Translational R & D. Su Y Nam, M.D., Ph.D. Chief Scientific Officer, Yuhan Corporation

Transcription

1 Translational R & D Su Y Nam, M.D., Ph.D. Chief Scientific Officer, Yuhan Corporation 1

2 Current Trends in Drug Development Innovation comes with a price Higher attrition, longer timelines, & higher costs The average drug developed by a major pharmaceutical company costs at least $4 billion, and it can be as much as $11 billion (Source: : InnoThink Center 2011) Industry is spending more to get less Cost of R&D investment has gone up from approx $2.5 billion in the early 1990 s to between $75 bn in 2010 (Source: Scrip July 2011) Number of annual NME approvals have not kept pace with this level of investment, with the current trend being < 20/year (Source: FDA CDER & CBER) <10% of INDs for NME progress to NDA. 2

3 The average drug developed by a major pharmaceutical company costs at least $4 billion, and it can be as much as $11 billion. Research Spending Per New Drug Company Number of Drugs approved R&D Spending Per Drug ($Bil) Total R&D Spending ($Bil) AstraZeneca GlaxoSmithKline Sanofi -Aventis Roche Holding AG Pfizer Inc Johnson & Johnson Eli Lilly & Co Abbott Laboratories Merck & Co Inc Bristol-Myers Squibb Co Novartis AG Amgen Inc Sources: InnoThink Center For Research In Biomedical Innovation; Thomson Reuters Fundamentals via FactSet Research Systems 3

4 Difficult Market Condition - Patients and end-users are more influential - Payers are increasingly pressuring pharma to demonstrate superior efficacy - Pricing pressure is driving market share of generics 10 % success rate 1.3 billions 8 years - Patent Expiry hits the blockbusters - FDA raises the bar/ changes the rules - Government takes over of health care constraining drug cost Marginal and Decision Economics 28 (4), 2007

5 Patent Expiration Impact Companies Share of Revenues (%) Novartis Femara $1.1bn Diovan $6.0bn 14 Eli Lilly Zyprex$4.8bn 22 Merck Cozaar /Hyzaar $3.2bn Singulair $4.5bn 22 GSK Advair $3.8bn Avandia $2.5bn 23 BMS US Plavix $4.8bn Avapro $1.3bn Abilify $2.1bn 30 Sanofi- Aventis Taxotere $2bn US Plavix $3.8bn Avapro $2.1bn Lovenox $3.1bn 34 AstraZeneca Arimidex $2.2bn Seroquel $4.7bn Symbicort $3.7bn 38 Pfizer Aricept $0.8bn Lipitor $12.1bn Xalatan $1.6bn Viagra $4.5bn Detrol $0.9 Geodon $1.1bn 41 5

6 Avoiding Haphazard Development To Develop in vitro and in vivo Models Predictive of Efficacy and Safety in Humans to Validate Target and Select Ideal Candidate Savitz SI, Fisher M. Ann Neurol May;61(5):

7 Why is Attrition High? Gap between preclinical and clinical development Efficacy & Safety in Preclinical Studies Efficacy & Safety in Patients - Lack of understanding of aspects of underlying pathophysiology thus flawed hypothesis - Unprecedented targets being pursued - Target engagement not confirmed - Preclinical animal models have poor clinical face and predictive validity - Human experimental test not assessing mechanism/ PoC based on etiology - Clinical trial design flaws

8 Traditional R & D Paradigm Target Discovery & Validation Lead Discovery & Optimization Pre-Clinical Development Phase 1 Phase 2 Phase 3 NDA PK, Safety POC, DRF Confirmatory Post-approval Separate Endeavors in their Own Silos without Integrated Translational Approach Leading to More Failures Than Success 8

9 Paradigm Shift Toward Translational R & D Data Generator To explore and validate animal models and biomarkers which are predictive, translational into target patient Population Integrated Endeavors, Bi-directional process from bench to bedside and back Back-Translation from what we learn from clinical trials to the bench to refine biologic principles underpinning heterogeneity of human disease & drug responses Data Translator

10 A New Development Paradigm Integrated approach using predictive biomarkers and animal models - Biological : genetic, biochemical, pathophysiological network - Pharmacological : PK-PD relationship - Innovative clinical development : adaptive, parallel, data-led Ann 1 st Super Santia 2011 Vol 47. No. 1:

11 Biomarkers as Cornerstones in Translational Medicine Discipline Definition : biological, biochemical, or biophysical parameters that can be monitored objectively and reproducibly in animal models or humans Feuerstein and Chavez, Stroke,

12 Application of Biomarkers at Each Stage of Clinical Development Improved Models Efficacy & Safety Validated Targets Disease Progression Product Differentiation Target Discovery & Validation Lead Discovery & Optimization Pre-Clinical Development Phase 1 Phase 2 Phase 3 Phase 4 PK-PD & Dosing New Indications Molecule Selection Patient Stratification 12

13 Animal Models Construct Validity Accuracy of the model with respect to the specific human disorder Face Validity The extent to which animal model exhibits behavioral, cellular and molecular characteristics of the human disorder Predictive Validity Current clinical treatments are effective in the model Treatments? Semiology? Etiology? 13

14 Refinement of animal models To Go from patients to models Similarity in etiology and natural course of the human disease Optimization of methodological rules Inclusion of a broad package of outcome measures to try to capture the multifaceted nature of target disease 14

15 To Maximize Translatability - Right target engagement: quality of target more validated, druggable, predictive biomarkers in human target tissues - Right tissue exposure : Bioavailability, PK-PD prediction - Right efficacy : predictive animal models, independent replication - Right safety : safety margin - Right patients : selection of homogeneous patients, genotypingpharmacogenetics on response - Right commercial: active comparator, outcome measures, COGS

16 R & D Success Technology Innovation = Value Creation 16

17 Translating Technology Innovation into Value Creation At Very Early Discovery stage 1. Determine Target Product Profile - Understand Unmet Medical Needs - Establish Clinical Benefit /Risk Profile - Identify Right Target Patient Population Who Benefit Most 2. Establish Commercialization Strategy - Define Competitive Advantage against SOC and/ or competitors - Enhance Market Access and expand reimbursement coverage 3. Develop Regulatory Strategy - Pursue Strategic Indications - Clarify Regulatory Path 4. Develop and Conduct Cost- & Time- efficient Clinical Studies accelerating into PoC - Adopt real-time feed back information - Incorporate appropriately validated biomarkers - Develop innovative, adaptive, flexible design - Implement modeling & simulation exercise for dose selection 17

18 The Reality-Driven R & D Goal for Korean Pharma is NOT to Obtain Global NDA BUT to achieve compelling PoC Realistic Goal of the R & D Success is to Achieve Compelling PoC which Enables to License-Out to Global Pharma Initial Goal of R & D is How Fast to reach PoC (P2a Study) Making Go-/No- Go Decision before Moving Forward to the Expensive, Lengthy Confirmatory P2b and P3 Studies 18

19 2012 년상반기글로벌제약사들의주요라이센싱계약 양수자 / 양도자기술 ( 물질 ) 적용증개발단계계약금계약규모계약내용 Forest /Jansen Bystolic 고혈압출시 357M 357M 미국및캐나다특허권취득 -> 로열티지급의무사라짐 Omega / GSK OTC 제품 - 출시 615M 615M Lactacyd, Abtei, Zantac 등 OTC 브랜드인수 Stiefil/ Basilea Toctino 습진출시 226M 305M Alcon / ThromboGenics Ocriplasmin 유리체황반견인 NDA 90M? 493M 1. 추가개발및마케팅은 Stiefil 책임 2. 미국판매 3년후부터두자리 % 로열티지급 1. 미국외시장에대한독점권 ( 미국시장은양도자판권유지 ) 2. 미국외시장에서판매에따른로열티지급 Royalty / Fumapharm BG-12 판상건선 NDA? 761M 독일에서 NDA 승인된약물 Merck / Endocyte Vintafolide+ EC20 자궁암 / 폐암 P3( 자궁암 ) P2 ( 폐암 ) 120M 1B 1. 미국판매이익분은양사간균등배분 2. 미국외지역판매에대한 2자리 % 로열티지급 Merck KgaA/ Threshold TH-302 육종 / 췌장암 Abbott / Galapagos GLPG0634 (JAK1 억제제 ) P3 ( 육종 ) P2 ( 췌장암 ) 25M 550M 1. 적용증확대위한추가임상시험진입중 2. 판매에대한 2자리 % 로열티지급 RA/ 면역질환 P2 150M 1.35B 임상 3 상부터 Abbott 가임상시험및제조책임 Ironwood / Bionomics BNC210 우울증 P1 3M 345M 초기공동연구후 Ironwood 가이후임상및개발책임 BI / Forma 후보물질암전임상 65M 815M 4 년간항암제공동연구 ( 상업화전마일스톤 $700M 수준 ) Celgene/ Inhibrx 항체프로그램 - 전임상? 500M 공동연구후판매시로열티지급가능. Genentech /.AC Immune Tau 항체 알츠하이머 / 퇴행성신경질환 전임상? 418M 1. 연구지원후판매에대한로열티지급 2. Genentech 이전임상, 임상, 제조, 및상업화에대한진행. Novartis / Enanta EDP-239 C 형간염치료제전임상 34M 440M 공동연구후판매에대한두자리 % 로열티지급 Janssen Biotech / Forma 후보물질암탐색연구? 700M 1. 공동연구후매출액에따른로열티가능 2. 북미지역에서의공동권리지위유지 Genentech / Xenon 후보물질 통증 탐색연구? 646M Genetech 의물질독점라이선스, 진단은비독점라이선스 LEO Pharma/ Virobay 후보물질 건선 탐색연구 7M 307M First-on-market 건선치료제공동연구 Roche / Savira 항바이러스제 독감 탐색연구? 302M 치료제공동연구후판매에따른로열티지급 AZ &BMS / Amylin 당뇨pipeline B 3.4B AZ와 BMS 간의당뇨병전략적제휴에따른 Amylin 인수합병 Merck / Ambrx Chemical-Protein Conjugate M 303M 특정적용증에대한전세계기술전용권 Top partnering deals so far in 2012 August 9th, 2012 partneringnews 19