personalized therapeutics the power of epigenetics€¢ hmts are part of regulatory system that...

Company Overview

June 2014

Personalized Therapeutics The Power of Epigenetics

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.

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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

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Company Overview

4 JUNE 2014


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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


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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


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**

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*Data disclosure in 2H14

**Gated to Phase 1 dose escalation data

2014 Clinical Milestones – 5 Planned POC Programs

4 JUNE 2014


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)

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EZH2 Inhibition for Genetically Defined Cancers

4 JUNE 2014


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• 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


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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


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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


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

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2 Kadoch, Cell (2013)

1 Rosen, Cancer (1994)

EPZ-6438 – Synovial Sarcoma

4 JUNE 2014


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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


• 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

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EPZ-6438 – Clinical Development Plan

4 JUNE 2014


Transcriptional

Changes

Site-Specific

Hyper-Methylation

Phenotypic

Changes Disease

Aberrant DOT1L

Recruitment by MLL-

Fusion

Chromosomal Translocation

Creates MLL-Fusion Protein

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DOT1L – MLL-r Oncogenic Mechanism

4 JUNE 2014


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

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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


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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


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• 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


H3K79me2

Total H3

Increasing dose

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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


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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)


− 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


• 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


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


− Preliminary assessment of

efficacy

4 JUNE 2014


• 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

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Intellectual Property

4 JUNE 2014


• 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


• 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

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2014 Clinical Studies and Data Disclosures

4 JUNE 2014


• 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

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Accomplishments in 2013 and 2014 to Date

4 JUNE 2014


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