EPZ-5676 DOT1L Inhibitor Program Phase 1 Dose Escalation Top-Line - - PowerPoint PPT Presentation
EPZ-5676 DOT1L Inhibitor Program Phase 1 Dose Escalation Top-Line - - PowerPoint PPT Presentation
Personalized Therapeutics The Power of Epigenetics EPZ-5676 DOT1L Inhibitor Program Phase 1 Dose Escalation Top-Line Data 14 November 2013 Forward Looking Statements The outcome of preclinical testing and early clinical
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Forward Looking Statements
The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial such as the results of our Phase 1 clinical trial of EPZ-5676 described in this presentation do not necessarily predict final results. The treatment effects
- bserved in our Phase 1 clinical trial of EPZ-5676 were achieved by only a small number of patients in an
- pen-label setting, were not statistically significant, might not represent any clinical benefit and might
not be achieved by any other patient treated with EPZ-5676. 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 the uncertainties inherent in the initiation of future clinical trials, expectations of expanding ongoing clinical trials, availability and timing of data from ongoing clinical trials, expectations for regulatory approvals, development progress
- f 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 10-Q filed with the Securities and Exchange Commission on October 23, 2013.
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14 NOVEMBER 2013
Agenda
- EPZ-5676 Program Overview and Phase 1 Dose Escalation Summary
- Phase 1 Dose Escalation Top-Line Data and Program Plans
- Pre-clinical Highlights
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EPZ-5676 – Program Overview
- First-in-class small molecule inhibitor of DOT1L, a histone methyltransferase that is a driving
- ncogene in acute leukemias with genetic alterations of MLL
- Therapeutic mechanism of action
– In cancers with MLL genetic alterations, sustained DOT1L inhibition expected to lead to terminal effects including blast differentiation and leukemia cell apoptosis – Pre-clinical data shows durable anti-leukemic effects and tumor regressions with well-tolerated DOT1L inhibition in MLL-r models with no anti-leukemic effects expected or observed in cancer cells without MLL genetic alterations
- Target indications
– MLL-r primary indication – genetically defined subset of AML and ALL, adult and pediatric – MLL-PTD expansion indication – genetically defined subset of adult AML
- Two-stage Phase 1 study ongoing
–
Dose escalation stage nearing completion – includes but does not require MLL-r patients
–
MLL-r only expansion cohort stage initiating December 2013
- Epizyme has 100% US development and commercialization rights
– Partnered with Celgene ex-US – Ongoing joint global clinical development
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EPZ-5676 – Phase 1 Dose Escalation Summary
- Four dose cohorts have been completed (12, 24, 36 and 54 mg/m2)
– Dosing schedule: 21-day continuous IV infusion, 7-day drug holiday per cycle – 16 total patients, 8 acute leukemia with MLL-r, 1 CMML with MLL-r – Fifth cohort (80 mg/m2, 21/7 schedule) enrolling
- Tolerability and safety profile has been favorable
–
No DLTs, drug-related treatment discontinuations, or dose-toxicity relationship
- Pharmacokinetics: dose-proportional exposure
- Pharmacodynamics: methyl mark reduction is dose- and time-dependent
- Treatment effects observed in 4 of 8 acute leukemia MLL-r patients
–
No effects seen in non-MLL-r patients
–
Heavily pre-treated population
- Initiating MLL-r expansion stage with uninterrupted administration
– Starting dose in expansion cohort 80 mg/m2 – Continuous enrollment design allows for further dose escalation
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Favorable safety profile, treatment effects observed in MLL-r patients
14 NOVEMBER 2013
Agenda
- EPZ-5676 Program Overview and Phase 1 Dose Escalation Summary
- Phase 1 Dose Escalation Top-Line Data and Program Plans
- Pre-clinical Highlights
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Epizyme’s Clinical Development Strategy
- Safety
- MTD
- PK
- PD including
methyl mark
- Initial assessment of
therapeutic effect
- Only patients with
genetically defined cancers
- Companion diagnostic
- Study plan based on
expansion cohort results
- Companion diagnostic
Dose Escalation Expansion Cohort Registration
2012-2013 2013-2014
Registration Study
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EPZ-5676 – Dose Escalation Demographics
Age Median (range)
- 55 (22-81)
Gender
- Male: 11
- Female: 5
Diagnosis
- AML: 13 (7 MLL-r)
- ALL: 1 (MLL-r)
- ALL (Ph +): 1
- CMML: 1 (MLL-r) 1
# Prior Therapies Median (range)
- 4 (1-8)
Prior Allogeneic SCT
- Yes: 6
- No: 10
- Four dose cohorts have been completed (12, 24, 36 and 54 mg/m2)
- 16 patients, 8 acute leukemia with MLL-r
- Heavily pre-treated population
- Dosing schedule: 21-day continuous IV infusion, 7-day drug holiday
per cycle
- Enrolling fifth cohort (80 mg/m2, 21-day continuous IV infusion, 7-
day drug holiday per cycle)
1 CMML patient in transformation with MLL-r translocation
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- No dose limiting toxicities (DLTs) or MTD
- No AEs requiring treatment interruption or dose reduction
- No evidence of dose-toxicity relationship to date
- 1 AE-related discontinuation, not drug-related1
- Only 1 patient with possible drug-related event (Gr 3 neutropenia,
not treatment-limiting)2
1 Intracranial bleeding in setting of disease progression, not drug-related 2 Excludes treatment-related leukocytosis (n=2)
EPZ-5676 Dose Escalation – Safety Summary
As of 3 November 2013
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EPZ-5676 Dose Escalation – PK Summary
Dose-proportional exposure (cohorts 1-4) with planned continued escalation in MLL-r expansion stage
*Adjusted mean value excludes a single outlier in cohort 3
500 1000 1500 2000 10 20 30 40 50 60 70 80
Individual Patient Values Data Point Excluded from Mean Adjusted Mean Value *
Systemic Exposure (ng/mL) Dose (mg/m2/day)
Steady State Exposure (Adjusted Mean Value)*
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20 40 60 80 100 120 10 20 30 40 50 60 % Control (H3K79me2) Days 20 40 60 80 100 120 10 20 30 40 50 60 % Control (H3K79me2) Days
100 60 Days
EPZ-5676 Dosing Period Drug Holiday
Methyl Mark Rebound During Drug Holiday
- Mean value of data from cohort 3 and 4 patients (7 patients total)
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EPZ-5676 – Pharmacodynamic Summary
1. Methyl mark continues to decline throughout 21-day treatment period 2. Methyl mark rebounds during 7-day treatment holiday 3. Modeling predicts continued methyl mark decline with uninterrupted treatment 4. Safety of drug allows for dose escalation and uninterrupted administration in MLL-r expansion stage
Projected time course with uninterrupted treatment
% control (H3K79me2)
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EPZ-5676 Dose Escalation – MLL-r Patient Summary
Cohort Dose Dx Treatment Effects Cycles Completed
2
(24 mg/m2)
ALL 90% circulating blast reduction (no bone marrow aspirate available) Resolution of fevers Cycle 1+ AML None observed Cycle 1+
3
(36 mg/m2)
AML Maturation in blood and marrow (no change % marrow blasts) Leukocytosis Resolution of cachexia Cycle 3+ AML Maturation in blood (no change % marrow blasts) Leukocytosis Resolution of leukemia cutis Cycle 2+ AML None observed Cycle 1+
4
(54 mg/m2)
AML None observed Cycle 2+ AML Maturation in marrow % marrow blast decrease (20%à à 2%) On study (2nd cycle) AML None observed Cycle 1+ CMML Too early to evaluate On study (2nd cycle) *Maximum inhibition during treatment period
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+Discontinuation due to disease progression
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Resolution of leukemia cutis in patient with AML MLL-r
Day 0 Day 28*
*Occurred in context of pleomorphic leukocytosis, onset ~ day 15
EPZ-5676 Dose Escalation – Treatment Effect
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EPZ-5676 Dose Escalation – Differentiation Effects
(Day 0) (Day 15)
Pleomorphic Leukocytosis Leukemic blasts Neutrophils
(MLL Break apart FISH)
Evidence of maturation of leukemic blasts (peripheral blood) Evidence of maturation of leukemic blasts (bone marrow)
(Day 0) (Day 28)
Consistent with pre-clinical data, EPZ-5676 differentiation effects
- bserved among patients with MLL-r
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Representative images from dose escalation
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MLL-r Expansion Stage and Pediatric MLL-r Trial
Adult MLL-r Expansion Stage
- Total enrollment ~20 patients
- Enrollment restricted to patients with acute leukemia with MLL
rearrangement (MLL-r)
- Starting dose 80 mg/m2 (continuous enrollment permits dose
escalation)
- Dose and schedule considerations:
– Switch to uninterrupted administration (no drug holiday) to optimize target inhibition
- Favorable safety profile to date allows
uninterrupted administration
- Design allows for dose escalation/optimization
based on PK/PD/safety
- Objectives: safety, preliminary assessment of efficacy
2013 2014
Oct Nov Dec Jan Feb Mar
Dose Escalation Stage (Adult) Starting dose 80 mg/m2/d IVCI with escalation 54 mg/m2/d (x21d) 80 mg/m2/d (x21d) Expansion Stage (MLL-r) (Adult)
Starting dose 60 mg/m2/d IVCI
Pediatric MLL-r Phase 1b Study
- Total enrollment ~20-30 patients
- Enrollment restricted to patients with acute leukemia with MLL
rearrangement (MLL-r)
- Dose and schedule considerations:
– Starting dose at 80% expansion stage dose in adult study – Continuous IV administration
- Design: dose escalation stage followed by expanded enrollment
at MTD or RP2D
- Objectives: determine MTD or RP2D, safety, preliminary
assessment of efficacy
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PTD study initiating in 2014 MLL-r pediatric study
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Clinical Milestones – 2013 & 2014
Target Indication 2013 2014
DOT1L
MLL-r adult ü Phase 1 dose escalation data
- Phase 1 expansion
initiation
- Phase 1 expansion data
MLL-r pediatric
- Phase 1b initiation
MLL-PTD
- Phase 2 expansion
initiation
EZH2
non-Hodgkin lymphoma ü Phase 1 dose escalation initiation
- Phase 1 dose
escalation data & Phase 2 expansion initiation* Synovial sarcoma
- Phase 2 expansion
initiation* INI1-deficient tumors
- Phase 2 expansion
initiation*
2013 2014
*Gated to dose escalation completion
14 NOVEMBER 2013
Agenda
- EPZ-5676 Program Overview and Phase 1 Dose Escalation Summary
- Phase 1 Dose Escalation Top-Line Data and Program Plans
- Pre-clinical Highlights
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HMTome Target Class
Copeland et al. (2012) Oncogene
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- 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 Oncogenic HMT
Misregulated gene expression
Disease
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DOT1L – Driving Oncogene in MLL-r
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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EPZ-5676 – Acute Leukemia with MLL Alterations
MLL-r MLL-PTD
Genetic Alteration
- Reciprocal chromosomal
translocations involving 11q23
- Partial 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
- PCR
- Research test in selected patients
Prognostic implications
- Poor DFS and OS compared with
non-MLL-r leukemias
- Association with short initial
remission duration with poor response to subsequent therapy1
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Graphs: Byrd J C et al., Blood 2002;100:4325-4336; Pui et al., N Engl J Med 2004; 350:1535-1548
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
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EPZ-5676 – Selective Killing of MLL-r Cells In Vitro
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Time (Days) Total Cells
2 4 6 8 10 12 14 105 106 107 108 109 101 0
Jurkat + Jurkat -
H3K79me2 Total H3
Blood, 120: 2379 (2012) Time (Days) Total Cells
2 4 6 8 10 12 105 106 107 108
MV4-11 + MV4-11 -
H3K79me2 Total H3
Non-MLL-Rearranged Cells MLL-Rearranged Cells
Untreated Treated Untreated & Treated Increasing dose Increasing dose
Target methyl mark inhibition leads to selective killing of genetically defined cancer cells
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EPZ-5676 – Pre-clinical Tumor Regressions
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- Profound and sustained in vivo
efficacy in animal models
- Dose-, exposure- and time-
dependent effects
- Sustained tumor regressions seen
at 70 mg/kg in rat models
Nude Rat MLL-r Xenograft Model
Blood, 120: 2379 (2012)
Potent and durable therapeutic effect of targeting oncogenes in pre-clinical studies
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H3K79me2 Total H3
Increasing dose
EPZ-5676 – Pre-clinical Mechanism of Action
Daigle et al., (2013) Blood 122(6): 1017 and unpublished data
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Inhibition of H3K79 methylation
T im e ( D a y s ) m R N A P e r c e n t C o n t r o l
2 4 6 8 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
1 2
A n n e x in + , A A D - V e h i c l e 0 . 0 5 0 . 1 6 0 . 5 1 . 5 4 . 5 1 0 2 0 3 0 4 0 5 0
Differentiation Apoptosis
(Annexin staining)
Morphologic evidence
- f maturation
Both differentiation and apoptosis are observed in MLL-r pre-clinical models
Increasing dose
EPZ-5676 EPZ-5676
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