morgan stanley global healthcare conference
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Morgan Stanley Global Healthcare Conference!September 17, 2015!
!
17 SEPTEMBER 2015!
2013 Accomplishments!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: uncertainties inherent in the initiation of future clinical studies or expansion of ongoing clinical studies; availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial such as the results referred to in this presentation will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products; 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 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 Form 10-Q filed with the SEC on August 6, 2015, and in our 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. 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. These forward-looking statements should not be relied upon as representing the Company's views as of any date subsequent to the date hereof. !
2!
17 SEPTEMBER 2015!
2013 Accomplishments!
3!
Epizyme Highlights!Leadership in
HMT Inhibition
First-in-class Inhibitors
Advancing Tazemetostat
Advancing Our Pipeline
IP
Financial Position
Pioneers and leaders in HMT field; pipeline of novel HMT inhibitors!
Two first-in-class HMT inhibitors already in the clinic!
Demonstrated PRs and CRs in DLBCL, FL and INI1-negative tumors; !Registration-supporting Phase II trials underway!
Proprietary efforts and partnerships with leading pharmaceutical companies to advance multiple new targets: Celgene, Eisai, GSK!
Novel compositions of matter through at least 2032!
Ended 2Q15 with $237 million in cash and equivalents: runway through at least the end of 2Q17!
17 SEPTEMBER 2015!
2013 Accomplishments!
4!
Seasoned Management Team with Deep Industry Expertise!
• Chief Operating Officer of Synageva through its acquisition in July 2015!
• President of Janssen Biotech, an immunology and oncology business with over $7 billion in revenues!
• B.S. from University of Georgia!
• 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!
Rob Bazemore, President and CEO!
17 SEPTEMBER 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!
5!
Pioneers and Leaders in HMT Inhibitors!
Lysine Methyl Transferases (KMTs)!
PRDM14: Breast!
WHSC1: Multiple Myeloma!
WHSC1L1: Lung, Breast!
NSD1: AML!
SUV39H1:!Colon!
SETDB1:!Melanoma!
EHMT1/2: Lung,
Prostate, HCC!
MLL4: Pancreatic, Glioblastoma!
MLL: Leukemia!
SMYD2: Esophageal Squamous!
SMYD3: Breast, Liver, Colon,
Gastric!
EZH2: NHL, INI1, !Breast, Prostate, Colon, Gastric, Bladder, Liver,
Melanoma!
Arginine Methyl Transferases (RMTs)!
CARM1: Breast,!Prostate!
PRMT1: AML, Glioblastoma!
PRMT5:!Lymphoma! DOT1L: MLL-r!
AML, ALL!
NSUN2:!Breast!
PRMT7:!Breast!
Source: Richon et al. 2011 Chem. Biol. Drug Desi;,Copeland 2011 Drug Discov. Today Ther. Strat., Copeland 2013 Clinical Cancer Research!
EZH1 SETD7! PRMT8!
PRMT3!PRMT6!
• Published Epizyme proprietary inhibitors
• HMT with literature association with cancer
• HMTs can become oncogenic drivers due to misregulated gene expression!
• 96-member target class!
17 SEPTEMBER 2015!
2013 Accomplishments!Pipeline of First-In-Class Epigenetic Therapeutics: Tazemetostat!
Phase 1 Dose Escalation and Dose Expansion:!NHL and Advanced Solid Tumors!
Tazemetostat (EPZ-6438)!
Clinical Pharmacology: Food Effect!
Phase 2 NHL: 5-Arm Study in Relapsed/Refractory NHL!
Clinical Pharmacology: Drug-Drug Interaction!
Phase 2: Adult INI1-Deficient Tumors!
Phase 1: Pediatric INI1-Deficient Tumors!
2015 Initiation Planned!
n=38 fully enrolled!
n=12 initiated September 2015!
n=13 fully enrolled!
n=150 initiated June 2015!
6!
Phase 1! Phase 2!Preclinical Development!
Initiated!
n=30!n=30!n=30!n=30!n=30!
1.!Germinal Center DLBCL!
Wild type EZH2!
2.! Mutant EZH2!
3.!Follicular Lymphoma!
Wild type EZH2!
4.! Mutant EZH2!
5! Non-Germinal Center DLBCL!n=up to 90; planned!4Q 2015 !
n=approx. 30; planned 4Q 2015!
A 5-arm, registration-supporting phase 2 trial of tazemetostat now enrolling patients
17 SEPTEMBER 2015!
2013 Accomplishments!
7!
Pipeline of First-In-Class Epigenetic Therapeutics: Pinometostat & Additional Targets!
Pinometostat (EPZ-5676)!
Phase 1 Dose Escalation and Dose Expansion: Pediatric Acute Leukemias!
GSK Targets!
PRMT5 (and two undisclosed targets)!
Three Undisclosed Targets!
Novel HMT Targets!Solid Tumors and Hematologic Malignancies!
Dose escalation: Under enrollment!
Phase 1! Phase 2!Preclinical Development!
7!
Celgene Targets!
Epizyme is a leader in HMT chemical biology, generating robust matter against 8 novel targets and continuing work on proprietary pipeline against chromatin remodeling targets.
Preclinical Development!
Initiated!
17 SEPTEMBER 2015!
2013 Accomplishments!Multiple Genetic & Pharmacological Factors May Sensitize B-Cell Lymphomas to EZH2 Inhibitors!
8!
Concurrent Treatment with Corticosteroids!
Concurrent Treatment with
BCL2 & 6!Inhibitors!
Concurrent Treatment with !
B-Cell!Signaling Inhibitors!
EZH2!ê!
H3K27me3!
MLL!LoF Muts!
HAT!LoF Muts!
KDM6A!LoF Muts!
EZH2!Hot Spot Muts!
PRC2 Subunit Amp/!Overexpression!
Wild- Type!EZH2!
Wild-Type!EZH2!
Wild- Type &!Mutant!EZH2!
17 SEPTEMBER 2015!
2013 Accomplishments!Tazemetostat (EPZ-6438):Potent and Highly Selective EZH2 Inhibitor!
Source: Knutson 2013, Knutson 2014 9!
Novel Structure, Potent Target Inhibition
EPZ-6438: Ki <2.5 nM Selectivity >20,000-fold (100-fold for EZH1) Rodent oral bioavailability: 15-55%
Selective for EZH2
PKMTs
PRMTs
In Vivo Efficacy with Oral Dosing
0 34
114 324
1140
mg/kg QD
17 SEPTEMBER 2015!
2013 Accomplishments!
• EPZ-6438: oral dosing from 100 mg to 1600 mg BID!• Population: relapsed or refractory B-cell lymphoma or solid tumors!• Study design: 3+3 dose-escalation!
– Expansion cohorts at 800 mg (n=6 planned) and 1600 mg (n=6 planned)!– Food effect sub-study at 400 mg (n=12 planned)!
• Primary endpoint: determination of RP2D/MTD!• Secondary endpoints: safety, PK, PD and tumor response (every 8 wks)!• Data cut-off: 8-Jun-2015!
Dose
(mg BID)!Patients
(n=45)!
Solid tumors
(n=26)!B-cell NHL (n=19)!
100* 6 5 1
200 3 1 2
400 3 2 1
800 14 6 8
1600 12 8 4
Food Effect 7 4 3
First-in-human Phase 1 Trial E7438-G000-001 (NCT01897571)
* 2 formulations
10!
17 SEPTEMBER 2015!
2013 Accomplishments!Patient Tumor Types!
Relapsed or refractory NHL n=19 *
Diffuse large B-cell lymphoma (DLBCL)
GCB 4
non-GCB 6
undetermined 3
Follicular lymphoma (FL) 5
Marginal zone lymphoma (MZL) 1
Relapsed or refractory solid tumor n=26
INI1-deficient tumor 10
GI malignancy 7
GU malignancy 5
Sarcoma 3
CNS tumor 1
* 14 NHL patients tested to date: 13 WT + 1 mutant by cobas® EZH2 Mutation Test (in development, Roche Molecular Systems, Inc.)
11!
17 SEPTEMBER 2015!
2013 Accomplishments!NHL Patient Demographics!
Characteristic Patients (n=19) n (%)
Median age, years (range) 61 (24 - 84)
Sex (M / F) 14 (74) / 5 (26)
# of prior therapeutic regimens
1 2 (10)
2 1 (5)
3 7 (37)
4 2 (10)
>5 7 (37)
Refractory to last prior regimen 7 (37)
Prior autologous hematopoietic cell transplant 5 (26)
12!
17 SEPTEMBER 2015!
2013 Accomplishments!Pharmacokinetics!
• Rapid absorption (tmax = 1-2 h) with a mean terminal t1/2 = 3 - 5 h • Dose-proportional Cmax and AUC0-12h at steady-state (day 15) through 1600 mg BID • Decrease in systemic exposure between day 1 and day 15 with no further reduction
afterwards ‒ 42% decrease in AUC0-12h on day 15 vs. day 1 at 800 mg BID ‒ Ctrough levels reach steady-state by day 15
D a y 1 1
2 h
D a y 15 0
h
D a y 15 1
2 h
D a y 29 0
h0
1 0 0
2 0 0
3 0 0
4 0 0
T ro u g h p la s m a c o n c . a t R P 2 D 8 0 0 m g B ID
EP
Z-6
43
8 p
las
ma
co
nc
. (n
g/m
L)
0 3 6 9 1 21
1 0
1 0 0
1 0 0 0
1 0 0 0 0
D a y 1 5
T im e (h )
EP
Z-6
43
8 p
las
ma
co
nc
. (n
g/m
L)
1 0 0 m g (s u s p ) , n = 31 0 0 m g ( ta b ) , n = 32 0 0 m g , n = 34 0 0 m g , n = 38 0 0 m g , n = 1 31 6 0 0 m g , n = 1 1
13!
17 SEPTEMBER 2015!
2013 Accomplishments!
Basale
PK-PD: EZH2 Inhibition in Surrogate Tissue H3K27Me3
Evidence of target inhibition in skin: • Reduction of H3K27-Me3 IHC signal
observed at week 4 at all doses • Exposure-dependent reductions in H3K27-
Me3 IHC signal • Differential effects by epithelial layer
‒ Minimal changes to stratum basale ‒ Pronounced changes in stratum spinosum ‒ Full epithelium represents composite signal
of stratum spinosum and basale
Screening Stratum Spinosum
Stratum Basale
Stratum Spinosum
Stratum Basale
Week 4
Full Epithelium
Full Epithelium
1 0 0 1 0 0 0 1 0 0 0 00 . 4
0 . 6
0 . 8
1 . 0
1 0 0 1 0 0 0 1 0 0 0 00 . 6
0 . 8
1 . 0
1 . 2
1 . 4
1 0 0 1 0 0 0 1 0 0 0 00 . 4
0 . 6
0 . 8
1 . 0
Full Epithelium
Frac
tio
nal
ch
ang
e fr
om
bas
elin
e o
f %
H3
K2
7M
e3 p
osi
tive
cel
ls
Spinosum
100 mg
200 mg
400 mg
800 mg
1600 mg
Day 15 AUC0-last (h*ng/mL) 14!
17 SEPTEMBER 2015!
2013 Accomplishments!Adverse Events!n = 45!
All Events! Treatment-Related!All Grades *! Grade >3! All Grades! Grade >3 ‡
Any patient with AE 42 13 29 5
Asthenia 23 1 10 0
Anorexia 11 2 4 1
Anemia 9 1 4 0
Dyspnea 9 0 0 0
Nausea 8 0 6 0
Constipation 7 0 2 0
Vomiting 6 0 3 0
Thrombocytopenia 6 2 4 1
Dyspepsia 5 0 5 0
Muscle spasm 5 0 2 0
Hypertension 4 1 2 1
Neutropenia 2 1 2 1
Transaminase ↑ 2 1 1 1
Patients with:
DLT (thrombocytopenia) = 1
Dose reduction = 1
Drug discontinuation = 1
Dose interruption = 7
* >10% of patients ‡ all patients
15!
17 SEPTEMBER 2015!
2013 Accomplishments!Overall Best Response: NHL 9/15 Evaluable Patients Have CR+PR!
months 0 6 12 18
Evaluable Patients (n=15)
DLBCL (n=9)
FL (n=5)
MZL (n=1)
CR+PR * 5 3 1
SD 0 1 0
* Cheson criteria / International Working Group
Remains on-study GCB non-GCB
G N
16!
17 SEPTEMBER 2015!
2013 Accomplishments!Target Lesion Activity: NHL!Evolution of Response!
weeks
DLBCL FL MZL
% c
han
ge
fro
m b
asel
ine
months * truncated
*
17!
17 SEPTEMBER 2015!
2013 Accomplishments!CR in Primary Mediastinal B-Cell Lymphoma!
Baseline
Week 40: CR
23 y.o. male 200 mg BID
PD PR Week 16: PR 2014 2013
PD 2015
EPZ-6438: ongoing response week 78
PD Week 40: CR
18!
17 SEPTEMBER 2015!
2013 Accomplishments!CR in Follicular Lymphoma (EZH2wt)!Baseline
78 y.o. male 800 mg BID
Week 60: CR
EPZ-6438: ongoing response week 60
2015 2002 2008 2006 2012 2014 PD PD PR CR Week 16:
PR Week 8:
SD Week 32:
CR CR PD PD
19!
17 SEPTEMBER 2015!
2013 Accomplishments!Response in DLBCL (EZH2Y646H)!
PD PR PR Week 16: PR 2014 2011 2010
SD 2012 2013
PD SD SD 2015 PD
EPZ-6438: ongoing response week 24
53 y.o. female 800 mg BID
Baseline Week 16: PR
Mutant by cobas® EZH2 Mutation Test (in development). Confirmed Y646H by NGS.
20!
17 SEPTEMBER 2015!
2013 Accomplishments!SWI/SNF & PRC2 Effect Chromatin Remodeling in Opposing Manners!
21!
PRC2
SWI/SNF
AEBP2&
SUZ12&RbAp48&
SAM&
SAH&
EZH2&&&&&
EED&
ARID1A/B INI1
SMARCA2/4
ATP ADP
PRC2
SWI/SNF
AEBP2&
SUZ12&RbAp48&
SAM&
SAH&
EZH2&&&&&
EED&
ATP
X
(A) Normal Cells: Balance between PRC2 & SWI/SNF Remodeling of Chromatin
(B) INI1-Deficient Tumors: INI1 Loss Abrogates SWI/SNF Activity. Cells now addicted to PRC2
ARID1A/B
SMARCA2/4
X
INI1 X
17 SEPTEMBER 2015!
2013 Accomplishments!CR in INI1-Negative Malignant Rhabdoid Tumor!
Baseline Week 4
55 y.o. male 800 mg BID
Baseline Week 8
6.7 mm: CR
Week 20 Week 8 Baseline
PD
Surgery + XRT
CR Week 8: CR 2014 2015
Diagnosis
2013
EPZ-6438: ongoing response week 58
22!
17 SEPTEMBER 2015!
2013 Accomplishments!Study Conclusions!
• EPZ-6438 has an acceptable safety profile!
• 800 mg BID dose confirmed as Recommended Phase 2 Dose!– Supported by PK, PK/PD in surrogate tissue, safety, efficacy!
• Impressive efficacy, with 9 of 15 patients NHL patients demonstrating CR or PR!– PR first observed as early as 2 months and as late 10 months !– Evolution of objective response (SD → PR, PR → CR) seen in 7 patients!– Relapsed DLBCL (both GCB and non-GCB) and FL!– Responses in patients with EZH2 wild-type and mutant tumors!
• Phase 2 study for DLBCL (GCB and non-GCB) and FL now enrolling!– Five parallel cohorts based on Cell of Origin and EZH2 mutation status!– First patient enrolled on 10-June-2015; First patient dosed 9-July-2015!– Continuing to add countries and study sites!
23!
17 SEPTEMBER 2015!
2013 Accomplishments!Phase 2 NHL Study Initiated; Phase 1 and 2 INI-Negative / Synovial Sarcoma Studies Planned!
24! *Incidence figures for major markets!
Phase 2 Study of EPZ-6438 in Relapsed/Refractory (R/R) B-Cell Non-Hodgkin
Lymphoma!n=150; 800 mg BID!
Initiated: 2Q15 in Europe, Australia!Incidence: 155,000 patients*
R/R Germinal Center DLBCL! Wild-Type EZH2!
n=30!Incidence: 24,000* !
R/R Germinal Center DLBCL!Mutant EZH2!
n=30!Incidence: 6,000*!
R/R Follicular Lymphoma! Wild-Type EZH2 !
n=30!Incidence: 30,000* !
R/R Follicular Lymphoma !Mutant EZH2 !
n=30!Incidence: 6,000*!
R/R Non-Germinal Center !DLBCL !n=30!
Incidence: 89,000*!
!Phase 2 Study of EPZ-6438 in Adult INI1-Negative Tumors and Synovial
Sarcoma!Expected initiation: 4Q15!
Incidence: 1,700*
!Phase 1 Study of EPZ-6438 in Pediatric
INI1-Negative Tumors and Synovial Sarcoma!
Expected initiation: 4Q15 !Incidence: 700*!
17 SEPTEMBER 2015!
2013 Accomplishments!
• Strong synergy with:!
– Corticosteroids!– Inhibitors of
kinases along B-cell signaling pathway!
25!
Strong Synergy Between Tazemetostat and Multiple Nodes of B-Cell Signal Transduction!
17 SEPTEMBER 2015!
2013 Accomplishments!
26!
Tazemetostat Combination Studies!
• R-CHOP is standard of care front line therapy for DLBCL !– R-CHOP components are rituximab, cyclophosphamide, doxorubicin, vincristine and
prednisone!• Plan to initiate additional trials:!
– R-CHOP combination!
– Combination with a B-cell signaling agent or other emerging targeted therapy!
!
Source: Knutson et al (2014) PLOS One!
17 SEPTEMBER 2015!
2013 Accomplishments!
• Mechanism of Action:!– DOT1L inhibition (and target H3K79 methyl mark reduction) results in
anti-leukemic effects in cancers with MLL genetic alterations!– No effects in cancers without MLL alterations!
• Target indications: MLL-r AML and ALL!– MLL-r primary indication – genetically defined subset of AML and ALL,
adult and pediatric!– Orphan drug designation granted in US and EU!
• 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!!!
27!
Pinometostat (EPZ-5676)First-in-Class Small Molecule Inhibitor of DOT1L!
17 SEPTEMBER 2015!
2013 Accomplishments!
Inhibitors for >13 targets
Epizyme: A Rich Portfolio of HMT Inhibitors
96 HMTs identified
Genetic ablation techniques Chemical biology
Understanding the pathobiological roles of HMTs in cancer
Impact of small molecule HMT inhibitors
Proprietary collection of small molecule HMT inhibitors
HMT enzymology and structural biology
Pipeline of novel HMT inhibitors
28!
17 SEPTEMBER 2015!
2013 Accomplishments!Pipeline: First-in-Class PRMT5 Inhibitor for MCL !
29!
Novel NCE!Unique Binding Mode!
Potent and Selective for PRMT5!
PD marker based on substrate methylation!
Robust tumor growth inhibition! With correlated PD!
Penebre et al. Nature Chemical Biology, 2015!
17 SEPTEMBER 2015!
2013 Accomplishments!
30!
• $131 million to date, including equity!• Worldwide option on two HMT targets and
ex-US option on one HMT target !• Up to $610 million in total potential
milestone payments! $75 million developed-based license payments! $365 million regulatory-based milestone
payments! $170 million sales-based milestone payments! Royalty to low double-digits!
• Global partnership on pinometostat (EPZ-5676)! Epizyme retains all US rights and funds Phase
1 studies! Celgene retains ex-US rights and pays royalties
to mid-teens! $35 million remaining in potential clinical
milestone payments! $100 million remaining in potential regulatory
milestone payments!
Significant Strategic Partnering!
• Epizyme has global development and commercialization rights ex-Japan!
• Epizyme made $40 million upfront payment to Eisai!
• Epizyme pays up to $20 million in clinical milestones and up to $50 million in regulatory milestones!
• Epizyme pays a mid-teens royalty for sales ex-Japan!
• Eisai pays a mid-teens royalty for sales in Japan!
• Partnership completed; $53 million to date!
• Epizyme delivered compounds against three targets, including first-in-class PRMT5 inhibitor!
• GSK has global development and commercialization rights!
• $620 million in remaining potential milestone payments for all three targets! $18 million in potential
preclinical milestone payments! $109 million in potential clinical
milestone payments! $275 in potential regulatory
milestone payments! $218 in potential sales-based
milestone payments!• WW royalties up to low double
digits!!
17 SEPTEMBER 2015!
2013 Accomplishments!Epizyme Financial Overview!
• Ended 2Q2015 with $237 million in cash and cash equivalents!
– No debt!
– Expected runway through at least the end of second quarter 2017!
• Shares outstanding as of June 30, 2015: 41.2 million!
• Fully diluted shares outstanding as of June 30, 2015: 44.5 million!
!
31!
17 SEPTEMBER 2015!
2013 Accomplishments!Multiple Catalysts Throughout 2015!ü Completed accrual of 14 patients in tazemetostat phase 1 dose expansion cohorts!
ü Presented updated dose escalation data and initial dose expansion data June 20 at ICML !– Present dose expansion data in INI1-negative solid tumors and synovial sarcoma at ESMO on
September 26, 2015!– Present additional phase 1 data in NHL before the end of 2015!
ü Initiated tazemetostat phase 2 five-arm NHL studies!ü Prospective stratification of EZH2 mutant and wild type patients, germinal and non-germinal center,
DLBCL and FL!– Initial data expected mid-2016!
• Initiate INI1-negative and synovial sarcoma phase 2 adult study and phase 1 pediatric study in 4Q 2015!– Interim read-outs from the phase 2 cohorts expected by year end 2016!
ü Conducting clinical pharmacology studies of tazemetostat!ü Completed enrollment in food effect study!ü Initiating drug-drug interaction study in September 2015!
ü Presented discovery research on HMT targets at AACR annual meeting: CARM1, SETDB1, SMYD3, PRMT6!
• Additional presentations at NCI-EORTC-AACR in November!• Complete enrollment in pinometostat phase 1 pediatric study expected in 1H 2016!
– Present data in 2H 2016!
32!
17 SEPTEMBER 2015!
2013 Accomplishments!
www.epizyme.com!
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