20 NOVEMBER 2014

2013 Accomplishments Forward Looking Statements

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Phase 1 first-in-human study of the enhancer of zeste-homolog 2 (EZH2)

histone methyl transferase inhibitor E7438 as a single agent in patients with advanced

solid tumors or B cell lymphoma V Ribrag,1 JC Soria,1 L Reyderman,2 R Chen,2

P Salazar,3 N Kumar,4 G Kuznetsov,4 H Keilhack,5 LH Ottesen,3 A Italiano6

1Institut Gustave Roussy, Villejuif, France; 2Eisai Inc., NJ, USA; 3Eisai Ltd., Hatfield, UK;

4Eisai Inc., Andover, MA, USA; 5Epizyme Inc., MA, USA; 6Institut Bergonié, Centre de Lutte Contre le Cancer de Bordeaux, Bordeaux, France;

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Disclosures

• VR: Advisory board, Eisai Inc. • JCS: Nothing to disclose. • AI: Honoraria–GlaxoSmithKline, Pfizer,

PHarmaMar; Threshold Research Funding–Novartis, Pfizer, PharmaMar, Roche.

• LR, RC, PS, NK, GK, and LHO are employees of Eisai Inc.

• HK is an employee of Epizyme Inc.

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EZH2 Inhibitor for Genetically Defined Cancers

4

HN O

HN

O

NON

O E7438

E7438 (EPZ-6438) is a highly selective EZH2 inhibitor2

INI1

Loss of Function Mutations • INI1: Malignant Rhabdoid Tumors1

E7438 induces durable tumor regressions in human MRT models2

SWI/SNF

PRC2 COMPLEX

EZH2 Change of Function Mutations • Non-Hodgkin Lymphoma3

E7438 induces selective cell killing in models of EZH2 mutant DLBCL4

Amplification of PRC2 Subunits3

• Non-Hodgkin Lymphoma

• Multiple Solid Tumors

Methylation

K27 K27 (me)3

Closed chromatin Open chromatin

RbAp48 EED

AEBP2

SUZ12

1Versteege et al, Nature 1998; 2Knutson et al, PNAS 2013; 3Chase and Cross, CCR 2011; 4Knutson et al, MCT 2014.

Phase 1/2 Study in Patients With Advanced Solid Tumors or With B Cell Lymphomas

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 cutoff: 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

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BID, twice daily; D, day; MTD, maximum tolerated dose; PK, pharmacokinetics; RP2D, recommended phase 2 dose.

Patient Characteristics

Characteristics Overall (N=24)

n (%) Median age, years (range) 62 (24–84) Gender Female 3 (13) ECOG performance status 0 8 (33)

1 16 (67) Number of systemic prior anticancer therapies

0–1 1*

2–4 14 (58) >4 9 (38)

*1 patient with MRT had definitive surgery and adjuvant radiation prior to study entry

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Patient Characteristics Characteristics Overall (N=24), n(%) Tumor types B cell lymphoma 12 (50)

Diffuse Large B-cell Lymphoma 6 (25)

Follicular Lymphoma 5 (21)

Marginal Zone Lymphoma 1 (4)

Advanced solid tumor 12 (50) Colorectal carcinoma 4 (17)

Sarcoma

Alveolar soft part sarcoma 1 (4)

Ewing’s sarcoma 1 (4)

Synovial sarcoma 1 (4)

Malignant rhabdoid tumor 1 (4)

Cholangiocarcinoma 1 (4)

Pancreatic adenocarcinoma 1 (4)

Prostatic adenocarcinoma 1 (4)

Urothelial carcinoma 1 (4) 7

Safety 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 (12.5)

Median no. of cycles received 3 Median duration of treatment, months (range) 2.5 (0.8–9.2)

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• The MTD for E7438 has not been reached

• 1 DLT occurred at

1600 mg BID – Grade 4

thrombocytopenia

AEs, adverse events; BID, twice daily; DLT, dose-limiting toxicity; MTD, maximum tolerated dose. *Grade 4 thrombocytopenia

Treatment-Related Adverse Events Overall (n=24)

Adverse Event Any Grade, n (%) Grade 3/4, n (%) Any AE 16 (67) 1 (4) Asthenia 9 (38) 0 Decreased appetite 3 (13) 0 Nausea 3 (13) 0 Anemia 2 (8) 0 Constipation 2 (8) 0 Diarrhea 2 (8) 0 Dysgeusia 2 (8) 0 Muscle spasms 2 (8) 0 Vomiting 2 (8) 0 Abnormal hair growth 1 (4) 0 Dry skin 1 (4) 0 Hypokalemia 1 (4) 0 Insomnia 1 (4) 0 Nail ridging 1 (4) 0 Night sweats 1 (4) 0 Non-cardiac chest pain 1 (4) 0 Thrombocytopenia 1 (4) 1 (4)

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The majority of AEs were

grade 1 and 2

Pharmacokinetics • E7438 is rapidly absorbed

and eliminated (t1/2 ~ 3–6 hours)

• E7438 exposure is greater than dose-proportional, and highly variable (% CV: 32–95%)

• Decrease in E7438 exposure upon multiple-dosing is associated with increase in metabolite formation

Cycle 1 Day 1

Time (hr)

E743

8 Pl

asm

a C

once

ntra

tion

(ng/

mL)

0 0 2 4 6 8 10 12

500

1000

1500

2000

2500

3500

4500

4000

3000

100 mg 200 mg 400 mg 800 mg 1600 mg

Cycle 1 Day 15

Time (hr) E7

438

Plas

ma

Con

cent

ratio

n (n

g/m

L)

0 0 2 4 6 8 10 12

500

1000

1500

2000

2500

3500

4500

4000

3000

100 mg 200 mg 400 mg 800 mg 1600 mg

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CV, coefficient of variation.

Pharmacodynamics in Skin

Maximal inhibition (IC90 = 4421 ng·hr/mL) is predicted at the exposure observed for the 800 mg dose (AUCday 15 = 4553 ng·hr/mL)

Perc

ent c

hang

e fr

om b

asel

ine

in

H3K

27M

e3 p

ositi

ve c

ells

0

−20

−40

−60

E7438 AUC (ng•hr/mL) 16000 14000 12000 10000 8000 6000 4000 2000 0

Imax = 44% IC50 = 487 ng·hr/mL

Example of biological activity (histone H3K27Me3 inhibition

demonstrated by IHC)

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Correlation between inhibition of histone methylation

and exposure

Baseline Cycle 2 Day1

Efficacy in B-Cell Lymphoma (n=12)

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1Transformed lymphoma by history and presentation. 2Primary mediastinal B cell lymphoma by history/presentation. → indicates ongoing patient

Type Cell-of-origin

Dose (mg BID)

Best Response

DLBCL GCB1 100 PR Non-GCB2 200 CR→ Non-GCB 200 PD Non-GCB 800 PR→ Non-GCB 800 PD

FL GCB 800 PR→ GCB 400 SD GCB 800 SD→ GCB 1600 SD→

MZL Non-GCB 1600 SD→

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

11/12 were analyzed for EZH2 mutations (hotspot codons Y646, A682, and A692)–

All were wildtype

CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Efficacy in Solid Tumors (n=12)

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Time (week)

Perc

ent c

hang

e fr

om b

asel

ine

75 50 25 0

125 100

150

−50 −75 −100

−25

8 0 16

Patient with malignant rhabdoid tumor

Tumor

Dose (mg BID)

Best Response

Colon adenocarcinoma 100 PD

Cholangiocarcioma 100 SD

Pancreatic adenocarcinoma 100 PD

Ewing’s sarcoma 100 PD

Synovial sarcoma 100 PD

Colorectal adenocarcinoma 200 PD

Alveolar soft part sarcoma 400 PD

Prostatic adenocarcinoma 400 SD

Malignant rhabdoid tumor 800 PR→

Urothelial carcinoma 1600 NE

Colon adenocarcinoma 1600 PD

Colorectal adenocarcinoma 1600 PD NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease → indicates ongoing patient .

11/09/2014 FDG-PET: Complete Response

27/11/2013 Baseline 35 x 27 mm

31/01/2014 Partial Response 27 x 16 mm

Patient 1: Primary Mediastinal B-Cell Lymphoma (non-GCB)

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• Male, 23 years • ECOG 0 • EZH2WT

• Clinical history • Diagnosed Feb 2013 • Refractory to initial and salvage

therapy: • R-ACVBP + methothrexate • R-DHAP • R-ICE

• Treatment: 200 mg po bid • Best response:

• Complete response ongoing • 27% H3K27me3 reduction

from baseline (skin biopsy)

05/05/2014 Baseline 33 x 19 mm

27/08/2014 Partial Response 22 x 11 mm

Patient 2: Follicular lymphoma

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• Male, 79 years • ECOG 0 • EZH2WT

• Clinical history • FL diagnosed in 2002 • Prior lines of therapy including

• CHVPi (partial response) • Cyclophosphamide-

mitoxantrone-rituximab (complete response)

• Progression on rituximab monotherapy

• Treatment: 800 mg po bid • Best response:

• Partial response (-61%), ongoing • Skin biopsy not available

Patient 3: Malignant Rhabdoid Tumor

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21/05/2014 15.2 mm Baseline

17/07/2014 6.7 mm

Partial Response

11/09/2014 5.5 mm

Partial Response

• Male, 55 years • ECOG 0 • INI1 loss (gene sequencing & IHC)

• Clinical history • MRT 2013 • Definitive surgery and

adjuvant radiotherapy • Recurrence in the cervical

nodes • Treatment: 800 mg po bid • Best response:

• Partial response (-53%), ongoing

• 40% H3K27me3 reduction from baseline (skin biopsy)

9/05/2014 25/06/2014

Conclusions

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• The emerging Phase I safety profile is acceptable • MTD not reached, no treatment discontinuation for toxicity,

limited grade 3/4 toxicity

• Acceptable PK profile and confirmed dose-related target engagement in skin

• This trial is the first demonstration of clinical activity associated with EZH2 inhibition • Encouraging activity of E7438 was shown in B-cell NHL and

INI1-deficient MRT across a wide dose-range

• Further investigation in B-cell NHL and INI-1 deficient tumours is under discussion

Acknowledgements

The authors thank the patients and their families, as well as the investigators and their teams who took part in this study, and

Dr. Scott Barrett for his contributions.

This study was funded by Eisai Inc.

Editorial support was provided by Oxford PharmaGenesis Inc., and funded by Eisai Inc.

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