global trend on cancer therapy: from bench to clinics at nhri€¦ · rank cancer types (2017)...

Hsing‐Pang Hsieh (謝興邦）Associate Director（研究員兼副所長）

Institute of Biotechnology and Pharmaceutical Research, NHRIDepartment of Chemistry, NTHU

August 3, 2018

Global Trend on Cancer Therapy: from Bench to Clinics at NHRI

科技創造經濟－工業4.0

2

Focus onPrecision Medicine

Cell therapies

2020

藥物發展歷史

3

時代巨變，知識爆炸

4

生物技術產業的特性

• 相對於其他產業的投資風險要高• 在產品生命週期與穩定性上來看生技產業絕對優於電子資訊產業

產業別

項目

生技

醫藥

電子

資訊

電腦軟體通訊

風險因素極高中等中等高

產品生命週期長短短短

穩定性高低低低

技術特性• 法規門檻高• 專業人才需求高• 技術日新月異• 低污染佔地小• 專業管理要求高• 以美、歐法規為指標

市場特性• 市場潛力大• 穩定性高• 成長機會高• 市場切入難• 全球化競爭

5

6

電子產業 vs. 生技產業

立普妥Lipitor - 輝瑞大藥廠

• Atorvastatin , marketed by Pfizer as a calcium salt under the trade name Lipitor, is a member of thedrug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque andprevents strokes through anti‐inflammatory and other mechanisms. Like all statins, atorvastatinworks by inhibiting HMG‐CoA reductase, an enzyme found in liver tissue that plays a key role inproduction of cholesterol in the body.

• Atorvastatin was first synthesized in 1985 by Bruce Roth of Parke‐Davis Warner‐Lambert Company(now Pfizer). The best selling drug in pharmaceutical history, sales of Lipitor since it was approved in1996 exceed US$125 billion, and the drug has topped the list of best‐selling brandedpharmaceuticals in the world for nearly a decade until Pfizer's patent on Lipitor expired onNovember 30, 2011.

• Initial launch in U.S. in 1996.7

Pregabalin was discovered by medicinal chemist Richard Bruce Silverman (born May 12, 1946) atNorthwestern University in the United States. The drug was approved in the European Union in2004. Pregabalin received U.S. FDA approval for use in treating epilepsy, diabetic neuropathic pain,and postherpetic neuralgia in December 2004, and appeared on the U.S. market in fall 2005.

The Successful Story of Lyrica

8

Global Pharmaceutical Sales (2010-2024)

Prescription drug sales CAGR for 2018 through 2024 six times that in 2011through 2017; Orphan drug market to almost double.2017年，全球製藥研發總支出約1650億美元，同比增長3.9％。報告顯示，未來行業將更多地考慮使用大數據來提高研發效率，包括轉化生物模型、早期研發的目標選擇優化、臨床試驗設計、以及療效和安全性追蹤，預計2018-2024年的全球研發投入CAGR將持續下降，研發支出占醫藥收入的比重不斷減少。

Evaluate Pharma, World Preview 2018, Outlook to 2024 9

New Drugs Approved by US FDA(1993-2017)

NATURE REVIEWS | DRUG DISCOVERY FEBRUARY 2018, 81-85 10

CDER Approval Trends over Time

NATURE REVIEWS | DRUG DISCOVERY FEBRUARY 2018, 81-85 11

2005全球十大處方藥排行榜Brand Name Ingredient Company Indication 2005 Sales

($ Billions)

Lipitor Atorvastain Pfizer 高血酯症 12.9

Plavix Clopidogrel BMS/Sanofi-Synthelabo

血管硬化 5.9

Nexium Esomeprazole AstraZeneca 胃潰瘍/胃食道逆流 5.7

Advair (Seretide)

salmeterol / fluticasone)

GSK 氣喘 5.6

Zocor Simvastatin Merck & Co 高血酯症 5.3

Norvasc Amlodipine Pfizer 高血壓症 5.0

Zyprexa Olanzapine Eli Lilly 精神分裂症 4.7

Risperdal Risperidone J&J 精神分裂症 4.0

Prevacid Lansoprazole Takeda/Abbott 胃潰瘍/胃食道逆流 4.0

Effexor Venlafaxine Wyeth 憂鬱症 3.8

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Brand Name

Ingredient Company Indication 2009 Sales

($ Billions)

2010 Sales

($ Billions)Lipitor Atorvastain Pfizer 高血酯症 12.45 11.7Plavix Clopidogrel BMS/Sanofi-Aventis 血管硬化 9.29 9.6Enbrel Etanercept Amgen/Pfizer/

Takeda類風濕性關節炎 8.0 8.4

Advair (Seretide)

salmeterol / fluticasone)

GSK 氣喘 7.764 7.8

Remicade Infliximab J&J/Merck, Mitsubishi Tanabe

類風濕性關節炎 6.91 7.4

Avastin Bevacizumab Roche 大腸癌 5.92 6.8Rituxan Rituximab Genetech/Biogen

Idec非何杰金氏淋巴

瘤5.80 6.7

Humira Adalimumab Abbott 風溼性關節炎 5.49 6.5

Abilify Aripiprazole Otsuka/BMS 精神分裂症 5. 6 6.2

Diovan Valsartan Novartis 高血壓 6.01 6.1

2010全球十大處方藥排行榜

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Brand Name Ingredient Company Indication 2012 Sales($ Billions)

2013 Sales($ Billions)

Humira Adalimumab Abbott 風溼性關節炎 9,616 11,014

Enbrel Etanercept Amgen/Pfizer/ Takeda 類風濕性關節炎 8,496 8,778

Remicade Infliximab J&J/Merck, Mitsubishi Tanabe

類風濕性關節炎 7,634 8,367

Advair (Seretide) Salmeterol / Fluticasone)

GSK 氣喘 8,088 8,341

Lantus Insulin Glargine Sanofi‐Aventis

高血糖症 6,378 7,592

Rituxan Rituximab Genetech/Biogen Idec 非何杰金氏淋巴瘤 7,155 7,503

Avastin Bevacizumab Genentech/Roche 大腸直腸癌 6,149 6,751

Herceptin Trastuzumab Roche 乳癌 6,283 6,562

Januvia/Janumet sitagliptin phosphate Merck

高血糖症 6,231 6,254

Crestor Rosuvastatin AstraZeneca 高血酯症 6,780 6,105


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Brand Name

Ingredient Company Indication 2016 Sales

($ Billions)

2017 Sales

($ Billions)


Rituxan Rituximab Roche/Biogen 非何杰金氏淋巴瘤

9,059 9,238

Revlimid Lenalidomide Celgene 多發性骨髓瘤 6,974 8,187

Enbrel Etanercept Amgen/Pfizer/ Takeda 類風濕性關節炎 6,974 8,187

Herceptin Trastuzumab Roche 乳腺癌 8,874 7,885

Eliquis Apixaban BMS/Pfizer 抗凝血劑 5,056 7,395

Remicade Infliximab J&J/Merck 類風濕性關節炎 8,234 7,152

Avastin Bevacizumab Genentech/Roche 大腸直腸癌 7,197 7,096

Xarelto Rivaroxaban Bayer/J & J 抗凝血劑 5,919 6,589

Eylea Aflibercept Bayer/Regeneron 視網膜靜脈阻塞 5,338 6,034


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Brand Name Ingredient Company Indication 2017 Sales($ Billions)

2022 Sales

($ Billions)


Revlimid Lenalidomide Celgene 多發性骨髓瘤 8,187 14,197

Opdivo Nivolumab BMS/Ono 黑色素瘤 4,9487 9,912

Keytruda Pembrolizumab Merck 黑色素瘤 3,809 9,509

Eliquis Apixaban BMS/Pfizer 抗凝血劑 7,395 8,486

Xarelto Rivaroxaban Bayer/J &J 抗凝血劑 6,589 8,131

Imbruvica Ibrutinib AbbVie/J &J 淋巴瘤 4,466 7,499

Eylea Aflibercept Bayer/Regeneron 視網膜靜脈阻塞 6,034 7,171

Ibrance Palbociclib Pfizer 乳腺癌 3,126 7,074

Januvia/Janumet

sitagliptin phosphate Merck 高血糖症 5,896 5,989

2022全球十大處方藥排行榜預測

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Top 10 Therapeutic Classes by Estimated Global Pharmaceutical Sales in 2017

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Top 10 Prescription Drug Therapeutic Area WW Market (2017-2024)

Evaluate Pharma, World Preview 2018, Outlook to 2024

2024年預計全球製藥業的研發支出將達到總銷售額的16.9％，低於2017年的20.9％，這表明未來的研發重點將放在提高研發效率上，或者說公司將更少的收入用於補充產品線。腫瘤學仍然是行業內一個重要的發展方向，2017-2024年的複合年均增長率預計為12％。

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Top 5 Oncology Products Worldwide in 2024

Evaluate Pharma, World Preview 2018, Outlook to 2024

PD-1抑制劑Keytruda和Opdivo出現在2024年的腫瘤藥物銷售額TOP5中，但預計Keytruda將從第三名上升到第一名，而Opdivo從第二名降至第三名，主要由於Keytruda在美國和歐盟獲批用於一線局部進展或轉移的非小細胞肺癌，而Opdivo則未獲批准。

19

百濟神州公司

Cancers in Scope for R&D: Poorer Countries Shoulder Large Burdens

Cancer is a globalepidemic and a leadingcause of death worldwide,accounting for 7.6 milliondeaths or around 13% of alldeaths in 2008.

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Trends in Incidence Rates, United States, 1975 to 2014

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Trends in Cancer Death Rates, United States, 1930 to 2015

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Lung

Prostate

Pancreas

CRC

Lung

Breast

東亞各國癌症排行：中國肺癌猖獗、台灣乳癌罹患率飆升

http://www.thenewslens.com/post/152667/ 24

台灣常見癌症發生趨勢（1996-2014）

25

惡性腫瘤自 71 年起已連續 35 年高居國人死因首位

26

Rank Cancer Types (2017) Mortality Rate New CaseAbsolute 5 Year Survival

Rate (2006-2010)1 Lung cancer 39.2 % 13,086 14.1 %

2 Liver and bile duct cancers 35.7 % 11,420 23.3 %3 Colorectal cancer 24.7 % 15,579 52.5 %

4 Breast cancer 20.1 % 12,360 82.5 %

5 Oral cancer 12.1 % 7,628 49.9 %

6 Prostate cancer 11.9 % 5,106 61.7 %

7 Gastric cancer 9.8 % 3,849 30.6 %8 Pancreatic cancer 8.8 % N/A ~ 5 %9 Esophageal cancer 7.6 % 2,587 80.2 %

10 Cervical and uterus cancers 5.5 % 3,925 67.6 %

2017 Top 10 Cancers in Taiwan, and Mortality Rate, Incidence Rate and 5-year

Survival Rate 2006-2010.

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ONIVYDE「安能得」

Emphasis is removing or killing cancer cells with little attention to adverse effects on normal cells Modalities include: Surgery Radiation Chemotherapy Hormonal Therapy Targeted Therapies (most new drugs: Inhibit enzymes or

receptors that are involved with cancer growth) Biological Therapy (monoclonal antibodies; cancer vaccines;

cancer growth blockers; anti-angiogenics; gene therapy drugs) Cell Therapy Photodynamic Therapy (PDT) Bone Marrow Transplants

Cancer Therapies

29




Cancer Therapies

30

Ligand‐targeted Therapy

Intracellular Signaling Molecules

Growth Factor Receptors

Cancer Cell

Therapeutic Antibodies ± Toxins

Apoptosis Agonists

Tyrosine Kinase Inhibitors

m‐RNAAngiogenesis Inhibitors

(Angiostatin, Endostatin & Anti‐VEGF)

Antisense

Immunotherapy

Metalloproteinase Inhibitors

Tumor Antigens

Anticancer Targeted Therapy

provided courtesy of Prof. HC Wu 31

Permanent alteration of the nucleotide sequence of DNA.Types:

• Single chromosome mutations

• Two-chromosome mutations:

Gene Mutation

https://en.wikipedia.org/wiki/Mutation 32

The Success of Kinase Inhibitors

33

To date, the US FDA has approved 39 small molecule kinaseinhibitors, 3/4 of which were approved in the past 7 years.To date, the US FDA has approved 39 small molecule kinaseinhibitors, 3/4 of which were approved in the past 7 years.

NSCLC

Tang Prize for Biopharmaceutical Science in 2018

34

Pharmacyclics（藥圈圈）的BTK（Bruton's TyrosineKinase）抑制劑Imbruvica（ibrutinib）。此新藥（IMB）於2013年4月8日獲得突破性治療後，接著在2013年11月13日，2014年7月8日與2015年1月29日取得美國FDA核准於治療三種血液方面的疾病。藥圈圈並於2015年3月5日以美金210億（約新台幣6千4百億）賣給AbbVie。公司所有的價值，基本上來自於IMB，充分說明了選題精準，一個小分子藥物創造了奇蹟式的成功。

藥圈圈成立於1991年，在1995年10月24日正式上市（IPO），股價是美金12元，其主要技術並未取得階段性的成功，因此股價一路下滑到2008年時，低於1美元。造成奇蹟似成功的IMB是在2006年由Celera買來。但在臨床前研究階段並未創造任何令人興奮的價值，所以到2009年大股東道格(Duggan)收購更多藥圈圈股票時，股價仍在美金1.28元。直到IMB成功進入臨床Ⅰ/Ⅱ期，獲得初步療效， J&J於2011年用美金9.75億買下共同行銷權（co‐promotion）後，藥圈圈才開始享受成功的果實。AbbVie的收購（每股美金261.25元）。

Imbruvica® （ibrutinib）

35

Survival by EGFR Mutation Status

36

First Description of EML4-ALK Translocation in NSCLC

(Hiroyuki Mano)間野博行

2001‐2013

Professor, Division of Functional Genomics, Jichi Medical University, Tochigi, Japan

2009‐2013

Professor, Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

2013‐present

Professor, Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

37

60

40

20

0

–20

–40

–60

–80

–100

Progressive diseaseStable diseaseConfirmed partial responseConfirmed complete response

Max

imum

cha

nge

in tu

mor

siz

e (%

)

–30%

Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC

*Partial response patients with 100% change have non-target disease present

*

Objective RR = 57% (95% CI: 46-68%)DCR (CR+PR+SD): 87%(95% CI: 77-93%)

Y Bang et al: ASCO 201038

May 23, 2017美國藥廠默克（Merck）的癌症新藥Keytruda，再度獲美國食品藥物管理局（FDA）核准。此次獲准的適應症，是用於治療含有MSI-H或是dMMR基因缺陷，而導致實體腫瘤的成人及兒童病患。這也是全球首個非針對腫瘤發生器官（癌症類別）治療的癌症藥物，該產品旨在改善病患的變異基因，以達到治療效果。這不但是癌症治療的新突破，也是精準醫療上的大躍進，對於藥廠而言，更是擴大了新藥開發的多靶點適應症。

個體化醫療－精準醫療(Precision Medicine)

39

• Announced by President Obama, January 20, 2015• $215 M USD investment in 2016 US government budget• Jump start various NIH/NCI studies/initiatives

The Precision Medicine Initiative

40

The Precision Medicine Initiative

Accelerate progress in cancer, including prevention & screening From cutting edge basic research to wider uptake of standard of care Encourage greater cooperation and breaking down silos Within and between academia, government, and private sector Importance of data sharing: Genomic Data Commons, annotated

patient level clinical data & -omics

癌症登月計畫資金重點支持的研究領域包括：癌症預防與癌症疫苗研發、早期癌症檢測、癌症免疫療法與合併療法、腫瘤及其周圍細胞進行基因組分析、加強醫療大數據共享、罕見兒童癌症研究、建立虛擬腫瘤卓越中心等。 41

The Promise of Precision Medicine Initiative

Targets/Mechanism

Algorithm‐Based

Data Analysis

RelevantBiomarkers

Precision Medicine(Prevention/Treatment)

Better Drugs(Predictive Models)

NG DiagnosticTechnologies

Up to 20 tumor types in as many as 20,000 patients by the year 2020.

42




Cancer Therapies

43

Building Better Monoclonal Antibody-based Therapeutics

George J. WeinerNature Reviews Cancer June 2015 44

The Ups and Downs of Therapeutic Antibodies

YearYear1986

Launch of many biotech companies that promise antibodies as anticancer “magic bullets”

Muromonab anti-CD3 for the treatment of kidney transplantation rejection

DNA/TNAX: Omalizumab (Xolair) for asthma

0393

Death, severe side effects halt clinical trials of antibodies

1981

Successful test of anti-lymphoma antibody

1975

First monoclonal antibodies

02

Abbott/CAT: Adalimumab (Humira)for RA

97

IDEC: Rituximab (Rituxan) for B cell lymphoma

Genetech: Trastuzumab (Herceptin)for breast cancerCentocor/JNJ: Infliximab (Remicade) for RA

98

Genetech: Bevacizumab ( Avastin) for CRC ImClone: Cetuximab (Erbitux) for CRC and HNSCC

04 06

Bevacizumabfor NSCLCPanitumumab(Vectibix) for CRC

45

The Ups and Downs of Therapeutic Antibodies

26.3B

07

Bevacizumab (Avastin) for breast cancer

08

32.0B

09

35.0BBevacizumab (Avastin) for RCC & glioblastoma

10

43.0BTrastuzumab (Herceptin) for gastric cancer

44.7B

11

Ipilimumab (Yervoy): anti-CTLA4Brentuximab vedotin (Adcetris): ADC therapeutics

Year13

Kadcyla/T-DM1: ADC

12

Pertuzumab (Perjeta) for breast cancer

50B

14

Pembrolizumab (Keytruda), Nivolumab (Opdivo): anti-PD1 Ramucirumab (Cyramza): anti-VEGFR2

78B

15

Dinutuximab (Unituxin): anti-GD2 for neuroblastomaDaratumumab (Darzalex) for myeloma

Necitumumab (Portrazza): anti-EGFR for NSCLC

86B

16

Reslizumab (Cinqair): anti-IL-5 for asthma

Atezolizumab (Tecentriq): anti-PD-L1 for urothelial carcinoma

105B

Avelumab (Bavencio):anti-PD-L1 for urothelial carcinomaDurvalumab (Imfinzi)anti-PD-L1 for urothelial carcinomaBrodalumab (Siliq):anti-IL17R for psoriasis

17 46

The Top 10 Best-Selling Drugs

No. Drug Disease Company 2015 Revenue 2016 Revenue

1 Humira® (adalimumab) rheumatoid arthritis (RA) AbbVie $14.0 bln $16.0 bln

2 Harvoni® (ledipasvir 90 mg/ sofosbuvir 400 mg)

chronic hepatitis C virus (HCV) Gilead Sciences $13.8 bln $9.0 bln

3 Enbrel® (etanercept) rheumatoid arthritis (RA) Amgen and Pfizer

$8.6 bln $8.8 bln

4 Rituxan® (rituximab, MabThera)

non-Hodgkin’s lymphoma; chronic lymphocytic leukemia; rheumatoid arthritis (RA)

Roche (Genentech) and Biogen

$8.3 bln $8.5 bln

5 Remicade® (infliximab) rheumatoid arthritis (RA)Crohn's disease

Johnson & Johnson and Merck

$8.7 bln $7.8 bln

6 Revlimid® (lenalidomide) multiple myeloma Celgene $5.8 bln $6.9 bln

7 Avastin® (bevacizumab) cancer Roche (Genentech)

$6.6 bln $6.7 bln

8 Herceptin® (trastuzumab) cancer Roche (Genentech)

$6.5 bln $6.7 bln

9 Lantus® (insulin glargine) diabetes Sanofi $6.7 bln $6.0 bln

10 Prevnar 13® / Prevenar 13® pneumococcal pneumoniaand invasive disease

Pfizer $6.2 bln $5.7 bln

Genetic Engineering & Biotechnology 2017

Market Trend for Biological Drugs

Ref: 1. Carter PJ et al. Cancer J. 2008;14(3):154‐169. 2. Senter PD. Curr Opin Chem Biol. 2009;13(3):235‐244. 3. Polson AG et al. Cancer Res. 2009;69(6):2358‐2364

(payload)

ADC Discovery

48

Steps Necessary for Antibody-Drug Conjugate to be Effective

ADCReceptor-Mediated

Endocytosis

LysosomeTargetAntigen

49

2011 Brentuximab vedotin (Adcetris) Hodgkin lymphoma(HL) and systemic anaplastic large cell lymphoma (ALCL); 2017 cutaneous T-cell lymphoma (CTCL)

2013 Trastuzumab emtansine (Kadcyla) HER2 positive breast cancer

2017 - Inotuzumab ozogamicin B-cell precursor acute lymphoblastic leukemia (ALL)[

免疫療法 (Cancer Immunotherapy)

50

James P. Allison - CTLA-4MD Anderson Cancer Center 是美國頂尖的癌症醫學研究

與醫療重鎮，艾利森（James Allison）1995年發現CTLA‐

4是T細胞抑制性受體。他的團隊隨即製造出阻斷CTLA‐4

活性的抗體，並且於1996年以動物實驗證明該抗體可以

排除小鼠體內數種腫瘤。其單株抗體藥物成功被研發,

經臨床試驗證明對末期轉移性黑色素瘤患者有顯著治療

效果，於2011年經美國FDA核准上市。(每三個星期注射

一次、一個療程總共注射四次的訂價約12萬美元。)

艾利森說，許多癌症可以預防，光是戒菸與健康的生活

方式，約可減少1/3癌症的發生，使用多重藥物是比較

有效的治療方式。

他說，黑色素瘤藥物即是併用阻斷CTLA‐4與PD‐1活性的

抗體，9成使用藥物的患者可延長2年壽命，比例相當高。51

1992年本庶佑的研究團隊發現PD‐1免疫抑制因子，72歲的本庶佑指出，他實驗室的一名學生意外發現PD‐1分子，花了10年的時間才了解PD‐1會抑制免疫系統發揮功能。

本庶佑的團隊在2002年開始進行動物實驗，發現這個方法在老鼠身上的效果非常好，於是說服日本製藥公司生產供人體使用的PD‐1抗體，將這個方法治療癌症病患。2006年開始進行臨床實驗，使用PD‐1抗體對轉移性黑色素瘤的治療成效良好。

Merck的抗PD‐1抗體Keytruda®(pembrolizumab， MK‐3475)，於2014年9月通過上市。。 Bristol‐Myers Squibb抗 PD‐1抗體新藥 Opdivo®(Nivolumab)，在2015年3月通過上市，一個月12,500美元(一年15萬美元)

本庶佑進一步說明PD‐1抗體的3大優點，首先不同於多數治療癌症的藥物只針對指定的癌症，PD‐1抗體治療法可用於不同種類的癌症，目前已被使用到超過80種惡性腫瘤的病例，都發揮治療的效果。

第2項優點，多數癌症的化學治療都有副作用，因為他們多是有毒的化學物，但PD‐1抗體是要促進人類體內的免疫系統，目前僅發現有少數自身免疫的副作用，如結腸炎、肺纖維化是主要的副作用，但只要停止使用PD‐1抗體治療，病人就可以恢復。

第3項優點，一旦注射PD‐1抗體腫瘤開始萎縮後，效果可以維持數年，腫瘤都不會再變大，臨床實驗證明，人體的免疫系統一旦被啟動，就會持續攻擊腫瘤。

本庶佑（Tasuku Honjo）- PD-1

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Cancer Therapies

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細胞治療 (CAR-T Cell Therapy)

諾華（ Novartis ）的 CAR-T （ chimeric antigen receptor T cell ）療法產品 Kyrmiah（tisagenlecleucel）於 2017 年 8 月 30 日獲得美國 FDA 核准，是全球第一款核准的 CAR-T 療法，為癌症治療開啟了新的里程碑──「以基因改造的免疫細胞為基礎」的治療模式。 Kymriah初期由美國賓夕法尼亞大學開發，並於 2012 年 8 月將全球商品化開發的權利授權給 Novartis。急性淋巴性白血病（acute lymphoblastic leukemia，ALL）一旦復發，能有的治療手段包含化療藥物、造血幹細胞移植（HSCT）等但效果有限，特別是在兒童與青少年這個族群，顯示出 r/r B-cell ALL 有高度未滿足需求。Novartis 公布定價為每次治療 475,000 美元，背後包含 Novartis 希望達到的銷售收入及 Kymriah製造成本、研發成本攤提、REMS 執行、長期藥物治療後追蹤成本等，並以 Kymriah 療效相較其他療法例如幹細胞移植（350,000~800,000 美元）而言是合理價格來對外宣稱。

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• Oct. 18, 2017 Kite’s (a Gilead Company) Yescarta™ (Axicabtagene Ciloleucel)Becomes First CAR T Therapy Approved by the FDA for the Treatment of AdultPatients With Relapsed or Refractory Large B-Cell Lymphoma After Two or MoreLines of Systemic Therapy2017/11/13 美國製藥公司朱諾(Juno Therapeutics)日前(10日)公布了關於去年失敗的CAR-T候選藥物JCAR015試驗計畫(ROCKET study)，造成五名臨床試驗患者死亡的分析報告。該藥物可能對患者有幾個致命神經毒性。神經毒性和細胞因子釋放綜合症(cytokine release syndrome)都是CAR-T治療的常見副作用，但朱諾此計畫的致命性腦水腫發生率遠高於其他研究。朱諾最終宣告終止計畫及其候選藥物JCAR015，並轉向另一個不同的候選藥物JCAR017。

• 恆瑞PD-1 臨床試驗部分受試者皮膚出現血管瘤！江蘇恆瑞醫藥,是國內創新藥企代表,2015年該公司PD-1項目SHR-1210在尚未上市前就有償許可給美國Incyte公司,收益2500萬美元首付外加7.7億美元總額里程金,即當SHR-1210項目每完成一個重要研究進展,Incyte就會從7.7億美元中拿出一定比例作為項目進度款支付。一些參加PD-1抑制劑臨床試驗的病友,皮膚出現血管瘤並對血管瘤表示出困擾和擔憂,特別是參加了恆瑞PD-1臨床試驗的病友,出現血管瘤症狀較多,部分受試者已經因此退組。

Adverse Effect of CAR-T /PD-1

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抗腫瘤藥物之大趨勢

• 1997 年至2016年， FDA 共批准132個抗腫瘤藥物，全球上市的抗腫瘤藥物有282個，全球抗腫瘤藥物市場規模超過1000億美元，靶向藥物佔比達到62%，已經成為抗腫瘤新藥的主流，全球抗腫瘤藥物市場集中度極高，羅氏是其中的領導者，各大藥企都對抗腫瘤藥物懷有極大的開發熱情。

• EvaluatePharma發表報告預測未來五年醫藥市場情況，腫瘤治療藥物仍然是全球市場銷售中最好的領域。到2022年抗腫瘤藥市場的規模預計將增長至1920億美元，複合年均增長率達12.7％。

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Cancer Dominated Licensing Deals, while Diabetes Gained Ground

https://blog.lifesciencenation.com/2015/12/31/licensing-deals-in-year-2015-early-stage-endocrine-assets-scored-big/ 57

2017 Therapy Area Focus for Top Large Pharma Dealmakers

https://clarivate.com/wp-content/uploads/2018/05/trends-in-dealmaking-fundraising-and-partnerships-050918.pdf 58

The Cost, Time, Success Rates of New Drug Discovery

24 M 49 M 146 M 62 M 128 M 185 M 235 M 44 M

Drug Discovery Today, 2016, 21, 1719-1727

281 M 592 M

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生物藥 vs. 小分子

Tailored Therapeutics

(Companion Diagnostic)

Right Drug

Right Patient (Disease)

Right Target

Ideal State of Personalized (Precision)Medicine

• Target - disease relationship (biology/translational research)

• Target - drug connectivity (drug discovery/SM/biologics)

• Right drug for the right patient (clinical trial/diagnosis)

Precision Medicine

標靶藥物＝精準醫療

Precise/Efficient Care

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Current and Investigative Treatment Options for Advanced or Metastatic NSCLC

Nature, 2018, Jan 24;553(7689):446‐454. 62

Artificial Intelligence Will Redesign Healthcare

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未來趨勢

Alibaba Group (阿里巴巴)/Amazon (亞馬遜)－WuXi

AppTec: Integrated R & D Services (藥明康德)

Uber－ Uberization of Medicine

大數據分析

健康老化

精準醫療

細胞治療

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未來趨勢

global trend on cancer therapy: from bench to clinics at nhri€¦ · rank cancer types (2017)...

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