Integrated Services

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Aurigene is a specialized biotech focused on

Oncology

Inflammatory disorders

Aurigene: Overview

Fully integrated drug discovery infrastructure, >500 scientists

Based in Bangalore, Hyderabad (India) and Kuala Lumpur (Malaysia)

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Business Model:

Pioneer in a “collaborative drug discovery”model, built on leveraging strengths.

Collaborative, Integrated and Standalone services.

Chemistry: Small Molecule and Peptide focused

Core technology strengthsSBDD (Structure based drug design): an effective & rational drug design toolbox guided by X-ray

crystallographic binding modes of small molecules (hit/lead) with target protein.

FBDD (Fragment based drug design): Aurigene’s TrugFragTM platform integrates biophysical and computational methodologies for fragment based hit generation.

Experience

• ~ 59 targets or programs

• Kinases, Proteases, Nuclear Hormone receptors & non-GPCR membrane proteins.

• 12 Partnerships in integrated discovery(6 of the top 10 pharma)

Track record• 8 candidates nominated for IND filling.

• Two of most advanced candidates in

Phase-1 and Phase-2.

Intellectual contribution

Aurigene scientists are inventors/co-inventors in 43 patent applications and 4 patent grants.

Aurigene: Overview

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Licensed multiple early-stage programs

Integrated Services: Overview

• Integrated Services: Medicinal Chemistry & Biology complement each other.

• Service offering : Target validation, Hit generation, Hit-to-lead & lead optimization.

• Leveraging Aurigene ‘s drug discovery Infrastructure and expertise .

Integrated Services

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Medicinal Chemistry

Synthetic Chemistry

Peptides

Scale up

Analytical R & D

Molecular Modeling

Pharmaceutical Development

Biology

Structural Biology

in vitro biology

in vitro toxicology

in vivo biology

ADME/PK

in vivo toxicology

Customized solutions

Integrated services: Key differentiators

Ability to Integrate: Knowledge/best practices from discovery collaborations to bring

novelty to routine Medicinal Chemistry Services

Successful track record:

• Focused at always achieving KPI’s/ SLA’s committed to the partner; evident from the

strategic partnerships with several large and mid-pharma companies

• Average tenure of Collaborations ~3 years

• Collaborations have scaled up with several partners doubling the FTE count over the

last 5 years

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Experienced Team:

• Average industrial experience of bench level chemist ~7 years

• Average tenure of middle management personnel ~6 years

Secured IP and IT infrastructure:

• All projects are secured in terms of IP through need-only IT access to project related

information/data and periodic trainings.

Chemistry Infrastructure and Capabilities

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Synthetic Chemistry

50 Modular chemistry labs; each fully equipped and self sufficient.

5-9 fume hoods per lab and all essential instrumentation

Biotage Microwave, Combi-flash MPLC systems

Parr Shaker, Ozonator, Auto Claves

BOHDAN blocks & Buchi Syncore Parallel Synthesizer

Scifinder/Reaxys/ Online journals: Access to every chemist.

Route Scouting/Design to delivery support

Diversity oriented synthesis, multi-component reactions

Metal catalyzed reactions, “Click” chemistry,

Heterocyclic & carbocyclic chemistry

Asymmetric synthesis, Carbohydrate chemistry

Solid phase synthesis, Peptide chemistry

Focused libraries

Infrastructure

Expertise

Proven expertise and excellent track record with challenging chemistry, multi-gram synthesis and focused libraries.

Peptide Chemistry

One of the few drug discovery companies in India with strong Peptide capabilities

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5 modular labs dedicated to peptide group

Synthesis : Manual & Symphony Automated Peptide Synthesizer.

Solid and solution phase synthesis capabilities

Lyophilisers

Microwave reactor-Biotage Initiator

Preparative HPLCs (4); Analytical HPLC (2), LC-MS

Infrastructure Linear and branched chain

Derivatisation of peptides with Lipids,

Steroids, Small molecules, Carbohydrate

Conjugated peptides.

Conformationally constrained peptides-

Lactams, Multiple disulfides, Stapled

peptides

Labeling – Biotin; Fluorescein

Peptide dendrimers

Peptide based affinity ligands

Peptidomimetics

Expertise

29%

27%

18%

6%

5%

5%

3% 2%

2%1% 1% 1%

Natural + Un natural AA

Branched Peptides

Lipidated Peptides

Lactam

Paptidyl resin

Disulphide / Nested

Stapled Peptides

Toxins

Labelled Peptides

Phospho Peptides

Pegylated

Head to tail Cyclization

Reagents for peptides

Scale-Up

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Dedicated scale up, 20L reaction volume capacity

Walk-in and low lying fume hoods

20L rotary evaporator

Kg level column purification facility

Vacuum oven, High pressure autoclave

Infrastructure

Case studies

Expertise

Scale-Up

Scale up NCEs

Prodrugs & Metabolite synthesis

Polymorph screening

Technology transfer

Salt selection

Intermediate & scaffolds

Alternative synthetic

routes

Analytical –R & D

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Chiral and peptide purification using Diacel &

LUX ,CSP and C18 and C4 columns

Support to GLP analysis for Tox studies

Protein-ligand binding studies

Stability studies

Impurity profiling

Specialized capabilities

NMR 200 MHz, 300 MHz, 400 MHz, 500 MHz,

600 MHz (Varian)

LCMS API 2000 (Applied Biosystems)

LCMS Single Quad (Agilent & Shimadzu)

HPLC Analytical (Agilent1100 &1200)

HPLC Preparative (Agilent & Shimadzu)

UV & ELSD detectors

Autotitrator (848Titrino Plus-Metrohm)

FT IR (Spectrum One -Perkin Elmer)

Polarimeter (Model 841 Perkin Elmer)

Chiral HPLC columns

- Analytical (Chiralcel , Chiralpak, LuxAmylose)

- Preparative (Chiralcel , Chiralpak, LuxAmylose)

Infrastructure

Molecular Modeling

Ligand-based approaches

Structure-based approaches

Medicinal Chemistry

Structu

ral Bio

logy

Support in SAR optimization

Molecular Modeling

Virtual screening -Structure & Ligand based modeling approaches

Ligand design-de novo, scaffold hopping, ligand hybridization,

fragment-linking & related techniques

Database exploring & virtual library generation

Macro-molecular modeling, molecular dynamics simulation

QSAR & Pharmacophore-space modeling

Predictive (in-silico) ADMET modeling

Wide range of computational and

creative expertise which complements

experimental data on structures

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Schrödinger suite-structure-based & ligand-based modeling applications

CCDC’s state-of-the art docking platform

ChemAxon modules- estimation of diverse molecular properties, topology & geometry

In-house developed tools for ADMET predictions

High-speed computing & 3D visualization facility

Infrastructure

Expertise

QSAR

Pharmacophoremodeling

Knowledge-based

Molecular docking

Homology modeling

Molecular dynamics

Pharmaceutical Development

Proven track record/competencies in offering insights/solutions to developability of compounds & generating data required for submission of IND

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High Pressure Homogenizer (Micro-fluidics)

Log P/pKA Analyzer

Single crystal X-ray crystallography (Rigaku)

Modulated-Differential Scanning Calorimeter

Thermo-Gravimetric Analyzer

Spray Dryer, Particle Size Analyzer

Tablet Compression Machine

Tox/IND enabling pharmaceutical developability

Preformulation, Polymorph/salt selection

Preclinical/Tox formulation & stability

Excipient compatibility & selection

API Stability Studies

Prototype clinical drug product/stability

Pre-CMC/CMC documentation

Capabilities Discovery/Development phase Track Record

Polymorph propensity

assessment/screening

Lead ID phase (preliminary) >50

Lead Opt to Candidate nomination or safety phase (preferred morph selection)

>15

Prior to Phase I and beyond (comprehensive)

>5

GLP formulation

development &

support

Formulation development >50

Support >100

Salt screening Lead ID to phase I >10

Oral BA issues Lead ID (early preclinical) >50

Lead Opt to Candidate nomination (Preclinical safety)

>50

Pre-formulation

package

Pre-CMC (to support candidate nomination)

>20

Phase I enabling (to support CMC/IMPD filing)

~5

Formulation package

for phase I prototype

product

Prior to phase I (Prototype for FIH)

~5

Infrastructure

Expertise

Biology

Infrastructure &

capabilities

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Structural Biology

150 Proteins expressed in Bacterial and Insect Cells

300 Structures of different protein classes determined

with inhibitors

In-house Rigaku Rotating anode RU300

Quick access to Synchrotron beamlines (APS, SLS, ESRF)

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1.5-2.0 Å, 20

2.0-2.5 Å, 80

2.5-3.0 Å, 40

3.0-3.5 Å, 10

Resolutions of the structures

Crystal structures of various target families

Integrated gene-structure capabilities for supporting Structure-based Drug

Discovery

ADME/PK

Physicochemical properties

• Solubility and stability

Drug Transport

• PAMPA, MDCK, Caco-2

Distribution

• Protein binding

Metabolism and drug-drug interactions

• Metabolic stability in

Rat/mouse/dog/human liver

microsomes or S9

• CYP Profiling, induction and inhibition

– Fluorescent and probe substrate

– Microsomes, S9, Hepatocytes

Oral bioavailability

• PK studies performed in mice, rats, rabbits, guinea-pigs, hamsters and dogs

Dose proportionality and multiple dose

studies

• Linear Pharmacokinetics of the NCE

Excretion studies

• Major route of elimination of the NCE

Tissue distribution studies in rodents

Human dose and PK projection for FIM

studies

• Interspecies PK scaling by allometry

Bioanalytical activities (An OECD - GLP

Accredited lab*)

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Extensive range of ADME/PK and Bioanalytical Studies for generating

robust and reliable data for high quality drug candidates

In vitro Screens: Assays & HTS Capabilities

Target Expertise Kinases Proteases Nuclear hormone receptors GPCRs Others: Dehydrogenases, nucleases,

phosphatases etcHTS Capabilities Tecan Freedom EVO Liquid handling system Tecan Ultra Fluorescence Microplate Reader

• Steady state, Kinetics • Luminescence• Polarization• Time Resolved Fluorescence

Spectramax Gemini• Detection in standard steady state

fluorescence and luminescence modes

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Expertise in wide variety of efficacy screening assays (~50 biochemical & 36 cell

based - functional & mechanistic) that allow for screening of compound libraries

against specific validated targets and PD assays in cellular models for utilizing in

pharmacology

In vivo Studies: Efficacy Models – oncology (1/2)

Origin Cell line Type

Xe

no

graf

tsw

ith

hu

man

tu

mo

rce

ll lin

es

Breast BT474, MDA-MB231 Subcutaneous and orthotopic

Colon HCT-116, HT29 Subcutaneous

Lung A-549, H1975 Subcutaneous

Ovarian PA-1, SKOV-3 Subcutaneous

Prostate PC-3, DU145, LnCap Subcutaneous and orthotopic

Pancreatic MiaPaca2 Subcutaneous

Melanoma A375 Subcutaneous

Bladder RT4 Subcutaneous

Endometrium AN3CA Subcutaneous

Epidermoid A431 Subcutaneous

Myeloma H929 Subcutaneous

Lymphoma Ramos, Karpas 299 Subcutaneous and intravenous

Syn

gen

eic

an

d

met

asta

tic Melanoma B16F10 and F0 Subcutaneous

Breast 4T1 orthotopic

Kidney Renca orthotopic

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In vivo Studies: Efficacy Models – Inflammation (2/2)

Type Animal Model Species/ strain Validation standard

AC

UTE

MO

DEL

S LPS induced systemic inflammation Female wistar rat Roflumilast

LPS induced paw edema Female wistar rat Nimesulide

Carrageenan induced paw edema Male wistar rat Celecoxib

Carrageenan induced mechanical hyperalgesia Male wistar rat Celecoxib

Acute Arthus reaction Female C57BL mice Kinase inhibitor

AR

THR

ITIS

Collagen Induced Arthritis (Prophylactic) Female Lewis rat Leflunomide

Collagen Induced Arthritis (Therapeutic) Female Lewis rat Enbrel, Dexamethasone

Adjuvant Induced Arthritis (Prophylactic) Female Lewis rat Celecoxib

Medial Meniscus Induced Tear Osteo Arhritic model Male Lewis rat Celecoxib

DTH

DNFB induced contact dermatitis (Psoriasis) Female CD1 mice Leflunomide

Oxazolone induced contact dermatitis (Psoriasis) Male SD rat Dexamethasone

CO

LITI

S Dextran Sulphate Sodium induced colitis Male SD Rat Leflunomide

Trinitrobezene sulphonic acid induced colitis Female Lewis rat Dexamethasone

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Poised with Well established in vivo models to expedite Oncology &

Inflammation drug discovery and development initiatives

In vitro Toxicology

In-vitro Toxicology

Cytotoxicity in primary cells (hepatocytes)

hERG functional Assay

• Electrophysiology using automated patch clamp

Mutagenicity

• In-vitro - AMES Test

• In-vitro - Micronucleus Test

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Robust in vitro Tox Assays to assess the potential genotoxicity of

compounds and support candidate selection

In vivo Toxicology/Preclinical Safety: GLP & non-GLP

In vivo Toxicology: GLP Rodent Studies

• 4 weeks, 13 weeks, FOB GLP Certification

• Food and Consumer Products Safety Authority, The Netherlands - 2003 & 2006

• National GLP Compliance Monitoring Authority, Indian GLP Certification – 2004; Indian GLP Surveillance 2005 and 2006

• Complete (90% Support for 1st in man) Toxicology Infrastructure

In vivo Toxicology: non-GLP Animals:

• Wistar rats• Sprague Dawley rats • Swiss Albino mice

Route of administration: Oral, IV, IM, SQ, IP Tolerated dose determination – ATD, MTD Repeat dose toxicity Dose range finding study in Beagle Dogs, MTD study in Beagle

Dogs

Clinical Chemistry

Hematology

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Operate in both GLP and non-GLP settings to generate complete toxicity

profile of compounds and analyze their safety

Target Validation

Services

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Target Validation: Objectives & Deliverables

Objectives Replicate published findings to support the launch of a full-fledged discovery program

Establish druggability through small molecule/peptide approach

Confirm efficacy in relevant in vitro and in vivo models

Identify and validate PD markers in cellular models

Determine potential mechanism-based toxicity

Establish TPP

Devise differentiation strategies (in the case of fast follower programs)

Deliverables Synthesize sufficient quantities of mutually agreed tool compounds to support in vitro and in vivo

studies

Express, purify proteins for biochemical assays and structural studies

Confirm feasibility of SGDD approaches and initial hit design strategies

Establish biochemical and cell based assays (mechanistic and functional) for potency determination and in vitro validation

In vivo pharmacological validation including biomarker assessment ad potential mechanism based toxicity

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Objectives & Deliverables will be mutually agreed depending on the nature

of project

Target Validation: Target to Tool compound

Targets to be chosen by Collaborator

Aurigene to pursue pharmacological validation; 9 to 12 months

Decision criteria and program parameters to be defined

Collaborator can choose to:

• Enter into a full fledged discovery Collaboration with Aurigene; if Program meets

the Defined criteria

• Drop the Program; if Program does not meet the Defined criteria

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Thank you!

www.aurigene.com

© Aurigene Discovery

Technologies Limited.24