1. R&D Activities and Future Prospects of Korean Pharmaceutical Companies on Chiral API and Intermediates 2001 년 7 월 12 일 한미약품중앙연구소 소 장 이 관 순 산업자원부 지원 : 중기거점기술개발과제 심포지움

2. Contents 1.General Aspects of Chiral Drugs –Advantages and Disadvantages of Chiral Drugs -US FDA ACT on Chiral Drugs -Market Potential of Chiral Drugs 2.Chirotechnology Research Consortium -Formation of Research Consortium –Project Overview 산업자원부 지원 : 중기거점기술개발과제 심포지움

3. Sales Proportion of Pharmaceutical Fine Chemicals * 산업자원부 지원 : 중기거점기술개발과제 심포지움 Typical Cost Breakdown for a Patent Protected Pharmaceutical * ClassificationAPI Advanced Intermediates Basic Building BlocksTotal Sales(%)12.1 bil$(55%)5.94 bil$(27%)3.96 bil$(18%)22 bil$(100%) R&DAPIFormulationSalesProfit 14%11%18%35%22% * Source: Arthur D. Little International(1999), excluding captive use * Source: Jackson(1992) (Typical total Cost $5,000~ $10,000/kg)

4. The Choice of the Stereochemical Form in Drug Development 산업자원부 지원 : 중기거점기술개발과제 심포지움 Achiral? Racemic? Chiral? Diastereomeric Mixture? Quality, Safety, Efficacy, & Risk-Benefit

5. Chiral Compounds(Drugs)  Advantages – provide much more information about receptor/enzyme - ligand/substrate interactions – improve drug efficacy by selectively interact with enzyme or receptor – reduce adverse effects by unwanted isomers – can be useful candidate for target-oriented drug development in the post- genomic era – create higher value utilizing chirotechnology - enlarge chemist's role in drug development  Disadvantages –regulatory requirements: should contain additional pharmacodynamic, pharmacokinetic, and toxicological documentations compared to achiral drugs –generally require more cost in chemical synthesis 산업자원부 지원 : 중기거점기술개발과제 심포지움

6. FDA ACT(1992) on Chiral Drug  Generally require pharmacokinetic and toxicological documentation of each/or unwanted isomers when the drug is developed as chiral or racemic ... a single-enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity... ▶ Considerable efforts of drug applicants 산업자원부 지원 : 중기거점기술개발과제 심포지움

7. FDA ACT(1997) on Chiral Drugs  Granted to the applicant five-year marketing exclusivity of the chiral drug which has already been approved as racemic drug ▶ Acceleration of the chiral switches of racemic drugs ▶ Another way of patent extention ▶ Fine chemical companies started to think “ Chirotechnology ” as more than an academic curiosity 산업자원부 지원 : 중기거점기술개발과제 심포지움

8. World Pharmaceutical Market Chiral Finished Products(API?) Market C&EN Forecast 산업자원부 지원 : 중기거점기술개발과제 심포지움 Year199420002005Growth(%) Market(bil.U$)2563704906 Year199019921994199619982000Growth(%) Market(bil.U$) 18.029.245.261.472.9126~ 20

9. ‘ 99 World Blockbursters* 산업자원부 지원 : 중기거점기술개발과제 심포지움 ★ : chiral, △ : racemic/or under chiral switch, ×: achiral, *Source: PharmaBusiness, No. 35, May 2000. '99 Rank Generic Name '99 Sales % GrowthChirality'99 RankGeneric Name'99 Sales% GrowthChirality 1Omeprazole 5,909.0 +23.1 △ 22Metformin.HCl 1,317.0 +53.0× 2Simvastatin 4,495.0 +13.9 ★ 23Filgrastim 1,260.0 +12.5 ★ 3Atorvastatin calcium 3,700.0 +68.2 ★ 24Clarithromycin 1,250.0 0.0 ★ 4Amlodipine besylate 3,030.0 +17.7 △ 25Lisinopril 1,221.0 +8.4 ★ 5Loratadine 2,700.0 +17.4×26Ceftriaxone sodium 1,197.7 +10.6 ★ 6Fluoxetine.HCl 2,613.4 -7.0 △ 27Pravastatin 1,128.1 +4.9 ★ 7Enalapril maleate 2,305.0 -4.0 ★ 28Congugated estrogens 1,090.0 -0.1 ★ 8Paroxetine.HCl 2,109.2 +22.8 ★ 29Human insulin 1,087.5 +13.4 ★ 9Sertraline.HCl 2,034.0 +10.8 ★ 30Fluticasone propionate 1,079.0 +30.7 ★ 10Lansoprazole 1,900.0 +46.2 △ 31Sumatriptan succinate 1,058.0 -8.6× 11Olanzapine 1,885.0 +30.7×32Alendronate sodium 1,045.0 +34.8× 12 Amoxicillin+Clavulanate1,819.3 +16.5 ★ 33Ranitidine.HCl 1,037.0 -17.4× 13Epoetin alfa 1,760.0 +27.5 ★ 34Sildenafil citrate 1,033.0 +31.1× 14Pravastatin sodium 1,704.0 +3.7 ★ 35Fluconazole 1,002.0 +9.4× 15Ciprofloxacin.HCl 1,625.3 -1.2×36Cisapride 975.0 +0.9 △ 16Epoetin alfa 1,760.0 +27.5 ★ 37Risperidone 970.0 +12.9× 17Celecoxib 1,500.0 -×38Nifedipine 954.2 -8.7× 18Paclitaxel 1,481.0 +22.8 ★ 39Diclofenac sodium 946.7 -9.6× 19Losartan potassium 1,385.0 +30.7×40Salmeterol xinafoate 922.0 +11.7 △ 20Cyclosporine 1,339.3 +5.0 ★ Total 68,705.7 +17.4 21Azithromycin 1,333.0 +28.0% ★

10. Classification of '99 Chiral Blockbursters 산업자원부 지원 : 중기거점기술개발과제 심포지움 (unit: mil.U$) Classification No. of Drugs MarketGrowthComments Chiral20(50%) 34,898.1 (50.8%) +16% Chemical: 16 Natural4.5 Semi-synthetic6.5 Total synthesis5 Biological: 4 Natural1 Recombinant3 Racemic/under chiral switch 6(15%) 15,349.4 (22.3%) +15.6% Racemic: 1 Chiral switch: 5 Achiral14(35%) 18,458.2 (26.9%) +21.8% (+11.9%) * * Celebrex contributed 10% increase Total40(100%) 68,705.7 (100%) +17.4% (+14.9%) * * With or without Celebrex

11. 98 Korean Pharmaceutical Market * 산업자원부 지원 : 중기거점기술개발과제 심포지움 unit: Bil.U$ * 1U$= 1,100 Won Product Domestic Production ImportExportNet Market Finished Product 5.97(91.4%)0.19(27.5%)0.13(23.6%)6.03(90.5%) API0.55(8.6%)0.50(72.5%)0.42(76.4%)0.63(9.5%) Total6.53(100%)0.69(100%)0.55(100%)6.66(100%)

12. 98 API Domestic Production 산업자원부 지원 : 중기거점기술개발과제 심포지움 unit: Mil.U$ Classification Production (Mil.U$) Main Products(Export) 100: Agents for nervous systems20.3(3.7%) 1. 7-ACA(72.2) Cephalosporin(39.8) Cefotaxime(25.9) Cefazolin(18.9) Cefradine(14.3) Ceftriaxone(13.7) Cefotaxime sodium(12.9) Cepha(sub-total): 197.7 2. Thymidine(44.9): Chirotech. Product 3. Cilostazol(15.8) 200: Agents for each organs36.8(6.7%) 300: Metabolic Agents43.0(7.8%) 400: Functional agents for cells2.1(0.4%) 600: Anti-infective Agents371.5(67.8%) 700: Other Agents74.3(13.6%) Total548.0(100.0%)

13. Timing of Research: Important 1) Feasibility Study(Research) ▶ Complete analysis on state of the art(Patents, Articles) ▶ Confirm the technological and economic situation of known processes ▶ Design new process and practice whether it is noble and economic ▶ File new patents(processes, product as intermediate, use,...) 2) Practical Approach(Development) ▶ Analyze the real market and contact the potential partner on the possibility of business ▶ Stabilize the patented process and run pilot production ▶ Prepare the documents for the product registration 산업자원부 지원 : 중기거점기술개발과제 심포지움 Stage of New Drug Discovery (Product) Preclinical Clinical (Phase I) Clinical (Phase II) Clinical (Phase III) Marketing (Monopoly) Intermediate Feasibility Study Practical Approach Most Korean Companies : too late API Feasibility Study Practical Approach Most Korean Companies : too late

14. 산업자원부 지원 : 중기거점기술개발과제 심포지움 원료 의약품과 의약품 중간체의 개발 전략의 차이 원료 의약품의약품 중간체 실제 시장국내, 제 3 세계, 선진국 (Generic)Original Company, 기타시장 ( 매우 적음 ) 개발 시점 신약이 Marketing 된 후에 단계적 전 략으로 접근 신약 Marketing 전 개발 완료, Original 사와의 전략적 제휴 개발후 시장진입 위험도 낮음높음 제품 특성 제품의 부가가치 위주 한가지 제품당 한가지 기술 기초 기술의 부가가치 위주 한가지 기술로 여러제품 Portfolio 형성 가능 생산설비특수의 소규모 생산설비대량 생산설비 + 소량 생산설비 부가가치높음중간정도 ( 기술에 따라 다름 ) 생산 수량소량생산 (~ 10 ton/year) 대량생산 (> 100 ton/year) Documentation 복잡하고 시간이 많이 걸림간단하며 단시간에 가능 개발회사 Pharmaceutical CompanyChemical Company 항목

15. 산업자원부 지원 : 중기거점기술개발과제 심포지움 Patent Coverage by the Originator Companies 28~3031~40year1~34~67~910~1216~1819~2122~2425~2713~15 Product Intermediate (Product & Process) Process Formulation Use Method of Administration Polymorphism (Product) Development DiscoveryPreclinicalClinical PMSLaunch Marketing Patent PTR Patent (Chiral?)

16. Total Worldwide Generic Drug Market(1996~2002) *** 산업자원부 지원 : 중기거점기술개발과제 심포지움 * Proportion of generic drug in value~ 45,648/370,000x100= ~12.3% ** CAGR: Compound Annual Growth Rate *** Source: Theta Report No. 741, May 1998 unit: U$m USJapan 9,294(29.8%)4,216(13.6%) 9,795(30.1%)4,350(13.4%) 10,716(30.6%)4,575(13.1%) 12,070(31.2%)4,895(12.7%) 14,888(32.6%)5,510(12.1%) 18,602(34.0%)6,350(11.6%) 21,568(34.5%)7,050(11.3%) Year 1996 1997 1998 1999 2000 2001 2002 CAGR ** (1997~2002) +17.1%+10.1% Europe 6,195(19.9%) 6,498(20.0%) 7,025(20.1%) 7,795(20.1%) 9,300(20.4%) 11,200(20.5%) 12,775(20.4%) +14.5% Rest of the World 11,379(36.7%) 11,891(36.5%) 12,675(36.2%) 13,925(36.0%) 15,950(34.9%) 18,500(33.9%) 21,200(33.8%) +12.3% Total Worldwide Revenues 31,084 32,534 34,991 38,685 45,648 * 54,652 62,593 - Total Worldwide Growth % - +4.7% +7.6% +10.6% +18.0% +19.7% +14.5% +14.0%

17. Patent Expiries on Major Products in the US (2000~2004) 산업자원부 지원 : 중기거점기술개발과제 심포지움 Comments CompanyBrandGeneric NamePatent Expiry Global sales($m) 19951999(+/-)% VasotecEnalapril20002,3002,305+Dec 24 1985 ProzacFluoxetine20012,0662,613.4+Dec 29 1987 CiproCiprofloxacin20021,6001,625.3+Oct 22 1987 Losec/PrilosecOmeprazole20011,3605,909+++++Feb 14 1988 AugmentinAmoxicillin/Clavulanate20021,3151,819.3+Aug 6 1984 MevacorLovastatin20011,260600--Aug 31 1987 Procardia XLNifedipine20031,134521--Sep 6 1989 RocephinCeftriaxone20001,0461,197.7+Dec 21 1984 PepcidFamotidine2000893910+Oct 15 1986 DiflucanFluconazole20048791,002+Jan 29 1990 ZestrilLisinopril20018621,221+Dec 30 1987 HumulinInsulin20007941,087.5+Apr 29 1992 ClaritynLoratadine20006282,700+++Apr 12 1993 NolvadexTamoxifen2002566572+Dec 30 1977 PrimaxinImipenem/Cilastatin2002565575+Nov 26 1985 AxidNizatidine2002548354.7-Apr 12 1988 Intron Aα-Interferon2002433650+Jun 4 1986 CarduraDoxazocin2000413794+Feb 8 1995 RelafenNabumetone2000410454.5+Dec 24 1991 PrinivilLisinopril2001340815++Dec 29 1987 AccuprilQuinapril2001312514+Nov 19 1991 BuSparBuspirone2000310605++Sep 29 1996 DuricefCefadroxil2002290165-Feb 17 1978 EulexinFlutamide2001290130--Jan 27 1989 SandostatinOctreotide2002224360.7+Oct 21 1988 LescolFluvastatin2003215459.3++Dec 31 1993 MonoprilFosinopril2001200424++May 16 1991 27 품목 26 성분 -21,253.030,384.4+43%- Merck Lilly Bayer Astra-Merck SB Merck Pfizer Roche Merck Pfizer Zeneca Lilly S-Plough BMS S-Plough Sandoz BMS Total S-Plough Pfizer SB Merck W-Lambert BMS Zeneca Merck Lilly

18. Patent Expiries on Major Products in the US (2005~ ) 산업자원부 지원 : 중기거점기술개발과제 심포지움

19. Research Consortium 산업자원부 지원 : 중기거점기술개발과제 심포지움 UniversitiesResearch InstitutesCompanies - Korea University - Sogang University(2) - Yonsei University(2) - Hankuk Universities of Foreign Studies - Hanyang University - Sungkyunkwan University - Kyunghee University(2) - Hanlim University - Korea Institute of Science and Technology(KIST) - Korea Research Institute of Chemical Technology(KRICT) - Chongkundang Corp. - Dongwha Pharm. Co., Ltd.(2) - Ildong Pharm. Co., Ltd. - Dong-A Pharm. Co., Ltd. - Kukje Pharm. Co., Ltd. - Hanmi Pharm. Co., Ltd. - Chungwae Pharm. Co., Ltd. - Daewoong Pharm. Co., Ltd. - Yuhan Corp. - Korea Fine Chemical Co., Ltd. - C-TRI - Kyungbo Chemical Co., Ltd. - Boryung Pharm. Co., Ltd. 8 Universities(11 teams)2 Research Institutes 12 Companies(13 Projects)

20. Role of Each Teams 산업자원부 지원 : 중기거점기술개발과제 심포지움 Companies (Production Technology) KDRA (Strategic Planning & Management) Universities (Basic Technology) Research Institutes (Application Technology)

21. Strategies for Developing Chirotechnologies 1.Using Chiral Pools or Chiral Reagents 2.Using Chiral Catalysts....... Chemical Synthesis 3.Using Enzymes or Microbial Strains 산업자원부 지원 : 중기거점기술개발과제 심포지움

22. Monocyclic beta-Lactams Using Chiral Reagents 산업자원부 지원 : 중기거점기술개발과제 심포지움 Synthetic Route to Monobactam Intermediate - Chongkundang Corp. & Korea University

23. Synthesis of Enol Phosphate Using Achiral Auxiliaries 산업자원부 지원 : 중기거점기술개발과제 심포지움 - Dongwha Pharm. Co., Ltd. & KRICT

24. Chiral Benzoxazine via Chiral Reducing Agents 산업자원부 지원 : 중기거점기술개발과제 심포지움 - Ildong Pharm. Co., Ltd. & Sogang Univ.

25. Epirubicin from Doxorubicin 산업자원부 지원 : 중기거점기술개발과제 심포지움 - Dong-A Pharm. Co., Ltd.

26. Stereospecific Synthesis of 2-Deoxy-L-ribose 산업자원부 지원 : 중기거점기술개발과제 심포지움 Kukje Pharm. Co., Ltd. - Yonsei Univ.

27. Synthesis of (2R,3S)-Phenylisoserine: Side Chain of Taxol & Taxotere 산업자원부 지원 : 중기거점기술개발과제 심포지움 Hanmi Pharm. Co., Ltd. - Hankuk Univ. of Foreign Studies

28. Chiral Glycidols and Product Specialization from Them 산업자원부 지원 : 중기거점기술개발과제 심포지움 Choongwae Pharm. Co., Ltd.- Sungkyunkwan Univ., Kyunghee Univ., Hanyang Univ.

29. Stereospecific Reduction of Cholic Acid: Synthesis of CDCA 산업자원부 지원 : 중기거점기술개발과제 심포지움 - Daewoong Pharm. Co., Ltd.

30. ACE Inhibitors & Intermediates 산업자원부 지원 : 중기거점기술개발과제 심포지움 - Korea Fine Chemical Co., Ltd. - KIST

31. Synthesis of Paroxetine - An antidepressant 산업자원부 지원 : 중기거점기술개발과제 심포지움 - C-TRI

32. Development of DHIQ, an Intermediate of AIDS Drug 산업자원부 지원 : 중기거점기술개발과제 심포지움 - Kyungbo Chemical Co., Ltd.

33. An Intermediate of AIDS Drug via Stereospecific Reduction 산업자원부 지원 : 중기거점기술개발과제 심포지움 - DongWha Pharm. Co., Ltd. & Hanlim Univ. -

34. Development of Tamsulosin from Chiral Amine 산업자원부 지원 : 중기거점기술개발과제 심포지움 - Boryung Pharm. Co., Ltd. & Kyunghee Univ.

35. Conclusion 1. Based on basic and application researches, production processes for chiral intermediates, chiral API, and related technologies will be developed until 2003 by the chirotechnology research consortium, which will be supported by the "Ministry of Commerce, Industries & Energy, Korean Government". 2. The research consortium will develop 21 chiral intermediates, 8 API's, and various kinds of chirotechnologies which are potentially useful in pharmaceuticals synthesis through this research program. 3. Total sales of developed products is expected to be around 100mil.U$ in 2003~2004, technology platform as well as corperative research consortium in chirotechnology will be formed in Korea through this research program, leading to facilitate the practical application of chirotechnology in pharmaceutical company, i.e., research to production. 산업자원부 지원 : 중기거점기술개발과제 심포지움

36. Acknowledgements ▶ Ministry of Commerce, Industries & Energy, Korean Government ▶ Chongkundang Corp.(Dr. T. W. Kang), ▶ Dongwha Pharm. Co., Ltd.(Mr. Y. H. Cho), ▶ Ildong Pharm. Co., Ltd.(Dr. J. H. Kang), ▶ Dong-A Pharm. Co., Ltd.(Dr. K. C. Im), ▶ Kukje Pharm. Co., Ltd.(Dr. Y. R. Choi), ▶ Hanmi Pharm. Co., Ltd.(Dr. Y. S. Byun), ▶ Choongwae Pharm. Co., Ltd.(Mr. C. J. Moon), ▶ Daewoong Pharm. Co., Ltd.(Dr. Y. S. Byun), ▶ Korea Fine Chemical Co., Ltd.(Dr. K. B. Chae), ▶ C-TRI(Dr. Y. K. Baek) ▶ Kyungbo Chemical Co., Ltd.(Mr. I. H. Kang) ▶ Dongwha Pharm. Co., Ltd.(Dr. Y. S. Oh), ▶ Boryung Pharm. Co., Ltd.(Dr. J. H. Kim) ▶ Korea Drug Research Association(KDRA) 산업자원부 지원 : 중기거점기술개발과제 심포지움