Build Effective Vaccine R&D Capabilities with Chinese Characteristics

建立有中国特色的疫苗研发体系

Sean Du, Ph.D. , Executive Director, Vaccine Research报告人：杜笑寒 博士，疫苗研究部执行总监

Shanghai, China, 2010.09.15

Global Vaccine Market 世界疫苗市场概况• The worldwide market for vaccines has more than doubled from 2005 to 2008,

having grown at a compound annual rate of 32%. From year 2008 to 2009, vaccine sales was up a another 16% and hit $22.1 billion in 2009.

世界疫苗市场从 2005 年到 2008 年，翻了一番，年增长 32 ％。从 2008 到2009 ，又增加了 16 ％，达到 2009 年的 221 亿美金。

• Five vaccines with over $1B in annual sales. 五个疫苗年销售额达到 $10 亿美金– Wyeth Prevnar (pneumococcus) 惠氏公司脑炎疫苗用以预防侵袭性肺炎球菌疾病– Merck Gardasil (HPV) 默克公司子宫颈癌疫苗用以预防人类乳头状瘤病毒– Merck Zostavax (shingles) 默克公司水痘疫苗用以预防带状疱疹– Merck RotaTeq (rotavirus) 默克公司轮状病毒疫苗– GSK RotaRix (rotavirus) 葛兰素史克公司轮状病毒疫苗

• Vaccine sales will continue to rise annually at a rate of 9.7% for the next five years, which could push annual sales as high as $35 billion by 2015.

全球疫苗的销售在近五年会继续以 9.7 ％增长，并于 2015 年达到 $350 亿美金 .

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Global Vaccine Leaders 世界疫苗的竞争格局

Sanofi Pasteur 26%

GSK 23%Merck 16%

Wyeth 12%

Chiron 5%

Acambis 2%

Berna 2%

Solvay 1%MedImmune 1%

Baxter 1% CSL 1% Other 10%

• The top 5 players accounting for around 80% of the total market 全球前五大疫苗企业占了全球疫苗市场的 80%• 2005, 3 out of the world top 10 pharmas involved in vaccine business

2010, 9 out of the world top10 pharmas involved in vaccine business2005 年，世界十大制药企业只有三家有疫苗；目前十家里九家有疫苗产业

2005

百特澳洲英联邦血液实验室

凯龙惠氏

Sanofi Pasteur (2008.07, $546M)赛诺菲－巴斯德Novartis 诺华 (2006, $5.5B)

AstraZeneca 阿斯利康 (2007.06, $15.6B)

博尔纳Crucell 科伯纳 (2005.12.8, $450M)

Pfizer 辉瑞 (2009.10.15, $68B)

Johnson & Johnson 强生(2009.09, EU302M=18%stock)

苏威Abbott 雅培 (2010.02, EU4.5B)

Merck 默沙东 (2009.9.3 Flu vaccine)

默沙东 葛兰素－史克

赛诺菲－巴斯德

Major Vaccines in Development 全球现处临床开发阶段的主要疫苗

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Infectious Diseases 传染病

Manufacturer 生产厂家 Vaccine疫苗名称 Development临床开发阶段 Notes 备注Traveler's diarrhea 旅行者腹泻 Intercell N/A Phase II

Tuberculosis 结核菌 GSK N/A Phase II

Intercell N/A Phase I With Sanofi-Aventis

RSV 呼吸道合胞病毒 MedImmune Motavizumab Phase III

HIV/AIDS 艾滋病病毒 Novavax N/A Preclinical

Sanofi-Aventis N/A Phase III

HSV-2 2 型单纯疱疹病毒 GSK Simplirix Phase III Formally Herpevac

Dengue fever 登革热病毒 GSK N/A Phase II

West Nile virus 西尼罗河脑炎病毒 Sanofi-Aventis ChimeriVax-WN02 Phase II

Malaria 疟疾 GSK RTS, S Phase III

GSK Mosquirix Phase II

EBV 艾普斯登 - 巴尔病毒 GSK N/A Phase II From MedImmune

Typhoid 伤寒菌 Norvatis N/A Preclinical With Wellcome Trust

CMV 细胞巨大型病毒 GSK N/A Phase I

Staph. aureus 金黄色葡萄球菌 Merck V710 Phase II With Intercell“Nice Shot - Why vaccines are pharma’s Next Big Thing. ” 　 By Megan Scudellari, The Scientist 2009 24:32

Domestic Vaccine Market 中国疫苗市场• World’s largest population; 17 million newborn babies each year.

世界 1/4 人口；每年的一千五到七百万新生儿。• The largest vaccine manufacturer by dose; the fourth largest vaccine market.

世界上最大的疫苗生产国；世界第四大疫苗市场 .• Over 30 manufacturers producing ~40 vaccines against over 20 diseases

共有疫苗生产企业 30 多家，可以生产预防 20 多种传染病的 40 多种疫苗• The growth rate for the past has been ~15%, exceeding 5 billion RMB on 2009.

中国的疫苗市场过去几年的增速大约是 15% ,2009 年超过 RMB ￥ 50 亿元， • The best selling vaccines (by sales) are Rabies and Influenza vaccines.

以狂犬病疫苗和流感疫苗销售最高。• The growth rate for next few years over 20%, reaching 8 billion RMB by 2012.

未来几年的增速有望达到 25% ；到 2012 年，市场的容量将达到 RMB ￥ 80 亿元。• Only 1/25th of the world vaccine market. 占全球疫苗市场的 25-30 分之一

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Room for Growth: Vaccine Supply vs. Demand 成长空间：中国疫苗产能• For many vaccines, current domestic production capabilities can’t meet demand.

Most production processes need a major upgrade.

中国许多疫苗品种的产能严重不足，生产技术急需提升

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MMR 麻腮风

Varicella 水痘

Hep A 甲肝

DTP 白百破

Rabies 狂犬

Influenza 流感

Demand 需求

Supply 供应

Room for Growth: Process Improvement Needed成长空间：国内疫苗需要提升的生产工艺

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Areas need future improvement 生产工艺需要提升的疫苗领域Large scale production technologies for mammalian cells and several viral vaccines

病毒型疫苗及其宿主细胞的大规模培养技术，包括流感裂解疫苗，轮状病毒疫苗和水痘疫苗

Effective yeast expression platform and HPV vaccine 酵母高效表达平台，及酵母表达的 HPV 疫苗Effective insect expression platform and HPV vaccine 昆虫细胞高效表达平台，及昆虫细胞 HPV 疫苗Recombinant vaccine development 各种新型基因工程构建的亚单位疫苗Large scale production and process upgrade for several vaccines newly added to the National Immunization Plan

扩大免疫计划疫苗的规模化生产和升级换代，包括脊髓灰质炎疫苗；无细胞百白破疫苗；麻腮风三联减毒活疫苗；甲肝疫苗

Scale-up production and QC techniques for Pneumococcal 23-valent polysaccharide vaccine

23价肺炎疫苗的规模化生产和质控关键技术Highly efficient expression and purification of carrier proteins for conjugate vaccines

结合疫苗载体蛋白的高效表达技术和分离纯化技术Conjugate vaccine technologies, including activation of polysaccharide, conjugation, purification, QC, and evaluation of conjugation efficiency, etc.

细菌多糖－蛋白结合疫苗技术，包括多糖活化，结合条件和纯化条件的优化；质量分析标准的研究；疫苗结合效果的评估。涉及疫苗包括肺炎，流脑，Hib ，伤寒，副伤寒，痢疾，及大肠杆菌疫苗

Pros and Cons of Chinese R&D Environment中国疫苗研发环境的优缺点比较

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Pros

优点

Affordable HR cost (~1/7 of USA HR cost) 容易负担的人力资源 Strong government supports on land and infrastructure 强大的政府支持力度High quality hardware (GMP plant, instrument) 高质量的硬件系统Good working ethics 优良的职业道德Strong wills to learn new technologies 强烈的求知欲望Vaccine R&D budget can be relatively high (10-20%) 　　 疫苗研发投入比例相对较高

　　

Pros and Cons of Chinese R&D Environment中国疫苗研发环境的优缺点比较

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Cons

缺点

Expensive instruments (150% of listed prices) 偏贵的进口设备Long waiting period for any imported goods (2-3 months) 对进口物品漫长的等待时间Frugal attitude towards consumables can be costly 对消耗品的节约可能适得其反Softwares (SOP, training, compliance) need improvement 软件部分需要改进Not often with R&D mind-sets, lack of innovative thinking 无研发和创新思维习惯Leadership & VC are mostly looking for short-term return 领导和 VC 多数只重短期效益Can’t often take “it’s not working” for an R&D result 通常难接受研发不利的结果Non-R&D functions can negatively impact R&D outcome 非研发部门可以影响研发全局IT security management close to non-existing 信息安全意识和管理几乎为零

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R&D Strategy of A Typical Vaccine Manufacturer 国内私营疫苗企业的研发策略　Most products have been developed through collaborations or tech transfer新产品开发主要采用联合开发或转让的方式

Basic research activities are often carriedout by academic collaborators基础研究由科研机构完成

R&D team takes over each project at pilot stage, often with established process研发团队在中试阶段进入

R&D ＝Tech Transfer and

Process Adaptation

This way, the R&D team can focus itslimited resources mostly on industrialization研发团队集中有限力量进行产业化研究

Success Example ： Recombinant HEV Vaccine 成功范例：基因工程戊肝疫苗

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• Seroprevalence data suggest that a third of the world's population has been infected with the hepatitis E virus. Currently there is no HEV vaccine.

血清学数据表面全球有三分之一人口曾感染过戊型肝炎病毒。国内外尚无疫苗。• Through a long term collaboration among Dr. Ning-Shao Xia at National Institute

of Diagnostics and Vaccine Development in Infectious Diseases, Beijing Wantai Biological Pharmacy, and Xiamen Innovax Biotech, a major breakthrough has been made in HEV vaccine development. The vaccine, HEV 239, has just passed a Phase III efficacy trial with 97356 participants, and is on SFDA’s fast approval track. The results were published in Lancet 2010.

由厦门大学国家传染病诊断试剂与疫苗工程技术研究中心夏宁邵博士、北京养生堂万泰生物药业股份有限公司、厦门万泰沧海生物技术有限公司等单位联合研制的戊型肝炎疫苗取得重大突破，由 97356 人参加的三期临床研究证实戊肝疫苗安全有效，等待药监部门批准后即可迅速上市。相关研究成果近日在《柳叶刀》发表。• Four international patents on the vaccine have been granted.

迄今已取得 4项国内外授权发明专利，是我国少见的高度原创性生物药物之一。Zhu, F-C, et al. 2010. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. The Lancet, 376 (9744):895 - 902,

401(K) Management vs. China Vaccine R&D Strategy

类比退休基金管理和中国疫苗研发策略

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85%

15%

Age 25

StockBond

50%50%

Age 45

StockBond

15%

85%

Age 65

StockBond

85%

15%

Multinational Vaccine Companies

InnovativeMe-too

15%

85%

R&D Budget of A ChineseVaccine Manufacturer

InnovativeMe-too

50%50%

Future of Chinese Vaccine R&D

InnovativeMe-too

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Innovation Drives Growth 创新刺激增长Simcere R&D Strategy: Increasing focus on innovation

先声研发策略：逐渐增加对创新的药和候选物的重视

2005 2006 2007 2008

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Simcere Snapshot 　先声药业集团简介

• A NYSE company, with highest standard of corporate compliance and transparency

• About 3000 sales reps and 1,500 distributors, covering over 3,000 hospitals and 70,000 retail pharmacies• 8 GMP facilities supporting small molecule and biologics manufacturing• China-leading R&D capabilities 中国领先的研发能力 14

A Leader in China’s Pharmaceutical Industry中国医药业的领袖

CAGR=33%

Ranking (排行 ):

#21 in Net Profit in China healthcare industry*

中国医疗业总利润排名第 21名#7 among the Top 20

most competitive public listed healthcare companies in China

中国最具竞争力的前 20 家医疗业上市企业中排第 7名* 2009 Chinese Medical Statistical Yearbook by Ministry of Industry and Information Technology of PRC

Revenue (M, RMB)

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Differentiated Products with Market Leadership in Oncology and CNS 　差别性产品和聚焦医疗领域　

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Therapeutic Area Brand Name Product

Oncology

Endu Proprietary recombinant human endostatin injection, NSCLC

Jiebaishu Nedaplatin injection

Sinofuan 5FU sustained release implant

Neuroscience Bicun/Yidasheng Edaravone injection, ischemic stroke

CardiovascularXinta Levamlodipine besylate tablets, hypertension

Shufutan Generic rotuvasatin tablets, hyperlipidemia

Infectious Disease

Anxin Biapenem injection, bacterial infection

Zanamivir Zanamivir inhalation powder, influenza

InflammationYingtaiqing Diclofenac sodium delayed release capsules , arthritis pain

Qiangke Etanercept , Ankylosing Spondylitis

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Simcere Biologics Capabilities 　先声生物制品Biopharmaceuticals

100%Simcere R&D Center 35%52.5%

Shanghai Celgen Bio-Pharmaceutical Co.

Ltd.

上海赛金生物制药

Jiangsu Yanshen Biological Technology Stock Co. Ltd.

江苏延申生物Humanized Rabbit MAbsCo-development with Epitomics

on humanized RabMab® antibody therapeutics for multiple tumors

Vaccine Research

EtanerceptDrug to treat auto-immune

diseases. Completed clinical trials and awaiting SFDA approval

VaccinesManufacturer of Influenza vaccine

(to be marketed on 2011)R&D pipeline with Hep A and Rabies

vaccine candidates, etc

Institute of Biologics Research 生物制品所Department of Vaccine Research 疫苗研究部

Shandong Simcere Medgenn Bio-

Pharmaceutical Co. Ltd. 山东先声麦得津生物制药Endu (Endostatin)

Innovative anti-cancer drug with sales of RMB124m in 2009

Platforms 　平台 MAbs 　单克隆抗体Mammalian cells 　哺乳细胞表达Pilot under construction 中试在建New-type vaccine research planned 　新型疫苗研究在计划中

Platforms 　平台 MAbs 　单克隆抗体Mammalian cells 　哺乳细胞表达Pilot & GMP 中试和 GMP 生产

Platforms 　平台 Egg-based split vaccine 　Cell-based inactivated vaccine 　－　 鸡胚裂解疫苗和细胞灭活疫苗Pilot & GMP 中试和 GMP 生产

Platforms 　平台 Recombinant protein 　重组蛋白E. coli Expression 　大肠杆菌表达Yeast Expression 酵母表达Pilot & GMP 中试和 GMP 生产

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New Vaccine Facilities and Products 　新厂址和产品• Build on a 19.5 acres land. 占地 130亩 .• R&D pilot plant has been used to develop Rabies vaccine based on a

bioreactor technology. 目前研发中试车间已经用于生物反应器狂犬疫苗的开发• Hep A and Flu vaccine facilities, Fill & Finish, as well as new QC lab, will be

completed this year 　甲肝、流感、分包装车间和新的 QC 实验室于今年完工

Simcere Vaccine Strategy 　先声疫苗战略• Enter Chinese vaccine market through acquisition of Jiangsu Yanshen

通过兼并疫苗企业进入中国疫苗市场• Ensure progress of the current product pipelines in Jiangsu Yanshen

确保目前江苏延申生物的产品线的进程• Establish Vaccine Research Department in Simcere R&D Center, with both

upstream discovery and downstream development capabilities, as well as a rich pipeline balancing short-, mid-, and long-term goals

在先声研发中心成立先声疫苗研究部，建立上游发现和下游攻关相结合的、短中长相匹配的、管线丰富的研发体系• Seek technology transfer and in-license opportunities for established vaccine

processes and products to enrich Simcere current product portfolio

寻找机会，对成熟的工艺和产品进行技术转让或项目引进以丰富先声疫苗产品• Seek collaboration opportunities for clinical- and/or pre-clinical stage vaccine

candidates both internationally and domestically

寻求对处于临床和临产前阶段的疫苗候选物的合作机会，放眼国际也关注国内19

Simcere Vaccine Strategy 　先声疫苗战略• Enter Chinese vaccine market through acquisition of Jiangsu Yanshen

通过兼并疫苗企业进入中国疫苗市场• Ensure progress of the current product pipelines in Jiangsu Yanshen

确保目前江苏延申生物的产品线的进程• Establish Vaccine Research Department in Simcere R&D Center, with both

upstream discovery and downstream development capabilities, as well as a rich pipeline balancing short-, mid-, and long-term goals

在先声研发中心成立先声疫苗研究部，建立上游发现和下游攻关相结合的、短中长相匹配的、管线丰富的研发体系• Seek technology transfer and in-license opportunities for established vaccine

processes and products to enrich Simcere current product portfolio

寻找机会，对成熟的工艺和产品进行技术转让或项目引进以丰富先声疫苗产品• Seek collaboration opportunities for clinical- and/or pre-clinical stage vaccine

candidates both internationally and domestically

寻求对处于临床和临产前阶段的疫苗候选物的合作机会，放眼国际也关注国内20

Simcere is the partner of choice for a number of multinational companies先声是各大跨国企业的首选合作伙伴

Continuous Improvement 　不断改进

We know we are not there yet. But we are fully committed to continuously improve ourselves. And we welcome all the helps and collaboration opportunities to reach this goal.

我们知道离目标还有差距，但我们承诺不断地改进自己 .

我们欢迎所有能够帮助我们实现这个目标的合作伙伴和机遇。21

China Vaccine Manufacturers

Global VaccineLeaders

Thank you!