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Cowen and Company 35th Annual Healthcare Conference March 2015
Personalized Therapeutics � The Power of Epigenetics
2 MARCH 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 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 November 6, 2014. !
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2 MARCH 2015!
2013 Accomplishments !
• Pioneers and leaders in histone methyltransferase (HMT) inhibitors: first two HMT inhibitors in the clinic!– Novel targets: EZH2 and DOT1L!– Strong evidence of clinical activity, with demonstrated objective responses:!
• Non-Hodgkin lymphoma (NHL), including one ongoing complete response!• Malignant rhabdoid tumor (MRT), with one ongoing partial response!• MLL-r acute leukemia, including two complete responses!
– Targeting both large patient populations and orphan populations!• Larger populations: germinal center and non-germinal center NHL – both wild type
and mutant EZH2 DLBCL and FL!• Smaller populations: INI1-deficient tumors such as MRT and synovial sarcoma,
MLL-r acute leukemia!– Partnerships with Celgene, Eisai and GlaxoSmithKline!– Strong intellectual property estate: eight issued patents with composition of
matter patent protection through 2032; chemical matter against 13 of 20 prioritized targets within the methylome!
– Solid financial position: expected to end 2014 with more than $170 million in cash!
!!!!
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Epizyme Investment Highlights!
2 MARCH 2015!
2013 Accomplishments
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Increasing Interest in Epigenetic Targets in Oncology!
2 MARCH 2015!
2013 Accomplishments
• HMTs are part of a regulatory system that controls gene expression, called epigenetics!
• HMTs turn gene expression off and on 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, 13 with chemical matter !
!!!
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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!
2 MARCH 2015!
2013 Accomplishments
6!
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, with 15 years 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!
2 MARCH 2015!
2013 Accomplishments
7!
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
2 MARCH 2015!
2013 Accomplishments
8!
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
2 MARCH 2015!
2013 Accomplishments
9!
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: CARM1, SETB1, SMYD3, PRMT6!– Additional patent issuances expected in 2015!
2 MARCH 2015!
2013 Accomplishments
10!
• First EZH2 inhibitor to enter clinical trials • Potent and selective for wild type and mutant EZH2 • Demonstrated single agent activity in DLBCL, FL and INI1-deficient tumors
– Objective responses seen in heavily pretreated patients – relapsed or refractory to multiple therapies!
– Three of five DLBCL, one of four FL, one of two INI1-deficient!– Durable responses – complete response in PMBCL patient on treatment for more
than one year; ongoing partial responses in DLBCL, FL and MRT!– Active in EZH2 wild type patients, both germinal center and non-germinal center!– Generally well tolerated
• No treatment-related discontinuations!• Ongoing duration of treatment as long as one year!
• Continuing to explore a broad spectrum of cancer indications and treatment combinations pre-clinically
• Long patent runway: composition of matter patent protection through 2032!
EPZ-6438 (E7438) !First-in-Class, Oral, Selective Inhibitor of EZH2!
2 MARCH 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
11 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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2 MARCH 2015!
2013 Accomplishments Six of 10 Evaluable B-Cell Lymphoma Patients Continue on Therapy as of January 2015!
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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
12!
All previously reported ongoing responses continue as of January 9, 2015!Six additional patients enrolled at 800 mg, not reflected in table !
2 MARCH 2015!
2013 Accomplishments Objective Responses Seen in 4 of 10 B-Cell Lymphoma Patients!
13 13!
Perc
ent c
hang
e fr
om b
asel
ine
75
50
25
0
125
100
150
−50
−75
−100
−25
0
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!
2 MARCH 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
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• 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 9,
2015
14!
2 MARCH 2015!
2013 Accomplishments Ongoing Partial Response Seen in INI1-Deficient MRT Patient among Solid Tumor Population!
15 15!
• 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%),
ongoing – Still on study as of
January 9, 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
2 MARCH 2015!
2013 Accomplishments Acceptable Safety Profile!
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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 ! 0!Dose reduction! 0!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
16!
2 MARCH 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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2 MARCH 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!!!
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EPZ-5676 First-in-Class Small Molecule Inhibitor of DOT1L!
2 MARCH 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!!Ex
posu
re!
Dose!
90 mg/m2!
28-day CIV!!
2 MARCH 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 of
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!20!
2 MARCH 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!
21!
2 MARCH 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!
22
2 MARCH 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 other cancer indications are ongoing!
• Partnered with GSK!
23!
2 MARCH 2015!
2013 Accomplishments Pipeline: First-in-Class PRMT5 Inhibitor for MCL !
24!
Novel NCE!Unique Binding Mode!
Potent and Selective for PRMT5!
PD marker based on substrate methylation!
Robust tumor growth inhibition! With correlated PD!
2 MARCH 2015!
2013 Accomplishments
• 3 targets!• $54M to date!• Research funding!• $620M in potential
milestones!• WW royalties to low double
digits!
25!
• EZH2 only, Epizyme US option!
• $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!
2 MARCH 2015!
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
26
2 MARCH 2015!
2013 Accomplishments
27!
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 ongoing 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: CARM1, SETB1, SMYD3, PRMT6
• Patent publications and issuances expected in 2015
2 MARCH 2015!
2013 Accomplishments
www.epizyme.com!
