EPIZYME, INC. Rewriting Treatments for Patients with Cancer and Other Serious Diseases
Rewriting Treatments for People with Cancer and Other Serious Diseases
37th ANNUAL JP MORGAN CONFERENCE JMAaNrUcAhRY3,22001290
NASDAQ: EPZM
NASDAQ: EPZM
FORWARD-LOOKING STATEMENTS
Any statements in this presentation about future expectations, plans and prospects for Epizyme, Inc. and other statements containing the words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: whether commercial sales of TAZVERIK for epithelioid sarcoma and follicular lymphoma in the approved indications will be successful; whether tazemetostat will receive marketing approval for epithelioid sarcoma or follicular lymphoma in other jurisdictions, full approval in the United States or approval in any other indication; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future trials, such as the ongoing confirmatory trials; whether results from clinical studies will warrant meetings with regulatory authorities, submissions for regulatory approval or review by governmental authorities under the accelerated approval process;
whether the company will receive regulatory approvals, including accelerated approval, to conduct trials or to market products; the impact of the COVID-19 pandemic on the company's business, results of operations and financial condition; whether the company's cash resources will be sufficient to fund the company's foreseeable and unforeseeable operating expenses and capital expenditure requirements; other matters that could affect the availability or commercial success of tazemetostat; and other factors discussed in the "Risk Factors" section of the company's most recent Form 10-K or Form 10-Q filed with the SEC and in the company's other filings from time to time with the SEC. In addition, the forward-looking statements included in this presentation represent the company's views as of the date hereof and should not be relied upon as representing the company's views as of any date subsequent to the date hereof. The company anticipates that subsequent events and developments will cause the company's views to change. However, while the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so.
2
Epizyme: Who We Are Today
ONE MISSION:
REWRITE TREATMENT FOR CANCER AND OTHER SERIOUS DISEASES THROUGH
NOVEL EPIGENETIC MEDICINES
4
Epizyme-Invented Molecules in Clinical
Development
Tazemetostat Evaluated in >1,100 Patients
4
Our Vision to Fuel Long-term Growth
5
Maximizing Commercial Effectiveness
2 3
6
Building on TAZVERIK's Potential
Promising Potential To Benefit A Significant
Number Of Patients In Need
7
Expand Pipeline to Bring Novel Epigenetic Therapeutics into Clinical Development
First approved EZH2 inhibitor and significant progress on multiple targets where Epizyme therapies could be 1st in classDevelop programs with single-agent activity and ability to complement important cancer pathways to create powerful combinations
Advance 5 clinical-stage programs over the next 5 years
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Working Collaboratively to Expand Patient Reach and Increase Shareholder Value
Become the leading partner for assessing innovation in oncology
Expand reach through strategic collaborations
Novel clinical trial design to accelerate signal finding and dataPursue the right deals to maximize value for all stakeholders
Carefully deploy our resources to become cash flow positive
9
TAZVERIK
Development Strategy
FDA-APPROVED FOR TREATMENT OF MULTIPLE CANCERS
INDICATED FOR
• Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection
• 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
11
SAFETY INFORMATION
MOST COMMON ADVERSE REACTION (>20%, ANY GRADE)
• ES: Pain, fatigue, nausea, decreased appetite, vomiting and constipation
• FL: Fatigue, upper respiratory infection, musculoskeletal pain, nausea and abdominal pain
WARNINGS & PRECAUTIONS
• Secondary malignancies: Across clinical trials of 729 adults who received TAZVERIK 800 mg twice daily, myelodysplastic syndrome or acute myeloid leukemia occurred in 0.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma.
• Embryo-fetal toxicity
DRUG INTERACTION
• Strong and Moderate Cytochrome P450 (CYP)3A Inhibitors: Avoid coadministration of strong and moderate CYP3A inhibitors with TAZVERIK. Reduce the dose of TAZVERIK if coadministration of moderate CYP3A inhibitors cannot be avoided
• Strong and Moderate CYP3A Inducers: Avoid coadministration with TAZVERIK
12
TAZVERIK Approvals and Launch Execution
Accelerated approval granted in epithelioid sarcoma (ES) Jan 2020
Accelerated approval granted in follicular lymphoma (FL) June 2020
NCCN GUIDELINES
Adapted to support TAZVERIK use in both ES and R/R FL
>90%
Lives covered in both indications1
96% | 50% |
100% | |
of Top Tier FL | |
accounts reached1 | |
60-65% | of Top Tier FL |
Post-approval awareness | Increase in new accounts |
accounts prescribing1 | |
among target physicians2 | prescribing TAZVERIK in 4Q 203 |
Not for promotional use. TAZVERIK approved for treatment of R/R FL on June 18, 2020; Full prescribing information is available atwww.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
TAZVERIK SAW 42% GROWTH IN TOTAL END USER DEMAND AND 31% GROWTH IN PRODUCT NET REVENUE FROM Q3 TO Q4
TAZVERIK Quarterly Total Bottle Demand
TAZVERIK Quarterly Net Revenue
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Total End User Demand
Net Revenue ($M)
Inclusive of commercial and free goods
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STRONG COMMERCIAL EXECUTION SINCE TAZVERIK FL LAUNCH
Share of FL Product Promotional Details (% of market details)2
80%
60%
40%
20%
0%
Competitor Product
Tazverik FL
1/20
2/20
3/20
4/20
5/20
6/20
7/20
8/20
9/20
Total Market Details
38
28
20
17
12
35
55
Chart represents a given brand's share of FL market details. Brands shown in the graph include Aliqopa, Copiktra, Gazyva, Zydelig, and R2. 1 Epizyme Internal Data . 2IQVIA Brand Impact, Data Jan-Sep 2020. N=475 US Oncologists.
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15
16
The Next EPIsode:
Rewriting Oncology Treatment with Epigenetics
Executing a
Multi-year Vision to Bring the Benefits of TAZVERIK to Patients in Need
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Epigenetic Therapies Have Demonstrated the Potential to Enhance Activity of Standard-of-Care Cancer Therapies Across Heme and Solid Tumors
Epigenetic Drug-induced Sensitization Mechanisms
Therapy Class
• 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
ChemotherapyRationale for Epigenetic Sensitization*
• Facilitate access to DNA, re-express tumor suppressors and increase ROS (DNMTi, HDACi, EZH2i)
• Differentiate cancer stem cells (DNMTi, EZH2i and LSD1i)
Targeted Therapies
• Revert EMT (DNMTi and HDACi)
• Promote HIF1α degradation and reduce oncoprotein stability (HDACi)
• Prevent oncogene transcription (BETi) or re-express tumor suppressors (EZH2i)
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
• Venetoclax in FL and DLBCL
• PI3K in FL
• D/T †† in melanoma
• Other combinations
• Abiraterone / Prednisone or Enzalutamide in mCRPC
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
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Expansive Tazemetostat Development Program into Potential New Indications and Combinations
THERAPEUTIC AREA
TREATMENT APPROACHINDICATIONS OF INTEREST
19
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 | Basket trials for heme and solid tumors offer an efficient signal finding mechanism while producing a wide and consistent flow of new data |
Combo with SoC and novel therapies | 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 |
Accelerate clinical timelines | The basket design optimizes shorter clinical development timelines anticipated to broaden TAZVERIK label and expand available patient populations for TAZVERIK |
Ongoing Heme
Studies
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 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 therapiesAdult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options
✓ Relapsed/refractory 2L+ patients who have unsatisfactory treatment options
✓ Physician discretion whether to test for EZH2 mutation status; if desired, option to use any FDA-approved test
✓ 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
R2 = Revlimid® in combination with a rituxmab product is indicated for the treatment of adult patients with previously treated follicular lymphoma
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Developing TAZVERIK® to Become the Backbone of Therapy for Patients with Follicular Lymphoma
2021 Follicular Lymphoma Epidemiology
~13,700 Patients Diagnosed Annually
3L+
~5,000
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.
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EZH-302 Phase 1b/3 Tazemetostat in Combination with R2 in Patients with R/R FL
Population | Patients with relapsed / rituximab refractory FL who have been treated with at least one prior systemic therapy. |
Key Objectives | Phase 1b (safety run-in)Phase 3 (efficacy) Safety, pharmacokinetics, anti-tumor activity Primary: PFS as determined by Investigator; interim analyses for futility 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
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.
EZH302: Study of Tazemetostat + R2 in 2nd Line+ Follicular Lymphoma
Rationale for Success in Phase 3 Confirmatory Study
✓ Pre-clinical evidence suggesting synergy between tazemetostat + lenalidomide and tazemetostat + rituximab, the two components of the R2 regimen
✓ Preliminary clinical activity with rituximab in Phase 1b study of R-CHOP + tazemetostat previously presented
✓ Unique 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
✓ TAZVERIK safety characteristics allows for extended treatment with high treatment compliance
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
Seven of 13 Patients Treated with Tazemetostat + R2 to Date Were Evaluable for Response; All Seven Patients Responded to Treatment
All but one patient remain on therapy
CR in Rituximab Refractory Patient with Extensive Extranodal Disease (600 mg Cohort)
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
Tx #3: Tazemetostat 600mg BID + R2, initiated tx on 9/8/20, CR to treatment
Case courtesy of Dr. Connie Batlevi
CR in Elderly Patient with Early POD24 (800 mg Cohort)
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
Tx #2: Tazemetostat 800mg BID +R2, initiated tx on 11/12/20 in CR
Case courtesy of Dr. Connie Batlevi
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
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
ACCELERATED APPROVAL SUPPORTED BY PHASE 2 DATA (n=62)
✓ First FDA-approved treatment specifically indicated for ES
✓ Safe and generally well-tolerated
✓ Prolonged disease stabilization
• | 15% overall response rate | |
• | 16.4 months median DOR | |
✓ Efficacy portion of global | ||
• | 6 month+ duration of response in 67% of patients (3.7, 24.5+) | confirmatory trial (EZH-301) |
assessing the combination of | ||
• | 21% disease control rate | |
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.
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Targeting EZH2 in mCRPC with Tazemetostat: Clinical Hypotheses
Varambally et al. 2002 Nature. 419:624
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 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
EZH-1101 Phase 1b Prostate Cancer Safety Overview
All 8 cohorts (5 enzalutamide, 3 abiraterone/prednisone) dosed without DLTs
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
To Date, We've Already Observed PSA50 Responses Across Dosing Cohorts
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
EZH-1101: Maximum PSA Reduction To Date
0.00%
-10.00% -20.00% -30.00% -40.00% -50.00% -60.00% -70.00% -80.00% -90.00% -100.00%
1010-1005 | 1001-1004 | 1001-1003 | 1010-1002 | 1010-1001 | 1010-1006 | 1010-1004 |
(1600mg) | (600mg) | (400mg) | (800mg) | (600mg) | (1600mg) | (1200mg) |
Tazemetostat + Abiraterone/Prednisone (n=1)Tazemetostat + Enzalutamide (n=6)
Signs of Early Response to Treatment with Tazemetostat + Enzalutamide in Prostate Cancer Patient
• 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)
Baseline (May 2020) | RECIST response |
C3 JUL2020 | -24% |
C5 SEP2020 | -32% |
C7 Nov2020 | -36% |
BeforeAfter 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
Randomized Portion of Phase 2 EZH-1101 Trial Ongoing
Primary Endpoint:
Radiographic Progression-Free Survival (rPFS)
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
RP2D: tazemetostat 1200mg BID plus enzalutamide 160mg DAILY
Planned Activities
Tazemetostat Potential in Heme Indications will be Evaluated Through Seven Combos Across Four Indications
HEME BASKET TRIAL DESIGN
Tazemetostat + Bispecific Ab Tazemetostat + CD-19+Len Tazemetostat + Gem/Ox Tazemetostat + Lenalidomide Tazemetostat + BTKi
Tazemetostat +Dex + Pom
Note: * Contingent upon FDA agreement that single arm study design is appropriate Source: Management discussions
• 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's Preclinical Efforts Establish In Vitro and In Vivo Scientific Rationale to Support the Design of the Heme Basket
TRIAL COHORT
SCIENTIFIC RATIONALE
FL Bispecific | Ab
|
DLBCL Len+ CD-1 Lenalidom Gem/Ox |
|
MCL BTKi |
|
MM Dex + Pom |
|
Source: Management data
A Phase 1/2 Open-Label Bayesian Basket Trial of Tazemetostat with Multiple Combinations in Hematological Malignancies
Basket trial provides an efficient signal finding mechanism while producing a wide and consistent set of new dataAdaptive study design leveraging Bayesian continuous monitoring based on predictive probability
Objective response (CR or PR) and Biomarker PD will determine go/no-go
Safety Run-in
Phase 2 Expansion
FL
Tazemetostat + Bispecific (N = 6)
R/R FL (N = 20)
Tazemetostat + Len+ CD19 (N = 6)
R/R DLBCL (N =20)
DLBCL
Tazemetostat + Gem+Ox (N = 6)
R/R DLBCL (N =20)
Tazemetostat + Len (N = 6)
R/R DLBCL (N =20)
MCL
Tazemetostat + BTKi (N = 6)
R/R MCL (N =20)
MM
Tazemetostat + Pom+Dex (N = 6)
R/R MM (N =20)
Plan to Initiate Cohorts in Heme Basket Study 2H 2021
Tazemetostat's Potential in Solid Tumors will be Evaluated in a Basket Trial of 4 Cohorts Across 3 Tumor Types
• 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
Source: Management data
A Phase 2 Open-Label Bayesian Basket Trial of Tazemetostat with a PARP inhibitor or IO in Patients with Solid Tumors
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
Safety Run-in
Phase 2 Expansion
Tazemetostat + PARP inhibitor
(N=6)
Advanced stage, metastatic cancer, progressed on PARPi
PARPi resistant Prostate Cancer
(N=20)
PARPi resistant Ovarian Cancer
(N=20)
Chemo resistant SCLC
(N=20)
Plan to Initiate Cohorts in Solid Tumor Basket Study 2H 2021
Robust Tazemetostat Development Program Will Produce a Stream of New Data Over the Next 5 Years
Ongoing Studies
EZH-302: R2
EZH-1401: Rituximab
R-CHOP
BR
Multiple ISTs Ongoing
Second-Line FL; Confirmatory Trial
Third-Line+
Phase 2
High-Risk Front-Line FL
Front-Line FL
Third-Line+
Front-Line FL; Confirmatory Trial
R/R Prostate Cancer;
Phase 1b/2
Enrollment in safety run-in complete;
Ph3 trial in process of initiation
Enrollment in safety run-in complete;
Ph2 trial enrollment initiated
Planned Studies
Gem+Ox Lenalidomide
R/R FL R/R DLBCL R/R DLBCL R/R DLBCL R/R MCL R/R MM
PARPi resistant Prostate Cancer PARPi resistant Ovarian Cancer
Chemo Resistant SCLC Chemo Ineligible Front-Line SCLC
Bi-Specific Antibody
Len + CD19
BTK Inhibitor
Pom + Dex
Checkpoint Inhibitor
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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 | Concept Stage |
Protocol ApprovedProtocol Pending
Partial List of Active Studies & Approved IST Concepts for Tazemetostat in Solid Tumors
Active StageProtocol ApprovedProtocol Pending
Key Takeaways
Broad expansion plan for TAZVERIK in multiple indications of interest, supported by preclinical data and biological rationale
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
Several ongoing clinical trials evaluating TAZVERIK combinations advancing; steady stream of data expected over next five yearsObjective 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
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
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Research Platform
Differentiated Research Platform to Create Next Generation of Targeted Epigenetic Medicines
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Robust Discovery Pipeline Across 3 Important Epigenetic Target Families
HAT INHIBITORS
HELICASE INHIBITORS
Preclinical Data Support Rationale for Investigating SETD2 Inhibitor
t(4;14) Myeloma is a High-Risk Subset of Multiple Myeloma with Poor Prognosis
Overall Survival
The (4;14) translocation occurs in | |
15-20% of multiple myeloma (MM) | |
patients | 1.0 |
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 |
months
0
Source: Perrot JCO 2019; Decision Resources (2019); ASCO Ed Book 2018; Nemec Leuk Lymph 2012
No complex karyotype* & No t(4;14)
Complex karyotype & No t(4;14)
No complex karyotype* & t(4;14)
Complex karyotype & t(4;14)
10
20
30
40
50
60
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
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 ? | CH3 Histone 3 Lysine 36 (K36) MMSET CH3 CH3 CH3 CH3 CH3 Histone 3 Histone 3 Histone 3 K36 K36 K36 MMSET SETD2 Cell Death |
t(4;14) drives high levels of MMSET and, therefore, H3K36me2 |
Epizyme has Discovered a Potent and Selective, Oral Inhibitor of SETD2
POTENT - low nanomolar inhibitor of enzymatic activity
SELECTIVE - >11,000-fold selectivity over other HMTs
EXCELLENT DRUG-LIKE PROPERTIES - potential for oral administration
MOLECULE TARGETING SETD2 was discovered from Epizyme's large internal library of compounds and significant structure activity relationship analysis
SETD2 Inhibition Impaired Growth of a t(4;14) Multiple Myeloma Cell Line
t(4;14) MM cell line
CellCount(RLU)
SETD2 Inhibitor conc. (uM)
10000
0
2
4
6
8
10
Time (Days)
12
14
16
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
SETD2 Inhibitor Concentration
DMSO
5000nM
1000nM
200nM
40nM
8nM
1.6nM 0.32nM
H3K36me2 (1:1K)
Total H3 (1:20K)
H3K36me3 (1:1K)
Total H3 (1:20K)
H3K36 trimethylation was inhibited with SETD2 inhibitor while H3K36 dimethylation was unaffected
Thomenius et al ASH Annual Meeting 2018
78
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
Vehicle_BID 3500
MeanTumorVolume(mm3)
3000
2500
2000
1500
1000
500 500
00
Start of dosing 76% |
100% |
3000
2500
Mean Tumor Volume (mm3)
2000
15.625mpk_BID31.25mpk_BID62.5mpk_BID
29%
1500
46%
1000
85%
0
5
10
15
20
25
30
0
5
10
15
20
25
Days Post Treatment
Days Post Treatment
56
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 |
Enhanced Anti-Proliferative Activity With Combination of SETD2 Inhibitor and Tazemetostat in t(4;14) Myeloma Cell Line Compared to Single Agents
P values derived from one-way ANOVA with Tukey's Multiple Comparisons of treatment compared to each of the dual combinations.
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 |
Summary
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
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
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
EPIZYME OVER THE NEXT 5 YEARS
1 MAXIMIZE COMMERCIAL EFFECTIVENESS | TAZVERIK adopted as backbone therapy for FL TAZVERIK utilized in multiple combination regimens |
BUILD ON TAVZERIK'S PIPELINE-IN-A-DRUG POTENTIAL | TAZVERIK approved in additional heme and solid tumor indications Robust flow of data read-outs |
3 EXPAND PIPELINE & PORTFOLIO TO OVERCOME UNDRUGGABLE TARGETS | Five new clinical-stage programs Evolving oncology portfolio company |
COLLABORATE TO EXPAND PATIENT REACH & BUILD VALUE | TAZVERIK partnered to reach ex-US markets Multiple clinical and scientific collaborations |
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Disclaimer
Epizyme Inc. published this content on 03 March 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 03 March 2021 18:41:02 UTC.
