EPZ-6438), an Inhibitor of EZH2: Preliminary Safety and Activity in Patients with Relapsed Or Refractory NHL and Advanced Solid Tumors

$EPZ-6438), an Inhibitor of EZH2: Preliminary Safety and Activity in Patients with Relapsed Or Refractory NHL and Advanced Solid Tumors$

A Phase 1 Study of Tazemetostat (EPZ-6438), an Inhibitor of EZH2: Preliminary Safety and Activity in Patients with Relapsed or Refractory NHL and Advanced Solid Tumors

Vincent Ribrag, Jean-Charles Soria, Jean-Marie Michot, Anna Schmitt, Sophie Postel-Vinay, Fontanet Bijou, Jean-Michele Coindre, Maud Toulemonde, Stephen J Blakemore, Ben Suttle, Scott Ribich, Blythe Thomson, John Larus, Harry Miao, Peter TC Ho, and Antoine Italiano

Participating Institutions Institut Gustave Roussy, Villejuif, France Institut Bergonie, Bordeaux, France

Sponsor Epizyme, Inc

Methylation2013 of H3K27me3 Accomplishments by PRC2 Mediates Transcriptional Repression

PRC2 • EZH2 is the catalytic subunit of the multi-protein PRC2 (Polycomb Repressive Complex 2) • PRC2 is the only protein methyltransferase complex that can methylate H3K27 – Generates mono-, di- and tri-methylation of H3K27 – H3K27me3 is a transcriptionally repressive histone mark, and is the only significant substrate for PRC2 • Aberrant trimethylation of H3K27 is oncogenic in a broad spectrum of human cancers, such as B- cell NHL Compacted Chromatin • Mutations in other proteins that affect H3K27 and chromatin accessibility in general are prevalent across almost all cancer types Transcriptional Repression

2 EZH2 Regulates2013 BAccomplishments-cell Maturation and Cell Fate

Lymph Node Plasma/Memory Cell

Native B cell Maturing B Cell

Apoptosis

EZH2 is the “gatekeeper” for cell fate decisions

3 EZH2 Gain2013 of Function Accomplishments Mutations Result in Elevated H3K27me3 Levels

NH 2 H3K27Me3 Production Wild-Type EZH2 ++ Y641 or Y646 Mutant EZH2 +/- Heterozygous WT/Y641 or Y646 Mutant EZH2 ++++

Wild Type Mutant

EZH2

H3K27me3

H3K27me2

H3K27me1

Total H3

Sneeringer et al, PNAS, 2010 4 Tazemetostat2013 Accomplishments (EPZ-6438): Potent and Highly Selective EZH2 Inhibitor Novel Structure, Potent Target Inhibition Selective for EZH2

PRMTs

Ki <2.5 nM PKMTs

Selectivity >20,000-fold (100-fold for EZH1) Antitumor Activity in EZH2 Mutant and WT Xenograft Models of DLBCL KARPAS-422 (EZH2 Y646N) OCI-LY19 (EZH2 WT)

Knutson et al., Mol. Cancer Therapeutics, 2014 5 Thomenius et al. Molecular Targets Conference, 2015 First2013-in- HumanAccomplishments Phase 1 Trial E7438-G000-001 (NCT01897571) • Population: relapsed or refractory B-cell lymphoma or solid tumors • Study design: 3+3 dose-escalation completed – Expansion cohorts (800 mg and 1600 mg BID) completed – Food effect sub-study (400 mg BID) completed – Drug-drug interaction sub-study (800 mg BID) completed • Primary endpoint: determination of RP2D/MTD • Secondary endpoints: safety, PK, PD and tumor response (every 8 wks) • Data cut: 7-Nov-2015 Dose Patients Solid tumors B-cell NHL (mg BID) (n=58) (n=37)** (n=21) 100* 6 5 1 * 2 formulations 200 3 1 2 400 3 2 1 800 14 6 8 1600 12 8 4 Food Effect 13 8 5 Drug-Drug 7 7 0 6 from Ribrag et al., ASH 2015 **Solid tumor data presented by A. Italiano, ESMO/ECC 2015 2013Patient Accomplishments Tumor Types

Relapsed or refractory NHL n=21

Diffuse Large B cell GCB 5 Lymphoma (DLBCL) Non GCB 6 undetermined 3 Follicular lymphoma (FL) 6 Marginal Zone lymphoma (MZL) 1 Relapsed or refractory solid tumors n=37 Malignant rhabdoid tumor 5 INI1-deficient or negative Epithelioid sarcoma 3

Synovial sarcoma 4 SMARCA4-negative tumors 3 Other solid tumors 22

2/17 NHL patients tested to date are EZH2 mutant by cobas® test (in development, Roche Molecular Systems, Inc.)

7 from Ribrag et al., ASH 2015 Clinical2013 Accomplishments Pharmacokinetics

D a y 1 5 ) 1 0 0 0 0 1 0 0 m g (s u s p ), n = 3 L 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

1 0 0 m g (ta b ), n = 3 m /

g 4 0 0

) 2 0 0 m g , n = 3

n L

4 0 0 m g , n = 3 (

m .

/ 8 0 0 m g , n = 1 3 c

g 1 0 0 0 1 6 0 0 m g , n = 1 1 n

n 3 0 0

(

a o

c 2 0 0

s a

1 0 0 a

l 1 0 0

4 -

6 0 Z

- 1 0 Z P h h h h P 0 E 2 0 2 E 1 1 9 5 2 1 1 5 y y 1 y a a y a D D a D 1 D 0 3 6 9 1 2 T im e (h )

● 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 8 from Ribrag et al., ICML 2015 PK-PD: EZH22013 Inhibition Accomplishments in Surrogate Tissue

Target inhibition in skin: ● Reduction of H3K27me3 by IHC at week 4 at all doses ● Exposure-dependent reductions in H3K27me3 ● Differential effects by epithelial layer ‒ Stratum basale - minimal change ‒ Stratum spinosum – pronounced change ‒ Full epidermis – composite signal of stratums spinosum and basale ● Reduction in H3K27me3 signal equivalent at 800 and 1600 mg BID

100mg 200mg 400mg 800mg 1600mg 9 from Ribrag et al., ASH 2015 Safety2013 Profile Accomplishments in All Patients (n=55: 20 NHL and 35 Solid Tumors)

All Events All Treatment-Related All Grades * Grade >3 All Grades Grade >3 ** Asthenia 23 0 13 0 Decreased appetite 9 1 4 0 Thrombocytopenia 8 2 7 1 Nausea 8 0 8 0 Constipation 7 0 2 0 Diarrhea 6 0 4 0 Vomiting 6 0 5 0 Anemia 5 0 3 0 Dry skin 5 0 4 0 Dysgeusia 5 0 5 0 Dyspnea 5 0 0 0 * All AEs with Muscle spasms 5 0 3 0 frequency >5% Abdominal pain 4 1 1 0 regardless of Hypophosphatemia 4 0 1 0 attribution Anxiety 3 0 1 0 shown Depression 3 2 1 0 Hypertension 3 1 2 1 ** All grade >3 Insomnia 3 0 0 0 treatment- Neutropenia 3 1 3 1 related Night sweats 3 0 3 0 events shown Peripheral edema 3 0 2 0 Hepatocellular injury 2 1 1 1 10 from Ribrag et al., ASH 2015 NHL2013 Patient Accomplishments Demographics

Characteristic n=21 (%) Median age, years [range] 63 [24-84] Sex (M / F) 15/6 1 2 (10) 2 1 (5) # of prior therapeutic 3 8 (38) systemic regimens 4 3 (14) >5 7 (33) Prior autologous hematopoietic cell transplant 8 (38) Prior radiotherapy 17 (57)

11 from Ribrag et al., ASH 2015 Objective2013 Accomplishments Response in NHL All Patients (n=21)

Food Effects (FE): 200 mg on day -8 and day -1 400 mg BID from day 1 12 Data as of 27-May 2015 Response2013 in Accomplishments EZH2-mutated DLBCL

53 year old female (EZH2Y646H) treated at RP2D (800 mg BID)

Baseline SPD: 8282mm2 Wk 16 SPD: 3864 mm2 (PR) Wk 40 SPD: 3506 mm2 (PR)

Images courtesy of A. Italiano, Institut Bergonie

Tazemetostat: Response through 15 months

PR SD PD PR CR PD SD SD PD 4 mos 15 mos 2010 2011 2012 2013 2014 2015 PR 13 Data as of 27-May 2016 Tazemetostat2013 Accomplishments Phase 2 Dose Selection

Efficacy Safety PK/PD Dose BID H3K27me3 Response in NHL (%) Grade ≥3 TEAE * Inhibition Emax ** <800 mg 2/9 (22%) 7/24 (29%) - 800 mg 5/8 (62%) 3/19 (16%) 81%

1600 mg 2/4 (50%) 4/12 (33%) 91%

* Treatment Emergent Adverse Events in all patients (n=55) H3K27me3 in Skin

** H3K27me3 Emax vs. Exposure

100mg 200mg 400mg 800mg

1600mg

Baseline

Week 4 Week

200 mg 800 mg 1600 mg Day 15 AUC (h*ng/mL) 14 from Ribrag et al., ASH 2015 0-last Subunits of2013 SWI/SNF Accomplishments Complexes Are Mutated Across Many Indications

Adapted from Kadoch 2015 15 Antagonism2013 of PRC2 Accomplishments and SWI/SNF- Dependent Chromatin Remodeling Regulates Pluripotency Stem or Progenitor Cells

Highly dependent on EZH2 activity

SWI/SNF PRC2

INI1

SMARCA4

 PRC2 target genes

Stem cell programs

Self-renewal and Block in differentiation 16 Adapted from Wilson 2010 EZH2 Activity2013 Accomplishments Is Down-regulated as Progenitor Cells Become Differentiated Stem or Progenitor Cells Differentiated Cells

Highly dependent EZH2 activity on EZH2 activity EZH2 Activity down-regulated

SWI/SNF PRC2 SWI/SNF PRC2

INI1 INI1

SMARCA4 SMARCA4

 PRC2 target genes  PRC2 target genes

Stem cell programs  Stem cell programs

Self-renewal and Quiescence and Block in differentiation Differentiation 17 Adapted from Wilson 2010 INI1 or SMARCA42013 Loss Accomplishments Can Creates an Oncogenic Dependency on EZH2 in Tumors

Stem or Progenitor Cellson EZH2 in TumorsINI1 or SMARCA4 -negative tumors ● Malignant rhabdoid tumor (MRT) Highly dependent ● Malignant rhabdoid tumor of the ovary on EZH2 activity (MRTO/SCCOHT) SWI/SNF PRC2 ● Epithelioid Sarcoma (ES) ● Renal Medullary Carcinoma (RMC)

INI1 EZH2 knockout reverses oncogenesis induced by INI1 loss

Hyper-repression of  PRC2 target genes PRC2 targets

Potentiation of stem   Stem cell programs cell programs INI1fl/fl CD4-Cre (n=8) INI1fl/fl EZH2fl/fl CD4-Cre (n=23) Oncogenic Transformation

18 Adapted from Wilson 2010 INI1- and SMARCA42013 Accomplishments-negative Rhabdoid Tumors are Aggressive in Children and Young Adults Malignant Rhabdoid Tumors Malignant Rhabdoid Tumor of the (MRT) Ovary (MRTO) ● Often pediatric, however adult cases ● Also known as Small Cell Carcinoma of reported the Ovary Hypercalemic Type (SCCOHT) ● Occur in the kidney, CNS and soft tissue ● Average age of diagnosis at 24 years ● Chemo-resistant ● Chemo-resistant ● Dismal prognosis with survival rates ● Dismal prognosis with survival rates <25% <35% MRT in an Infant MRTO in a 15-Yr Old

Image courtesy of S. Goldman, MD Bailey et al., 2014

19 INI1- and SMARCA42013 Accomplishments-Negative Rhabdoid Tumor Models are Sensitive to Tazemetostat

In vitro and in vivo cell killing In vitro and in vivo cell killing of of mutant INI1 MRT cells mutant SMARCA4 MRTO cells

1 0 0 1 0 0

)

) M

1 0 M 1 0

 

(

5 5

1 1

y a

a 0 .1 0 .1

D D

0 .0 1 0 .0 1 INI1 Mutant INI1 WT SMARCA4 Mutant Non-MRTO

MRT Non-MRT MRTO Ovarian )

) V e h ic le 3 3 3 2 0 0

1 2 5 m g / k g m V e h ic le m 2 0 0 0

m 1 2 5 m g / k g

m 2 8 0 0 2 5 0 m g / k g

(

( 5 0 0 m g / k g 5 0 0 m g / k g

2 4 0 0 M 1 6 0 0

2 0 0 0 

 1 2 0 0 e e 1 6 0 0 E P Z -6 4 3 8

m E P Z -6 4 3 8

u l

u 1 2 0 0 8 0 0

v 8 0 0

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m u

u 0

0 T T 0 1 0 2 0 3 0 4 0 5 0 6 0 0 1 0 2 0 3 0 4 0 5 0 6 0

D a y s D a y s

Knutson et al. PNAS , 2013 20 Penebre et al, EORTC, 2015 EZH2 Target2013 InhibitionAccomplishments in Tumor Tissue

Pre-Dose Post-Dose: Week 4 Rhabdoid Tumor of Kidney H3K27me3 H3K27me3 INI1-negative Diffuse positive 1+: 100% tumor Negative: 100% tumor

Epithelioid Sarcoma H3K27me3 H3K27me3 INI1-negative Diffuse positive 1+: 100% tumor Negative: 50% tumor

21 2013Patient Accomplishments Tumor Types

Relapsed or refractory solid tumor N=30

INI1-negative Malignant rhabdoid tumor 5 (SMARCB1)* Epithelioid sarcoma 3 Malignant rhabdoid tumor of 2 SMARCA4-negative* ovary (SCCOHT) Thoracic sarcoma 1 Synovial sarcoma 3 GI malignancy 9 GU malignancy 2 GYN malignancy (non-SCCOHT) 2 CNS tumor/other sarcoma 3 Relapsed or refractory NHL N=21

* INI1- or SMARCA4-negative by IHC 22 from Italiano et al., ECC 2015 Best Response2013 in Accomplishments Patients with Solid Tumors

75% *

50%

25% *

-25% % change from % changefrom baseline

-50% INI1-negative SMARCA4-negative Other solid tumor** -75%

* Patients censored at time of progression ** Four additional other solid tumor patients with pending disease evaluation 23 from Italiano et al., ECC 2015 CR in2013 Patient Accomplishments with INI1-Negative Malignant Rhabdoid Tumor Baseline Week 4 Week 8: CR Week 20

INI1 IHC

55 y.o. male 800 mg BID

Surgery Diagnosis + XRT Tazemetostat: ongoing response week 65+

CR PD Week 8: Week 20: 24 from Italiano et al., ECC 2015 2013 2014 CR pathologic CR 2015 PR in Patient2013 Accomplishmentswith SMARCA4-Negative Malignant Rhabdoid Tumor of Ovary

Baseline Week 8 Week 16

27 y.o. female 1600 mg BID

Tazemetostat: ongoing week 24+

CR CR PD Week 8: Week 16: 2013 2014 2015 PR PR 25 from Italiano et al., ECC 2015 2013Clinical Accomplishments Pharmacology: Food Effect and Drug-Drug Interaction

• The effect of food on tazemetostat pharmacokinetics – Patients (n=13) received tazemetostat 200 mg after an overnight fast and immediately after a high-fat breakfast in a randomized crossover fashion with 7 days between doses – Plasma tazemetostat concentrations were determined over 24 hours after each dose – Patients received tazemetostat 400 mg BID after completing the food effect component of the study • The effect of tazemetostat on CYP3A4/5-mediated metabolism – Patients (n=13) received an oral dose of midazolam 2 mg on Day -1 and Day 15 – Tazemetostat 800 mg BID administration started on Day 1 and continued throughout the study – Plasma midazolam concentrations were determined over 24 hours after each dose

26 Clinical2013 Pharmacology: Accomplishments Food Effect

Cmax AUC(0-∞)

000

1500 7

Fed:Fasted Parameter 90% CI

Ratio

(ng*h/mL)

(ng/mL)

C 000

max

∞) 5

0.72 0.52, 1.00 -

1000 (0

(ng/mL) max

AUC(0-∞)

0.93 0.66, 1.30 000

(ng*h/mL) 3

500

• AUC(0-∞) and Cmax decreased by 7%

000

Tazemetostat Tazemetostat

and 28%, respectively AUC Tazemetostat

0 0

• The 90% CI for both ratios contained 1 Fasted Fed Fasted Fed

Administration of tazemetostat with a meal resulted in a non-clinically relevant effect on systemic disposition and overall systemic exposure

from Suttle et al., AACR 2016 27 Clinical Pharmacology:2013 Accomplishments CYP3A4/5 Interaction

Pharmacokinetic results after administration of midazolam with and without tazemetostat demonstrate that tazemetostat is a weak inducer of Cyp3A4/5

Induction Inhibition Geometric Mean Ratio

(90% CI)

C 0.79

max (0.59, 1.06)

Weak Weak Induction

Strong Induction Strong 0.60 AUC(0-∞)

Moderate Induction Moderate (0.47, 0.76)

Fold Change and 90% 0.2 0.5 0.8 1.0 Confidence Intervals

Change relative to administration of midazolam alone from Smith et al., AACR 2016 28 2013Phase Accomplishments 1 Summary

• Tazemetostat demonstrates clinical activity as monotherapy in patients with both B-cell NHL and solid tumors • Relapsed or refractory DLBCL (both GCB and non-GCB), FL and MZL – Objective responses in B-cell NHL with either wild-type or mutated EZH2 – Responses are durable – patients ongoing at 10+ to 21+ months • Relapsed INI1- and SMARCA4-negative tumors – Malignant rhabdoid tumor, malignant rhabdoid tumor of ovary (SCCOHT), epithelioid sarcoma – Objective responses (CR and PR) and SD ≥6 months • Pharmacodynamic inhibition of H3K27me3 demonstrated in tumor tissue and in surrogate tissue (skin) • Safety profile as monotherapy is favorable for both monotherapy and combination development • Pharmacokinetic results demonstrate that tazemetostat may be taken without regard to meals and is a weak inducer of CYP3A4/5 • RP2D dose of 800 mg BID supported by safety, efficacy, PK/PD 29

Current2013 Tazemetostat Accomplishments Development

• Non-Hodgkin Lymphoma – Phase 2 trial for DLBCL and FL – France, Australia, UK, Italy, Canada, US, Germany. • Five cohorts – prospectively stratified according to cell-of-origin and EZH2 mutation status – Phase 1/2 trial in DLBCL of tazemetostat in combination with R-CHOP in front-line elderly high-risk patients to start in 2016 – Phase 1b trial in DLBCL of tazemetostat in combination with a checkpoint inhibitor to start in 2016 • Rhabdoid and non-rhabdoid INI1-negative or SMARCA4-negative Tumors and Synovial Sarcoma – Phase 2 trial in adults – US, Belgium, France, Italy, Australia, Canada, Germany, Taiwan – Phase 1 trial in children (oral suspension formulation) – US, Australia, Denmark France, Canada, UK, Germany. • Mesothelioma – Phase 2 trial in mesothelioma with BAP1 loss of function to start in 2016 in US, France and UK

30 2013Acknowledgements Accomplishments

We thank our co-investigators and their teams and, most importantly, the patients and families who participated in the study