Simultaneous filing in US/EU/JPN

Japan/Asia Clinical Research Product Creation Unit

Oncology Group, Clinical development

Tomio Nakamura

EU USA Japan

Eisai Oncology : Clinical Development

2

Lab. Location

Tsukuba Research Lab Tsukuba, JPN (1982)

Eisai Inc. Andover, MA, USA (1987)

Morphotek Inc. Philadelphia, USA (2007)

H3 Biomedicine Inc. Cambridge, MA, USA(2010)

Eisai Oncology; Research Laboratories

ERI, Andover, MA, 1989 100 Federal Street (Pilot Plant)

4 Corporate Drive Research FacilityBOSTON

ANDOVER

Eisai Research Institute

Eribulin: Eri (Eisai Research Institute)

+(Tu)bulin

3

4

Eribulin: Background of discovery

ハリコンドリンB

12.5mg HB from

600kg Halichondria okadai 200g from 1 batch

Halaven

(Eribulin mesilate) : Chiral carbon

•Halichondrin B (HB) was isolated from Halichondria

okadai in Japanese seacoast, determined its

chemical structure (Hirata et al. 1985) and

chemically synthesized by Japanese investigators

(Kishi et al. 1992)

•Eribulin mesilate is an analogue of HB active portion

which is more stable and of higher efficacy.

Halichondrin B (HB)

Halichondria okadai

5

Eribulin

Antimitotic Drugs Bind to Microtubules at Diverse Sites

Eribulin binds to (+) ends of microtubules

Modified from Nature Reviews Cancer 4, 253-265, 2004

Vinblastine binds to (+) ends and along sides of microtubules

Paclitaxel, docetaxel and epothilone B bind to βsubunits inside of microtubules

(-) end

(+) end PaclitaxelVinblastine

(+) end

(-) end

β

(+) end

(-) end

β

Eribulin

6

Clinical studies of eribulin for breast cancer

3rd/later line

Study 201 - POCSingle armStudy 211

Single arm

Study 305 , vs TPCMedian OS: 399 vs 324 daysp-value=0.041

EU, USsubmission

Japan submission

Study 221 Late line, Japan

Study105

Approval : Total 54 countries / regions

March 30th ,2010Approved Country NDA under examination, etc

• Locally recurrent or MBC

• 2-5 prior chemotherapies

• Progression ≤6 months

of last chemotherapy

• Neuropathy ≤grade 2

• ECOG ≤2

Eribulin mesylate

1.4 mg/m2, 2-5 min IV

Day 1, 8 q21 days

Treatment of Physician’s

Choice (TPC)

Any monotherapy (chemotherapy,

hormonal, biological)* or

supportive care only†

Randomization 2:1

• PFS

• ORR

• Safety

• Overall

survival

Primary

endpoint

Secondary

endpoints

Stratification:

– Geographical region, prior capecitabine, HER2/neu status

Global, randomized, open-label Phase III trial (Study 305)

Patients (N=762)

− ≥2 for advanced disease

− Prior anthracycline and

taxane

Cortes et al 2010 Lancet 2011; 6736: 60070-6

Study 305 (EMBRACE) design

7

Study 305: TPC treatment received

ITT population; *Taxanes: paclitaxel, docetaxel, abraxane, ixabepilone†Anthracyclines: doxorubicin, liposomal doxorubicin, mitoxantrone

96% of patients treated with chemotherapy

No patient received best supportive care or ‘biological’ therapies only

Total patients = 247

% o

f p

ati

en

ts

n=61

n=46n=44

n=38

n=24 n=25

n=9

n=61

n=46n=44

n=38

n=24 n=25

n=9

30

20

10

0

8

Overall survival (updated data requested by FDA/EMA)

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 362624222018161412108642

Overa

ll s

urv

iva

l (%

)

Eribulin

TPC

28 30 32 34

2.7 months

p-value†=0.014

HR* 0.805 (95% CI 0.667, 0.958)

TPC (n=254)

Eribulin (n=508) 13.2

Median OS (mon)

10.5

Cortes et al 2010 Lancet 2011; 6736: 60070-6

9

Core clinical data package for Japan NDA

10

Study

StatusIndication Study Region

Phase 1 Solid Tumor Studies 101 and 102,

Study NCI-5730Global

Study 105 JPN

Phase 2 Breast

cancerStudies 201 and 211 Global

Study 221 JPN

Phase 3 Breast

cancerStudy 305

(pivotal study)Global

Clinical

Pharmacology

Solid tumor Studies 103, 108, 109

and 110Global

Asian country: CPP(Certificate of Pharmaceutical Product)

-Clinical studies with people in each country : Korea, Taiwan, India and China-

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Study 305 & 221: Conclusions

• Study 305 was the first Phase III, single-agent study which

achieved a prolonged OS (primary endpoint: a statistically

significant improvement ) in heavily pretreated MBC patients.

– Improvement of median overall survival was 2.5 months (23%)

– Clinically meaningful in this patient population

• Favorable efficacy of eribulin was observed in Japanese MBC

patients in study 221 (ORR: 21%).

• These benefits ensured manageable safety profiles.

These results support Eribulin as a new treatment

option for patients with heavily pretreated MBC.

Simultaneous NDA submission in JP/US/EU:

Tasks and Actions

1. Communication with global team: Differences in language, time zone, role & responsibility

- Needed an established communication loop with a hub function of RA and

IPT plus direct contact among responsible members to follow up

- Dispatched Japanese project manager in US/EU

2. Consensus-building with global members

- Japanese project leader and project manager were dispatched in US and

responsible for decision-making and coordinating teams

- Global members gradually became familiar with Japan-specific

circumstances

3. Preparation process of CTD for clinical data

- Agreed to prepare CTDs in dual ways (Japan and global in parallel)

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Responses to Queries in JP/US/EU

13

COD: Committee on Drug, PAC: Pharmaceutical Affairs Committee, NHI: National Health Insurance

Timing and numbers of queries : each H.A.s

JPN: Frequently, Many

EU: Regulatory, Moderate

US: Rare, A little

Japanese team asked Global team’s agreement

about the major answers of PMDA’s queries

frequently and urgently.

Korea: NDA Sep/11 , Approval Aug/12

Taiwan: NAD Sep/12, Approval Sep/13

India: NDA May/11, Approval Apr/13……

In Closing• The weight of significance in simultaneous

NDA submission for eribulin included:– Achieved expeditious launching of eribulin for patients

without drug lag

– Early Asian NDAs

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• Ethnic difference for molecular classification of adenocarcinoma of lung

･ Post-study treatment and OS between Caucasians and Asians

against EGFR-positive NSCLC (FLEX trial, Lancet 2009 )

15

EGFR-mt KRAS ALK BRAF Non

JPN(NCC) (%) 56 9 5 0 30

USA(MSKCC) (%) 24 25 6 3 40

VNB+CDDP(CT)

±cetuximab

CT + cetuximab

(n=557)

CT alone

(n=568)

MST (M) 11.3 10.1

VNB+CDDP(CT) ±cetumimab Caucasian

(n=946)

Asian

(n=121)

Asian subgroup

CT+ cetu (62) CT alone (59)

MST (M) 9.6 19.5 17.6 20.4

Post-study treat. : EGFR TKIs (%) 17 61 50 73

P=0.044 (95% CI :0.762-0.996)

The role of pharmaco-ethnicity in the development of cytotoxic

and molecular targeted drugs in oncology Yonsei Med.J. 2013 Jan;54(1):1-14

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Thank you for your attention!