Personalized Therapeutics The Power of Epigenetics€¢ HMTs are part of regulatory system that...
-
Upload
truonghanh -
Category
Documents
-
view
214 -
download
0
Transcript of Personalized Therapeutics The Power of Epigenetics€¢ HMTs are part of regulatory system that...
4 JUNE 2014
2013 Accomplishments Forward Looking Statements
This presentation contains forward-looking statements that involve substantial risks and uncertainties. All
statements, other than statements of historical facts, contained in this presentation, including statements
regarding our strategy, future operations, prospects, plans and objectives of management, are forward-
looking statements. The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘estimate,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’
‘‘predict,’’ ‘‘project,’’ ‘‘target,’’ ‘‘potential,’’ ‘‘will,’’ ‘‘would,’’ ‘‘could,’’ ‘‘should,’’ ‘‘continue,’’ and similar
expressions are intended to identify forward-looking statements, although not all forward-looking
statements contain these identifying words. We may not actually achieve the plans, intentions or
expectations disclosed in our forward-looking statements, and you should not place undue reliance on our
forward-looking statements. Actual results may differ materially from those indicated by such forward-
looking statements as a result of various important factors, including: uncertainties inherent in the
initiation of future clinical studies, expectations of expanding ongoing clinical studies, availability and
timing of data from ongoing clinical studies, whether interim results from a clinical trial will be predictive of
the final results of the trial or results of early clinical studies will be indicative of the results of future
studies, expectations for regulatory approvals, development progress of the Company’s companion
diagnostics, availability of funding sufficient for the Company’s foreseeable and unforeseeable operating
expenses and capital expenditure requirements, other matters that could affect the financial performance
of the Company, other matters that could affect the availability or commercial potential of the Company’s
therapeutic candidates or companion diagnostics and other factors discussed in the "Risk Factors"
section of the Company’s Quarterly Report on Form 10-Q filed with the Securities and Exchange
Commission on May 14, 2014.
2
4 JUNE 2014
2013 Accomplishments
Biopharmaceutical company creating personalized therapeutics for patients
with genetically defined cancers n diagnostics
• First-in-class small molecule inhibitors targeting histone methyltransferases
(HMTs), a 96-member class of epigenetic enzymes that drive many cancers and other
diseases
• Clinical programs for genetically defined cancers
– EPZ-5676 DOT1L inhibitor (demonstrated objective responses in adult Phase 1 dose escalation)
– EPZ-6438 EZH2 inhibitor (Phase 1/2 ongoing)
• Product platform generating pipeline of novel personalized therapeutic programs
• Intellectual property with earliest composition of matter expected expirations in 2032
• Rx collaborations with Celgene, Eisai, and GSK
• CDx collaborations with Abbott and Roche
3
Company Overview
4 JUNE 2014
2013 Accomplishments
4
Oncogenic
HMT
Misregulated gene
expression
Disease
• HMTs are part of regulatory system that controls gene expression, called epigenetics
• HMTs regulate gene expression by placing methyl marks on histones
• Genetic alterations can alter HMT activity making them oncogenic due to misregulated
gene expression
• 96-member target class, 20 prioritized based on oncogenic mechanism
HMTome Target Class
4 JUNE 2014
2013 Accomplishments
5
Clinical Development
<200 nM
<50 nM
<600 nM
GSK3
EPZ-5676 DOT1L
EPZ-6438 EZH2
GSK Target 1
Preclinical Development
Pipeline of First-In-Class Personalized Therapeutics
• Acute leukemias
• NHL and INI1-deficient tumors
GSK Target 2
GSK Target 3
Development candidate milestone 2013
Lead candidate milestone in 2014
Lead candidate milestone in 2014
Solid tumor programs • Novel HMT targets in
Epizyme’s product platform Hematological malignancy programs
4 JUNE 2014
2013 Accomplishments
HMT Indication Annual
Incidence 2014
Objectives Partner
DOT1L
1. MLL-r adult • 3,600 patients
• Phase 1 dose escalation and MLL-r expansion stage POC data*
• Epizyme 100% US rights
• Celgene
2. MLL-r peds • 1,300 patients
• Phase 1b POC initiated
3. MLL-PTD • 2,300 patients
• Phase 1 POC expansion stage enrollment
EZH2
4. Non-Hodgkin lymphoma
• 12,100 patients
• Phase 1 dose escalation data*
• Phase 2 POC initiation**
• Epizyme 50% US rights
• Eisai
5. Synovial sarcoma/INI-1
• 1,700 patients
• Phase 2 POC initiation**
6
*Data disclosure in 2H14
**Gated to Phase 1 dose escalation data
2014 Clinical Milestones – 5 Planned POC Programs
4 JUNE 2014
2013 Accomplishments
Methylation
Demethylation
Change of function mutation • Non-Hodgkin lymphoma
PRC2 COMPLEX
K27(me)3 K27
Loss of function due to INI1 deficiency • Synovial sarcoma, MRT, others
SWI/SNF COMPLEX
INI1
At least 3 distinct genetically defined cancers, growing list • Non-Hodgkin lymphoma, germinal center (EZH2 point mutations)
• Synovial sarcoma (SSX-SS18 fusion)
• MRT (INI1-deletion)
7
EZH2 Inhibition for Genetically Defined Cancers
4 JUNE 2014
2013 Accomplishments
8
• Potent against intended target in WT and mutant
form – 2.5 nM biochemical assay
• Highly selective vs. HMTs and other targets
– Biochemical – >20,000-fold by Ki
– Cellular – only inhibits target associated methyl mark
• Orally bioavailable
• Target methyl mark inhibition that leads to specific
killing of genetically defined cancer cells in vitro
• Combinations with glucocorticoid receptor agonists or
signaling pathway modulators extends activity to all
germinal center derived NHL cells
• Profound and sustained in vivo efficacy in animal
models following inhibition of target methyl mark
H3K27Me3
EPZ-6438 (mM)
0 1
H3K27Me2
H3K27Me1
H3K4Me3
H3K79Me2
H3K9Me3
H3K36Me2
H3K27Ac
H3
EZH2 Products
EPZ-6438 – EZH2 Inhibitor Clinical Candidate
4 JUNE 2014
2013 Accomplishments
9
H3K27me3
H3
Methylation IC50 = 0.008 µM Methylation IC50 = 0.0091 µM
µM
E7438
µM E7438
Day Day
EZH2 Non-Mutant Cells EZH2 Mutant Cells
Target methyl mark inhibition leads to specific killing of
genetically defined cancer cells as function of dose and time
EPZ-6438 – Selective Killing of EZH2-Mutant Cells
Knutson et al., Nature Chemical Biology (2012)
4 JUNE 2014
2013 Accomplishments
10
EPZ-6438 in Nude Mouse Xenograft
(28-day BID)
Potent and durable therapeutic effect of targeting
oncogenes in pre-clinical studies
• Durable in vivo efficacy in animal
models
• Dose-, exposure- and time-
dependent effects
• Sustained tumor regressions seen
at well-tolerated dose
EPZ-6438 – Pre-Clinical NHL Tumor Regressions
Keilhack et al., Blood (2012)
4 JUNE 2014
2013 Accomplishments
Knutson et al. (unpublished data)
• Synovial sarcoma is a soft tissue sarcoma, affecting primarily adolescents and young adults, and
represents 7-10% of soft tissue malignancies
• Clinical course characterized by frequent and late local or metastatic recurrence; no specific or
effective treatments after failure of ifosfamide-based therapy1
• Characterized by t(X;18) (SSX-SS18), which inactivates SWI/SNF via displacement and degradation of
INI12
• EPZ-6438 selectively kills mutant SSX-SS18 cells in vitro
SSX-SS18 fusion positive SSX-SS18 fusion negative
11
2 Kadoch, Cell (2013)
1 Rosen, Cancer (1994)
EPZ-6438 – Synovial Sarcoma
4 JUNE 2014
2013 Accomplishments
12
Selective Killing of Mutant MRT Cells
in vitro
Complete and Sustained Regression of Mutant
MRT Xenografts
• MRT is a deadly childhood cancer caused by a gene alteration that misregulates EZH2 activity
• Typical presentation in kidney or brain in children less than 2 years of age with event-free survival
rates less than 20%
• Current therapy is intensive chemotherapy and radiation with significant treatment-related morbidity
• EPZ-6438 selectively kills mutant MRT cells in vitro
EPZ-6438 – Malignant Rhabdoid Tumor (MRT)
Knutson, et al., PNAS (2013)
4 JUNE 2014
2013 Accomplishments
• Phase 1 dose escalation ongoing – advanced solid tumors and B-cell
lymphomas
– Initiated in June 2013
– Expected 2014 completion and 2H14 data disclosure
• Phase 2 POC programs planned for 2014 – gated to data from dose
escalation
– EZH2-mutated Germinal Center NHL
• In design of current Phase 1/2 study
• Relapsed/refractory EZH2-mutant GC DLBCL and Grade 3 FL
• Multinational site participation
– Synovial Sarcoma
• Initiation in parallel with NHL Phase 2
13
EPZ-6438 – Clinical Development Plan
4 JUNE 2014
2013 Accomplishments
Transcriptional
Changes
Site-Specific
Hyper-Methylation
Phenotypic
Changes Disease
Aberrant DOT1L
Recruitment by MLL-
Fusion
Chromosomal Translocation
Creates MLL-Fusion Protein
14
DOT1L – MLL-r Oncogenic Mechanism
4 JUNE 2014
2013 Accomplishments
MLL-r MLL-PTD
Genetic Alteration • Reciprocal chromosomal translocations involving 11q23
• Partial tandem duplication of MLL gene
Disease • 5-10% AML and ALL • In adults and pediatrics • 4,900 annual incidence in major
markets
• 5-8% of AML in adults • 2,300 annual incidence in major
markets
Diagnostic Test • Cytogenetics, FISH • Standard test in all patients
diagnosed with acute leukemia • Abbott partnership
• PCR • Research test in selected patients
Prognostic Implications • Poor DFS and OS compared with non-MLL-r leukemias
• Associated with short initial remission duration with poor response to subsequent therapy1
15
Graphs: Byrd J C et al., Blood 2002; Pui et al., N Engl J Med 2004
Overall survival by cytogenetic risk groups in adult AML Patients
Event free survival by genetic abnormality in pediatric ALL patients
1 Doehner K et al., J Clin Oncol 2002
EPZ-5676 – Acute Leukemias with MLL Alterations
4 JUNE 2014
2013 Accomplishments
16
Target methyl mark inhibition leads to specific killing of
genetically defined cancer cells as function of dose and time
EPZ-5676 – Selective Killing of MLL-r Cells
Time (Days)
To
tal C
ells
0 2 4 6 8 10 12 14105
106
107
108
109
101 0
Jurkat +
Jurkat -
H3K79me2
Total H3
H3K79me2
Total H3
Non-MLL-Rearranged Cells MLL-Rearranged Cells
Untreated & Treated
Increasing dose Increasing dose
D a y s
0 2 4 6 8 1 0 1 2 1 4
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
5 0 .0
1 2 .5
3 .1 2 5
0 .7 8 1
0 .1 9 5
0 .0 4 8
0 .0 1 2
0 .0 0 3
V e h ic le
E P Z -5 6 7 6 mM
Via
ble
C
ell
s/m
L
Time (Days)
Daigle et al., Blood (2013) and unpublished data
4 JUNE 2014
2013 Accomplishments
17
• Durable in vivo efficacy in animal
models
• Dose-, exposure- and time-
dependent effects
• Sustained tumor regressions seen
at well-tolerated doses
Nude Rat MLL-r Xenograft Model
Durable therapeutic effect of targeting DOT1L in
pre-clinical studies is dose- and time-dependent
EPZ-5676 – Pre-Clinical Tumor Regressions
Daigle et al., Blood (2013)
4 JUNE 2014
2013 Accomplishments
H3K79me2
Total H3
Increasing dose
18
Inhibition of H3K79
methylation
T im e ( D a y s )
mR
NA
Pe
rc
en
t C
on
tro
l
0 2 4 6 8
0
2 5
5 0
7 5
1 0 0
1 2 5
H O X A 9
M E I S 1
Reduction in MLL-r target
genes
EPZ-5676
CD14 upregulation
Vehicle
An
ne
xin
+,
AA
D -
Ve
hi c
l e
0. 0
5
0. 1
60
. 51
. 54
. 5
0
1 0
2 0
3 0
4 0
5 0
Differentiation
Apoptosis (Annexin staining)
Morphologic evidence
of maturation
Both differentiation and apoptosis are observed in
MLL-r pre-clinical models
Increasing dose EPZ-5676
EPZ-5676
EPZ-5676 – Pre-Clinical Mechanism of Action
Daigle et al., Blood (2013) and unpublished data
4 JUNE 2014
2013 Accomplishments
19
Dose Escalation Expansion
• Patients with advanced hematologic
malignancies (including MLL-r
patients)
• MLL-r patients (also permits MLL-
PTD)
• Outcome measures − Safety and tolerability
− PK (dose and exposure)
− PD (methyl mark inhibition)
Enrollment completed 2013 Currently enrolling
• Up to 12 sites (US + Europe)
• Outcome measures − Safety and tolerability
− Assessment of efficacy in MLL-r
and MLL-PTD patients
• 21-day on/7-day off administration
with dose escalation - Uninterrupted administration as
IRB-approved exception
• Uninterrupted administration with
possible dose escalation
EPZ-5676 – Phase 1 Adult Program
• 6 sites
4 JUNE 2014
2013 Accomplishments
• Dose escalation stage (advanced hematologic malignancies, including MLL-r)
– 21 day on/ 7 day off schedule evaluated, doses of 12 mg/m2/day-80 mg/m2/day
– Heavily pre-treated population
– No DLTs, drug-related treatment discontinuations, or dose-toxicity relationship
– Dose-proportional exposure
– Dose- and time-dependent methyl mark reduction
– Objective responses observed in 2 cohort 4 (54 mg/m2/day) patients (switched to
uninterrupted administration)
– Cohort 5 enrolled 80 mg/m2/day
• Expansion cohort stage (restricted to MLL-r and MLL-PTD patients)
– Initiated December 2013, currently enrolling
– Starting dose 90 mg/m2/day, uninterrupted continuous IV infusion
– Dose escalation permitted
20
Favorable safety profile and anti-leukemic activity
EPZ-5676 – Phase 1 Adult Status as of December 2013
4 JUNE 2014
2013 Accomplishments
21
Dose Escalation Expansion
• Pediatric patients between 3
months and 18 years of age with
MLL-r leukemia (AML/ALL)
• MLL-r patients at recommended
Phase 2 dose
Initiated in May 2014
• Outcome measures − Further assessment of safety and
tolerability − Continued preliminary assessment of
efficacy
• CIV infusion for 28 days of a 28-day
cycle
• Uninterrupted administration with
possible dose escalation
EPZ-5676 – Phase 1 Pediatric Program
• Outcome measures − Safety and tolerability
− Preliminary assessment of
efficacy
4 JUNE 2014
2013 Accomplishments
• Composition of matter claims for therapeutic candidates – EPZ-5676 issued 2013, expected to expire in 2032
– EPZ-6438 issued 2013, expires in 2032 • In 2014, complementary claims were issued covering the diagnosis of patients with EZH2 mutations and
their subsequent treatment with an EZH2 inhibitor, with expected expiration date in 2031
• Broad IP position covering platform and therapeutic candidates – Composition of matter all created in-house
– Methods of use including treatment, combination therapy and biomarkers
– Formulations, polymorphs and methods of manufacture
– Research and screening methods
22
Intellectual Property
4 JUNE 2014
2013 Accomplishments
• 3 targets
• $48M to date
• Research funding
• $620M in potential
milestones
• WW royalties
23
• EZH2 only, Epizyme US
option
• $35M to date
• Eisai funds 100% through
POC
• Epizyme option for US profit
share and co-
commercialization
• $195M in additional
milestones
• Ex-US royalties
Platform Expansion
January 2011 50% US Rights
April 2011
• Epizyme retains all DOT1L US
rights
• $117M to date (includes equity)
• Ex-US option for other
programs for 3 years
• Global co-development and
funding
• $135M remaining DOT1L
milestones
• $160M in potential milestones
for each non-DOT1L target
selected
• Ex-US royalties to mid teens
ex-US Rights
April 2012
$178 million non-equity funding with significant retained US rights
Collaborations as Business Drivers
4 JUNE 2014
2013 Accomplishments
• Ongoing Phase 1 clinical study expansion stage of EPZ-5676 in MLL-r adult patients
and MLL-PTD adult patients - planned clinical data disclosure of the dose escalation and
expansion stage results at a medical conference in the second half of 2014
• Initiated Phase 1b clinical study of EPZ-5676 in MLL-r pediatric patients in May 2014
• Ongoing Phase 1 dose escalation study of EPZ-6438 in patients with advanced solid
tumors or B cell lymphoma - planned clinical data disclosure of dose escalation stage in
the second half of 2014
• Planned Phase 2 POC clinical study of EPZ-6438 in non-Hodgkin lymphoma patients
with EZH2 point mutations, pending Phase 1 results
• Planned Phase 2 POC clinical study of EPZ-6438 in INI1-deficient tumors, such as
synovial sarcoma, pending Phase 1 results
24
2014 Clinical Studies and Data Disclosures
4 JUNE 2014
2013 Accomplishments
• Advanced EPZ-5676 DOT1L inhibitor program
– $25 million proof of concept milestone with Celgene
– Initiated Phase 1 study expansion stage for adult MLL-r and MLL-PTD patients
– Initiated Phase 1b study in pediatric MLL-r patients
• Initiated ongoing EPZ-6438 EZH2 inhibitor Phase 1 dose escalation study
– $6 million study initiation milestone with Eisai
• Achieved three pre-clinical milestones with GlaxoSmithKline
– $4 million development candidate milestone for 1st target in December 2013
– $2 million lead candidate milestone for 2nd target in February 2014
– $4 million lead candidate milestone and license payment for 3rd target in March-April 2014
• Advanced intellectual property position with U.S. patents issued, including
composition claims for EPZ-5676 and EPZ-6438 expected to expire in 2032 and Rx and
Dx claims expected to expire in 2031
• EOY 2014 more than $170 million cash guidance
– Cash runway through at least mid-2016 prior to any additional milestones
25
Accomplishments in 2013 and 2014 to Date