Simultaneous filing in US/EU/JPN Japan/Asia Clinical Research Product Creation Unit Oncology Group, Clinical development Tomio Nakamura
Eisai Oncology : Clinical Development EU USA Japan Eisai Oncology; Research Laboratories 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) 2
Eribulin: Eri (Eisai Research Institute) +(Tu)bulin Eisai Research Institute ERI, Andover, MA, 1989 100 Federal Street (Pilot Plant) ANDOVER 4 Corporate Drive Research Facility BOSTON 3
Eribulin: Background of discovery Halichondrin ハリコンドリン B (HB) B Halaven (Eribulin mesilate) : Chiral carbon 12.5mg HB from 600kg Halichondria okadai 200g from 1 batch Halichondria okadai 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. 4
Eribulin Antimitotic Drugs Bind to Microtubules at Diverse Sites (+) end Eribulin (+) end Vinblastine (+) end Paclitaxel β β (-) end (-) end (-) end Eribulin binds to (+) ends of microtubules Vinblastine binds to (+) ends and along sides of microtubules Modified from Nature Reviews Cancer 4, 253-265, 2004 Paclitaxel, docetaxel and epothilone B bind to β subunits inside of microtubules 5
Clinical studies of eribulin for breast cancer Approval : Total 54 countries / regions Study 211 Single arm Study 201 - POC Single arm 3 rd /later line Study 305, vs TPC Median OS: 399 vs 324 days p-value=0.041 Study105 Study 221 Late line, Japan EU, US submission Japan submission Approved Country NDA under examination, etc March 30 th,2010 6
Study 305 (EMBRACE) design Global, randomized, open-label Phase III trial (Study 305) Patients (N=762) Locally recurrent or MBC 2-5 prior chemotherapies 2 for advanced disease Prior anthracycline and taxane Progression 6 months of last chemotherapy Neuropathy grade 2 ECOG 2 Eribulin mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Randomization 2:1 Treatment of Physician s Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only Primary endpoint Overall survival Secondary endpoints PFS ORR Safety Stratification: Geographical region, prior capecitabine, HER2/neu status Cortes et al 2010 Lancet 2011; 6736: 60070-6 7
% of patients Study 305: TPC treatment received 96% of patients treated with chemotherapy 30 n=61 Total patients = 247 20 n=46 n=44 n=38 10 n=24 n=25 n=9 0 No patient received best supportive care or biological therapies only ITT population; *Taxanes: paclitaxel, docetaxel, abraxane, ixabepilone Anthracyclines: doxorubicin, liposomal doxorubicin, mitoxantrone 8
Overall survival (%) Overall survival (updated data requested by FDA/EMA) 1.0 Median OS (mon) Eribulin (n=508) 13.2 0.8 0.6 TPC Eribulin TPC (n=254) 10.5 p-value =0.014 HR* 0.805 (95% CI 0.667, 0.958) 0.4 0.2 2.7 months 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) Cortes et al 2010 Lancet 2011; 6736: 60070-6 9
Core clinical data package for Japan NDA Study Status Indication Study Region Phase 1 Solid Tumor Studies 101 and 102, Study NCI-5730 Study 105 Global JPN Phase 2 Breast cancer Studies 201 and 211 Study 221 Global JPN Phase 3 Breast cancer Study 305 (pivotal study) Global Clinical Pharmacology Solid tumor Studies 103, 108, 109 and 110 Global Asian country: CPP(Certificate of Pharmaceutical Product) -Clinical studies with people in each country : Korea, Taiwan, India and China- 10
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. 11
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) 12
Responses to Queries in JP/US/EU Korea: NDA Sep/11, Approval Aug/12 Taiwan: NAD Sep/12, Approval Sep/13 India: NDA May/11, Approval Apr/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. 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 14
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 Ethnic difference for molecular classification of adenocarcinoma of lung EGFR-mt KRAS ALK BRAF Non JPN(NCC) (%) 56 9 5 0 30 USA(MSKCC) (%) 24 25 6 3 40 Post-study treatment and OS between Caucasians and Asians against EGFR-positive NSCLC (FLEX trial, Lancet 2009 ) VNB+CDDP(CT) ±cetuximab CT + cetuximab (n=557) CT alone (n=568) MST (M) 11.3 10.1 P=0.044 (95% CI :0.762-0.996) 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 15
Thank you for your attention! 16