卫博士BiosimilarsYFW——生物仿制药的机遇及挑战2009.10

1、13SBio Inc.Biosimilars - Opportunities and Challenges生物仿制药的机遇及挑战Yingfei Wei, Ph.D.October 17, 2009, Beijing, China2ContentslBiosimilars Overview 生物仿制药的概况lBiosimilars vs Innovators, Case Study 案例lOpportunities and Challenges 机遇及挑战纵观生物仿制药纵观生物仿制药l专利过期的生物药的复制品或仿制品(蛋白、抗体)l不同于小分子非专利药 不可能完全等同于品牌生物药l大分子、多元化

2、蛋白修饰l多种亚型与构象l免疫原性复杂的生产工艺l注射l高生产成本l需要特殊的质量、药效监管条例与标准l安全性l体内外分子特性及活性分析l免疫原性检测l上市后监察l需要特定法规lYears of exclusivity 创新品牌产品保护lInterchangeability/automatic substitution 处方药不可替换Higher success rate, lower development cost生物仿制药厂家需具备较高而全面的能力非专利化药非专利化药专利报批生产生物仿制药生物仿制药市场临床试验Pharmacovigilance药物警戒生产发展生物仿制药的推动力量发展生物

3、仿制药的推动力量lBiological drugs market is about $86 B 2007 and will exceed $135B by 2011快速增长的市场lLarge number of biological drug patents expire soon ($60B by 2015) 大量专利生物药专利即将到期lIncreasing market demand市场需求不断增长lAging population老龄人口增加lHealth awareness对健康的关注增加lAffordability and insurance coverage用于健康、医疗的费用不断

4、增加lIncreasing healthcare cost 健康医疗成本增加lIncreasing innovative drug R&D cost研发成本不断增加 廉价、安全、有效的生物药廉价、安全、有效的生物药提高成功率，降低研发生产成本，支持创新提高成功率，降低研发生产成本，支持创新15%85%20012003200520062007200820093%35%62%2010BiosimilarsCAGR 103%AntibodiesCAGR 27%RecombinantProteinsCAGR 10%20002001 20022003 2004 2005 200620102015

5、Large Molecule DrugsCAGR 18%Small molecule drugsCAGR 9%+10%Worldwide Market size (B)$255B$680B1. 2007 to 2010 based on forecastsNote: Biologicals from players in emerging markets, non-protein antiinfectives, vaccines, pregnancy hormones and non-protein hormones are excluded from the current analyses

6、 Source: Datamonitor; BCG生物药市场增长速度超过化药生物药市场增长速度超过化药Worldwide Market size (B)Market Size By Drug TypeBiologics Market By Segment1 Global StatelEU欧洲lEMEA: general guidelines in 2005lEU Commission: legislative framework in 2004lOver 10 products marketed since 2006 (hGH, EPO, GCSF, Insulin and IFN)lOver

7、 $10B WW sales by 2011lUSA: 1 (Omnitrope) approved as regular biologicalslCongress working on the new legislationlFDA working on new regulatory guidelineslJapan日本lGuideline established in fall 2008lThe first biosimilar drug filed for approvallIndia: activelChina: No clear guidelines available, activ

8、e生物药的中国市场生物药的中国市场lNew generation of biological drugslEPO, TPO, 3SBio + many developerslGCSF, many developerslEnbrel (益赛普 ), CITIC, Celgenl“Legacy” biological drugslInterferonlhGHlInsulinlInterleukinsSFDA Regulatory RequirementslMarketed product outside of China国外上市产品lComparable manufacture process a

9、nd QA/QC standardslComparable biological activity in vitro and in vivol1 month tox on 1 species*l1-2 efficacy modelslFull clinical triallMarketed product in China国内上市产品lComparable manufacture process and QA/QC standardslComparable biological activityl1 month tox on 1 species*l1-2 efficacy modelslPha

10、se III trial* Based on the comparability to the known drug, the pharmacology and toxicology study can be reduced or eliminated 10Biosimilars Market in China中国市场潜力中国市场潜力Central cities 10%County & mid-size cities 28%Town, Rural Areas 62%人口分布人口分布11生物仿制药与品牌创新药Process工艺 = product产品lHost cell expressi

11、on宿主细胞表达系统lFormulation配方lManufacture生产lRoute of administration给药途径12Case Study实例分析实例分析 重组促红细胞生成素重组促红细胞生成素Biochemical Assessment of Erythropoietin ProductsFrom Asia Versus US Epoetin alfa Manufactured byAmgenSUNGAE S. PARK,1 JIHEA PARK,1 JASON KO,2 LOUISE CHEN,1 DAVID MERIAGE,1 JILL CROUSE-ZEINEDDINI

12、,3WENDY WONG,4 BRUCE A. KERWIN2JOURNAL OF PHARMACEUTICAL SCIENCES 2008Published online in Wiley InterScience (). DOI 10.1002/jps.215461Amgen Inc., Process and Product Development, Formulation and Analytical Resources Group, Thousand Oaks,California 913202Amgen Inc., Process and Product Development,

13、Analytical and Formulation Sciences Group, Seattle, Washington 981193Amgen Inc., Process and Product Development, Cellular Sciences Group, Thousand Oaks, California 913204Amgen Inc., Department of Quality Assurance, Thousand Oaks, California 9132013Recombinant Human Erythropoietin (rHuEPO) Sample Li

14、st from AsiaMarketed Country Trade Name Company Exp. Date HSA CHO Cell Label Conc. (IU) Lot # Container Type USA Epogen1 Amgen August 5, 2007 Yes, 0.25% Yes 2000 P029954 Vial USA Epogen1 Amgen February 2, 2007 Yes, 0.25% Yes 3000 P008951 Vial USA Epogen1 Amgen January 8, 2007 Yes, 0.25% Yes 10000 P0

15、28155 Vial Korea Eporon Dong-A February 2007 Yesa Yes 4000 ED50398 Vial Korea Eporon Dong-A March 2007 Yesa Yes 4000 IU/0.4 mL PD50908 PFS Korea Espogen LG November 2007 Yes, 2.5 mg/mL NA 2000 IU/0.5 mL EPO05017 PFS Korea Epokine CJ March 2007 Yesa Yes 4000 IU/0.4 mL 5530 PFS China Epiao SS-Pharm No

16、vember 2007 Yes, 0.25% NA 2000 20051101 Vial China Jia Lin Hao Shandong E-Hua December 2007 Yesa Yes 3000 20051203 Vial China Ji Mai Xin Hua-Bae Pharm August 2007 Yesa NA 3000 Y20050931 PFS China Ji Mai Xin Hua-Bae Pharm September 2007 Yesa NA 3000 Y20051031 PFS China Huan Er Bo Beijing Four Rings M

17、arch 2008 Yesa NA 3000 IU/0.6 mL 20060305 PFS China Huan Er Bo Beijing Four Rings February 2009 Yesa NA 3000 IU/0.6 mL 20060203 PFS China SEPO China-SPG August 2007 Yes Yes 4000 20050905 Vial India Zyrop Imported from March 2008 Yes, 0.25% Mammalian 10000 H10-4031H01 Lyophilized Argentina (Bio Sidus

18、) cell In vial India Wepox Wockhardt August 2008 NA Mammalian 40000 XF10336 PFS cell India Shanpoietin Shantha Biotech April 2008 NA Yes 4000 EPO2206 PFS India Shanpoietin Shantha Biotech July 2008 NA Yes 4000 EPO2806 PFS India Epotin Imported from April 2008 Yes Yes 4000 Y20060541 PFS China (NCPCGB

19、) 14(A) samples from China (lanes 29) and Korea (lanes 1013) and (B) samples fromIndia (lanes 15).Iso-electro-focus (IEF)等电聚焦等电聚焦 Gel with Western blots for isoform detection:15SDSPAGE with Western blot analysis for detection of aggregation 聚合聚合16Relative denaturation by 9G8A antibody assay to detec

20、t unfolding structureSamples from China, Korea and India were compared to Amgen Epogen. A value of1 indicates no difference in folding between the sample and the EPO standard17Concentration determination by enzyme-linked immunosorbent assay (ELISA)Striped bars represent the labeled concentration and

21、 solid barsrepresent the concentration measured by ELISA. 18Conclusion结论结论 lrHuEPO from Korea, China, and India were compared with the innovator product, Epoetin alfa, in vitro for molecular integrity, glycoforms, and ELISAlrHuEPO from Korea, India, and China contained more glycoforms and other impu

22、ritieslThese data emphasize potential biochemical discrepancies resulting from different cell lines and manufacturing processes. lThese data formed the basis for a strong argument in favor of establishing high standards of quality control in product manufacturing and processing.Challenges for Biosim

23、ilars Development生物仿制药发展所面临的挑战生物仿制药发展所面临的挑战$SCompetitionInnovationRegulationIP$检测标准检测标准专利保护专利保护创新创新竞争竞争Challenges for BiosimilarslHigh cost, longer term相对高成本、长周期lComplicated analytical techniques复杂的分析技术l“innovative like” clinical studies临床试验lEffective brand patent protection for over 20 years专利lEnter the market at risk (against innovative drug and other competitors)风险lNo interchangeability, brand marketing requiredlMicrobial and/or mammalian cell manufacturing capability 蛋白细胞表达与生产lOverall, high barriers to entry, but high