On Campus Workshop – UCSD

September 25, 2012

Rick Lindberg, Site Head of CTI-California

What we will cover today…

What is CTI? – How does the CTI partnership work?– In what ways is CTI different than other programs on campus?

What kind of research is CTI interested in? – Focus on Translational Research via biologic modality– Successful characteristics and attributes of funded projects– Case studies of successfully funded proposals

Next Steps for submitting a proposal to CTI– Why choose to collaborate with CTI?

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Challenges to Pharmaceutical Industry and Academic Centers

CTI New partnership to deliver on the promise of innovative discoveries to treat diseases of high unmet medical need

with differentiated new medicines

Stakeholders investorsPhysicians

Patients

Payors

Regulators Legislators

Pressure from:Slow progression of pipeline

Cost of drug discoveryCost of drug development

Productivity

Academia

PIs challenged to translate discoveries to the clinic while maintaining "control"

Funding pressures

Focused on Translational MedicineVC funding mechanism

• Industry

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Increasingly, major biomedical institutions and industry share common objectives…

Basic research

Patient access

Clinical material

Applied research

EnablingFunctions

TherapeuticTechnologies

Novel targetsInnovative drugsPrecision medicinePatient impact

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Centers for Therapeutic Innovation (CTI)

CTI STRATEGYCo-localize Pfizer R&D resources where

breakthrough science is happening and leverage complimentary expertise

CTI APPROACHA new entrepreneurial partnership at Academic

Medical Centers focused on translational medicine

CTI VISIONAccelerate the translation of innovative discoveries from

bench to the clinic

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Core Elements of the CTI ModelDifferentiation of CTI vs. NIH, VC, Other Pharma

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Enable Translational Medicine via accelerating innovative discoveries from target to proof of mechanism

Focused on protein therapeutics (e.g mAb)

Understand patient heterogeneity and stratification

Equitable IP Rights

Broad publication rights

Co-location with technology, scientists, drug development expertise

Collaborative use of Pfizer’s proprietary drug discovery tools and technologies

Support for IND- & clinical-enabling functions (e.g., toxicology, regulatory, etc)

Success-based funding/financial incentives (milestone & royalty payments)

Role for CTI Partnership:Establish Proof or Mechanism in the clinic with innovative new therapeutics to treat diseases of high

unmet medical need

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Centers for Therapeutic Innovation – CTI Network

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• CTI-Boston

• CTI-New York

• CTI-California

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CTI - San FranciscoAddress: Mission Bay CampusOccupancy for ~40 Scientists6 funded programs

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CTI – California

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CTI - San DiegoAddress: Pfizer La Jolla CampusOccupancy for ~12 Scientists2 funded programs

Collaboration governance via Joint Steering Committee (JSC)

Semi-autonomous via Joint Steering Committee (JSC) governanceEqual CTI-AMC decision making member representationResponsible for proposal selection and funded program progression

Processes

Anthony Coyle, Rick Lindberg, Scott Glaser, Charles Baum, Gary Woodnutt

Gary Firestein, Jerry Olefsky, David Brenner, Catriona Jamieson, Michael Jackson

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• Decision point

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AMC

Pfize

rSh

ared

Stee

ring

com

mitt

ee g

over

nanc

e

New targets and associated IP

Early clinical studies conducted at AMC

Candidate Drug Selection • 2–3 years

POC• Project

Selection and Execution

• Co-developmentIND Endorsement• 3–4 years

• POM (+/-)

• 4 years

PK/PD studiesNon-clinical safety assessmentRegulatory Support

Program support including clinical and translational sciences

Go / No-godecision to

exercise license option

• Decision point

• Milestone payment

Drug discovery tools and expertiseProject execution and leadership

CTI’s Partnership and Governance Model

$2M to enable PoM clinical trial

$8M for IND enabling studies

$100-$250k provided to PI’s project budget per

year$2M $12M

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CTI Project PlanR&D Stages, Budgets & Milestones

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Exploratory

• ESD• 5 months

Validation of target biologyDevelopment of primary/secondary screening assay(s)

• SG0

• Initiation

• SDS• 12 months

Primary selection and screening of protein or scFv phage libraries

Sequence-based manufacturing assessment & seq. optimization

Lead OptimizationLead Identification

• SG1

• SG2

• Start Screening • Leads Identified

• LD• 8 months

In vitro, ex vivo, or in vivo PK/PD studies of leads in mechanistic modelExploratory toxicity studies

Lead Development

• SG3

• Leads Optimized

• PreClin• 14 months

Scale-up and manufacturing of batch for clinical studiesGLP toxicity studies

Pre-Clinical Development

• Candidate Drug• SG4

Phase 1 POM study in stratified patient population

Clinical Development

• IND / CTA

• FIH POM• SG5

• SG6

• Estimated Investment (per program) – assumes program continues all the way to Phase 1 clinical study; • contingency coverage for post-doc salary if project terminated during discovery phase of the project

• Academic

• Budget:

• ~$100-250,000

• ~$100-250,000

Pfizer Matching Investment:

• $1 million

• $1 - $2 million

• $6- $7 million

• ~$2 million

• 1st Year • 2nd Year • 3rd Year • 4th Year

• ~$100-250,000

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• TBD

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Partnership Model Encourages Collaboration at all levels

• CTI AMC

TargetsIn vivo studiesClinical studies

Proposal WritingProject Strategy

Reagent GenerationIn vitro characterizationBiomarker Development

Patient Selection StrategyJoint Steering Committee

Protein TherapeuticsAntibody EngineeringIND Enabling Studies:

• PK analysis• Safety/Tox studies• Manufacturing

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IP and Publishing Rights

Licensing Option– One year following achievement of the PoM, Pfizer has an

option to obtain exclusive license rights

Publication Rights– Findings can be published via submitting materials to the JSC

30 days prior to publication for review to ensure that no confidential or patentable information is disclosed

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What We Look for: Key Attributes of Successful Programs

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Essentials– Targetable with a biologic

• Primarily monoclonal antibodies, peptides, proteins– Novel mechanism addressing unmet medical need– Strong link of pathway to human disease

Differentiators– Ability to streamline path to proof-of-mechanism in humans– Translating basic biological research into the clinic

• Connection of basic scientific researcher & clinical investigator• Clinical differentiation opportunity via patient stratification,

molecular signatures, genetic associations, biomarkers

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Target DiscoveryWhat Makes a Good Target?

Compelling validation of target/pathway

Target identification often comes from an association of target with disease (e.g. expression pattern) and validation is the process of defining the functional consequence (e.g. siRNA KD, KO mouse)

Considerations for defining an attractive target– Link of mechanism to disease – Target validation/biological evidence

• Evidence of translation to human disease– Potential safety liabilities associated with target modulation– Technical feasibility (e.g. druggability)

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Proposal Evaluation Criteria

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Link of mechanism to disease

Target Validation/Biological Evidence• Evidence of Translation to Human Disease

Technical Feasibility (e.g. druggability with a protein therapeutic)

Potential safety liabilities associated with target modulation

Clinical Trial Design/Feasibility

Potential to generate intellectual property

Clinical Differentiation • How mechanism might provide an advantage over current therapies

Alignment with Pfizer strategy to ensure project uptake into pipeline

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• Peptides

• Therapeutic Proteins

• ADCs

• Human• Antibodies

• CovX Bodies

• Bispecific Abs

• Humanized• Antibodies

• Fc Fusion• Proteins

Diversity of Biotherapeutic Formats

Monoclonal antibody therapeutics• Platforms to generate fully human monoclonal

antibodies• Humanization technologies

Non-antibody biotherapeutics• Fc fusion protein• Secreted protein

Peptide therapeuticsNovel biotherapeutic modalities• Antibody drug conjugates (ADCs)• CovX bodies

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Focused on Monoclonal AntibodiesAntibody Modes of Action

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Neutralizing Antagonist– Antibodies that bind to a target and block an interaction

Agonist– Antibodies that bind to a receptor and stimulate a downstream

process

Effector Function (Cell killing mechanisms)– ADCC: Antibody-Dependent Cell-Mediated Cytotoxicity

• Recruits macrophages, monocytes, or NK cells

– CDC: Complement-Dependent Cytotoxicity • Recruits complement serum proteins

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Additional Modes of Action in the CTI portfolio

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Antibody Drug Conjugate (ADC)– Antibody linked to a toxic drug via a linker; method to deliver into

specific cell types

Fc Fusion– Used to extend half-life of peptides and/or small proteins

Peptide or Protein– Often requires modification to become drug-like

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Proposals have been funded across many therapeutic areas

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CTI received over 350 proposals across our network in 2011 ranging from ideas/validated pathways to pre-

existing mAbs

Oncology (7) 35%

Cardiovascular and Metabolic Diseases (5)

25%

Inflammation & Immunology (3)

15%

Rare Diseases, (3) 15%

Other (2) 10%

Funded Proposals (20)

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CTI Project Portfolio

Stage-gate

Pre-clinicalDevelopment

LeadDevelopment

LeadIdentification

LeadOptimization

ClinicalDevelopment

Early-Stage Discovery

3 4 5(IND)0 1 2

mAb (17)

Fusion Protein (3)

Peptide

Protein

ADC (1)

6(POM)

NeuroSciOncologyInflammation and Immunology CV MED Rare Disease Other

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CTI Case Study: Humanized Antibody Program

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Background: Cell surface antigen target up-regulated on tumor cells Antigen expressed on few normal tissues Target not down-regulated upon antibody binding Mabs in hand

Aim: To generate a humanized mAb with the following modes of action: Antibody effector function: ADCC/CDC Potential opportunity to generate an ADC (antibody drug conjugate) given

selective expression on tumor cells

POM trial:(1) Incorporate patient stratification to enhance POM measures (e.g. IHC, mutation status)(2) Measurable endpoints in line with pre-clinical activity

Measurable biomarker deposition in tumor biopsies (CDC) Demonstrate increase in tumor necrosis and presence of immune infiltrate in post-treatment

biopsies (ADCC/CDC)(3). CT scans to monitor tumor regression

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CTI Case Study: MOA via Target Modulation

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Background:

Target antigen is a cell surface receptor located on cells in the blood and intestinal tissue Genetic markers in the receptor are associated with Inflammatory Bowel Disease These genetic markers define a “high risk” IBD population with elevated receptor levels Dysregulation of pathway also occurs in this subset of patients

Aim: To generate a mAb to block receptor activity and inhibit down-stream signaling, reducing the inflammatory cascade in patients whose disease is driven by this defined pathway

POM Trial:

(1) Use genetically defined “high risk” and “low risk” patient subgroups for POM.(2) Measurable endpoints in line with pre-clinical activity

.Evidence of inhibition of pathway activation in blood cells pre- and post-treatment. RNA signature in gut biopsies provides further evidence of reduced inflammatory cascade.

(3) Known measurements from serum and stool samples pre- and post treatment provide additional mechanistic information.

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Inaugural CTI-UCSD/SBMRI Collaborations

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Dr. Carl Ware (SBMRI)

Professor, Laboratory of Molecular Immunology

Dr. Michael Karin (UCSD)

Distinguished Professor of Pharmacology; Head – UCSD

Laboratory of Gene Regulation & Signal Transduction

Submitting a Proposal to CTI

CTI Proposal Solicitation & Selection ProcessScientifically Rigorous, but Light on Bureaucracy

1 CTI Conducts a Call for Proposals – Annually at each AMC

2 PIs Submit a 2-3 page, Non-confidential Pre-proposal for Consideration

3 CTI Convenes a Local Joint Steering Committee to Select Finalists

4 Finalist PIs Author a Confidential Full Proposal, Working Together with a CTI Scientist

5 Joint Steering Committee Reviews Full Proposal and Selects Projects for Funding

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Proposals are selected for funding within 3 months of submission

Evolving the Request for Proposal (RFP) Search ProcessFrom Broad to Targeted

CTI Project IdentificationVersion 1.0: Broad RFPs

• 350+ proposals• 20 projects funded

across many therapeutic areas

CTI Project IdentificationVersion 2.0: Targeted RFPs

Broad RFPDisease Agnostic

Agreement on Top Projects with Pfizer

Targeted RFP

Identified Disease Areas of Interest to

Pfizer

Focused Review – ‘Translatability’

• New approach to foster a deeper partnership with AMCs

• Upfront link to Pfizer research and commercial strategy

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Key Question: What are the specific areas of research that Pfizer/CTI is interested in?

Request for Proposal – Inflammation(Systemic Lupus Erythematosus / Lupus Nephritis)

Proposals are sought for novel large molecule applications with a path to a clinicalproof of mechanism study†

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Clinical Concept

Mechanisms of interest

Precision Medicine

New and more effective treatments that can induce and maintain remission

- Prevention of underlying dysregulation of B- and T- cells - Modulation of innate immunity- Targeting or interrupting inducers of persistent immune activation/inflammation- Inhibition or modulation of inflammatory processes involved in flares (renal,

synovial or cutaneous)- Regulation of handling and clearance of apoptotic bodies- Promotion of immune homeostasis and immunoregulation (i.e., functional

tolerance).

It is preferred if submissions incorporate a hypothesis-driven strategy for patientselection, i.e. rationale for patient subset where drug would be most efficacious

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Proposals are sought for novel large molecule applications with a path to a clinicalproof of mechanism study†

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Clinical Concept

Mechanisms of Interest

Precision Medicine

• Novel approaches (targets, pathways or interventions) that would alter the course of a disease which directly or indirectly results in kidney injury and failure

Request for Proposal – Renal Disease(Kidney Injury/Lupus nephritis, IgA Nephropathy)

• - Block intrarenal inflammation• - Regulation of leukocyte-endothelial cell interactions• - Prevention of tubular atrophy and interstitial injury• - Inhibition of specific components of the immune response related to renal

damage (i.e., aberrant mesangial Ab:IC deposition or handling). • - Approaches aimed at promoting responses leading to improved renal function,

such as repair and/or restoration of renal epithelium and nephron integrity)

• It is preferred if submissions incorporate a hypothesis-driven strategy for patient selection, i.e. rationale for patient subset where drug would be most efficacious

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Proposals are sought for novel large molecule applications with a path to a clinicalproof of mechanism study†

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Clinical Concept

Mechanisms of Interest

Precision Medicine

• Cardiac remodeling events post-MI and in CHF leads to progressive deterioration of health with few options for patients and physicians.

• Reduced mortality, CV events, and/or improved cardiac function is the ultimate goal

• - Those that impact extracellular matrix turnover, fibrosis, restore cardiac tissue & function, apoptosis & proliferation, cardioprotection and neovascularization.

• - Novel mechanisms that impact endothelial repair (beyond standard of care) such as plaque stabilization and dissolution, mast cell & macrophage regulation

• Defined patient populations at highest risk of CV events that would most benefit most from this therapeutic approach is required

Request for Proposal – Cardiovascular(Congestive Heart Failure, Post-Myocardial Infarction and Acute Coronary Syndrome)

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2012 Proposal Process Flow and Timeline

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UCSD

Jun 2012

Jul 2012

Aug 2012

Sep 2012

Oct 2012

Nov 2012

Dec 2012

Targeted Call for

Proposals

Stage IPre-

proposal

Proposal Review

JSC Meeting

DecisionMakingMeeting

Stage IIFull-

proposal

1:1 meetings with the Office of Contract and Grant Administration (OCGA) and CTI staff in September and October

2–3 page non-confidential Pre-Proposals to be submitted to the Office of Contract and Grant Administration (OCGA) by October 19th

If selected, a full confidential proposal co-authored by academic PI and CTI scientist will be submitted to the JSC by mid December

Funding Decisions to be made in early 2013

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An open, informal discussion session has been scheduled after today’s presentation in this room for PIs in attendance to discuss their research with CTI colleagues

– Please do not disclose any confidential information

If interested, please contact the Office of Contract and Grant Administration (OCGA) to inquire about meeting with CTI staff prior to submitting a proposal

– Cortlandt Urquhart, surquhart@ucsd.edu, 858-534-0244– Jennifer Ford, jjford@ucsd.edu, 858-534-3335

Pre-proposals due to the Office of Contract and Grant Administration (OCGA) by October 19th

Next Steps

To learn more and obtain the pre-proposal template, please visit https://cti.ideareach.com/ and create a user profile

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Co-lead project team to ensure sustained involvement from discovery to clinic

Collaborative use of Pfizer’s proprietary drug discovery tools and technologies

Support for IND- & clinical-enabling functions (e.g., toxicology, regulatory, etc.)

Co-location near academic laboratory with access to Pfizer scientists, technology, and drug development expertise

Equitable IP and publication rights

Success-based funding/financial incentives (milestone & royalty payments)

Comparable attrition and funding success rate to NIH R01 grant

Streamlined but scientifically rigorous 3 month awarding process from time of proposal submission

Incentives to collaborating with CTI

Partnering leading academics with drug discovery experts to rapidly translate novel research from discovery into meaningful mechanistic studies in the clinic

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Acknowledgements – CTI Leadership

Tony CoyleCSO & VP

CTI

Margi McLoughlinSr. Director

WW Bus Dev & Innovation

Louisa DanielsVP and Assistant General Counsel

Alex Fayne (RIP 2012)Chief Operating Officer

Strategy & Operations CTI

Jose Carlos Gutierrez-Ramos

SVP Biotherapeutics Research

Rick LindbergSite Head

CTI – California

Michael NorsenAlliance Management

Strategy & Operations CTI

Questions