Bispecific Ab vitro; additionally, EZH2 inhibition is expected to enhance anti-CD3 activity
DLBCL • 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 Len+ CD-19 • In vitro work performed by Epizyme found combination effects of tazemetostat and lenalidomide in a Lenalidomide 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 Gem/Ox enhancement of cytotoxic cell killing by GemOx with tazemetostat in DLBCL cell lines
MCL • Tazemetostat demonstrated combinatorial activity with BTK inhibitors in a panel of MCL cell lines as well BTKi as in vivo murine xenograft model in preclinical studies performed by Epizyme. Tazemetostat inhibited in vitro cell line growth in BTKi-resistant cell lines
MM • Epizyme preclinical studies show that EZH2 inhibition strongly synergizes with Dex + Pom in multiple MM Dex + Pom cell lines and xenograft models
54 Source: Management data Tazemetostat + CD-19 Combination Opportunity in DLBCL
↑ CD19 increase > 2-fold CD19 Expression Increased in Various Sub-Types of DLBCL Cell Lines in Presence of Tazemetostat, Particularly in GCB EZH2 Mutant
55 Source: Management data Tazemetostat + Dex + Pom Combination Opportunities in MM
Combination Benefit of EZH2i with Pom/Dex in MM.1S Xenograft Model
56 Source: Management data A Phase 1/2 Open-Label Bayesian Basket Trial of Tazemetostat with Multiple Combinations in Hematological Malignancies
Safety Run-in Phase 2 Expansion
FL Tazemetostat + Bispecific (N = 6) R/R FL (N = 20) Basket trial provides an efficient signal finding mechanism while producing Tazemetostat + Len+ CD19 (N = 6) R/R DLBCL (N =20) a wide and consistent set of DLBCL Tazemetostat + Gem+Ox (N = 6) R/R DLBCL (N =20) new data Tazemetostat + Len (N = 6) R/R DLBCL (N =20)
Adaptive study design MCL Tazemetostat + BTKi (N = 6) R/R MCL (N =20) leveraging Bayesian continuous monitoring based on predictive probability MM Tazemetostat + Pom+Dex (N = 6) R/R MM (N =20) Objective response (CR or PR) and Biomarker PD will determine go/no-go Plan to Initiate Cohorts in Heme Basket Study 2H 2021
57 Partial List of Active Studies & Approved IST Concepts for Tazemetostat in Hematologic Malignancies
TKI-resistant CML 1L DLBCL 1L FL +TKI +R-CHOP +BR
r/r FL r/r NHL 3L GCB-DLBCL +venetoclax +venetoclax +axi-cel
R/R FL r/r FL/PTCL DH/TH DLBCL + ubi/umbra +belinostat +DA-EPOCH-R
Active Stage Protocol Approved Protocol Pending Concept Stage 58 Tazemetostat’s Potential in Solid Tumors will be Evaluated in a Basket Trial of 4 Cohorts Across 3 Tumor Types
SOLID TUMOR BASKET • U.S. based trial TRIAL DESIGN SCLC Prostate Ovarian • Intended to build the TAZVERIK cancer cancer opportunity in solid tumors as well as larger indications with higher unmet need • Supported by preclinical models Tazemetostat + PARP Inhibitor validating synergistic effects of combinations • Indications selected based on where Epizyme has the highest degree of confidence in PARP activity; if successful, several Tazemetostat + Checkpoint Inhibitor other indications could be pursued • Assumes potential for approval based on single-arm study design allowing for shorter timelines
59 Source: Management data EZH2 Inhibition and Response to DNA Damage: Hypothesis for Synergy Between EZH2 and PARP Inhibitors
DNA Damage PAR polymers
EZH2 activity No Inhibitors
PARP1 EZH2 Gene activation Activated EZH2 Active histone marks PRC2 Complex PARP1 Dissociated PRC2 Complex
PARPi-induced stabilization of EZH2 activity PRC2 complex PARP1 PARP1 Inhibition may lead to PRC2 Complex Gene silencing resistance PRC2 Complex H3K27me3 PARPi EZH2 EZH2 CELL SURVIVAL
EZH2 inhibition PRC2 Complex may sensitize PARP activity Combined PARP1 cell to PARP EZH2 PARP1 EZH2 activity and EZH2 Inhibition inhibitor treatment EZH2i PARPi CELL DEATH
Schematic adaptation from Tempera lab(http://www.temperalab.org/research/)
1Yamaguchi Oncogene 2018 2Caruso Oncotarget 2018 60 3 Martin Mol and Cell Biology 2015 Moderate Combinatorial Activity Observed of Tazemetostat with SOC in Chemo-Refractory OVCAR8 Murine Xenograft
H3K27me3 (PD Biomarker) Decreases Tazemetostat + Niraparib with Tazemetostat Treatment
2000 Vehicle--; po; bid to end Niraparib 12.5 mg/kg; po; qd to end Tazemetostat 125 mg/kg; po; bid to end 200 Tazemetostat + Niraparib 1500 150 ) 3 m m
( 11% Percent
e 100 of Control m 1000 l u 28% P = 0.011 o V
r 50
o 46% Individual tumor volumes m
T u 3000 (day 35) 500 0
) *P = 0.0108 3
m e g m (
2000 e
m Vehicl u l o
0 V
r 1000 0 10 20 30 40 o Combination
m Taz 125 mg/k u
Time (Days) T
0 Dosing Niraparib 12.5 mg/kg
- 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 Rationale for Combination of Tazemetostat with Cancer Immunotherapy
The Cancer Immunity Cycle: Targeting EZH2 Reprograms Intratumoral EZH2 Plays a Role in Multiple Processes T-regs to Enhance Cancer Immunity
Trafficking of T cells 4 to tumors (CTLs) Priming and activation 3 (APCs & T cells) Infiltration of T cells 5 into tumors (CTLs, enodothelial cells)
Cancer antigen presentation 2 Recognition of (dendritic 6 cancer cells by cells/APCs) T cells (CTLs, cancer cells)
Release of cancer cell Killing of cancer cells antigens (cancer cell death) 1 7 (Immune and cancer cells)
Wang et al. 2018 Vcell Reports. 23:3262 62 Rationale for Combination of Tazemetostat with Cancer Immunotherapy
EZH2 inhibition suppresses MC38 tumor growth and enhances number CD8+ T cells
Wang et al. 2018 Vcell Reports. 23:3262
63 A Phase 2 Open-Label Bayesian Basket Trial of Tazemetostat with a PARP inhibitor or IO in Patients with Solid Tumors
Safety Run-in Phase 2 Expansion
Study evaluating patients PARPi resistant Prostate Cancer (N=20) previously treated with a Tazemetostat + PARP inhibitor PARP inhibitor or (N=6) PARPi resistant Ovarian Cancer chemotherapy ineligible (N=20) Advanced stage, metastatic cancer, progressed on PARPi Chemo resistant SCLC Adaptive study design (N=20) leveraging Bayesian Tazemetostat + CP inhibitor continuous monitoring based (N=6) Chemo ineligible front-line SCLC on predictive probability (N=20) Advanced stage, metastatic SCLC chemotherapy resistant Objective response (CR or PR) and Biomarker PD will determine go/no-go Plan to Initiate Cohorts in Solid Tumor Basket Study 2H 2021
64 Partial List of Active Studies & Approved IST Concepts for Tazemetostat in Solid Tumors
Urothelial CAIRE Pediatric MATCH Ovarian +pembro +durvalumab
IO res SCCHN IO resistant Lung ATRT 1L Meso +pembro +pembro +nivo/ipi +cis/pem
BRAF-m Melanoma mCRPC SCLC/NSCLC Solid Tumors with +DT +talazoparib Topo+pembro EZH2 Mutation
Advanced Triple ARID1AMT in Solid INI 1 loss Sarcoma SCCHN MPNST Negative BC Tumors +doxo/ifosfamide + nivo +atezo
Active Stage Protocol Approved Protocol Pending 65 Summary
66 Robust of New Data Over the Next 5 Years Planned Studies Ongoing Studies Heme Basket HemeBasket Basket Study SolidTumor Lymphoma Epithelioid Sarcoma Follicular Prostate Cancer Study Tazemetostat Multiple ISTs Ongoing ISTs Multiple EZH EZH Checkpoint Inhibitor Checkpoint Bi EZH - SpecificAntibody - PARPInhibitor Lenalidomide - - 301: 1101: Len+ CD19 1401: EZH BTK Inhibitor BTK PomDex+ Gem+Ox R - - CHOP Doxorubicin BR 302: Abi / / Abi Rituximab R 2 Development Program Will aProduce Stream Enza Chemo PARPi PARPi High R/R Prostate Cancer; Cancer; R/R Prostate Chemo Resistant SCLC Confirmatory Trial Confirmatory Trial resistant Prostate Cancer Cancer Prostate resistant resistant Ovarian Cancer Ovarian resistant Second Ineligible Front Front - Front Phase Phase 1b/2 Risk Front Risk Third Third R/R DLBCL R/R DLBCL R/R R/R MCL Phase Phase 2 R/R MM R/R - - DLBCL Line FL; - - Line FL - Line+ Line+ Line FL; FL - Line FL - Line SCLC SCLC Enrollmentsafety in run Enrollmentsafety in run Enrollmentsafety in run Initiating Heme & Solid Tumor Basket Ph3 trialPh3 in process of initiation trialPh3 in process of initiation Investigator Initiated Studies Ph2 trialPh2 enrollment initiated Study Cohorts Study 2H 2021 Ph2 trialPh2 ongoing - - - in complete; in complete; in complete; in 67 Key Takeaways TM
PSA50 and Objective Response demonstrated in Broad expansion plan for TAZVERIK in multiple EZH-1101 Phase 1 safety run-in study in indications of interest, supported by preclinical combination with Abiraterone or Enzalutamide data and biological rationale in mCRPC; advancing to Phase 2 portion in combination with Enzalutamide
Heme basket trial evaluating 7 combinations Several ongoing clinical trials evaluating across 4 indications & solid tumor basket trial TAZVERIK combinations advancing; steady evaluating 4 combinations across 3 indications stream of data expected over next five years on track to initiate 2H21
Objective Responses demonstrated in EZH-302 Over 30 active or approved IST concepts across Phase 1b safety run-in study of TAZ+R2 with no heme and solid tumors, supporting broad new safety signals; advancing to Phase 3 interest in TAZVERIK combinations randomization trial
68 The Future of Epizyme’s Pipeline
Jeffery Kutok, M.D., Ph.D. Chief Scientific Officer
69 Jeffery Kutok, M.D., Ph.D. Chief Scientific Officer
70 Epizyme Epigenetic Experience
Pipeline of Novel Drug Candidates Across Multiple Classes of Epigenetic Targets Epizyme Proprietary Platform
71 Differentiated Research Platform to Create Next Generation of Targeted Epigenetic Medicines
APPLY ASSESS POOL OF ANALYZE TARGET EPIGENETIC DRUG EPIGENETIC GENE CREDENTIALS DISCOVERY ENGINE & FAMILIES • VIABLE CLINICAL PATH COMPOUND LIBRARY • FILLS UNMET NEED • VALIDATED DISEASE BIOLOGY • DRUG-ABILITY
APPLY CRISPR SCREENING SMALL MOLECULE DRUG TECHNOLOGY AND IDENTIFY PRIORITY DEVELOPMENT USING FUNCTIONAL TARGETS MULTI-DISCIPLINARY GENOMICS APPROACH APPROACH
72 Robust Discovery Pipeline Across 3 Important Epigenetic Target Families
TARGET LEAD DEVELOPMENT PROGRAM POTENTIAL INDICATIONS LEAD DISCOVERY IND-ENABLING VALIDATION OPTIMIZATION CANDIDATE
HMT INHIBITORS
SETD2 Heme Malignancies Heme & Solid HMT2 Malignancies HMT3 Heme Malignancies
HAT INHIBITORS
Heme & Solid HAT1 Malignancies HAT2 Solid Malignancies
HELICASE INHIBITORS
HEL1 Solid Malignancies Heme and Solid HEL2 Malignancies HEL3 Solid Malignancies
HEL4 Solid Malignancies
HEL5 Solid Malignancies
HEL6 Solid Malignancies
73 SETD2 is a Histone Methyltransferase That Plays Important Roles in Cellular Homeostasis
Histone H3K36 trimethylation
• 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) SETD2 • Recruitment of splicing machinery and selection of splice sites
Non-Histone Functions • Interaction with TP53 and modulation of specific TP53 downstream targets • STAT1 methylation and Interferon response • Tubulin methylation: mitotic spindle integrity
Chen R. J Cancer 2020 • Other transcription factors for regulation of specific gene sets
Mar BG Blood 2017; Licht JD Blood 2017; Li J Oncotarget 2016; 74 Preclinical Data Support Rationale for Investigating SETD2 Inhibitor
Targeted therapy for mutation- Broader activity in non-mutant specific multiple myeloma multiple myeloma
Combination activity with standard Potential beyond multiple myeloma of care and tazemetostat in other B-cell malignancies in multiple myeloma
75 Multiple Myeloma (MM): Clinical Overview MM: Bone Marrow Plasmacytosis 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 Mehta et al, Cjasn, 2006 with chemotherapy, immuno-modulating agents, proteasome inhibitors or monoclonal antibodies with results varying depending on the subtype of MM
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
76 t(4;14) Myeloma is a High-Risk Subset of Multiple Myeloma with Poor Prognosis
Overall Survival
The (4;14) translocation occurs in No complex karyotype* & No t(4;14) Complex karyotype & No t(4;14) 15-20% of multiple myeloma (MM) No complex karyotype* & t(4;14) patients 1.0 Complex karyotype & t(4;14) 0.9 • Associated with high risk disease 0.8 and poorer prognosis (mSMART 0.7
3.0) 0.6 • Bortezomib combined with iMIDS 0.5 or stem cell transplant plus 0.4 bortezomib have improved 0.3 outcomes in t(4;14) MM patients, 0.2
but unmet need persists 0.1
0.0 0 10 20 30 40 50 60 months
Source: Perrot JCO 2019; Decision Resources (2019); ASCO Ed Book 2018; Nemec Leuk Lymph 2012 77 SETD2 is a Therapeutic Target, Particularly in MM with (4;14) Translocation
• 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
CH3 CH CH Does the CH3 3 3 CH3 CH3 overexpression of
MMSET and Histone 3 Histone 3 Histone 3 Histone 3 subsequent increase Lysine 36 (K36) K36 K36 K36 in H3K36me2 in t(4;14) MMSET MMSET SETD2 MM lead to a dependency on SETD2 for MM cell growth Cell Death and survival ? t(4;14) drives high levels of MMSET and, therefore, H3K36me2
78 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
POTENT – low nanomolar inhibitor of enzymatic activity
SELECTIVE - >11,000-fold selectivity over other HMTs
EXCELLENT DRUG-LIKE PROPERTIES – potential for oral administration
79 SETD2 Inhibition Impaired Growth of a t(4;14) Multiple Myeloma Cell Line
t(4;14) MM cell line SETD2 Inhibitor Concentration SETD2 Inhibitor 10000000 conc. (uM)
10 5000nM 1000nM 40nM 8nM 0.32nM 3.3 DMSO 200nM 1.6nM 1.1 H3K36me2 (1:1K) 1000000 0.37 Total H3 (1:20K) 0.12 0.04
100000 0.014
Cell Count (RLU) Cell H3K36me3 (1:1K) 0.005 0.0015 Total H3 (1:20K) 0.0005 10000 0.2% DMSO 0 2 4 6 8 10 12 14 16 Media Time (Days) t(4;14) MM cell line, had a cytotoxic response H3K36 trimethylation was inhibited with to SETD2 inhibitor with an 80nM proliferation SETD2 inhibitor while H3K36 dimethylation IC50 in a 14-day long term proliferation assay was unaffected
78 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
t(4;14) MM model Non-t(4;14) MM model
4000 3000
Vehicle_BID 3500 Vehicle_BID 2500 15.625mpk_BID ) ) 3 3 3000 31.25mpk_BID 31.25mpk_BID
2000 62.5mpk_BID 2500 62.5mpk_BID 29%
2000 1500 46%
1500 1000 Mean Tumor Volume (mm Mean Tumor Volume
Mean Tumor Volume (mm Mean Tumor Volume 1000 Start of dosing 76% 500 85% 500
100% 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 Days Post Treatment Days Post Treatment
81 SETD2 Inhibitor Exhibited Synergy With Existing Myeloma Therapeutic Agents in Both t(4;14) and Non-t(4;14) MM Cell Lines
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
Additivity Synergy No effect Pending
82 Enhanced Anti-Proliferative Activity With Combination of SETD2 Inhibitor and Tazemetostat in t(4;14) Myeloma Cell Line Compared to Single Agents
10000000
DMSO
1000000 SETD2 inhibitor Taz
Taz+SETD2 100000 inhibitor
**** **** p< 0.0001 Cell Counts (RLU)
10000
1000 0 2 4 6 8 10 12 14 16 Time (Days)
P values derived from one-way ANOVA with Tukey’s Multiple Comparisons of treatment compared to each of the dual combinations.
83 SETD2 Inhibitor Elicited Robust Tumor Inhibition in DLBCL In Vivo Models
Germinal Center Cell type DLBCL Activated B Cell type DLBCL
Vehicle_BID 60mpk_BID Vehicle_BID 60mpk_BID 2000 2500
1800 ) ) 3 3 1600 2000
1400
1200 1500
1000
800 1000
600
400 500 84% Mean Tumor Volume (mm Mean Tumor Volume (mm 87% 200
0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Days Post Treatment Days Post Treatment
84 SETD2 Inhibitor Summary and Milestones
Preclinical data to support rationale for investigating SETD2 in:
t(4;14) MM and non – t(4;14) MM t(4;14) MM as a single agent Synergy with tazemetostat
t(4;14) MM and non – t(4;14) MM B-cell malignancies Synergy with existing MM therapies as a single agent
Key Milestone for SETD2 inhibitor in 2021 • IND filing planned mid-year
85 Robust Discovery Pipeline Across 3 Important Epigenetic Target Families
TARGET LEAD DEVELOPMENT PROGRAM POTENTIAL INDICATIONS LEAD DISCOVERY IND-ENABLING VALIDATION OPTIMIZATION CANDIDATE
HMT INHIBITORS
SETD2 Heme Malignancies Heme & Solid HMT2 Malignancies HMT3 Heme Malignancies
HAT INHIBITORS
Heme & Solid HAT1 Malignancies HAT2 Solid Malignancies
HELICASE INHIBITORS
HEL1 Solid Malignancies Heme and Solid HEL2 Malignancies HEL3 Solid Malignancies
HEL4 Solid Malignancies
HEL5 Solid Malignancies
HEL6 Solid Malignancies
86 Realizing Epizyme’s Vision
Matt Ros EVP, Chief Strategy & Business Officer
87 Matt Ros EVP, Chief Strategy & Business Officer
88 Continuing Momentum Over Next 5 Years
R&D and Pipeline in solid & Ability to deliver Well funded to commercial heme indications via 5 clinical stage execute; ~$370M capabilities to build basket trials to bring programs over the of cash provide a thriving oncology additional value- next 5-year horizon financial runway company generating into 2023 milestones and inflection points across each basket cohort
89 Business Development Strategic Imperatives
Preferred partner of choice for accessing innovation in epigenetics
Leverage research collaborations to interrogate multiple assets
Access markets ex-U.S.
Clinical Trial collaborations with other compounds where TAZVERIK combination makes sense
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 Q&A
Robert Bazemore Dr. Shefali Agarwal Jeffery Kutok, M.D., Ph.D. Matt Ros President & CEO EVP, Chief Medical and Chief Scientific Officer EVP, Chief Strategy & Development Officer Business Officer
92 EPIZYME OVER THE NEXT 5 YEARS
1 TAZVERIK adopted as backbone therapy for FL MAXIMIZE COMMERCIAL EFFECTIVENESS TAZVERIK utilized in multiple combination regimens
2 TAZVERIK approved in additional heme and solid BUILD ON TAVZERIK’S tumor indications PIPELINE-IN-A-DRUG POTENTIAL Robust flow of data read-outs
3 Five new clinical-stage programs EXPAND PIPELINE & PORTFOLIO TO OVERCOME UNDRUGGABLE TARGETS Evolving oncology portfolio company
4 COLLABORATE TO EXPAND TAZVERIK partnered to reach ex-US markets PATIENT REACH & BUILD VALUE Multiple clinical and scientific collaborations
93