Academia-Industry Alliance for Drug Discovery ... ·...

Shuh NarumiyaKyoto University

成宮周京都大學

2013 Taiwan-Japan Science & Technology Forum2013 台日科技高峰論壇September 23-24, 2013

Academia-Industry Alliance for Drug Discovery & Development

～Challenge and Experience of Kyoto University～

推動創藥的產學合作〜京都大學的挑戰與經驗〜

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Missions of Medical School • Education: Making the next generation of doctors and medical scientists• Research: Widening our knowledge on human body and diseases• Innovation: Creating new therapies and modalities by exploiting our current knowledge and experiences

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Two Past Problems in Japan

Copyrightⓒ 2010 Kyoto University. All rights reserved.

One of medical innovations is drug development, and, in this mission, alliance with industry is essential!

One of medical innovations is drug development, and, in this mission, alliance with industry is essential!

1. Japanese medical schools didn’t have an efficient system linking their research to innovation with industry.

2. Pharmaceutical companies traditionally thought that drug development could be accomplished by their own efforts.

Change in Pharma:Demand for Open Innovation

for Drug Development

2Change to Open Innovation Strategy Change to Open Innovation Strategy

Globally the number of approval of new medicine is decreasing even though R&D cost has much increased.

Failure of the Companies’ Closed Innovation R&D Model

High Drug Development Technology such as HTS has drained drug-able targets within the company, which cannot be supplied by their weakened basic research



Formulation of drug discovery model in post genome era capable of creating game-changing drugs

from Japan建構後基因圖譜時代的創藥模式並創

製日本研發的新作用藥

Center for Innovation in ImmunoregulativeTechnology and Therapeutics

以次世代免疫控制為目標的創藥醫學融合據點

Kyoto Univ.京都大學

Astellas Pharma.Astellas

製藥株式會社Fusion Lab.

創藥醫學融合實驗室

Overcome intractable diseases 難治疾病的克服Allergy過敏．Autoimmune diseases自我免疫病Chronic inflammation 慢性發炎．Cancer 癌症．Infection 感染症

Next generation therapy 次世代的醫療Organ transplantation 臓器移植．Regenerative medicine再生醫療

Innovative Immunregulative Therapeutics革新性免疫控制藥Matching Fund

(The Third Basic Sci. and Tech. Plan)$ 6 M/year for first 3 years

$15 M/year for next 7 years

Matching Fund(The Third Basic Sci. and Tech. Plan)$ 6 M/year for first 3 years

$15 M/year for next 7 years

Open innovation＝Use of Wisdom of Both

Build. C

Build. F

Build. E

Library

TR Center

Substantial interaction of university and company researchers

大學與企業研究者互相合作的園區

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Build. B AK ProjectFusion Lab.(ca. 2000m2)

Build. D

Build. A

Organization of AK Project 創藥醫學融合據點的研究體制

Satellite Lab.(Astellas)附屬實驗室（Astellas）

HTS and Compound Optimization

3 Astellas drug discovery G

3 企業派遣創藥研究小組

Technical support G技術支援

小組

TR center探索醫療

中心（京大醫院）

TR center探索醫療

中心（京大醫院）

Advice on research and development研究活動的建言與統籌

Coordinates publication and rightManages IP and trade secret公開發表與權利化的建言秘密資訊保護．智慧財產管理

Kyoto Univ. Kyoto Univ. AstellasAstellas fusion lab.fusion lab.京大京大AstellasAstellas

創藥醫學融合實驗室創藥醫學融合實驗室（醫學部（醫學部校區校區內Ｂ棟）內Ｂ棟）

Lab. SupervisorLab. Subsupervisor融合實驗室統籌者（專任教授）融合實驗室副統籌者

（特任教授（互相合作））

Intellectual Property Office資訊智慧財產管理辦公室

（智慧財產經理）

3 Univ. key researcher G.

3 校內核心研究者小組

８ Clinical and 1 Basic Research

Groups 8個臨床科、1個基

礎與共同研究

Search for Biomarkers and Verify Clinical Utility for Targets found in the Fusion Lab.

Search for Biomarkers and Verify Clinical Utility for Targets found in the Fusion Lab.

Group Member : PI (Associate Prof. ) + 1 Pos. DocTerm : 5 years,

Each pursues individual research and asked to identify unique targets.

17 Young Investigator G.

17 創藥青年研究小組


What has caused “Patent-Cliff”?

Two reasons;

Firstly, drug discovery based genomic information has achieved only

limited success because most human diseases are caused by a combination of many genetic and environmental factors; 利用基因圖譜解析，並不容易鑑定藥物標的。

Secondly, advances in life science have indeed identified many physiological principles, but most of them are used context-dependently, fruits hanging high in the tree We have to find out the pathological context for the use of developed drugs. 在基礎研究中發現的見解對於何種疾病和病態有所作用，目前仍不明朗。

6Copyrightⓒ 2012 Kyoto University. All rights reserved.

臨床．基礎．企業研究者的融合Forming a team of clinicians, basic and company scientists

各對象疾病的群聚構成

AK Project的對象疾病如類風濕性關節炎（RA)、SLE、移植免疫等，係針

對各主題，由京大醫院的各臨床領域專家、相關的基礎醫學從業人員、Astellas派遣的企業研究者組成小組，展開研究活動。藉此建立回饋循環機制，以促進臨床資訊、病理標本、基礎醫學見解與開發研究的發展。

Making up a team targeted to each disease

AK Project has made teams each targeted to RA, SLE, tissue transplantation and etc consisting of clinical specialists in targeted disease, basic and company scientists, integrating clinical information, analysis of clinical samples, knowledge in basic science and company technology.


如何結合大學的創意與企業的技術種子？此外，如何獲知標的之臨床有用性？

How ideas at academia are converted to seeds at company And how clinical validation is achieved for companies’ seeds.

如何結合大學與企業; AK Project的錯誤嘗試Bridging activities at AK Project



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如何結合大學的創意與企業的技術種子？How can we convert ideas at academia to seeds at company?

企業的技術種子/ seeds ＝可以實施HTS，且最好已證明臨床上的有用性，或是顯示其有用性的標的分子; target molecules ready for HTS and validated for clinical utility

大學的創意/ ideas ＝與疾病惡化相關的基因圖譜資訊、生理過程中運作的細胞、分子; genomic information associated with disease and molecules operating in physiological processes

二者間的想法有落差；大學提出了創意，因此希望由企業負責整合，企業則希望大學先將創意整合之後再交付給企業。在企業目前所處的狀況下，尚無此種餘力。那麼，應該如何是好呢？; a “Wide Gap” between academia’s idea and companies’ seeds

依生化學的角度解析基因圖譜資訊的意義。解析基因圖譜中發現的異常周邊，例如，基因控制的機轉和周邊的信號傳達（pathway 解析）、特異的細胞subset的誘導機轉等。（pathway analysis）使用臨床樣本，透過確認人體疾病相關性的Clinical Verification （Validation with clinical samples）Phenotypic screening，找出背後的機轉。

絲聚合蛋白異常為異位性皮膚炎的主要罹患因子1.人體的遺傳學根據

Palmer CN et al. Nat Genet. 2006; 38(4):441-6

絲聚合蛋白基因的異常不僅是異位性皮膚炎，亦與併發的支氣管氣喘之發病有關（過敏性風濕的存在）

何謂絲聚合蛋白；What is filaggrin?

絲聚合蛋白原

去磷酸化

MatriptaseCAP1/Prss8PAD1,3

Caspase 14CalpainBleomycin hydrolase

絲聚合蛋白

天然保濕因子Natural moisture factors

角蛋白纖維的收束

轉穀氨醯胺酶

保持角質水分量維持經皮水分蒸散量保持pH

Filaggrin is expressed in the skin and oral and nasal mucosa and is critical for the skin barrier function.

基底膜

皮膚樹狀細胞（朗格漢斯氏細胞等）

過敏原的滲透Allergen infiltration

表皮角化細胞

角層

異位性皮膚炎發病Atopic Dermatitis

絲聚合蛋白缺損造成的皮膚防禦機能的喪失

過敏進行曲Allergic March

Howell MD et al. J Allergy Clin Immunol. 2007;120(1):150-5

皮膚的絲聚合蛋白mRNA表現水準與AD

絲聚合蛋白異常為異位性皮膚炎的主要罹患因子2. AD患者與基因異常無關，皮膚的絲聚合蛋白量呈現降低。

異位性皮膚炎患者正常．非發病者

無基因異常有

異位性皮膚炎患者皮膚與基因異常無關，患部、非患部的FLG表現呈現降低。

絲聚合蛋白異常為異位性皮膚炎的主要罹患因子2. 皮膚細胞的FLG表現在Th2環境下降低。

Howell MD et al. J Allergy Clin Immunol. 2007;120(1):150-5

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COMMENT

Mining for therapeutic gold

Francis Collins

A comprehensive and collaborative strategy to enable the investigation of new uses ofapproved and abandoned drug compounds could advance translational research.

NATURE REVIEWS DRUG DISCOVERY VOLUME 10 JUNE 2011 397

造成FLG表現上昇的物質之篩檢

探索誘導絲聚合蛋白表現上昇的化合物

• 進行篩檢：1000以上的chemical library

• Real time PCR與啟動子作用分析（Promoter Assay）

JTC801

2.2K FLG promotor

檢討Ca+IL4/13存在下的FLG表現變化

*

JTC801是否針對keratinocyte以ORL1 antagonist的型態產生作用，使FLG的表現上昇？

JTC801 J113397

亦具有ORL1 antagonistµ opioid receptor antagonist的作用

ORL1 antagonist

JTC801對keratinocyte如何產生作用，使FLG的表現上昇？

J113397

ORL1 antagonist

3D培養皮膚的FLG蛋白表現誘導

JTCxxx於3D培養中，在蛋白質的層級造成FLG單體上昇

初代培養人體角化細胞

化合物添加

1 control2 X3 JTCxxx4 Y

FLG單體

1 2 3 4

Nc/Nga小鼠

AD自然發病模式小鼠SPF飼育未發病（蝨子）自7-8週齡起發病

1 2

1. 未發病2. 發病（同週齡）

FLG 單體

每隔1日對JT化合物（15 mg/kg)經口投予，針對已發病小鼠檢討皮膚FLG量、皮膚炎、TEWL的變化，判定治療效果、疾病進展抑制效果。

ctrl（甲基纖維素）內服前

ctrl內服2個月（每隔1天）

皮疹僅限頭部

右耳廓、頭部的皮疹逐漸惡化

臉部皮疹發病

JTC內服前 JTC內服2個月 15mg/kg（每隔1天）

右耳頭部右耳頭部

皮疹的改善脱毛的消失

The total clinical score for skin lesions was designated as the sum of individual scores, graded as 0 (none), 1 (mild), 2 (moderate), and 3 (severe), for the symptoms of pruritus, erythema, edema, erosion, and scaling. Pruritus was observed clinically for more than 2 minutes.

Clin

ical

ski

n to

tal s

ever

ity s

core

The total clinical score

ctrl內服結束後1個月 JTC內服結束後1個月C

lini

cal sk

in tot

al

seve

rity

sco

re

臨床症狀

JTC − +

投予第 8週

正常上限

g/h．

m2

經皮水分蒸散量


從創意到技術種子； From ideas to seeds, an example透過機轉解析進行標的認定（實施案例）

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某疾病患者集團的基因變異與發病的相關性; a disease-associated gene mtation

該基因的機能與變異和機能之間的關係解析; functional study

不活化變異Inactive mutation

基因表現的減少與該疾病一般的關係解析Association of gene expression with general population with that disease

表現機轉的檢討Expression mechanism analysis

利用既知化合物檔案庫phenotype screening with commercial library

化合物為活性，與已知的藥理活性不同Hit compoundsBut different mechanism

活性化合物標的檢討Target finding for a hit compound

孤兒藥受體Orphan GPCR

HTS的啟動

新化合物探索Search for new compounds

異型發病，或該疾病

病態與變異無關，其

基因表現呈現減少

Open Innovation 為企業無法做到的創藥實驗工房

Reverse PharmacologyVSPharmacology

Reverse PharmacologyVSPharmacology

Genome -> High Throughput Screening -> Combinatorial ChemistryVSPhenotype -> Phenotypic Screening

Genome -> High Throughput Screening -> Combinatorial ChemistryVSPhenotype -> Phenotypic Screening

Screening with commercial libraryScreening with commercial library

Persistent commitment of researchers making original findingsPersistent commitment of researchers making original findings

Target Validation using clinical samples

Target Validation using clinical samples

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Coordination of patent application and publication專利申請與公開發表的協調

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• IP Office 智慧財產辦公室：Three IP Managers handle patent applications, publications and contracts in the Fusion Lab. 3名智慧財產經理人在融合實驗室透過網路管理專利申請、公開發表、契約等所有的智慧財產。

Minimize conflict of interest. 使利害衝突最小化

智慧財產承辦人掌握研究進度，協調專利申請與公開發表。研究者輕鬆諮詢智慧財產相關事項。

PL PL PL

Organization of Medical Innovation Center

TechnologyPlatforms

Translational Research Center

Evidence –based Medicine Center

Human Genome CenterExperimental Animal CenterAnatomy/Pathology CenterExperimental Instrument Center

Medical Innovation Center

Dean

DirectorSystematic Alliance

In Each Disease Area

PL

MIC Committee（Director, Vice Director, Project Leaders）

Vice Director

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Kyoto University Medical Area-Business Liaison Office (KUMBL)

Kyoto University Medical Area-Business Liaison Office (KUMBL)

Takeda

Project on CN

S

DSK Project on Cancer

TM Project on CK

D

SK Project on synapse

TK ProjectSchizophrenia & Central Control of ObesityDSK ProjectCancerTMK ProjectChronic Kidney DiseaseThe Fourth ProjectAny other area


De

New MedicineNew Treatment

Outcome (Performance)

Research on Mechanism

New Research

ResearchersIP ManagersSpecialized in

Drug Development

Nurturing people

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1.Utilizing new drugs and instruments, we can make another discovery (Reproduction cycle of science).

2.With investment by the company, we can create positions for young scientists and initiate new research, nurture people specialized in drug development.

3.We can expose medical graduates and clinicians to drug development and make role models for next generation.

Discovery of new mechanism and

molecule.

DrugToxin

AntibodysiRNA

Creation of new drug

New Target

Speed‐up of Basic and Clinical Research

University’s Benefit of Strategic Alliance: Reproduction Cycle of Science

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“Best Drugs on Best Science”~AK Project~

Thank you for your attention!

Filaggrin ProjectKenji Kabashima, Atsushi Otsuka, Gyohei Egawa, Hiromi Doi, Tomoko Fujita, Shuh Narumiya

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