Biotech Collaboration in Taiwan

Chung-Hsiun Wu, Ph.D., CEODevelopment Center for Biotechnology

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Outline

1. About DCB

– R&D capabilities

– BD capabilities

– Collaboration cases

2. Future Prospects

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The best partner for biotech industry!

Mission:To facilitate the development of the biotech industry in Taiwan

• 35 years of history, a government founded non-profit organization

• 400 employees (60% R&D)

• 5 spun-off companies

• 2500+ former employees → workforce in pharmaceutical / healthcare

industry• Promoter for governmental policies• Think-tank for biotech policy• R&D: New drug development (biologics, small molecules)• Developing emerging technology • Training professional workforce• Promoting collaborations among industry, academia, and research institutes

About DCB

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USA

CHINA

JAPAN

TAIWANHeart of Asia

• National Biotechnology Research Park• Xizhi Campus• Nankang Software Park

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Three Campuses

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A: Translational Medicine Research Center B: Core Thematic Center C: BioHub Taiwan D: Bioinformatics Center E: Development Center for Biotechnology F: Taiwan Food and Drug Administration G:National Laboratory Animal Center Academia Sinica (0.5km away)

Basic Research

Translational MedBioinformatics

New Drug DevelopmentPreclinical

Study

RegulatoryOffice

Commercialization Incubation

We are here !Eco-Friendly Campus

Innovation/ Incubation/ Integration

National Biotechnology Research Park

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Board of DirectorsChairman

Supervisors

Auditing Office

Occupational Safety & Health

Human Resource

Accounting

Strategic Planning & Project Management

President Office

Translational Medicine

Laboratory

Division of Industrial

Development

Division ofAdministration

Innovation & Entrepreneur Core (IEC)

Legal Affairs & IP Management

Drug Commercialization Center (DCC)

Biotechnology and Pharmaceutical Industries Promotion Office (BPIPO)

Public Affairs

Project Management

Institute of Pharmaceutics

Institute for Drug

Evaluation Platform

Institute ofBiologics

President

Global Research Collaboration

400 Employees (2019)

Ph.D.: 68 Associate: 17

M.S.: 212 Others: 8

B.S.: 52

Alumni Club

Special Tasks

Organization

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RD Focus ---New Drug Development

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Services for Preclinical

Studies

Business

Development

New Drug

Development

From Bench-top to Commercialization

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Lead

Discovery

Validation

Optimization

Preclinical

ADME ToxIND

Clinical Trials

Phase I, II, IIINDA Market

Innovative projects

Clinical Trial

R&D Focus --- New Drug Development

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• Drug Design, Medicinal Chemistry, and Formulation

• DM/PK (ADME), Animal Pharmacology , and Toxicity Testing

• Process Development for GMP Production

Per-Clinical Research IND Clinical Study NDA Market

Regulatory Support

Cell Line Development Process Development & Process Characterization(QbD)

Analytical Development CGMP Manufacturing (Mammalian cell& Microbial)Protein Characterization

Documentation SupportBiosafety Test (TFBS)Toxicology (QPS)

Quality Management

Integrated R&D Core Capability

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BioengineeringProtein

EngineeringProtein

ExpressionProtein

Characterization

Biologics Development-1Infectious Diseases

Institute of Biologics

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Biologics Development-2Immunotherapy

Institute of Biologics

• Protein expression/ purification- Parallel system scale-down development (100-250ml) - Bioreactor process development (5L/50L )- Purification process development- Continuous bioprocess

•Biofunctional assay •Antibody engineering

- Humanization- Affinity maturation- Mono-glycosylated Ab

• Phage display• B cell/plasma cell• High throughput screening system

• Ab types – IgG, BsAb, ADC, scFv, Fab, CAR-T

• Antibody Characterization - Physical, chemical, biological, formulation and stability studies

•CHO/vector engineering - High yield cell line screening

• Microbial cell line development for scFv, Fab, BsAb(secreted)• Medium optimization / Metabolic engineering • Minibioreactor system

PreclinicalDevelopment

LeadAntibody

Candidateantibody

LeadOptimization

Antibody Screening

IND Filing

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Biologics Capabilities

Her2/CD3Globo H/

CD3

EpCam/CD3

ICOSL-VEGFR2

ICOSL-MSLN

MSLN/ CD3

Pharmacology

PK / PD

Toxicology

CMC

Clinical Phases

Bio Safety

CAR-T

VEGFR2 Globo H

Globo H

TMCC3

MSLN

PDL1

Phage Display

HSV

MDR-01

STAPH Human Library

HSV

H7N9One-Step

Conversion

Human Single B Cell Sorting

Mouse Library

Phage Display

Globo H

TMCC3

CSC-1

VEGFR2

ENO-1

CSF1R

CD73

TMCC3

IL-20

TIM3

PD1

PDL1Humanization

Hybridoma

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Integrated Antibody Platform

© 財團法人生物技術開發中心版權所有 保留一切權利

Cell line development

Bioprocess development &Scale-up process

Purification &Initial formulation

development

Tox materialproduction

Cell line development Bioprocess development

Purification process development Tox material production

5L & 50L

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Cell Line Development & Bioprocess Development

LeadDiscovery

ValidationOptimization

Preclinical, Tox, CMC IND Phase I Phase II

Infectio

nIm

mu

ne

LT-Flu Vaccine 2012 IND

LT-Hib Vaccine 2012 IND

MAb HSV 2014 IND

Therapeutic MAb for MDR Bacteria

MAb H7N9

MAb IL-20

MAb ENO-1

MAb Globo H

ICOS ligand/anti-VEGFR2 bifunctional protein drug

MSLN/CD3 BsAb

Globo H/CD3 BsAb

Her2/CD3 BsAb

CAR-T for Cancer

Mab Tim3

Mab PDL1

MAb CD73

On

colo

gy

Out licensed

LT-Allergy Vaccine 2018 IND

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Pipeline in Biologics

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Medicinal Chemistry

Computer Modeling

Medicinal Chemistry

Institute of Pharmaceutics

In vitro Assays

Mode of Action Analysis

In Vitro Biology

Institute of Pharmaceutics

PreclinicalDevelopment

Hit to Lead

CandidateSelection

LeadOptimization

Target Screening

IND Filing

Small Molecule Synthesis Platform• Ligand-based/structure-based rational drug design• Lead Optimization• Compound library synthesis• Chemical processes optimization• Protein drug modification

In Vitro Anti-Cancer Drug Screening Platform• Kinase activity assay• Human cancer cell cytotoxicity assay• Human normal cell cytotoxicity assay• In Vitro ligand-dependent cell proliferation assay• Tubulin polymerization assay• Colchicine site competitive binding assay

Mode of Action Analysis• Cell-based kinase assay• Cell apoptosis test• Cell cycle analysis

Safety Pharmacology• hERG K+ channel competitive

assay

Caco-2 Permeability assay

Customized Services

Average throughput: Lead to candidate, 1.5 y, 2.5 FTE, ~ 180 compoundscandidate to backup, 1.0 y, 1.5 FTE, ~ 70 compounds

Pharmaceutics Capabilities

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LeadDiscovery

ValidationOptimization

Preclinical, Tox, CMC IND Phase I Phase II Phase III

On

colo

gy

Diabetes

DCB-CA1 2007 TFDA IND

mTOR 2013 US IND; 2014 TFDA IND

Raf 2016 US IND; 2019 TFDA IND

DCB-BO1301 2017 US IND

Hedgehog

ADC

FLT-3

CSF-1R

AXL

PROTACs

PI3K gamma

DCB-WH1 2008 TFDA IND

DCB-BO0101 2015 TFDA IND

Botanical Drug for Periodontic Disease

DCB-AD1 2004 TFDA IND

Inflammation

CNS

IDH1

SYK

Out licensed

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Pipeline in Chemical & Botanical Drugs

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Pharmacology &Drug Disposition

IND Core TeamPreclinical Pharmacology

Development Service of Analysis &

Formulation

Preclinical ADME/PK Services

Institute of Pharmacology & Drug Disposition

Drug Discovery Stage

Early Discovery-Compound Screening

Mid-stage Discovery-Lead Optimization

Late Stage Discovery-Candidate Selection

Oncology• Subcutaneous xenograft models• Orthotopic xenograft models• Syngeneic murine models• Xenograft models in humanized mice• Patient derived xenograft (PDX) models

Metabolism Disorders• Diabetic model• Hyperlipidemia model• Hypertensive model• Hyperuricemia model

Immune-Related Disorders• Rheumatoid arthritis model• Asthma model• Skin diseases• Inflammatory bowel disease (IBD)

Other Models • Wound healing model• Alzheimer's disease model• Pharmacokinetics (PK)• Acute Toxicity Test• Customized service

In-vivo Study (Efficacy Evaluation) Ex-vivo Study(MOA/Biomarker discovery)

DiseaseAnimalModels

Serum biochemistry

Microbiota-related Assay

Serum cytokine analysis

Histopathological analysis

Immune cell polarization

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Preclinical Pharmacology

• Pharmaceutical companies

• Academia

• Biotechnology

• Botanical Drugs

• Health food

• Cosmetic/ Skin care products

Customer / Service Category

• Provides formulation development and analysis for small molecule drugs, protein drugs, herbal medicine, health food and skin care products.

Goals

• Oral (Liquid, Tablet, Capsule; Immediate release/ controlled release/ Sustained release /Long-acting /Enteric)

• Parenteral (Liquid, Lyophilized, Implant)

• Topical (Cream, Ointment, Gel)

• Mucoadhesive/Oral cavity (Gel, Ointment, Patch, Spray)

• Inhalation/Nasal spray (MDI, nebulizer)

Formulation Development/Product Design

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Services in Analytics & Formulation

In vitro ADME

Caco-2 Permeability and PAMPA Protein binding Microsomal stability Metabolite identification CYP P450 reaction-phenotyping

In vivo DMPK

Bioavailability In vivo metabolite identification In vivo drug-drug interaction evaluation Toxicokinetics (TK) Allometric PK scaling PK/PD modeling and simulations

Biologics Analysis mAb characterization Drug-to-antibody ratio distribution for ADCs PK assays for antibody-drug conjugate

Do not copy or distribute without permission from DCB

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Services in Preclinical ADME/PK

Initiation Project charter,Requirements

gathering

Plan Schedule,Estimate costTest facility

Confirm TimelineTracking Progress

Control qualityproblem-solving

Study ProtocolAgreement/Approval

Study Conduct

Final Report

Archive

Planning

Project close

Execution& control

Archive

Drug Development

PK

PD

CMC

Tox.

Early clinical development

plan

Assist to IND filing

Study plan

Draft report

Sponsor Request

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Project Management

IND Core Team

Anti-ENO-1 Therapeutic Antibody

H2L LO CS PCTarget discovery

NHRI DCB Biotech Company in Taiwan

FY100

• Pharmacology Analysis• Indication Analysis (Multiple Sclerosis)

• Efficacy Examination• Candidate Selection (High Yield Cell Line

MCB Development)

• Non-GLP PK/TOX in Rodent• Patent Application and Deployment

• Process Development• Stability Test• Consultation for Technology

Development• Chemistry, Manufacturing, and

Controls (CMC)• IND Application

(Aimed for Year 2019)

• Target Generation

This project was initiated by NHRI for exploratory development. DCB carried on and added value to this biologics, and licensed out to a biotech company in Taiwan. DCB further provides the services and developmental consultation to the licensee. It is the indicative case for successful commercialization of a basic science research in Taiwan.

FY104

Multiple sclerosis results from neuron injury caused by the immune system attack.

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Zhaohe Cao (Crassocephalum crepidioides)-based anti-cancer botanical drug (DCB-BO1301) is a first and successful case that Academia Sinica transferred their findings to DCB for further research, and then co-exclusively licensed the technology to a domestic company.

102 106

LO CS PCTarget discovery I

Academic Unit Academia Sinica

Value added-• Scale-up and establish a Chemical

Manufacturing Control (CMC)• Validate anti-tumor activities• Complete toxicology analyses to

prove safety in animals• IND Application & Submission• US FDA Approval(Middle-stream research and development)

• Take over to translate potential herbal medicines from the bench top to human clinical trials

• Mode of action• Discover anti-inflammatory • Discover anti-melanoma

bioefficacy

Non-profit Governmental Organization Development Center for Biotechnology (DCB)

Local Pharmaceutical Company

(Upstream discovery research)(Downstream

Commercialize Product)

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Crassocephalum crepidioides ExtractsBotanical Drug for Cancer Therapy

Misoprostol Long-Acting,1994Misoprostol Fast-Acting,1997

mTOR injection, 2011

Calcitonin Nasal Spray Solution. 1996, 2005

台灣寶Bio-Bac生物農藥(百泰 1995;日本市場 2004)

ACE intermediate, 1998 (駿瀚)

Fluconazole manufacturing process(Matrix Lab.2002; US market)

DCB-BO0101 Botanical Drug,2014

DCB-CA1癌症治療輔助藥物, 2013

Calcitonin for injection, 1993Granisetron Prolonged-action injection, 2008

DCB-WH1 Botanical Drug, 2007

Anti-HSV mAb, 2012

LT adjuvant platform, 2013

Zhaohe Cao (Crassocephalum crepidioides)-based anti-cancer botanical drug 2017

Anti-VEGF mAb,2013Raf inhibitor, 2015 Anti-ENO-1 mAb, 2015

DCB-AD1 Botanical Drug

CSF1RAnti-Cancer inhibitor

Raf Anti-cancer inhibitor

HC Botanical drug

Nek2/Hec1 Anti-Cancer inhibitor

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Partners and Licensees

2013.4CGMP Biopharmaceutical

Pilot Plant Facility acquired by EirGenix, Inc.

2016.10Spun off TFBS Bioscience, Inc.

for GLP Biosafety Testing

2011.1GLP Toxicology Lab (acquired by QPS

Taiwan)

2000.6Professional Testing for

Drug Residues and Food Safety

(acquired by TAB )

2018.12Spun off

Botanical Group

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DCB Spin-off Companies

Business Development

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Drug Commercialization

Center

Biotechnology and Pharmaceutical

Industries Promotion Office

Industry & Technology Intelligence Service

Nangang Biotech Incubation Center

Industrial DevelopmentDivision

InternationalLinkage

Licensing &Collaboration

Commercial-ization

IntelligenceHub

Start upIncubation

BPIPO

Business Development Group

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BPIPOTaiwan

Biotech

Industry

One-stop Window

bridging the world to

Taiwan

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Biotechnology and Pharmaceutical Industries Promotion Office (BPIPO)

Start up Creation

• Innovation Assessment

• Business Plan made perfect

• Business Modeling

• Talents Scouting

Early Stage

• Fund Raising

• Coaching and Mentoring

• Training

• Hosting

• Commercialization

• Business Partnering

• Legal , IP

Expansion

• Innovation Diagnostics

• International Networking

• Technology Commercialization

• Clustering

• Business Development

Incubation

Accelerator

Post Incubation

• First Biotech accelerator in Taiwan

• MassChallenge Taiwan chapter

• CEO Clubs, Shared Facilities, Co-working Space.

Nankang Biotech Incubation Center (NBIC)

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Supported by

Qualified Industrial

Analysis and Consulting

Team

Policy

Regulation

Industrial

Dynamics

Market Forecast

Technology Trends

Operational Strategy

Policy planning

EnterpriseManagement

Research Innovation

From Information, Intelligence to

Policy and Decision

Industry & Technology Intelligence Service (ITIS)The Biotech Thinktank

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>30 ExpertsTargets: Academia to Start-ups

High-Potential Project SelectionTechnology Commercialization

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Drug Commercialization Center (DCC)

International Collaborations— Technology Transfer

Business Case& Strategic Planning

Marketing& Partnering

Licensing Negotiation& Due Diligence

Post-licensing Planning & Management

May 2013/ May 2014Assisting in US provisional application & PCT application

May 2013/May 2014Domestic Showcase& Business Partnering

Apr.-Aug. 2014Assisting in exploring the inventor team’s expectation, setting licensing goals and discussing the feasible solutions for financial concerns

Oct. 2013Inviting the lead inventor to bethe speaker in the first annualsymposium of the TaiwanAntibody Association, where hemet the champion of the licensee

Aug.-Dec.2014Assisting KMU in D.D. including preparingIP-related English documentation andnotarizing documents; coordinating withthe external supporting resources toresolve problems or clarify legal concerns.The deal was closed in Dec. 2014, and thedeal value was the highest among thelicense deals of Taiwan academic

Jan.-Oct. 2015Assisting KMU in awardingresearch collaboration with thelicensee, providing suggestions forco-author regarding publicationand consultation for post-licenseIP management, coordinating thesite visit to the licensee’s company

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BD Services Case Report

Future Prospect in Therapies

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Future Prospect in Therapies

Precision Medicine

Nanoparticles

Artificial IntelligenceBig Data

Cell Therapy& Gene Therapy

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Collaboration Welcomed

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Thank You

39

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陽明大學生技醫藥產業課程

生技產業深耕學院

數位生醫產業分析師

第9屆藥物藥理研討會

生物製程開發暨生物反應器操作

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包含蛋白質藥物製程開發、細胞量產等實作課程，共19家學術機構及生技公司參與，可提升產業藥物開發能量(2梯次分別39及14人)

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