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Precision Medicine and Cancer Genomics:An Industry Perspective

David R. Cox M.D., Ph.D.Senior Vice President and Chief Scientific Officer, AQG

Pfizer Inc.

david.cox3@pfizer.com

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Bedside to Bench

Molecular Targets

Target to clinic:

Poor alignment of molecularunderstanding to clinical need

Clinical Outcome

Clinic to target:

Defined unmet clinical need

Translation from human geneticvariation, to optimized therapybased on an understanding of

biology

VS.

Human genetics links clinical outcomes of interest to the relevant biology

Human Genetics

Traditional Discovery

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Patient Stratification

Genetic knowledge will reclassify disease based on

biological causality

Individuals will receive “group” assignments

based on this information

Selection of clinical trial participants based on

biological knowledge prior to therapeutic intervention

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Targeting Somatic Cancer “Driver Mutations”

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Crizotinib Target Profile

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Shaw AT, et al. Phase 3 randomized study of crizotinib versus pemetrexed or docetaxel chemotherapy in advanced, ALK-positive

NSCLC (PROFILE 1007). Vienna, Austria: European Society for Medical Oncology; September 30, 2012. Abstract LBA1.

The study met its primary endpoint of progression-free survival(PFS): median PFS was 7.7 months with crizotinib versus 3.0months with chemotherapy, representing a 51% reduction in risk ofprogression for the ALK inhibitor (P < .0001)

Phase III PROFILE 1007 Trial- a global study conducted at more than 100sites in 20 countries. The study randomized 347 patients with ALK+, stageIIIb or IV NSCLC to crizotinib 250 mg/bid; pemetrexed 500 mg/m2; ordocetaxel 75 mg/m2 on a 21-day cycle. Median number of cycles oftreatment was 11 for crizotinib and 4 for chemotherapy.

Crizotinib superior to single agent chemotherapy in advanced, previously

treated ALK-postive, non- small cell lung cancer (NSCLC)

Recent Good News

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Shaw AT, et al. Phase 3 randomized study of crizotinib versus pemetrexed or docetaxel chemotherapy in advanced, ALK-positive NSCLC (PROFILE1007). Vienna, Austria: European Society for Medical Oncology; September 30, 2012. Abstract LBA1.

According to independent radiologic review, crizotinib tripled theoverall response rate compared with chemotherapy: 65.3%versus 19.3%, respectively (P < .0001).

Quality of life was superior for crizotinib-treated patients, basedon patient reported outcomes regarding time to deterioration inlung cancer symptoms: median of 5.6 months with crizotinibversus 1.4 months with chemotherapy (P < .0001).

Toxicities of crizotinib were mild and manageable,

Recent Good News

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The Bad News

With a median progression free survival of 7 months,patients will develop resistance to this targeted therapy.

Two next-generation ALK inhibitors are in phase II studies—LBK 178 and AB6 273

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This article was published on October 1,2012, at NEJM.org. DOI: 10.1056/NEJMoa1209124

Antibody- Drug Conjugates

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Recent Good News

Among 991 randomly assigned patients, median progression-freesurvival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratiofor progression or death from any cause, 0.65; 95% confidence interval[CI], 0.55 to 0.77; P<0.001Rates of grade 3 or 4 adverse events were higher with lapatinibplus capecitabine than with T-DM1 (57% vs. 41%).

Randomly assigned patients with HER2-positive advanced breastcancer, who had previously been treated with trastuzumab and a taxane,to T-DM1 or lapatinib plus capecitabine. The primary end points wereprogression-free survival (as assessed by independent review), overallsurvival, and safety.

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ADC Development Focus Areas

1. Design new inkers and payloads with tumor selectivity

2. Cancer target expression levels not predictive for pharmacology

3. Imporve understanding of factors affecting pharmacodynamics

and toxicity

4. Improve biodistribution- less than 0.01% of ADC injected reaches

the tumor

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Bioconjugation Methodologies

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Cancer Immunotherapy

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Conclusions

Anti–PD-1 antibody produced objective responses in approximately one in four toone in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer;the adverse-event profile does not appear to preclude its use.

Preliminary data suggest a relationship between PD-L1 expression on tumor cells

and objective response.

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Tumor PD-1L Expression is Associated with Objective Response

to PD-1 Antibody Therapy

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PD-1 and PD-1L have overlapping but not identical binding partners

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Committee on a Framework for Development a New Taxonomy of Disease;

National Research Council

Toward Precision Medicine:Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease

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The pharmaceutical industry needs to engage internationalscientific and healthcare communities in a more collaborative

fashion in order to achieve the goal of improving health outcomes

A critical unmet need is access to cohorts of individuals with wellcharacterized differences in disease progression and treatment

outcomes

Money alone does not provide access to the critical scientificcollaborative relationships

Key Insights

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BBMRI: A pan-European infrastructure for work onBiosamples and Clinical Data

Preparatory Phase

2008-2011

5 mio €

53 Participants

222 Ass. Partners

33 Countries

BBMRI: Biobanking and Biomolecular ResourcesResearch Infrastructure

Objectives:

Infra-structure and collaboration models for

working with biosamples in Europe.

Provide a European and global ethical and

legal framework for work on biosamples

Current Initiatives

BBMRI – ERIC: Legal framework for working with biosamples will be rolled out Q1 2013

BBMRI – LPC: EU F7P program to facilitate sharing of samples and data in 50 European populationbiobanks

BBMRI Expert Centers: Vehicles for collaboration on biosamples and clinical data

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•Linking biospecimens to multiple sources ofhealthcare information, while protecting all

stakeholders

•Reconciling altruism and open collaborationwith intellectual property and profit

Major Challenges

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•Keep the detailed clinical data and related biospecimens withthe clinicians and scientists who generated them and who

have established relationships with the study subjects and thelocal culture.

•Use public-private scientific collaborative expertise andresources to obtain the key biologic knowledge required to

address specific health outcomes.

•This key biologic knowledge can then be used by all toimprove health outcomes

Potential Solution: “Expert Centres”

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BBMRI Expert Centres

Collaborative Research in Public and Private Sectors

Medical data

Biological samples

Knowledge

Primary

data

generation

Diagnostics

Drugs

Public

(not-for-profit)

Private

(for-profit)

Public-private

(not-for-profit)

Data

Insights

Products

ExpertiseExpertise

Funds

Common good

(donations)

Industry

(sales)

www.bbmri.eu/

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Expert Centres as Highways forTransnational Research Collaborations

Samples

Medical

Data

Country 1

Biological

Resource

Centre

Expert

Centre

Samples

Medical

Data

Country 2

Biological

Resource

Centre

Expert

Centre

Research

Data

Samples

Medical

Data

Country 3

Biological

Resource

Centre

Expert

Centre

www.bbmri.eu/

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June 13, 2011April 22, 2002