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1 從國際觀點論台灣新藥創新研發策略及產學合作機制 : 以 RSV Vaccine 為例顧曼芹博士 M. Sherry Ku, Ph.D., R.Pharm Kus_98@yahoo.com TWi Biotechnology Inc. 生醫創新研發技術商化論壇 _ 暨 _ 第九屆國家新創獎說明會議 April 19, 2012

2 Presentation Outline Introduction Current US New Drug Trend Open Innovation Model Unmet Medical Needs End-Game Based Project Selection Process High Barrier RSV Vaccine NHRI-Twi Biotech RSV Strategy Q&A 2

3 EvaluatePharma World Preview 2016 Prediction Slower Worldwide Prescription Drug Sales Total $785bn in 2016; 2.9% (CAGR) over ; Over $267bn of Sales at Risk from Patent Expirations ; Slower Global Pharmaceutical R&D Growth 2.3% CAGR to $145bn by % CAGR, 2009 down 0,9% to 124bn Biotech Products Fail to Overtake Small Molecule within Top 100 Drugs by 2016 partly due to Biosimilar entries 3

4 2011 US FDA in Review: A turning point from conservatism on Drug Safety to patient needs??? 1. CBER integrated into CDER. 2. Estimated 2010 based on 9 approvals by August 4

5 2011 US FDA 35 NME Approval Mostly from Specialty Pharma on Rare Diseases 13 from Large Pharma, 23 from smaller firms 10 orphan Drugs (paitent population < 200,000) 16 Priority Review (Review in 6 Months) 13 Fast Track (Rolling review and Frequent FDA consultation) 3 Accelerated Approval (by pass clinical end point (survival) but surrogate (shrink tumor)) 2 with companion diagnostic kits Xalkari ALK NSCLC (Pfizer/Abbott) Zelboraf Braf Melanoma (Genetech) FDA Draft Guidance, In Vitro Companion Diagnostic Devices, issued on July 14,

6 2011 US FDA 35 NME Approval Mostly Small Molecules but No nanoparticles 27 Small molecules, 7 biologicals, 1 polypeptide 7 Biologicals including 1 vaccines and 1 diagnostic 7 Cancer drugs (3 Kinase, 2 Mab, 2 NCE) 3 antiviral 2 antibiotics 1 head lice 2 imaging agent, 1 cosmetic agent 2 DPI 1 prodrug Drug delivery 6

7 Why even the most efficacious therapy do not have 100% response rate Ref: Spear et al Clinical applications of pharmacogenetics. Trends in Mol. Med. 7; ,2001 4/9/2012 M.Sherry Ku 生醫創新研發技術商化論壇 7

8 Open Innonvation Model

9 Product Life Cycle Curve Determination of Net Present Value Time to market Technology available Technical expertise Proximity Quick reaction Proven quality system High capacity Low cost Low cost 12/16/2010 學界研發策略及與產業合作模式 9 9

10 Product-related Deals by Stage of Development Source: MedTRACK, pulled 2/5,

11 Phase 2 Attrition due to Lack of Efficacy Create Opportunity for In-Licensing of Phase 2 POC Compounds 4/9/2012 4/19/2012 M.Sherry Ku Ku Opportunity 生醫創新研發技術商化論壇 in Specialty Pharma 11 11

12 Big Pharma s Collaborative Open Source: Nature Medicine may 2009 Innovation Model 12 12

13 Principal Investigators in US IND are 41% from foreign countries in 2007 Murray M. Lumpkin, FDA Deputy Commissioner of international Programs Within the next 3 years, upto 65% of clinical studies will be conducted outside the US. 35% remains in US. 13

14 Project Selection based on Unmet Medical Needs

15 Cardiovascular disease has been treated successfully and few options remain wanted. Unmet needs No interest 1. Heart Failure drugs 1. Fibrates 2.Atrial Fibrillation 2. PPAR 3. Anti-coagulants 3.ACE inhibitors 4. Anti-platelet agents 4. B-blockers 5.Adrenergic agents 6. Heparins 7.Treatment of acute Myocardial Infarction 8.Treatment of restenosis 15

16 Why Diabetic Mellitus has many treatment options but remains an area of interest??? Merck is interested in: 1. Liver targeting insulin 2.Non injectable insulin 3.Best in class GLP-1 4.Non-PPAR insulin sensitizer 5.Glucose dependent insulin secretagogue (GDIS) 6.B-cell protection 7.Combine c/metforminin Merck has no interest in: 1. B-cell transplant 2. Non-GDIS 3. PPAR 4.Any lead with unknown molecular target 5. Neutraceutical TWi AC-201 meet 4 criteria 16 16

17 Project/Target Selection Process

18 Project Selection Due Diligence End Game based Marketable Approvable Clinical Study Feasible Animal Model based on Medical Practice Market protection by IP or Trade secret or Contracts Move toward Individualized Medicine for a subset of population 18

19 End-Game Project Selection Process Project Selection Clinical Feasibility Animal Model Design In-Vitro Screening Lead Optimization Tech Transfer Medical Needs Established Market Size New Market Building (Herceptin was an orphan Drug) Patient Availability Study Duration Study Size Clinical End Points Clinical Safety Risk Translatable to Human Biomarker Available Dosing Regimen Milligram Potency Toxicity Evaluable in Animals Organ (target vs Vital) Distribution Fast Translatable Nanomolar Potency Clinical End Points Clinical Safety Risk Oral Bioavailability Metabolic Stability Biological half life Dosing Frequency Dose- Formulation Small Molecules Proteins Vaccines 19

20 RSV Vaccine Story

21 The global RSV disease rampant with no vaccine available or in Phase 3 trial to date Human Respiratory syncytial virus (RSV) was first isolated and in 1957 from children with acute respiratory disease. Infected cells attack neighboring cells to form syncytium. In 1960, infants vaccinated with formalin-inactivated RSV vaccine was not protected but had more severe disease. In 1990 more research done on the fusion or G protein subunits resulted in poor efficacy. Each year, around 3% of all infants 1 year or younger are admitted to hospital with lower respiratory tract viral infection. US estimated 14,000~62,000 hospitalizations with pneumonia associated with RSV infection in over 65 years of age The global RSV disease burden is estimated at 64 million cases and 160,000 deaths every year. In Taiwan, approximately 1,000 cases of infant infected with RSV per year have been reported. 21

22 RSV Therapy and Market Currently, the most successful product for RSV treatment is the prophylactic monoclonal antibody Synagis (FDA approved in 1998), which is directed against the fusion (F) glycoprotein of the RSV virus in high-risk pediatric patients with stable sales of $1.2 billion over 2009 ~ It has been estimated that an RSV vaccine could have peak sales of USD million at least (Datamonitor, 2010) 22

23 What is RSV? Why vaccine so difficult? An enveloped single-stranded RNA Pneumovirus of the Paramyxoviruidae family Two subgroups A and B, it was found that the G protein is only 43% homology in sequence whereas F protein is over 90% so most research focus on F protein. The disease aggravation Seen with FIRSV may be due to inhibited celluar immuneth1 CTL respnse by activated humoralth2. Currently strategy includes life attenuated and RNAi nucleocapsid and a Sendai virus vector. 23

24 Proliferating helper T cells differentiate into two major CD4+ cells known as Th1 and Th2 and CD8+ Cytotoxic T cells 24 24

25 生策會生醫創新商機媒合產學合作開發模式 Reviewed 生策會 2010 國家新創獎說明書 TWi 遴選 several 具市場競爭力與商品價值之投資標的 in 生策會 arranged meetings to review these projects and TWi visited several sites. 生策會 helped to chart the pathway for the collaboration with several follow up meetings Established 產學合作 co-development 3 year plan in February US IND and tfda submission is planned 6 months post production of GMP materials in NHRI. 25

26 NHRI RSV Vaccine Program Must inducing a balanced Celluar and Humoral response Infect the cell with non-replicating Adenovirus vector to induce cellular responses. RSV vaccine is capable of preventing infection by different strains of RSV Expressing E1, E2 target RSV B1 strand F-protein rad-f0, with 90% homology to A2 and etc rad-f0 TM Bioengineered recombinant Human Embryo Kidney 293A cell with truncated ΔE1/ΔE3 (replication-incompetent) Ad5 vector encoding gene and 1. RSV-B1 fusion (F) glycoprotein gene, F0, 2. Or F0ΔTM (Transmembrane truncated version) 4/9/2012 M.Sherry Ku 生醫創新研發技術商化論壇 26

27 Study Protocol Immunization followed by RSV challenge Day 0 (Prime; i.n.) 1x10 7 pfu/50µl 1.rAd-F0 2.rAd-F0 TM 3.rAd-LacZ 4.HIRSV-B1 Day 20 (Boost; i.n. s.c. i.p.) 1x10 7 pfu/50µl 1.rAd-F0 2.rAd-F0 TM 3.rAd-LacZ 4.HIRSV-B1 Day 50 (Challenge; i.n) 1x10 6 pfu 1.Live RSV-B1 Day 14 (Collect Serum) 1.Ab titer against HIRSV-B1 2.Ab titer against Ad5 3.Virus Specific neutralizing activity Day 30 (Collect Serum) 1.Ab titer against HIRSV-B1 2.Virus Specific neutralizing activity Day 55 (Sacrifice) 1.Viral load determination in lungs by plaque forming assay 27 27

28 RSV Vaccine immunized mices showed protection against RSV 28

29 Cross reactivity of Immune sera IgG antibodies titer against 3 strains of RSV Subgroup B Subgroup A 29

30 Virus-neutralizing activity of Bronchioaveola Lavage from immunized mice via the intranasal route. Infected HEp2 cell Plaques counts after incubation with sera and B1 strain RSV virus 30 30

31 Induction of Th1 Th2 and Inflammatory IL-17 from immunized mice splenocytes cultured in the presence of HIRSVB1 for 48 h Th-1 Th-2 Th-2 Th-2 Th-2 Inflammation 31 31

32 Acknowledgement 財團法人國家衛生研究院 -- 周彥宏莊再成謝鐸源研究團隊 -- 疫苗研發中心國家生技醫療產業策進會 -- 廖繼洲處長張益華組長林伯熔經理安成生物科技股份有限公司 -- 黃嬿倫雷佑甯 32

33 Q & A

(Microsoft PowerPoint - ku \245\315\302\345\254\343\265o\262\243\276\307\260\323\244\306 RSV example.ppt [\254\333\256e\274\322\246\241])

$(Microsoft PowerPoint - ku \245\315\302\345\254\343\265o\262\243\276\307\260\323\244\306 RSV example.ppt [\254\333\256e\274\322\246\241])$ 從國際觀點論台灣新藥創新研發策略及產學合作機制 : 以 RSV Vaccine 為例顧曼芹博士 M. Sherry Ku, Ph.D., R.Pharm Kus_98@yahoo.com TWi Biotechnology Inc. 生醫創新研發技術商化論壇 _ 暨 _ 第九屆國家新創獎說明會議 April 19, 2012 Presentation Outline Introduction Current