DRUG DISCOVERY

PIPELINE

DDP Overview 2014

1

February 19, 2014

致力于科学研究

Mission of the Drug Discovery Pipeline

(DDP)

2

G

I

B

H

Stem Cell Biology

& Regenerative

Medicine

(iSCBRM)

Chemical Biology

(iCB)

Infection &

Immunity

(I3)

Drug Discovery

Pipeline

(DDP)

GIB

H A

cad

em

ic I

nsti

tute

s

Drug

Candidates (3)

Clinical

Trials 60+

Staff (0)

DDP Mission: Act as a translational center for GIBH by providing:

• Expertise

• Platform/core technologies,

• Integrated project teams

• Funding to develop new drugs

New department

created in 2009

GIBH consists of 3 scientific institutes and 1 translational center

Milestones for the DDP

3

(1) Formation and integration of project teams to enable the advancement of

drugs

(2) Centralization of core technologies to support drug development

(3) Development of a sustainable pipeline of projects with novel intellectual

property

(4) Establishment of key international partnership for the co-development of

drugs

(5) Recruitment of international experts with discovery experience to enable

effective drug discovery science at GIBH

(6) Provision of technical services and internal expertise to local universities

and companies in Southern China

(7) Licensing of intellectual property and drugs matured in the DDP to

pharmaceutical companies in Guangzhou for advanced clinical

development.

G

I

B

H

DDP continues to approve upon seven important milestones

Formation of Project Teams

4

Project

Chemistry Leader

Team Members

Molecule design

Synthesis

Purity

Crystallography

Scale-up

Formulations

Team Members

Protein

Screening

Enzymology

Biomarker validation

Animal models

PK/ADME

Safety

Biology Leader

High Through-Put Screening Capable of screening thousands of compounds per week in various enzyme and cell based assays at a low price

Structural Biology Allows us to optimize lead compounds using computer aided design as well as virtual screening

Pharmacokinetics/Pharmacodynamics/ADME Defines the PK and safety properties of our lead compounds

Biomarkers and Epigenetics Validates the efficacy and safety of our drugs in pre-clinical models

Medicinal Chemistry Design, synthesis and formulation of new drugs with IP

Bio-Therapeutics The use of proteins as active agents to treat diseases

Integrated Project Teams Centralized Core Technologies

Project teams provide the critical mass and expertise needed to advance drugs in the pipeline

i. “Project” vs. “PI” centric structure

ii. Core labs primarily support projects

G

I

B

H

Research Project Teams (RPT)

5

Lead

Development

EE HI LD CS IND Phase 1

Candidate

First in

Humans Idea

Department Head

(DH)

Research Project

Leader (RPL)

Research Project Team

RPTs are responsible for projects from early exploration to first in humans

The Research Project Leader (RPL) leads the project team and is empowered to declare milestone

decisions for all stage gates of the program

Department Head(s) (DH) is responsible for selecting RPLs and for configuring and providing

resources for research project teams based on evolving needs of the program

Research Project Teams are the core of the DDP

G

I

B

H

Centralization and Expansion of Core

Technology Labs 6

Chief Technology Officer

(Micky Tortorella) Chemistry (Ding Ke): 13 RA

Director of

Chemical

Biology

Biology (Team Leaders): 8 RA

HTS (Zhengchao Tu): 6 RA

PK/PD/ADME (Xiaorong Liu): 7 RA

Structure (J.Liu & R.Jauch): 6 RA

Epigenetics (A. Strunnikov): 5 RA

Bio-Therapeutics (D. Yu): 4 RA

Analytical Chem (Y. Zhang): 6 RA

Administration

Business

Development:

3 FTE

Co

re L

ab

ora

tori

es

G

I

B

H

DDP has 8 core labs that support and comprise project teams

Core technologies were

centralized and expanded

and now include 8 labs

Each lab is led by an

experienced scientist

Members from core labs

comprise project teams

High-Throughput Screening

7

The high-throughput screening (HTS) core lab has

been fully equipped:

Tecan liquid handling workstation

Envision multiple plate reader

Echo520 ultrasound liquid transfer system

Genpix400B chip scanner

The HTS Center has the capacity to perform more

than ten-thousand drug screening reactions per day

Tecan Envision Echo Genpix

High-throughput screening center has been established at GIBH

G

I

B

H

Drug Screening Assays

8 HTS lab now offers >100 different screening assays against various targets

Drug Target Cmpd (hits)

Protein kinases ABL 683 (214)

ABL(T315I) 96(78)

ABL（E255K） 263(88)

ABl（G250E） 259(85)

Abl（Y253F） 258(79)

ABl（Q252H） 258(84)

ABl（H396P） 258(83)

ABl（M351T） 258(82)

ALK 213 (25)

Kit (GIST) 63 (48)

Her2 69 (43)

AKT1 200 (38)

AKT2 8 (6)

AKT3 8 (7)

EGFR 361(165)

EGFR (T790M) 123(106)

EGFR（L858R） 155(129)

EGFR（L861Q） 117(108)

EGFR(T790M&L868R） 177(123)

AuroraA 24(3)

AuroraB 24(3)

DDR1 112(91)

DDR2 70(26)

Met 17(0)

Proteases DPP4 28(28)

DPP8 35(2)

DPP9 35(3)

Cathepsin D 36(9)

Cathepsin E 36(20)

BACE-1 62(14)

PMII 125(99)

Pepsinogen C 11(1)

Pensinogen A 9(7)

ADAMTS13 227(20)

HIV-1 Protease 11 (3)

Drug Target Cmpd (hits)

HDACs

HDAC1 10(4)

HDAC2 17(11)

HDAC3 256(33)

HDAC4 10(5)

HDAC5 17(5)

HDAC6 17(15)

HDAC7 10(2)

HDAC8 122(116)

HDAC9 17(14)

HDAC10 17(15)

HDAC11 10(1)

Anti-inflammatory

COX-1 75 (32)

COX-2 75(62)

PGE2 75(48)

TXB1 75(32)

TNFa 156(6)

IL1b 130(16)

Anti-Influenza virus

NA-S 80 (41)

NA-R 80 (35)

M2 126 (67)

NP 242 (45)

CPE assay 6272(231)

Plaque Reduction Assay 45 (45)

CYP450 Assay

CYT450

CYP2C9 21(20)

CYP3A4 21(17)

CYP2D6 21(15)

CYP1A2 21(5)

CYP2C19 21(18)

Drug Target Cmpd (hits)

Cancer cell toxicity A549 3162(146)

BGC823 372(44)

DU145 385(63)

Molt-4 372(65)

K562 62(47)

Hela 372(54)

HT1080 572(54)

MCF-7 672(47)

U937 372(61)

Othe cell-based assay

SNX10 3176(262)

Boris antagonist 3200(19)

GPCRs

BMP4 antagonist 2540(179)

BMP4 agonist 2540(3)

CCKB agonist 975(2)

OPRM1 antagonist 975(0)

Assay formats include

96, 384, and 1536 well

plates and FRET,

polarization, alpha screen,

cell, luminescence etc.

G

I

B

H

Creation of a Chemical Library

9

1. GIBH internal compounds

- All compounds submitted for screening are now ID, categorized, plated and deposited

in a central library

-These compounds are the most valuable

2. Purchased Compounds

- Structurally diverse compounds selected

- Include FDA approved drugs and pharmacologically active compounds

- Obey the rule of 5 including logP (<6), MW(300-700), no reactive groups, good

solubility etc.

GIBH library contains ~28K compounds and include:

G

I

B

H

Footnote: New

CCKBR agonists

identified from

the library

Novel 3D surface

Carbene chemistry

Compound Microarrays

10

Universal Immobilization of Small Molecules

Surface plasmon resonance imaging for rapid screening of targets

Drug Protein Conc. (nM) KD (M)

(Avg)

IC50

PO1 PMII 50 &100 5.08e-8 1.2e-8

PO2 PMII 50 &100 7.46e-8 0.4e-8

~1500 GIBH compounds successfully

immobilized and screened on chips

Goal is to immobilize 5000 compounds

5000 spots per chip

2 plasmepsin inhibitors successfully bound to their target PMII protein and Kd values were similar to reported IC50 values from enzyme assay

Collaboration with Plexera to develop chemical microarrays for easy screening

G

I

B

H

PK/PD/ADME Laboratory

11

Analysis Compounds Tested

Pharmacokinetics 260

Protein binding 85

Metabolic stability 120

Drug-drug interaction 91

Glucose tolerance 4

Hepatocyte (toxicity) 8

Caco-2 21

Blood-brain penetration 7

Acute toxicity 9

Zebra fish (toxicity) 39

Core Competencies Productivity

G

I

B

H

Footnote: PK

determinations

obtained early in

the testing funnel

Understanding the PK/PD relationship of our lead molecules

New In Vivo Pharmacology

Services 12

(4) Rat adjuvant arthritis

model

(1) Rat air pouch model

of inflammation (2) Rat acute carrageenan

induced edema model

(3) Hyperalgesia pain

model

New in vivo pharmacology services

offered in 2013

1. Acute rodent toxicity testing

2. Developed several new disease

animal models for screening anti-

inflammatory based drugs

G

I

B

H

Services provided increase the survivability of our lead drug candidates

Highlight: These

animal models of

inflammation

enabled the

nomination of drug

candidate GIBH-

1014

Model Drugs Tested

Air pouch single dose 36

Air pouch ED50 30

Rat acute edema 24

Rat hyperalgesia 24

Rat arthritis 5

In Vivo Cancer Models

13

G

I

B

H

Tumor Type Target # Drugs Tested

K562

(blood)

Bcr/Abl 12

Ba/F3-T315I

(blood)

Bcr/Abl(T315I) 11

A549

(lung)

EGFR(WT) 9

H1975

(lung)

EGFR(T790M/L

858R)

9

HT29

(colon)

bRAF(V600E) 7

HCT116

(colon)

bRAF(WT) 7

Rodent xeno/allograft models for determining efficacy of lead cancer drugs at GIBH

Normal Tumor Treatment

Xenograft Model:

Vehicle 5mg/Kg 20mg/kg

Allograft Model:

Highlight: These

animal models of

cancer enabled

the nomination of

drug candidate

D824

In vivo cancer model's lab is dedicated to

determining the efficacy of lead compounds

targeting blood, lung and colon cancers

Medicinal Chemistry Group

14

Chemical Biology

~47 Chemists

DDP

16 Chemists

10

DDP has a “project dedicated” core of medicinal

chemists

DDP works closely with members in Chemical Biology

Several senior chemists in Chemical Biology have

projects with the DDP

This model of collaboration maximizes (doubles) the

chemistry resources for research project teams

Target Disease ~ Compounds

Made

Cancer 320

Arthritis 60

Alzheimer’s 230

Diabetes 330

Flu 120

Malaria 210

Pain 100

Productivity

G

I

B

H

The group has made several thousand new proprietary chemical entities

Center for Analytical and Formulation

Chemistry 15

I. The Center has a brand-new lab site, which was completed in 2013 and

designed to form a modern analytical laboratory

II. The Center provides drug formulation, chemical analysis and quality

control for all molecules made at GIBH

III. The Center has been equipped with key instruments including a heavy

pressure tablet machine, zetasizer, HPLC, LC-MS, GC- MS, LC-

MS/MS, element analyzer, Prep HPLC, NMR(400MHz),

NMR(500MHz), IR spectrometer, UV spectrometer, X-ray diffraction,

Polari meter, melting point machine and PH meter

IV.Certification of ISO 17025 is expected in March of 2014

G

I

B

H

Center has the capability to provide chemical analysis and solid dosage formulation

Analytical Center Core Competencies

and Productivity 16

Instrument

Name

Total

Usage

(Times)

Chromatographic Lab

HPLC（Analysis） 572

HPLC（Chiral Analysis） 754

HPLC（Preparation） 345

LC-MS 396

Spectrometer Room

Ultraviolet-Visible

Spectrophotometer 0

Infrared spectrometer 93

Automatic control

temperature type

polarimeter

143

Chemical Analysis

Lab

Acidimeter 0

X-6 series digital

melting point tester 51

Electronic Balance 76

Total 2430

Center has conducted over 2000 analyses

1) Chemical Analysis Core mainly

performs analysis on organic

compounds and is equipped with

HPLC, LC-MS, GC-MS, LC-MS/MS,

element analyzer, Prep HPLC, NMR

(400MHz), NMR (500MHz), IR

spectrometer, UV spectrometer, and

X-ray diffraction

2) Formulation Core provides services

related to chemical formulation and

contains key equipment including a

high-performance coating machine,

centrifugal granulation coating

machine, freeze dryer, zetasizer,

heavy pressure tablet machine and

high pressure homogenizer

G

I

B

H

Structural Biology

17

3. Plasmepsin Project: PMII and PMIV expression,

purification and co-crystal screening of lead

compounds.

4. Cox-2 Project: predicting the binding mode and

interactions of lead compounds to drive potency.

1. New Super Computer Platform with a total peak

performance of up to 1.2T flops, plus 192GB

memory and 10TB storage, which provides

enormous support for high-throughput virtual

screening and biological macromolecule modeling.

2. CCKBR Agonist: CCKBR agonist design by CADD

(computer aided drug design), ~150 hit compounds

were selected for activity testing. CCKBR homology

model building and in silico screening of internal compound

database (~30,000), 124 hits were ID for testing.

Team supports target validation, lead generation and lead optimization for discovery projects

G

I

B

H

Impact Highlights

Footnote:

Invested 3M

rmb into

platform

Bio Therapeutics & Recombineering Lab

18

G

I

B

H

(2) Therapeutic protein development

The lab is developing a recombinant protein of

ADAMTS-13 for the treatment of thrombotic

thrombocytopenic purpura (TTP)

ADAMTS-13 cleaves and disaggregates vWF

in the blood preventing blood clots

(1) A core for gene knockout and transgenic mice

Lab uses “recombineering” technology for construction

of DNA targeting vectors

KO mice are used for target validation, toxicity evaluation

and disease models

Gene Knockout and Transgenic

Construction 19

G

I

B

H

Gene knockout targeting vector construction

Mouse ES clone generation

Develop knockout mice

Gene

Name

KO

Type

Targeting

Vector

ES cell

Clone

Blastocyst

Injection Chimeras

Het and

Hom

Jhdm1a KO Completed Completed Completed Completed Processing

Jhdm1b KO Completed Completed Completed Completed Processing

Snx17 KO Completed Completed Completed Completed Processing

NeuroD1 iKO Completed Completed Completed Processing

Nras KO Completed Processing

Setdb1 CKO Completed Processing

Snx21 CKO Completed Processing

Pcgf5 CKO Completed Processing

Cckbr

KO Completed Processing

Core Competencies

Productivity

KO, Conventional; iKO, Inducible; cKO, Conditional

Dr. Daiguan Yu, head of Bio-therapeutics Lab is an inventor of “recombineering” technology

Project Progress for ADAMTS13

20 Recombinant ADAMTS13 and its stealth

versions constructed and cloned

rADAMTS13 protein expressed

folded and purified ~120 kDa

rADAMTS13 is active in a peptide

assay of FRETS-WF73

rADAMTS13 is proteolyticly

active against native human vWF factor

Studying PK/PD relationship in mouse model of TTP

Initiating manufacturing of GMP grade protein

Control ADAMTS13

176 kDa

140 kDa

vWF Control Cleaved vWF

5 ng ADAMTS13-MDTCS

4 ng ADAMTS13-MDTCS

3 ng ADAMTS13-MDTCS

2 ng ADAMTS13-MDTCS

No ADAMTS13-MDTCS

Invisible to auto antibodies

Peptide spanning the

cleavage site in vWF

1

2

3

4

5 rADAMTS13 proteins degrade

vWF multimers in plasma of TTP patients

GIBH

A single proteinase molecule can inactivate or activate thousands of target molecules

1 .patient 1

2. patient 1 + rADAMTS13-MDTCS

3 .patient 2

4. patient 2 +rADAMTS13-MDTCS

5. normal1

6. normal1 +rADAMTS13-MDTCS

1 2 3 4 5 6

Molecular Epigenetics Laboratory

(MEL) 21

Core Competencies

- Cell-based screening assays

- Protein-protein interaction assays

- Chromosome and chromatin analyses

using NGS and ChIP-seq

Ongoing Projects

1. Cancer biomarkers: mAbs being generated to 50 identified cancer-testis

(CT) specific genes

2. Anticancer drug discovery: Developing inhibitors of BORIS, an 11-zinc-

finger epigenetic reprogramming factor, specific for testis and turned on in

many cancers – Hits identified from internal compound library

3. Novel cancer pathways: Using epigenomics in mapping chromosomal

breakpoints associated with dysfunction of specific pathways of chromosome

integrity and cancer

G

I

B

H

New biomarkers lab created in the DDP

MEL to Study Cancer and Biomarkers

22

An epigenetic approach to find new cancer biomarkers and therapeutics:

- Readers of epigenetic marks such as global transcription

regulators

- Targeting proteins only expressed in testis and cancer

Potent biomarkers Ideal anticancer targets for chemical inhibitors

and cancer immunotherapy

No expression in normal somatic tissues

• Current CT database includes 268 gene families

• Using human testis CAGE, MEL has identified hundreds more

• MEL is currently working on two cancer targets Boris and meiotic cohesin complex

CT genes = genes expressed

specifically in cancer and testes

G

I

B

H

CT genes may be safe targets for drug intervention

Genome Regulation Laboratory

(GRL) 23

Core Competencies

- Structural Biochemistry

- Computational Genomics

- Genome Regulation

- Cellular Reprogramming

Research Program

1. Decoding/manipulating genome regulation: Elucidating how transcription

factors combinations selectively target enhancer DNA and the enhancer code that

determines cell fates and how transcription factors “ read” this code

Drug Discovery Projects

2. SOX18: Identifying novel small molecule blockers of SOX18 as possible anti-

cancer drugs

3. Disease modeling & cell therapies: Producing synthetic factors for cellular

reprogramming (i.e. small molecules and proteins)

G

I

B

H

Decoding and Manipulating Genome Regulation for Cell Therapies and Drug Development

Product Portfolio 2011

24

Early Exploration

Hit Identification

Lead Optimization

Drug Candidate Selection

Out-License

Clinical Testing

Discovery Pre-Clinical Development Clinical

Development

G

I

B

H

Cartilage

Re-growth

ADAMTS-13

3rd Gen. COX-2

inhibitors

Plasmepsin

inhibitors

Anti-OA siRNAs

2nd Gen. Kinase

inhibitors

Oral Anti-AD drug

The beginning of a sustainable pipeline of projects

Product Portfolio 2014

25

G

I

B

H

Early Exploration

Hit Identification

Lead Optimization

Drug Candidate Selection

Out-License

Clinical Testing

Plasmepsin

inhibitors

Anti-OA siRNAs

ADAMTS-13

CCKBR agonist

DDR1 inhibitor

EGFR inhibitor

Cartilage

Re-growth

BCL11b

BORIS

SOX18

Discovery Pre-Clinical Development Clinical

Development

2nd Gen. Kinase Inhibitor

GZ824

Guangzhou Shunjian Pharma

Oral Anti-AD drug

GIBH130

SCCIP

3rd Gen. COX-2 Inh

Movement of projects forward:

3 projects advanced to CS

2 CS projects were out-licensed

2 projects moved to LD

3 projects entered HI

Significant addition and advancement of projects forward in the Pipeline

Inhibitors of Neural Inflammation as New Agents

for Alzheimer’s Treatment

O

OH

O

NH2NH2/ethanol

N NH

O

Br2/CH3COOH

80-100 ¡æ, 2h N NH

O

POBr3/CH3CN

N N

Br

CuCN/ dry DMF

N N

CNcon. HCl

90¡æ, 4h

N N

COOH

HN N

N

N

EDC/HOBt/TEA/DCM N N

N

O

N

N

N

400.0g 374g

450g(300g)

24g(3g) 25g(15g)

yield: 93.9%

yield: 40.5%yield: 92.1%

yield: 91.6%

yield: 68%,over night

yield: 63.2%

360g

100¡æ, 4h

140¡æ, 5hrefluxed, 3h

GIBH 130

MW = 360

cLogP 0.59

LogP 3.1

Project Leaders: Wenhui Hu, GIBH and Donghai Wu, GIBH

Neuro-inflammation mediated by microglia cells in the brain is responsible for progression of AD

Potency

Microglia Activation IC50 = 0.002 uM

Toxicity

hERG IC50 = >100 uM

Pharmacokinetics

BA 75 %F

Tmax 0.6 hr

Cmax 33,387 ug/L

Vd

T1/2 hr 4.3 hr

BBB

Brain AUC 17,706 ng/ml

CSF AUC 889 ng/ml

In Vivo Efficacy in Rodent Models Aβ-model of AD >90% reduction at 0.25mg/kg

APP/PS1 transgenic mouse >80% reduction at 0.25mg/kg

model of AD

Ischemia stroke model >50% reduction at 1.0 mg/kg

Collagen induced arthritis >70% reduction at 0.5mg/kg

In Vivo Safety

Acute Rat MTD > 600 mg/kg

Compound Profile In Vivo Efficacy

Group Dose

（mg/kg） Latency

(s)

Control 173.74±94.66

Model 78.78±117.73#

Donepezil 1.3 218.12±110.36**

Memantine 2.6 179.20±113.03*

GIBH-130 0.25 186.75±81.70*

0.028 238.25±75.87**

0.0031 141.93±87.41

APP/PS1 Transgenic Mice

Memory Improvement

Progress:

Lead Optimization to Clinical Candidate in 2012

Licensed candidate to SCCIP in 2013 where GIBH

maintains 50% ownership of the IP

SCCIP will pay 12M rmb to complete the IND package and

file with sFDA and USA FDA

SCCIP is responsible for clinical development costs

Next milestone is IND acceptance in 2014

>250 analogs synthesized >1000 grams of GMP grade

Excellent CNS

penetration

26

G

I

B

H

CF3

N

NH

O

N

N

HN

N 2CH3SO3H

New Bcr-Abl Inhibitors for the Treatment of

Chronic Myeloid Leukemia (CML) Resistance Project Leader: Ke Ding, GIBH

Bcr-Abl kinase mutation is primarily responsible for CML resistance against Imatinib

GZD824

MW = 533

Potency

IC50 values nM

Bcr-Abl WT 0.34

Bcr-Abl T315I 0.68

K562 CML cells 0.2

Ku812 CML cells 0.13

SUP-B15 ALL cells 2.5

Kd values:

nonphosphorylated

Bcr-AblWT 0.32

Bcr-AblT315I 0.71

phosphorylated

Bcr-AblWT 0.34

Bcr-AblT315I 3.20

Pharmacokinetics (oral)

BA 48.7%F

Tmax 4.0 hr

Cmax 390 ug/L

T1/2 hr 10.6 hr

In Vivo Efficacy in mice xenograft models

K562, Ku812, Bcr-Abl WT, Bcr-Abl T315I,

Bcr-Abl E255K, Bcr-Abl G250E and Bcr-Abl F317L

Compound Profile In Vivo Efficacy >400 analogs synthesized

>1000 grams GMP grade Vehicle

1 100 mg/kg

10a 2 mg/kg

10a 5 mg/kg

10a 10 mg/kg

10a 20 mg/kg

10a 1 mg/kg

Day 0 Day 7

Vehicle

1 100 mg/kg

10a 2 mg/kg

10a 5 mg/kg

10a 10 mg/kg

10a 20 mg/kg

10a 1 mg/kg

Day 0 Day 7

Progress:

Lead Optimization to Clinical Candidate in 2012

Licensed to Guangzhou Shunjian Pharmaceutical, in 2013 who will

cover the costs for IND and beyond and provide GIBH with up to

100M RMB in milestone based payments

Next milestone is IND acceptance in 2014

Efficacious

dose is between

1 to 10 mg/kg in

a model of

leukemia

Luciferase

detection (blue

intensity) as a

measure

of leukemia

G

I

B

H27

Renal Sparing COX-2 Inhibitors for the Treatment of

Inflammation and Acute Pain Project Leaders: Yanmei Zhang, GIBH and John Talley, USA

COX-2 is responsible for the production of prostaglandins at sites of inflammation

GIBH 1014

MW = 340

S-isomer

Potency

COX-2 IC50 = 0.014 uM

Selectivity

COX-1 IC50 = >100 uM

Pharmacokinetics

BA 107 %F

Tmax 0.47 hr

Cmax 35,300 ug/L

Vd 0.53 L/kg

T1/2 hr 5.2 hr

In Vivo Efficacy in Rat Models

Air pouch inflammation ED50 = 0.34 mg/kg

PGE2 Levels

Thermal hyperalgesia ED50 = 2.2 mg/kg

Paw edema ED50 = 3.0 mg/kg

Adjuvant Arthritis ED50 = 0.42 mg/kg

O

Br CO2H

CF3

CD3

Progress: 1. Hit ID to Lead Optimization in 2012 and 2. LO to Clinical Candidate selection in 2014

Compound Profile In Vivo Efficacy

Rat Thermal

Hyperalgesia

Adjuvant Arthritis Model

Low volume of

distribution may

explain selective

localization

>250 analogs synthesized

GMP manufacturing initiated

G

I

B

H

28

EC50 = 0.42 mg/kg 16

14

12

10

8

6

4

2

0 Veh Ind 0.01 0.1 0.3 1 3 10

GIBH1014 mg/kg

Art

hritis S

core

GIBH1014

（mg/kg）

PWTL (%)

Pain

Vehicle 100

1 64.5±7.8

3 41.3±5.9

10 15.1±4.8

30 4.8±2.0

Compound Profile In Vivo Efficacy

Plasmepsin Inhibitors as Novel Anti-malarial Agents

GIBH 117

MW = 393

cLogP = 3.6

achiral

Progress: Hit Id to Lead Optimization in 2012, next milestone is clinical candidate selection in 2014

Project Leaders: Xiaoping Chen, GIBH and Marvin Meyers, SLU

Plasmepsins are aspartyl proteases important for malaria survival

>300 analogs synthesized

G

I

B

H29

Dose-dependent inhibtion of compound

GIBH117 in the P. chabaudi ASCQ-infected

murine four-day suppressive test.

Potency IC50 (µM)

Pf 3D7 72h 0.463

Pf Dd2 72h 0.480

Pf 3D7 48h 0.751

Plasemepisn II 0.004

Plasemepisn IV 0.015

Selectivity IC50 (µM)

BACE 12

CatD >10

CatE 1.2

In vitro safety IC50 (µM)

CYP1A2 >10

CYP2C19 5.48

CYP2D6 >10

CYP3A4 0.449

Pharmacokinetics

MLM t1/2 (min) 81

RLM t1/2 (min) 61

HLM t1/2 (min) 29

hPPB (%) 98.5

Rat PK t1/2 (h) 2.9

Rat PK oral bioavailability (%F) 16

Red blood cell ,

infection assays

Highlight: Project was

awarded the

NIHR01/NSFC USA-

Chinese collaborative

research grant in 2014

~6M¥

1000

100

10

1

0.1

0.0

01

0.0

1

0.1

1

10

Lo

g p

f3D

7 C

ell

IC

50 (m

M)

Log PMII Enzyme IC50 (mM)

Correlation between

inhibition of PMII & red

blood cell infection

by malaria

30

Therapeutic siRNAs for Treating Osteoarthritis Project Leaders: Biliang Zhang and Micky Tortorella, GIBH

Genes R001 and R002 mediate cartilage breakdown and inflammation, respectively in OA

Compound R001 and R002 consists of ~ 20 base pairs of dsRNA

R001 is selective for gene ADAMTS-5 and R002 is specific for gene R002

The 3’ends of both molecules are conjugated to a cholesterol analog for

enhanced cell permeability

1.2

1.0

0.8

0.6

0.4

0.2

0

Rela

tive

Ex

pre

ss

ion

R001 R002

siRNA

No Target

Synovial Fibroblasts In vitro both siRNAs permeate

synovial fibroblasts (major cell type

of the joints)

Targeted genes effectively blocked

by synthetically designed siRNAs

1

2

3

G

I

B

H

Compound

Potency

Delivery and Retention in the Joints

ECM (reservoir for agent)

Intra articular injection

(IA)

Cartilage

A proprietary formulation using polyarginine peptides

was developed

Retention in the cartilage of cy3red-labeled siRNA is

observed even after 2 weeks following IA injection

Intense staining seen both in the ECM and cells

Once a quarter dosing a FDA requirement may be

achievable with such a vehicle

Chondrocytes (target)

R001

30

>100 molecules synthesized

GIBH-R001/2

31

Inflammatory (CIOA)

osteoarthritis model • 6 week model

• Severe Fibrosis

• Cartilage erosion

Intra-articular

treatment with siR001

• Dosed 2x a week

• 10 nmols/knee (100ul)

Severe fibrillation down to the layer immediately below the superficial layer

Low grade fibrillation

Severe fibrosis and loss of cartilage in meniscus

No structural changes

Healthy cartilageCalcified cartilage

Disease siR001-2

siR001-2 effectively blocked disease

progression

Blocked all components of the disease - Fibrillation

- Fibrosis

- Cartilage erosion

Unprecedented efficacy for a DMOAD

Therapeutic efficacy also demonstrated

Next step is optimizing the formulation of

siR001-2

Candidate Selection planned for early 2014

Histology of knee joints

Therapeutic siRNAs for Treating Osteoarthritis

In Vivo (Histological) Validation

G

I

B

H

siRNA Team Members

Bio-Surgery approach for treating OA

New Project Entries

32

Target Function Drug Class Therapeutic

Indication

Project Leaders

Cholecystokinin B

Receptor (CCKBR)

Influences neuro-

transmission in the

brain, regulating

memory

Oral, small molecule

agonist

Dementia

Downs Syndrome

Alzheimer's

Jufang He

Yanmei Zhang

Discoidin domain

receptor family,

member 1 (DDR1)

Regulation of cell

growth, differentiation

and metabolism

Oral, small molecule,

tyrosine kinase inhibitor

Kidney Fibrosis

Lung Fibrosis

Lung Cancer

Ding Ke

Epidermal growth

factor receptor (EGFR)

with drug resistant

mutations

Overexpression has

been associated with a

number of cancers

Oral, small molecule,

tyrosine kinase inhibitor

to mutant forms of

enzyme

Lung Cancer

Liver Cancer

Colon Cancer

Breast Cancer

Reversible inhibitor

Ding Ke

Irreversible Inhibitor

Zhang Jiancun

Yanmei Zhang

Brother of Regulator of

Imprinted Sites

(BORIS)

Testis specific, 11-zinc

finger factor involved in

gene regulation

Oral, small molecule

blockers

Various cancers that

express BORIS

Alex Strunnikov

B-cell

lymphoma/leukemia

11B (BCL11B)

C2H2-type zinc finger

protein that maybe

linked to leukemia's

Oral small molecule

modulators

Leukemia's

Li Ping

SOX18

Transcription factor

involved in the

determination of cell

fate

Oral, small molecule

blockers

Cancer Ralf Jauch

G

I

B

H

Newly endorsed or projects under consideration

Footnote:

Cancer and

inflammation are

becoming the

major focus at

GIBH

Project Evaluation and Ranking

33

Projects are evaluated and ranked

based on:

1. Meeting key principles of drug

discovery including demonstration

of (I) drug exposure at the target

site of action; (II) drug binding to

the pharmacological target and;

(III) expression of pharmacology

2. Timely advancement from one

stage gate to the next

Projects that meet key criteria are

supported with significant resources

and are deemed Tier I.

Exp

osu

re

Co

nfi

den

ce

Pharmacology Confidence

None or Partial Principles

Binding to target but no data to

show relevant downstream

pharmacology effect; exposure

only in plasma, not at target site

(eg CNS); PKPD not well

established

Serious concerns that

mechanism can be tested &

clinical studies unlikely to be

definitive

Principles I and II

Target exposure and target binding

concur but no data to show relevant

downstream pharmacology effect or

data is not at site of action.

Risk in relying only on exposure

and binding; study design &

decision-making from clinical

endpoint needs to be crisp

Principles I,II,III

Target exposure shown and

concurs with target binding which

results in expression of relevant

downstream pharmacology affect at

site of action. PKPD well

established. Maximum confidence

in translation of drug exposure

and pharmacology & of testing

the mechanism

Principles II and III

Binding to target shown but

exposure only in plasma, not at

target site (eg local administration

to target); data showing relevant

downstream pharmacology effect.

Reasonable risk being carried

forward if confident that drug

reaches target in humans &

clinical endpoint relevant to site

of action

Hi, Hi

Lo, Lo

Risk Management with respect to ensuring project success

G

I

B

H

Mo

st p

roje

cts

fall h

ere

Project Evaluation and Ranking

34

Stage Gates Symbol DDP Average Times

Early exploration EE 6 months

Hit Identification HI 5 months

Lead Optimization LO 1-2 years

Candidate Selection CS 1-2 years

Clinical Testing CT NA

Out-License OL 1 year

Target Progress

Mutant

Bcr-Abl

kinase

2009: HI

2010: LO

2011: LO

2012: CS

2013: OL

Microglia macrophages

of the brain

2009: HI

2010: LO

2011: LO

2012: CS

2013: OL

COX-2

enzyme

2010: HI

2011: LO

2012: LO

2013: CS

Plasmepsins Aspartyl

proteases

2010: HI

2011: HI

2012: LO

2013: LO

Target Progress

ADAMTS-5 +

ADAM-17

2009: EE

2010: HI

2011: HI

2012: LO

2013: LO

ADAMTS-13 2010: EE

2011: HI

2012: LO

2013: LO

EGFR mutant

kinase

2012: HI

2013: LO

Cholecystokinin

B Receptor

(CCKBR)

2012: EE

2013: HI

Average time needed for projects to advance to the next stage gate

G

I

B

H

Projects in the DDP have advanced at

timelines consistent with industry

averages published by various

pharmaceutical companies over the

years

Key International Collaborations

The Center for World Health & Medicine at Saint Louis University

Development of inhibitors of plasmepsin V as novel anti-malarial agents

Dr. John J. Talley, inventor of Celebrex and Bextra

Development of 3rd generation Cox-2 selective inhibitors for inflammation and pain

Professor Jufang He at Hong Kong Polytechnic University

Advancement of CCKBR agonists for the improvement of memory

Plexera Inc.

Development of compound micro array chips for repositioning of clinical candidate drugs

Professor Anne-Marie at Rush Medical Center

Understanding chondro- genesis and the biology of OA pain using engineered cells/mice

Shanghai Institute of Material Medica

Development of EGFR inhibitors for the treatment of cancers

Collaborations allow GIBH to share the risk and expenses associated with drug development

GIBH

35

Recruitment of international experts

36

Micky Tortorella is a former Senior Principal Investigator at Pfizer (2001-2009) with 15 years’ experience

in the pharmaceutical industry. Prior to working at Pfizer he had a successful tenure as a Research

Scientist at DuPont Pharmaceuticals (1993-2000). He is regarded as a key opinion leader in the United

States as well as internationally in drug discovery, osteoarthritis and metalloproteinase biology.

Dr. ZhengchaoTu obtained his Ph.D. from Northwest A&F University and Kunming Institute of Zoology,

Chinese Academy of Sciences in 1996. He did his post-doctoral research at Fudan University (1996-

1998). Before joining GIBH in 2010, he was a senior scientist and director in Reaction Biology Corp. USA,

where he focused on high throughput drug screening.

Dr. Ralf Jauch studied Biology in Jena (Germany) and Manchester (UK) before doing his PhD in a

molecular biology program from 2001-2005 at the Max-Planck-Institut für biophyskalische Chemie in

Göttingen, Germany. In 2006 he joined the Genome Institute of Singapore From 2008-2013 he continued

at the GIS as a research scientist. In 2013 he joined GIBH.

Dr. Alex Strunnikov received his Ph.D. from the Institute of Cytology, St. Petersburg, Russia, where he

cloned and characterized the SMC1 gene. Then,the United States, where he got a postdoctoral position at

the Carnegie Institution of Science, Department of Embryology. In 1996 Dr. Strunnikov was recruited by

NIH, where he stayed, at NICHD and then NIAID, up until 2011.

International team of scientists with overseas training

G

I

B

H

Recruitment of international experts

37

Dr. Daiguan Yu previously was a Research Fellow working at National Cancer Institute-Frederick,

Maryland where he invented “Recombineering”, an advanced gene engineering technology. From 2001 to

2009, he took a position in Lexicon Pharmaceuticals Inc. in Texas. He was then invited as Scientific

Specialist to Sanger Institute at Cambridge, UK from 2009 to 2010.

Dr. Yanmei Zhang got her Ph.D. from Technical University of Munich, Germany in 2004. Her work focused

on organic catalysis and methodology. Before joining GIBH, Dr. Zhang worked at the drug discovery center

of UCSD Cancer Center with Prof. Dennis Carson on the design and synthesis of AdSS inhibitors and the

formulation of active small molecules in liposome form.

Dr. Chris Zhang received a PhD in Immunity from the Sheffield Medical School followed by a postdoctoral

fellowship in the Department of Cardiovascular Research at Royal Hallamshire Hospital. He then joined

industry as a Senior Research Scientist at Molecular Devices, before joining GIBH in 2013. As a Principle

Investigator he is developing new applications across a number of instrument platforms using iPSCs.

Diversity allows the research teams to approach each project in a very unique way

G

I

B

H

Provision of Services to Local

Universities 38

G

I

B

H

As a means for stimulating scientific excellence in China, GIBH offers its drug development expertise and

platform technologies to universities and small companies in Guangdong province

GIBH offers services in compound screening, drug pharmacokinetics and analytical chemistry

High-throughput screening center

Company Name Service Provided

• South China Sea Institute of Oceanology, CAS. Guangzhou Anti-cancer cell based assays

• Kunming Institute of Botany, CAS. Kunming Anti-cancer and anti-flu screening

• China Pharmaceutical University. Nanjing Anti-cancer assay

• East China University of Science and Technology Shanghai Anti-cancer

• Sun Yat-Sen University. Guangzhou Anti-flu screening

• WuXi AppTec. Shanghai Anti-cancer assays

• Jinan University. Guangzhou Anti-Cancer and anti-flu screening

• The Hong Kong Polytechnic University. Honghong GPCR assays

• Minzu University of China. Beijing Anti-TB assay

Center of drug metabolism and pharmacokinetics

Company Name Service Provided

• Guizhou institute of biology Analysis of biological samples using LC/MS/MS

• Guangdong Lingnan Pharmaceutical Co., Ltd Analysis of biological samples using LC/MS/MS

• Guangzhou Hua Po Biotechnology Co.,Ltd Analysis of biological sample using LC/MS/MS

• High-tech Da An Health Industrial Investment Co.,Ltd

LC/MS/MS to screen for early genetic metabolic

markers for neonate

1

2

Intellectual Property

39

Publications 19 Papers

Intellectual Property 20 Patents

Research Grants 6 Grants

Technology Transfer 2 Licenses

• ACS Med. Chem. Lett. 2010, 1 (9), 454–459

• Current Medicinal Chemistry, 2011: 18(14):2146-57

• Bioorg.Med.Chem.Lett,2011,21(7), 1965-1968

• Mol Biol Rep DOI 10.1007/s 11033-011-0800-8

• Physical Chemistry chinese Science Bulletin. 2011 Vol.56 No.1: 1–6

• Bioorganic & Medicinal Chemistry Letters, 2011, 21, 2949-2952

• Protein Sci. 2011 Apr; 20(4):735-44

• J Med Chem. 2012 Mar 8; 55(5):2144-53

• Bioorganic & Medicinal Chemistry Letters, 2012, 22, 1208-1212

• J. Med. Chem. 2012, 55 (5), pp 2144–2153

• J. Med. Chem. 2012, DOI: 10.1021/jm201591k

• Current Pharmaceutical Design, 2012, 18, 3421-3431

• European Journal of Medicinal Chemistry 49 (2012) 164-171

• Int. J. Mol. Sci. 2012, 13, 6620-6638

• 200910039366.9

• 200910039897.8

• PCT/CN2009/000243

• 201010216603.7

• 201010600967.5

• 201110007772.4

• GIBH Drug Discovery Pipeline, DDP Construction 2010

• GIBH Drug Discovery Pipeline, DDP Construction (Phase Ⅱ) 2011

• Thousands of People Plan “High-end Foreign Experts Project 2012

• NSFC Grant for Synthesis of New Nucleoprotein Small Molecule Inhibitors 2012

• NSFC/NIH R01 Grant for Anti-Malaria Research 2014

• NSFC Research Grant to Study Chonrogenesis 2014

• SCCIP for the development of GIBH-130

• Guangzhou Shunjian Pharma, Inc. for the development of GZ-824

• 200910031106.7

• PCT/CN2011/000935

• 201110156399.9

• 201110267163.2

• 2011103351754

• 201210236713.9

• 201210265997.4

• 201110007547.0

• 201210202059.X

• 200710028696.9

• 200910039442.6

• 200910030051.8

• 201010279888.9

• PCT/CN2010/076652

G

I

B

H

Innovation in the drug discovery pipeline

Models for Collaboration

40

G

I

B

H

R&D Partner

Lead Opt. Candidate

Hit Identification

New Target ID

Drug Repositioning

Licensing GIBH Candidates

Contract Research

Assay Development

In Vivo Pharmacology

PK

HTS

Collaboration policies are flexible at GIBH; Open to many different types of agreements

De nova drug discovery Reliable partner in China

Drug Discovery Requires Patience

41

Idea! Drug

• Traditional

Med.

Chem.

• Rational

drug design

• In vitro

• Ex vivo

• In vivo

• In silico

• High

throughput

U.S (FDA)

E.U. (EMEA)

Japan

(MHLW)

China

(cFDA)

• Testing

starts at

Phase I

(Phase

I/II/III

• Bioavailabili

ty

• Systemic

exposure

Target

Discovery

Discovery

& Screening

Lead

Optim. ADMET Development Registration

2-3 yr 1-2 yr 1-3 yr 1-2 yr 5-6 yr 1-2 yr

• Expression

analysis

• In vitro

function

• In vivo

validation

• Bioinformat

ics

Preclinical validation and drug selection

(5 to 10 Years)

Clinical & drug approval

(6 to 8 Years)

Drug discovery is a long process that requires patience, long term commitment and investment!

Infra-structure and integration of core technologies is critical for doing proper drug development and has

been achieved at GIBH

Many Institutes in the USA and Europe have been successful - Northwestern with Lyrica, Florida State

with synthetic Taxol, and many more example to inspire us to move forward

60% of new drugs originally come from Institutes and small bio-tech

G

I

B

H

42

Drug

Discovery

Center

Stem Cell

Institute

G

I

B

HBridging with the Stem Cell Institute

Innovative drug discovery using stem cells for new target ID and compound screening

A. Tissue bank of induced pluripotent stem cells from well defined diseased patient populations

B. Robust protocols for somatic cell differentiation including neurons, hepatocytes,

cardiomyocytes and others cell types

C. Cell phenotype analysis via high content screening

D. Compound library screening for phenotype modulation

Analyzing Diseased Linked SNPs or

Splice Variants using iPSC 43

Tissue Bank

150 iPS cell Lines

iPSC Expansion

Rapid identification of

hetero- and mono-

zygote clones carrying

the SNP or SV by PCR

Expression of gene

containing SNP or SV

by qPCR and WB

Efficient neuronal

differentiation

Phenotype

Analysis

Drug

Screening

SNP or SV Wild type Hetero Mono Expression Phenotype

rs1 14 20 3 Confirmed In Progress

rs2 22 25 6 In Progress In Progress

G

I

B

H

SNPs and SVs linked to CNS diseases are currently being evaluated at GIBH

“Thank You” from the DDP Team

44

G

I

B

H

Serving the citizens of China and the world through commitment and discovery