NIBR Postdoctoral Program

Stanford University 21 September 2010

W. Ross Tracey, PhD

Associate Director, Education Office

A B Jefferson, PhD

Investigator III, Cancer Biology, Oncology

Agenda

Novartis and NIBR background

Emeryville: research and postdocs in Cancer Biology

Postdoctoral training program highlights

Novartis at a Glance

Unique portfolio to meet changing healthcare needs:• Leading innovative pharmaceuticals

• High-quality, low-cost generics

• Preventive vaccines

• Consumer health products

World’s third largest pharmaceutical company by sales ($44.3 billion)

One of 20 largest companies by market capitalization

Ranked among most respected companies worldwide

R & D investment of ~ $7.4 billion/year

Our mission at Novartis

We want to discover, develop and market successfully, innovative products to prevent and cure diseases, to ease suffering, and to enhance quality of life.

We also want to provide a shareholder return that

reflects outstanding performance and to adequately

reward those who invest ideas and work in

our company.

Coartem® (malaria):84 million treatments shipped in 2009 – cumulatively delivered 300 million treatments which helped save

an estimated 750,000 lives

Leprosy medication free of charge:>4.5 million patients cured since 2000

TB donations (DOTS):500,000 patients in five years

Global patient assistance:Medicines free or at reduced cost to 143,000 patients, valued

at $1.1 billion

NITD1 in Singapore:Focus on TB, dengue fever and malaria

NVGH² in Siena, Italy:Vaccines Research Institute for neglected diseases

Access to medicine programs –in 2009 we contributed 3.4% of net sales

1 Novartis Institute for Tropical Diseases; 2 Novartis Vaccines Institute for Global Health; 3 Based on approximate market value

2009:

79.5 million patients supported

Programs and research valued at USD $1.51 billion3

Novartis Institutes for BioMedical Research (NIBR)

15 sites worldwide

Approx. 7000 employees globally

Approx. $1.8 billion budget ($1 billion pre-clinical)

Specific centers focus on different disease areas and several platforms

NIBR Sites

Emeryville Cambridge

East Hanover

HorshamRueil/

Malmaison

Basel

Vienna

Madhapur/

Hyderabad

Shanghai

Beijing

Tokyo

NIBR Sites

Translational Sciences Sites

NIBR Disease Areas

Autoimmunity, Transplantation & Inflammation

(ATI)

Cardiovascular & Metabolism

(CVM)

Gastrointestinal (GI)

Infectious Diseases (ID)

Musculoskeletal Disease (MSD)

Neuroscience (NS)

Oncology (ONC) Ophthalmology (OPH)

Respiratory Diseases (RD)

NIBR Platforms

Global Discovery

Chemistry

Developmental &

Molecular Pathways

Center for Proteomic

Chemistry

Biologics Center

Metabolism and

Pharmacokinetics

(MAP & DMPK)

Biomarker Development

Preclinical Safety

Translational Medicine

Scientific Operations

Research Focus at NIBR sites

United States

Cardiovascular & Metabolism

Infectious Diseases

Oncology

Ophthalmology

Musculoskeletal

Center for Proteomic Chemistry

Developmental and Molecular

Pathways

Global Discovery Chemistry

Biologics Center

Translational Sciences

IT Automation & Support

United Kingdom

Gastrointestinal

Respiratory

Global Discovery Chemistry

Translational Sciences

Switzerland

Neuroscience

Oncology

Autoimmunity, Transplantation &

Immunology

Center for Proteomic Chemistry

Global Discovery Chemistry

Biologics Center

Translational Sciences

China

Infectious Diseases

Oncology

Epigenetics

Chemistry

Translational Sciences

Japan

Translational Sciences

India

Translational Sciences

~110 postdocs in Basel,

Cambridge, East Hanover,

Emeryville, Horsham, Shanghai

Specific centers focus on

different disease areas and

several platforms

Extensive External Collaborations Enhance the PipelineJoint ventures in research, technology and therapeutic products

Academia

Almost 300 alliances with academic centers

Industry

More than 150 alliances with major biotech companies

Drug Discovery & Development Takes a Long Time

10’000 compounds in the beginning

1 new Medicine10 compounds in the clinic

Preclinical

Research

Clinical

Phase I

1’000 compounds in vitro testing

~14 years

Clinical

Phase II

Clinical

Phase IIIRegistration

Knowledge of mechanism

Unm

et M

ed

ical N

ee

d

NIBR’s Research Strategy

Basic

Research

X

Drug

Discovery

Science-Driven

Business

Rationale

Pathways thinking...

Translation of the Genome to TherapeuticsDefining the key druggable nodes within the network

Genome

Human Disease

Pathways: Collections of Targets for Multiple Indications

Cancer (colon/breast)Tuberous sclerosis

Immune diseases,

Tx rejection

Vascular proliferation

(stent implant)

Retinitis pigmentosa

mTOR pathway

Postdoctoral Program at Emeryville

A B Jefferson, PhD, Investigator III, Cancer Biology, Oncology

Departments currently with post-doc

18 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

EMV NIBR Research Organization

NIBR SITE HEAD

Emma Lees

Cellular

Assays

Biological

Therapeutics

Cancer

BiologyProject

Mgmt.

Bio-

informatics

ONC HEAD

Emma Lees

125 FTE

Pharmacology

Protein

Sciences

Biochemical

Lead

Discovery

Structural

Chemistry

Chem-

informatics

MAP Medicinal

Chemistry

Medicinal

Chemistry

Medicinal

Chemistry

Computatl.

Chemistry

Analytical

Chemistry

GDC HEAD

Mike Dillon75 FTE

Emeryville is a Fully Integrated NIBR-Oncology Site

Target identification through early clinical trial

Small molecule and antibody therapeutics

10-12 drug development programs in addition to early discovery

| Presentation Title | Presenter Name | Date | Subject | Business Use Only19

D0 –

D2

PoC Outcome

sPoCLead Selection

D3 D4 &

PoC

Full

Dev

Drug Discovery Innovation Chain Development

CSP Initiation

1 Quelle: Bain 2003Target Selection,

Assay Development

&

HTS / Lead Selection

Lead

Optimization

Candidate

Selection

Process

Early Clinical

Safety

and EfficacyRegistrat

ion

Large Clinical

Trials

20 | Cancer Biology Organization | Chuck Voliva | January 16, 2009 | Business Use Only

Cancer BiologyWhat we do

Support the pipeline in three major area:

Target Identification

& Validation

Mechanistic

BiologyTranslational

Sciences

Cancer Drivers Amplicon

Discovery

SNP 6.0 across cancer cell lines

Identification of Oncogenes at Focal Amplified Chromosomal Region Found in Pancreatic cancer

Mentor: Albert Lai, Cancer Biology, ONC

Post-doc: Bosun Min| Presentation Title | Presenter Name | Date | Subject | Business Use Only21

Co-Amplified RegionCCNE1

30

00

+ P

rim

ary

Tu

mo

r &

Ce

ll lin

es

SNP 6.0 (CNV Analysis of Tumor Samples)

Coding genes

Novartis Cell Line Encyclopedia Cancer Targets Identification

Validation by TMA-FISH

Fine-mapping by qPCR

Identification of Amplicon

dependent gene by pool shRNA screen

Gain of function studies

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Understand the role for p90 S6 kinases in supporting an EMT

Which of the EMT characteristics is dependent on signaling via RSK?

Does an active K-Ras-driven EMT = an active B-Raf-driven EMT?

What happens to the dependency on RSK for this process in the face of additional pathway mutations as occur in tumors?

Thiery et al, CELL 2009

Mentor: A B Jefferson, Cancer Biology, ONC

Post-doc: TBD

23 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Matthew Holderfield: Molecular Mechanisms of KRAS Oncogene Dependence

Mentor: Tobi Nagel, Cancer Biology

Debbie Chang: Tumor-Associated Macrophages in Breast Cancer

Mentor: Dylan Daniel, Pharmacology

Prasenjit Mukherjee: Protein Family Modeling

Mentor: Eric Martin, Computational Chemistry

Jing Lu: Cancer dependency on survival signaling pathways

Mentor: Pablo Garcia

Bosun Min: ID of Oncogenes at Focal Amplifications in Pancreatic Cancer

Mentor: Alberta Lai, Cancer Biology

Meghna Das Thakur: Mechanisms of Resistance to Novel Kinase Inhibitors

Mentor: Darrin Stuart, Pharmacology

Current Emeryville Post-docs

Highly interactive working environment

State of the art facilities

NIBR Research Facility at EMV

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All research departments centralized in one building

Objectives

Support the postdocs’ scientific and career development

Inform next generation of scientists of NIBR’s approach to drug discovery

Effectively partner with academic centers of excellence

2 application tracks:

NIBR Postdoctoral Fellowships

Presidential Postdoctoral Fellowships

NIBR Postdoctoral Program

NIBR Postdoctoral Fellowship

Proposal from

Disease Area/Platform

reviewed and approved

Candidate interviewed

and hired

NIBR Presidential Postdoctoral Fellowship

CV Review

~2 weeks Variable <4 weeks~3 – 4 weeks 8 - 12 weeks

• Outline project

• Identify academic mentor

1st Interview

EO

(phone)

2nd Interview

DA/Platform

(phone)

3rd Interview

DA/Platform

(on site)

Proposal

writing

Proposal

review

EO: Education Office

DA: Disease Area

3 years

Well-defined project proposal

Yearly progress reports

Scientific seminars: 2-3/week

Postdoctoral seminar series

Participation in scientific conferences

Annual Postdoctoral Retreat

Academic Mentor

NIBR Postdoctoral Training Program

Some Topics for Postdoctoral Research at NIBR

Autoimmunity: T cell activation, lymphocyte trafficking, Th17 cells

Biologics: metabolic stability of siRNAs

Chemistry: computer-aided drug design

Dev & Mol Pathways: CNS lipid storage, vascular biology

Gastrointestinal: gut epithelial function, sensory neurobiology

Infectious Diseases: pathogen-host interactions

Neuroscience: neurodegeneration; protein misfolding

Oncology: apoptosis, Raf/Ras/MAPK, bioinformatics tools

(Work) Life after a postdoc at NIBR

2007 - 2009 Alumni

Scientist - Novartis ~25%

Scientist – other pharma/biotech ~25%

Faculty – academic/research institute ~ 5%

Non-research (including Novartis) ~20%

Another postdoc position/transition to faculty ~10%

Other/unknown ~15%

What do we look for in postdoc candidates?

Solid scientific background in almost any area – molecular and cell biology, biochemistry, mouse models, etc.

Strong critical abilities

Scientific vision

Passion for science

Apply Online

http://nibr.com

=> Careers

=> Working at NIBR

=> Search for jobs, keyword “postdoc”

NIBR Postdoctoral Fellowship

Presidential Postdoctoral Fellowshiphttp://nibr.com

=> Careers

=> Postdoctoral positions

Please mention that you attended this presentation.

Thank you!

Back-ups

| Presentation Title | Presenter Name | Date | Subject | Business Use Only34

Challenges facing the pharmaceutical industry

Internal challenges

Organizational complexityand mindset

Advancing patent expiries

Identifying/understanding newtargets

Rising costs of research anddevelopment

Increasing complexity andbreadth of developmentprograms

External challenges

Public perception

Product safety concerns (FDA and public)

Aging population

Declining industry productivity

Scientific and technologicaladvances

Rise of generics and biotechs

Price control pressure frompayors

Parallel imports

R&D investment has increased by 80% while NME output has remained stationary

Data referenced to 2002 data

R&D spend is predicted to grow more slowly over the next 6 years (~2% pa)

NME = New Molecular Entity (both small molecule and biologics)Evaluate Pharma World report 2016

Sensitive Insensitive

What are the Molecular Mechanisms That Determine KRAS Oncogene Dependence?A Novartis Post-Doc Project in Cancer Biology

Post-Doc: Matthew HolderfieldMentor: Tobi Nagel

KRAS mutations occur in ~20% of NSCLC.

KRAS mutant cancers are frequently refractory to MAPK or PI3K inhibitors.

Use an shRNA screen to identify genes that determine sensitivity to KRAS suppression.

KRAS

PI3KRAF

Proliferation and Survival

38 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Mission: Support drug discovery with murine cancer models reflecting

target biology and addressing drug mechanism of action

Subcutaneous, orthotopic and metastatic tumor models

• ~100 tumor cell line models

• Primary human tumor model collection

Genetically engineered mouse models

• MMTV-PyMT mammary; K14-HPV16 cervical squamous cell carcinoma models; BRAF mutant melanoma model

Nude rat tumor models to estimate therapeutic index

• PK, PD, efficacy, and preclinical safety readouts

Pharmacodynamic measurements in tumors and normal tissues

• ELISA, Western blot, FACS, IHC (w/ Experimental Pathology)

Imaging

• Bioluminescence, fluorescence and ultrasound imaging

pERK1/2 PE

0

300

600

900

14 16 18 20 22 24 26 28Days Post Implant

Vehicle

RAF265

Mean

Tu

mo

r V

olu

me (m

m3)

0

300

600

900

14 16 18 20 22 24 26 28Days Post Implant

Vehicle

RAF265

Inhibition of p-ERK in rat PBMCs by MEK inhibitor BYQ738

PharmacologyWhat we do

Mechanisms of Resistance to Novel Kinase Inhibitors

Mentor: Darrin Stuart, Pharmacology, ONC

Post-doc: Meghna Das Thakur| Presentation Title | Presenter Name | Date | Subject | Business Use Only39

Transgenic and xenograft mouse models of human cancer to predict

mechanisms of drug resistance to kinase inhibitors in Novartis pipeline- In contrast to in vitro screens, selective pressure is applied at pharmacologically

relevant drug concentrations

Resistant Sensitive

Selection Validation Molecular Characterization

0.0001 0.001 0.01 0.1 1 10 1000

20000

40000

60000

80000

Drug Concentration (mM)

Mentor: Dylan Daniel (Pharmacology)

Postdoc: Debbie Chang

Project Overview:

• Rationale: Increased inflammation is correlated with decreased survival in breast cancer patients

• Goal: To identify the molecular pathways regulating pro-tumorigenic macrophage differentiation

• Model: Transgenic mouse model for breast cancer (MMTV-PyMT)

• Hypothesis: M-CSF/CSF1R pathway promotes pro-tumorigenic differentiation of tumor-associated macrophages(TAMs)

• Approach: Novartis has developed a highly selective CSF-1R inhibitor, BLZ945, that we are using to test howloss of CSF1R signaling affects the survival, recruitment and/or differentiation of TAMs [in collaboration with theCoussens Lab at UCSF]

Tumor-Associated Macrophages in Breast Cancer

Angiogenesis

Growth

Metastasis

EGF

Cancer cells

Pro-tumorigenic macrophages

Differentiation

Recruitment

Survival

M-CSF/CSF1R

BLZ945

41 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Matthew Holderfield: Molecular Mechanisms of KRAS Oncogene Dependence

Mentor: Tobi Nagel, Cancer Biology

Ting Gong: Computation Dissection of Tissue Samples with Applications to Complex Samples from Clinical Trials

Mentor: Joseph Szustakowski, Biomarker Development, Translational Sciences

Sonya Fonseca: Enhancement of β-cell Function through ER Stress Signaling Modulation

Mentor: Mark Burcin, Cardiovascular and Metabolism

Zachary Newby: Structure and Function of Intramembrane Proteases: The Rhomboid and SPP/SPPL Families

Mentor: Michael Romanowski, Center for Proteomic Chemistry

Nicolas Guérard: Characterization of specific patterns for Torsade de Pointes in isolated rabbit heart using transmural unipolar electrograms

Mentor: Berengere Dumotier, Preclinical Safety, Translational Sciences

Ken-Ichi Umehara: In vitro transporter assays and their use to understand hepatic and renal disposition of new drug candidates in clinics using PBPK techniques

Mentor: Gian Camenisch, DMPK, Translational Sciences

Current NIBR Post-docs