ezh2 inhibitor epz-6438 (e7438) in non-hodgkin lymphoma ... · ezh2 inhibitor epz-6438 (e7438) in...
TRANSCRIPT
EZH2 Inhibitor EPZ-6438 (E7438) in Non-Hodgkin Lymphoma: Pre-Clinical Models and Early Clinical
Observations!!!!
Robert A. Copeland*, Heike Keilhack, Antoine Italiano, Sarah K. Knutson, Akira Yokoi, Satoshi Kawano, Yukinori Minoshima, Kuan-Chun Huang, Natalie M. Warholic, L. Danielle Johnston, Christine R. Klaus, Tim J. Wigle, Dorothy Iwanowicz, Bruce A. Littlefield, Margaret Porter-Scott, Jesse J. Smith, Roy M. Pollock, Kevin W. Kuntz, Alejandra Raimondi, Eric E. Hedrick, Scott Barrett, Lone H. Ottesen, Vincent Ribrag !!
!12 August 2014!
12 AUGUST 2014!
2013 Accomplishments!
Disclosure Information ASH Lymphoma Biology Meeting
12 August 2014 Robert A. Copeland, Ph.D.
!
2!
I have the following financial relationships to disclose:!!• Grant/Research support from: LLS, MMRF, GSK, Eisai & Celgene!• Stockholder in and Employee of: Epizyme, Inc.!• Scientific Advisory Board Member of: Mersana!• Ad hoc Consultant for: New Enterprise Associates!!and !
• I will not discuss off-label use in my presentation!
Disclosures!
12 AUGUST 2014!
2013 Accomplishments!Key Topics!
Pre-Clinical Data!• Mutant EZH2 plays a key role in germinal center (GC) B-cell NHL!• Emerging biology suggests additional roles of wild type (WT) EZH2 in GC NHL!• EZH2 inhibitor single agent activity in pre-clinical models of mutant and WT
EZH2 NHL1,2!
• EPZ-6438 synergy in combination with CHOP components in pre-clinical models of mutant and WT EZH2 NHL3!
!Clinical Data!• EPZ-6438 (E7438) Phase 1 design!• Safety, PK and PD among first three cohorts!• Early anti-lymphoma observations in NHL patients to date (cohorts 1-3)!!
3!
1. Knutson et al. 2014 MTC!2. Beguelin et al. 2013 Cancer Cell !3. Johnston et al. 2013 Blood (ASH abstract) submitted for publication!
12 AUGUST 2014!
2013 Accomplishments!EZH2 Catalyzed Chromatin Remodeling!
• EZH2 is the catalytic subunit of the multiprotein PRC2 (polycomb repressive complex 2) complex!
• PRC2 is the only PMT in humans that can methylate H3K27!• H3K27 is the only significant substrate for PRC2!• PRC2 catalyzes mono-, di- and tri-methylation of H3K27!• H3K27me3 is a transcriptionally repressive histone mark!• Hyper-trimethylation of H3K27 is tumorigenic in a broad spectrum of
human cancers, including GC NHL!
4!
H3K27! H3K27me! H3K27me2! H3K27me3!PRC2! PRC2! PRC2!
Gene Transcription!
Chase A, Cross NC, (2011) Clin Cancer Res!
12 AUGUST 2014!
2013 Accomplishments!
Nature Reviews | Cancer
Naive B cellGCB cell
Mantle zone
Marginal zone
Germinal centre
Splenic marginal-zone lymphoma
B-CLL (unmutated V gene)
DLBCL (ABC-type)Primary mediastinalB-cell lymphoma
Hairy-cell leukaemiaProlymphocytic leukaemia
B-CLL
MALT lymphoma
Multiple myeloma
Lymphoplasmacytic lymphomaPrimary effusion lymphoma
Mantle-cell lymphomaB-CLL (unmutated V-region genes)
Classical Hodgkin's lymphoma
Post-transplantlymphomas
Follicular lymphomaBurkitt's lymphomaDLBCL (GC-type)Lymphocyte-predominantHodgkin's lymphoma
Plasma cell
Plasmablast
Memory B cell
Gene Regulation in B-Cell Maturation and Lymphoma!
5!
Kuppers 2005 Nat Rev Cancer!*Source: Clarion Report (2014), incorporating SEER and GLOBOCAN epidemiology, and recent literature from ASH, NCI, NIH, and academic investigators!!
↓↓EZH2!↓↓Bcl6!
↓↓EZH2!↓↓Bcl6!
EZH2!Bcl6!
Follicular lymphoma!Burkitt’s lymphoma!DLBCL (GC-type)!Nodular lymphocyte predominant Hodgkin lymphoma !
EZH2!Bcl6!Bcl2!
Incidence: 72,000*!Prevalence: 185,000*!
12 AUGUST 2014!
2013 Accomplishments!Gene Regulation in B-Cell Maturation and Lymphoma!
6! Nature Reviews | Cancer
Naive B cellGCB cell
Mantle zone
Marginal zone
Germinal centre
Splenic marginal-zone lymphoma
B-CLL (unmutated V gene)
DLBCL (ABC-type)Primary mediastinalB-cell lymphoma
Hairy-cell leukaemiaProlymphocytic leukaemia
B-CLL
MALT lymphoma
Multiple myeloma
Lymphoplasmacytic lymphomaPrimary effusion lymphoma
Mantle-cell lymphomaB-CLL (unmutated V-region genes)
Classical Hodgkin's lymphoma
Post-transplantlymphomas
Follicular lymphomaBurkitt's lymphomaDLBCL (GC-type)Lymphocyte-predominantHodgkin's lymphoma
Plasma cell
Plasmablast
Memory B cell
↓↓EZH2!↓↓Bcl6!
↓↓EZH2!↓↓Bcl6!
EZH2!Bcl6!
Follicular lymphoma!Burkitt’s lymphoma!DLBCL (GC-type)!Nodular lymphocyte predominant Hodgkin lymphoma !
EZH2!Bcl6!Bcl2!
Incidence: 72,000*!Prevalence: 185,000*!
Genetic Alterations Affecting H3K27me3!!
• Point mutations of EZH2!!• Overexpression of EZH2!!• Overexpression of other PRC2 subunits!!• LoF of HATs!!• LoF of MLL2!
!
Kuppers 2005 Nat Rev Cancer!*Source: Clarion Report (2014), incorporating SEER and GLOBOCAN epidemiology, and recent literature from ASH, NCI, NIH, and academic investigators!!
12 AUGUST 2014!
2013 Accomplishments!
7!
Pre-Clinical Characterization of the Clinical Candidate EPZ-6438: Robust Single-Agent Activity !
EPZ-6438 !Ki = < 2.5 nM!
Selectivity > 20,000-fold!Rodent Oral Bioavailability: 15-55%!
!!
Knutson et al. 2014 MCT!
Novel Structure, Potent Target Inhibition! Selective for EZH2!
0
200
400
600
800
1000
1200
1400
1600
0 5 10 15 20 25 30
Tum
or V
olum
e (m
m3 )
Day
Vehicle
80.5 mg/kg
161 mg/kg
322 mg/kg
*
**
Vehicle, N/A!
BLLQ!211 ng/mL!
781 ng/mL!
Ctrough (before last dose)!
Correlative PK/PD!KARPAS422 Tumor!
Potent Tumor Growth Inhibition!KARPAS422 (Y646N)!
PKMTs!
PRMTs!
12 AUGUST 2014!
2013 Accomplishments!EPZ-6438 Synergy with CHOP Components: Driven by GR Agonists and Extends to GC DLBCL with WT EZH2!
8!
* Data only available for combinations with GR agonists!
Johnston, Knutson et al. 2013 Blood (ASH Annual Meeting Abstracts) and submitted for publication!
Cell Lines!
!WSU-DLCL2 !(mutant EZH2
GC)!
SU-DHL-10 !(mutant EZH2
GC)!
SU-DHL-6!(mutant
EZH2 GC)!
DOHH2 !(WT EZH2
GC)!
SU-DHL-5!(WT EZH2
GC)*!
OCI-LY-19!(WT EZH2
GC)*!
Toledo !(WT EZH2
ABC)!
C Mafosfamide! Additive! Additive! Additive! No effect! --! --! No effect!
H Doxorubicin! Synergy! Additive! Additive! No effect! --! --! No effect!
O Vincristine! Additive! Additive! Additive! No effect! --! --! No effect!
P Prednisolone! Synergy! Synergy! Synergy! Synergy! Synergy! Synergy! No effect!
Dexamethasone! Synergy! Synergy! Synergy! Synergy! Synergy! Synergy! No effect!
! Synergy also seen with B-cell signaling pathway agents and BCL2 antagonists in mutant and WT cell lines!
!
12 AUGUST 2014!
2013 Accomplishments!
9!
Johnston, Knutson et al. 2013 Blood (ASH Annual Meeting Abstracts) Submitted for publication!
Synergy: Increased Potency!WSU-DLCL2 (EZH2 Y646F)!
Synergy: Extended Activity !to WT EZH2 GC DLBCL!
EPZ-6438 Synergy with CHOP Components: Driven by GR Agonists and Extends to GC DLBCL with WT EZH2!
EPZ-
6438
IC50
(nM
), D
ay 7 !
12 AUGUST 2014!
2013 Accomplishments!EPZ-6438 (E7438) – Phase 1 Dose Escalation Study!
10!
1600 mg!enrolling!
Ongoing Phase 1 Study (clinicaltrials.gov: NCT01897571)!• Primary Objectives: Define MTD or RP2D!• Secondary Objectives: PK/PD, safety!• Advanced solid tumors & hematologic malignancies!• Modified Fibonacci dosing scheme!
• Dose-proportional PK!• 12 evaluable patients!• 4 of these NHL*!
800 mg!enrolling!
200 mg!3 pts!
100 mg!6 pts**!
400 mg!3 pts!Ex
posu
re!
3 cohorts completed!
*Includes full cell-of-origin and EZH2 sequencing information!** First dosing cohort included three patients on liquid formulation and three patients on tablet formulation being used in study currently!! !
Dose (BID)!
12 AUGUST 2014!
2013 Accomplishments!EPZ-6438 (E7438) – Phase 1 Dose Escalation Study!
11!
• MTD not reached; no DLTs or AE-related treatment discontinuations!• PD evidence of target inhibition in skin (IHC)!• Single agent anti-lymphoma activity seen among NHL patients!
!!Dose!
(mg BID)!!
Disease!EZH2 Mutant
Status!Best
Response to Date!
Weeks on Treatment!
100! Transformed DLBCL (GC)! WT! PR! 23!
200! DLBCL, non-GC! WT! PD! 6!
200! PMBCL! WT! PR! 34+!
400! Follicular (GC)! Y646S! SD! 17!
Baseline (Day 1)!
Day 29!
Skin H3K27me3 IHC!
Cell of origin determination by central IHC (Hans) !Mutation status determination by NGS!
12 AUGUST 2014!
2013 Accomplishments!Patient Case 1, Cohort 1, 100mg: 66% Reduction in Lesion Size, CT!
12!
• 58-year-old male with transformed DLBCL, ECOG 0!
• WT EZH2!• Clinical history:!
– FL diagnosed in 2006!– 6 prior lines of therapy, including
CHOP (complete response), rituximab/carboplatin, DHAP, BEAM/ ASCT (complete response), investigational Ab, oxaliplatin/gemcitabine (progressive disease)!
• Treatment: EPZ-6438 (E7438) 100mg PO BID, single agent!– PD H3K27 trimethylation in skin
biopsy: 21% reduction from baseline!
• Best Response: PR!
03 June!2013!
BASELINE!!
01 August !2013 !
12 AUGUST 2014!
2013 Accomplishments!Patient Case 2, Cohort 2, 200 mg: 73% Reduction in Lesion Size, CT!
13!
• 23-year-old male with primary mediastinal B-cell lymphoma (clinical presentation), ECOG 0!
• Cell-of-origin (IHC): non-GC!• WT EZH2!• Clinical history: !
– Diagnosed Feb 2013!– 4 prior lines of therapy, including R-
ACVBP, R-DHAP, R-ICE, primary progression through last 3 regimens!
• Treatment: EPZ-6438 (E7438) 200mg PO BID, single agent !– PD H3K27 trimethylation in skin
biopsy: 39% reduction from baseline!
• Best Response: PR!
23 May !2014!
27 November !2013 !
BASELINE!
12 AUGUST 2014!
2013 Accomplishments!Patient Case 2, Cohort 2, 200 mg: Reduction in FDG Uptake!
27 November 2013 BASELINE!
23 May 2014!
14!
12 AUGUST 2014!
2013 Accomplishments!EPZ-6438 (E7438): Summary and Future Plans!
• Summary: Pre-Clinical Data!– Demonstrated utility of single agent EPZ-6438 in mutant-bearing GC NHL!– In combination with steroids, potency increased and activity broadened to all GC
NHL independent of EZH2 mutant status!!• Summary: Clinical Data for Cohorts 1-3 (100mg-400mg)!
– MTD not reached; no DLTs or AE-related treatment discontinuations!– Dose-proportional PK!– PD evidence of target inhibition in skin (IHC)!– Single-agent anti-lymphoma activity seen among NHL patients!
• Future Plans!- More complete Phase 1 dose escalation data from all five dosing cohorts to be
presented at a medical conference later in 2014!- Initiate Phase 2 studies in GC DLBCL, PMBCL and FL, mutant and WT EZH2 as
single agent (late 2014) and in combination with steroids !- Initiate Phase 2 study in INI1-deficient tumors in late 2014!
15!
12 AUGUST 2014!
2013 Accomplishments!EPZ-6438 (E7438): Acknowledgements !!
!
We would like to thank the principal investigators and their institutions, the employees of Epizyme and Eisai, and most importantly, the patients participating in the Phase 1 study!
16!