Leerink Global Healthcare Conference February 2015 2013 - - PowerPoint PPT Presentation

Leerink Global Healthcare Conference

February 2015

Personalized Therapeutics Ÿ Ÿ The Power of Epigenetics

12 FEBRUARY 2015

• 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

• ur 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

• f 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 November 6, 2014.

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12 FEBRUARY 2015

• 2013 Accomplishments
• Clinically validated targets

– Clinically demonstrated objective

responses in non-Hodgkin lymphoma (NHL), malignant rhabdoid tumor (MRT), and MLL-r leukemia with the first two HMT inhibitors ever to enter clinical trials (EPZ-6438 and EPZ-5676)

– Complete responses in Phase 1

studies with EZH2i and DOT1Li

• Robust Intellectual Property

– Chemical matter against 13 of 20

prioritized targets within the methylome

– Eight issued patents with first expiries

in 2032

• Strong financial position

– Funded until at least mid-2016, prior to

including any potential future milestone payments

• 3
• Pioneers and Leaders in the Field of Histone

Methyltransferase (HMT) Inhibitors

Clinically advancing proprietary HMT inhibitor candidates from an efficient research operation with deep scientific, clinical and managerial expertise

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• 2013 Accomplishments

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• Seasoned Management Team with Deep Industry

Expertise

• 20 years at Merck in

positions of increasing leadership, including VP of Licensing and External Research

• Former Director of Novel

Therapeutics at the Broad Institute of MIT and Harvard

• B.A. from Spring Arbor

College, Ph.D. from University of Iowa

Robert Gould, Ph.D. President and CEO

• Former Vice President,

Cancer Biology at GSK

• Held scientific positions of

increasing leadership at Merck and BMS

• Held faculty position at

University of Chicago Pritzker School of Medicine

• B.S. from Seton Hall

University, Ph.D. from Princeton University

• Former Vice President of

Oncology Development at J&J

• Former Senior Vice

President of Oncology at GSK

• Former fellow at Dana-

Farber, NCI and FDA

• B.A. from Johns Hopkins,

M.D. and Ph.D. from Yale University School of Medicine

• Nearly 20 years of financial

experience in life sciences field

• Former Managing Director,

Healthcare Investment Banking in Life Sciences Group at RBC Capital Markets

• B.A. from Yale University,

M.B.A. from Harvard Business School

Robert Copeland, Ph.D. President of Research and CSO Andrew Singer Chief Financial Officer Peter Ho, M.D., Ph.D. Chief Development Officer

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• 2013 Accomplishments

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Clinical Development Pre-clinical Development

Pipeline of First-In-Class Personalized Therapeutics

ü Development candidate milestone in 2013 ü Lead candidate milestone in 2014 ü Lead candidate milestone in 2014

<200 nM <50 nM

PRMT5 (GSK Target 1) EPZ-5676 DOT1L Acute Leukemias EPZ-6438 EZH2 NHL and INI1- Deficient Tumors ü Phase 1 dose escalation ongoing with MLL-r expansion stage ü Phase 1 peds study ongoing ü Phase 1 dose expansion ongoing q Initiation of three studies planned 2015 (2 Phase 2; 1 Phase 1) GSK Target 2 GSK Target 3 Novel HMT Targets Solid Tumors Novel HMT Targets Hematologic Malignancies q Pipeline update 1H15

12 FEBRUARY 2015

• 2013 Accomplishments

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• 2014: Clinical Validation of HMT Targets, Pipeline

Progress

Clinical Progress

ü Demonstrated durable objective responses in Phase 1 study of EPZ-6438 (EZH2i) in NHL and solid tumor patients

• PR or better in 3 of 5 DLBCL patients, including 1 ongoing CR at more than 41 weeks

ü Demonstrated clinical and biological activity in Phase 1 study of EPZ-5676 (DOT1Li) in adult MLL-r patients

• Two complete responses (CR) and one partial response (PR) achieved in Phase 1 dose

escalation study ü Initiated expansion cohorts in multiple programs

• Six additional patients enrolled at 800 mg in EPZ-6438 Phase 1 study dose escalation

expansion cohort, currently enrolling up to six patients at 1600 mg in expansion cohort ü Initiated EPZ-5676 Phase 1 study in pediatric MLL-r patients

Pipeline Milestones

ü Demonstrated in vivo and in vitro activity of first-in-class PRMT5 inhibitor in models of mantle cell lymphoma in pre-clinical study data presented at ASH – 1st target in GSK collaboration ü $2 million lead candidate milestone for 2nd target in GSK collaboration; $4 million lead candidate milestone and license payment for 3rd target in GSK collaboration ü Patent notice of allowance granted for PRMT5 inhibitor; patent applications published on novel chemical matter against multiple HMT targets, including CARM1, PRMT3, PRMT6, PRMT8

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• 2013 Accomplishments

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• 2015: Focus On Execution
• EPZ-6438

– Complete accrual of up to 12 patients in Phase 1 dose escalation

expansion cohorts (1Q15)

– Initiate Phase 2 studies in partnership with Eisai - NHL study with

prospective stratification of mutant and wild type EZH2 patients

• EPZ-5676

– Complete accrual of up to 20 patients at 54 mg/m2/day (2H15) – Complete enrollment in Phase 1 pediatric study (2H15)

• Progress Pipeline

– Present discovery research on HMT targets at AACR annual

meeting (abstracts submitted)

– Additional patent issuances expected in 2015

12 FEBRUARY 2015

• 2013 Accomplishments

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• Potent and selective for mutant and wild type

EZH2

• Durable objective responses demonstrated in

Phase 1 study: –

PR or better in 4 of 10 evaluable NHL patients to date

• PR or better in 3 of 5 DLBCL patients, including 1
• ngoing CR at more than 41 weeks

–

Ongoing PR in 1 of 2 INI1-deficient patients

• Unmet need in NHL:

–

Poor prognosis for patients who fail R-CHOP

–

Need for active drugs that avoid long-term myelosuppression and immunosuppression

• Continuing to explore a broad spectrum of

cancer indications

• H3K27Me3

EPZ-6438 (µM) 1 H3K27Me2 H3K27Me1 H3K4Me3 H3K79Me2 H3K9Me3 H3K36Me2 H3K27Ac H3

EZH2 Products

EPZ-6438 (E7438) First-in-Class, Oral, Selective Inhibitor of EZH2

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12 FEBRUARY 2015

• 2013 Accomplishments

Study design: Open-label, multicenter

• Single agent, oral BID dosing,

28-day cycles

• Histologic/cytologically confirmed

advanced solid tumors or B-cell lymphomas

• “3+3” dose-escalation design

Study initiation: June 2013 Data cut-off: October 20, 2014

100 mg (n = 6) 200 mg (n = 3) 400 mg (n = 3) 800 mg (n = 6) 1600 mg (n = 6)

Primary Endpoint

• MTD/RP2D

Secondary Endpoints

• Safety
• PK
• Anti-tumor activity

Safety assessments:

• Baseline, D1 and D15 of every cycle

Tumor assessments:

• Baseline and every 8 weeks

PK samples:

• Cycle 1, D1 and D15; Cycle 2 D1

Skin biopsies:

• Baseline and Cycle 2 D1

9 ¡

BID, twice daily; D, day; MTD, maximum tolerated dose; PK, pharmacokinetics; RP2D, recommended Phase 2 dose

EPZ-6438 First-in-Human Phase 1 Study

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12 FEBRUARY 2015

• 2013 Accomplishments

Six of 10 Evaluable B-Cell Lymphoma Patients Continue on Therapy as of January 2015

10 ¡

1Transformed lymphoma by history and presentation 2Primary mediastinal B-cell lymphoma by history/presentation

Type Cell-of-origin Dose (mg BID) Best Response Ongoing Treatment DLBCL GCB1 100 PR Non-GCB2 200 CR X Non-GCB 200 PD Non-GCB 800 PR X Non-GCB 800 PD FL GCB 800 PR X GCB 400 SD GCB 800 SD X GCB 1600 SD X MZL Non-GCB 1600 SD X

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

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All previously reported ongoing responses continue as of January 2015 Six additional patients enrolled at 800 mg, not reflected in table

12 FEBRUARY 2015

• 2013 Accomplishments

Objective Responses Seen in 4 of 10 B-Cell Lymphoma Patients

11 ¡

11

Percent change from baseline

75 50 25 125 100 150 −50 −75 −100 −25

Time (week)

8 16 24 32 40 Lymphoma DLBCL (GCB) DLBCL (non-GCB) FL MZL

PR

• PR
• PR
• CR
• CR, complete response; PR, partial response;

SD, stable disease; PD, progressive disease

Data Presented in November 2014 at EORTC-NCI-AACR Data cut-off: October 20, 2014

12 FEBRUARY 2015

• 2013 Accomplishments

11/09/2014 FDG-PET: Complete Response 27/11/2013 Baseline 35 x 27 mm 31/01/2014 Partial Response 27 x 16 mm

Ongoing Complete Response in Primary Mediastinal B-Cell Lymphoma (Non-GCB) Patient

12 ¡

• Male, 23 years
• ECOG 0
• EZH2WT
• Clinical history
• Diagnosed Feb 2013
• Refractory to initial and salvage

therapy:

• R-ACVBP + methotrexate
• R-DHAP
• R-ICE
• Treatment: 200 mg PO BID
• Best response
• Complete response ongoing
• 27% H3K27me3 reduction

from baseline (skin biopsy)

• Still on study as of January

2015

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12 FEBRUARY 2015

• 2013 Accomplishments

Ongoing Partial Response Seen in INI1-Deficient MRT Patient among Solid Tumor Population

13 ¡

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• Male, 55 years
• ECOG 0
• INI1 loss (gene sequencing

& IHC)

• Clinical history

– MRT of cerebellum in 2013 – Definitive surgery and adjuvant radiotherapy – Recurrence in the cervical nodes

• Treatment: 800 mg PO

BID

• Best response

– Partial response (-53%),

• ngoing

– Still on study as of January 2015

21/05/2014 15.2 mm Baseline 17/07/2014 6.7 mm Partial Response 11/09/2014 5.5 mm Partial Response 9/05/2014 25/06/2014

12 FEBRUARY 2015

• 2013 Accomplishments

Acceptable Safety Profile

14 ¡

Parameter Overall (N=24), n (%) AEs 22 (92) Treatment-related 16 (67) Grade ≥3 AEs 5 (21) Treatment-related 1 (4) Serious AEs 4 (17) Treatment-related 1 (4) AEs leading to Drug withdrawal Dose reduction Dose interruption 3 (13) Median no. of cycles received 3

• 1 DLT occurred at

1600 mg BID

– Grade 4 thrombocytopenia with concurrent sepsis

AEs, adverse events; BID, twice daily; DLT, dose-limiting toxicity; MTD, maximum tolerated dose

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12 FEBRUARY 2015

• 2013 Accomplishments

EPZ-6438 2015 Planned Activities

• Enrolling up to 12 additional patients in Phase 1 dose

escalation expansion cohorts

– Complete accrual expected in 1Q15 – Updated data expected 2H15

• Molecular characterization of patient samples ongoing
• Design of Phase 2 studies being refined in partnership with

Eisai

– NHL study to prospectively stratify mutant and wild type EZH2 patients – Companion diagnostic for EZH2 mutations available for Phase 2 enrollment – INI1-deficient studies in adults and pediatric patients

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12 FEBRUARY 2015

• 2013 Accomplishments
• Therapeutic mechanism of DOT1L inhibition and target methyl mark reduction

demonstrates anti-leukemic effects in cancers with MLL genetic alterations; no effects in cancers without MLL alterations

• Target indications: Orphan drug designation granted in US and EU

– MLL-r primary indication – genetically defined subset of AML and ALL, adult and pediatric, including MLL-PTD subset

• Unmet need:

–

MLL-r: Five-year OS rate in adult MLL-r AML ranges from 5 to 34 percent, no approved therapies specifically indicated for MLL-r

–

MLL-PTD: Short durations of remission with current therapies, with poor response to subsequent therapy

• Two complete responses (CR) and one partial response (PR) achieved in

Phase 1 dose escalation study –

Dose escalation stage – enrollment completed in 2013, allowed but did not require MLL-r patients

–

90 mg/m2/day MLL-r expansion stage – completed in 2014

• Phase 1 MLL-r pediatric patient trial initiated in May 2014

–

Enrolling patients between the ages of 3 months and 18 years to evaluate safety, PK, PD, with preliminary assessment of efficacy

–

PK modeling from study presented at ASH Annual Meeting 2014

• 16

EPZ-5676 
 First-in-Class Small Molecule Inhibitor of DOT1L

12 FEBRUARY 2015

• 2013 Accomplishments

EPZ-5676 
 Phase 1 Dose Escalation and Expansion Study

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• Primary Objectives: Define MTD or RP2D
• Secondary Objectives: PK/PD, safety, activity
• Advanced hematologic malignancies in dose escalation; MLL-r only in expansion
• Extensively pre-treated: median number of prior systemic therapies: 2 (Range: 1 to 6)
• Data cut-off: October 6, 2014

80 mg/m2

• 21-day CIV
• Dose-proportional PK
• 42 pts evaluable for safety

and activity

54 mg/m2

• 21-day CIV
• 24 mg/m2
• 21-day CIV
• 12 mg/m2
• 21-day CIV
• 36 mg/m2
• 21-day CIV
• Exposure
• Dose
• 90 mg/m2
• 28-day CIV

12 FEBRUARY 2015

• 2013 Accomplishments
• 9 patients (8/34 MLL-r) had:

– Marrow response and/or – Resolution of leukemia cutis and/or – Leukocytosis or differentiation

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Clinical and Biological Activity Observed in 9 Patients

Dose mg/m2/day Number

• f

patients (n=42) Marrow Response (n=3) Leukemia cutis resolved (n=2) Leukocytosis or Differentiation (n=8) 12 1

• 24

5

• 1

36 4

• 1

2 54 6 2 CR 1 1 80 3

• 2

90

(28 day CIV)

23 1 PR

• 2

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12 FEBRUARY 2015

• 2013 Accomplishments

Acceptable Safety Profile

• Treatment-related adverse events (all grades): 16 patients

(38%)

– 10 patients < grade 2

• Majority gastrointestinal

– 4 patients with grade 3

• Leukocytosis (n=3)
• Anemia (n=1)
• Dose-limiting toxicities

– 90 mg/m2/d dose escalation cohort (n=6)

• None

– 90 mg/m2/d expansion cohort (n=17)

• Grade 4 reversible cardiac failure with concurrent sepsis
• Grade 4 reversible hypophosphatemia during rapid WBC drop

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12 FEBRUARY 2015

• 2013 Accomplishments

EPZ-5676 2015 Planned Activities

• Enrolling < 20 MLL-r adult patients at 54 mg/m2/day

– Complete accrual expected 2H15

• Complete molecular characterization of patient samples

from expansion cohort to identify patient selection and response biomarkers

• Complete enrollment in Phase 1 pediatric study expected

2H15

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12 FEBRUARY 2015

• 2013 Accomplishments

Pipeline: PRMT5 Inhibitor Shows In Vitro and In Vivo Activity in MCL Models

• EPZ015666 is a first-in-class potent, selective and orally

bioavailable inhibitor of PRMT5; tool compound – Demonstrated potent cellular activity as measured by its ability to block symmetric dimethylation and inhibit proliferation of MCL cell lines – Displayed robust anti-tumor activity as a single agent in MCL xenograft animal models

• Pre-clinical studies of the effects of PRMT5 inhibition in
• ther cancer indications are ongoing
• Partnered with GSK

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12 FEBRUARY 2015

• 2013 Accomplishments

Pipeline: First-in-Class PRMT5 Inhibitor for MCL

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Novel NCE Unique Binding Mode Potent and Selective for PRMT5 PD marker based on substrate methylation

• Robust tumor growth

inhibition

• With correlated PD

12 FEBRUARY 2015

• 2013 Accomplishments
• 3 targets
• $54M to date
• Research funding
• $620M in potential

milestones

• WW royalties to low double

digits

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• EZH2 only, Epizyme US
• ption
• $38M to date
• Eisai funds 100% through

POC/Epizyme opt-in

• Epizyme option for US profit

share and co- commercialization

• $195M in additional

milestones

• Ex-US royalties in mid single

digits

Platform Expansion

• January 2011
• 50% US Rights
• April 2011
• Epizyme retains all US rights
• $119M to date (includes equity)
• Ex-US option for other

programs for 3 years

• Global co-development and

funding

• $135M remaining DOT1L

milestones

• $165M in potential milestones

for each non-DOT1L target selected

• Ex-US royalties to mid teens

100% US Rights

• April 2012
• $189 million non-equity funding with significant retained US rights
• Collaborations as Business Drivers

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• 2013 Accomplishments

Fully Funded Through Mid-2016

• Cash runway until at least mid-2016 prior to any additional

milestones

• End of 2014 cash guidance: more than $170 million
• Shares outstanding as of September 30, 2014: 34.1 million
• Fully diluted shares outstanding as of September 30, 2014:

37.6 million

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12 FEBRUARY 2015

• 2013 Accomplishments

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• Clinical Validation, Pipeline Progress in 2014;

Focus on Execution in 2015

Clinical Progress ü Demonstrated durable objective responses in Phase 1 study of EPZ-6438 (EZH2i) in NHL and solid tumor patients –

PR or better in 3 of 5 DLBCL patients, including 1

• ngoing CR at 41 weeks

ü Demonstrated clinical and biological activity in Phase 1 study of EPZ-5676 (DOT1Li) in adult MLL-r patients –

Two complete responses (CR) and one partial response (PR) achieved in Phase 1 dose escalation study

ü Initiated expansion cohorts in multiple programs –

Six additional patients enrolled at 800 mg in EPZ-6438 Phase 1 expansion cohort

ü Initiated EPZ-5676 Phase 1 study in pediatric MLL-r patients Pipeline Milestones ü $2 million lead candidate milestone for 2nd target in GSK collaboration; $4 million lead candidate milestone and license payment for 3rd target in GSK collaboration ü Demonstrated in vivo and in vitro activity of first-in- class PRMT5 inhibitor in models of mantle cell lymphoma in pre-clinical study – 1st target in GSK collaboration

2014 2015

Execute on Clinical Plans

• Complete accrual of up to 12 patients in EPZ-6438

Phase 1 dose escalation expansion cohorts in expected in 1Q15

– Present updated data 2H15

• Initiate EPZ-6438 Phase 2 studies in partnership with

Eisai

– NHL study with prospective stratification of EZH2 mutant and wild type patients

• Complete accrual of up to 20 patients in EPZ-5676 54

mg/m2/day expansion cohort in 2H15

– Present data in 2016

• Complete enrollment in EPZ-5676 Phase 1 pediatric

study expected in 2H15

– Present updated data in 2016

Progress Pipeline

• Present discovery research on HMT targets at AACR

annual meeting (abstracts submitted)

• Patent publications and issuances expected in 2015

12 FEBRUARY 2015

• 2013 Accomplishments

www.epizyme.com