This document provides an outline of a presentation and is incomplete without the accompanying oral commentary and discussion. Conclusions and/ or potential strategies contained herein are NOT necessarily endorsed by Pfizer

management. Any implied strategy herein would be subject to management, regulatory and legal review and approval before implementation.

Accelerating clinical evaluation of

biotherapeutics: can cost, speed and

throughput be improved without

compromising quality?

Tanya Shang, Jeff Salm, Anthony Barry, Tom

Porter, Tim Charlebois

CMC Strategy Forum Europe

May 7, 2014

Outline

• Decline in R&D Productivity and Unsustainable Cost of BioTx

Development

• Innovation as Evolution

• Case Study: Low Cost Low Volume Development Option

• Next Steps

The Decline in R&D Productivity:

Increased Spending, Lower Output

3

0

20

40

60

80

100

120

140

160

Worldwide Total Pharmaceutical R&D Spend

WW

Ph

arm

a R

&D

Sp

en

d (

$b

n)

+10.6% CAGR 2002-08

+2.3% CAGR 2009-16

0

10

20

30

40

50

60

70

FDA Approval Count (NMEs & Biologics)

Total mol. NMEs Biologics

No

. of

Mo

lecu

les

Ap

pro

ved

Source: EvaluatePharma April 30, 2010

CGAR: Compound Growth Annual Rate

Development Costs Impact Patients

• Why Should we care about Cost?

• Current cost of developing drugs is unsustainable

• Inhibitory to bringing innovation in biomedical research to patients

• Direct influence on drug costs

• Huge investment required drives focus on few “safe”

targets

• Innovative solutions need to be developed from every front

• Innovations in CMC development (speed, cost, flexibility) can

enable innovations in many areas

Pfizer Approach for CMC Innovations

•Foundation of Innovation: Existing Systems based on

internal and industry-wide mAb Platform knowledge

•Understanding stage-specific innovation drivers

Molecular Stability •Platform formulations

•Formulation selection

•Pre-screen for stability in discovery

•Confirmatory GMP stability studies

Foundation: How We Do Things Now

(Examples)

Standardized,

Robust

Analytics

Platform

Processes

GxP Systems

Clone Selection

Screening (e.g. Sequence

Variants)

Molecular Assessment

new mAbs assessed based on

platform knowledge

Product Quality •Cell bank testing

•In-process testing

•Release testing

•Representativeness of non-clinical materials

pI, Mw,

sequence

liabilities,

modeling

Titer Platform

Process

performance, in-

process stability

Stability,

viscosity, F/T,

handling

Structure, PTM

heterogeneity,

method

suitability

Assessment of “Platform Fit” of Pre-

development Candidates

Material Production

(Exploratory Toxicology, Non-clincal

PK/PD) Candidate

Selection

•Designed to maximize alignment with platform

process, formulation, and methodologies used for

clinical materials

•Not just Manufacturability, but increased probability

of consistent quality!

Molecular Assessment

mAb Platform Knowledge

•Platform process, formulation, and methods have evolved

over the last decade

– Platform expression systems e. g. CHO

– Upstream and downstream process standardization

– Same raw materials, media, filters, buffers and resins

– Platform formulations e.g. histidine/sucrose and standardized DP

configurations

– Standardized analytical methods and specifications

• Many companies have arrived at similar platform

processes and methods

Platform Evolution: Current Best Practices to Ensure

Consistent Quality

Platform: Streamlined

Body Shape

Common Selection Pressure: Sustained Rapid Swimming

in Marine Environment

Common Selection Pressure: Achieving Consistent

Process Performance, Product Quality, Meeting Clinical

Demand and Regulatory Requirements

Platform process,

formulation and

analytics

What Will Drive the Next Evolution?

What drives the need to innovate in biologics

development & manufacturing?

Pfizer Confidential │ 10

• R&D Productivity (ROI)- driven by clinical costs

• High cost to reach futility

• Breakthrough therapy designation- critical path issues

• Proof of mechanism trials, biomarkers, precision medicine

R&D

Drivers

• Enterprise costs: capital, operating expenses, compliance

• Product costs: response to price, reimbursement pressure

• Market access, regionalization

• Cycle times, inflexible capacity, tech transfer, comparability

Manuf.

Drivers

LOW COST LOW VOLUME (LCLV) DEVELOPMENT OPTION

Case Study

Design of LCLV

Implementation of First LCLV Project

Pre-IND and IND Experience

What is LCLV, and Why Did We Build it?

• Developed to provide appropriate amount of material to project

teams for toxicology and early phase clinical studies in a cost

and resource-sparing manner

• Built to enable fast progression of mAb programs to clinical

evaluation with targeted, efficient investment

– Ideal for novel mechanisms, small mechanistic clinical evaluations

12

Key Elements of LCLV

• Limited quantities of toxicology and clinical materials

manufactured

– All DS converted to DP

• Minimal process, product, and analytical development

– “Plug and Play” standardized process, formulation and analytics

• Molecular Assessment to Identify mAbs that fit the platform

13

LCLV Relies Upon Molecular Assessment

• To leverage LCLV process/strategy, mAb must meet pre-defined

criteria – established based on relevance to process and product

performance

– Sequence Analyses—no obvious “red flags”

– Productivity in CHO-SSI (clonal pools titer)

– Fit with purification platform (impurity, HMW removal, compatibility)

– Analytical methods suitable without development

– Stability and concentration/viscosity suitable in fixed formulation

• All criteria evaluated prior to selection of final candidate

– Enables development criteria to be used as screening tool

– Provides requisite data to minimize process, formulation and analytical

development

14

How Does LCLV Compare?

15

*Cost includes Transferrables, overhead and FTE

Std mAb Option LCLV Option

Toxicology Material >200 g in ~8 months

• From non-GMP batch

250 g in ~6 months • From non-GMP batch

Drug Substance >2 Kg >400 g

Drug Product >10,000 vials

• Configuration adaptable

~2,500 vials • Fixed config

IND

~15 months ~14 months • US currently

Cost 100% ~50%

1 SSI Implementation (reduced cell line dev)

2 Streamlined Process Development

3 Modified Cell Bank method

4 Combined RegTox FIH

5 Modular Virus Clearance

6 Smaller Scale Process

7 Bioassay as characterization only

8 Reduced development stability testing

9 Reduced assay development and verification

10 All DS filled into DP (No GMP DS Stability)

11 No Reference Material

12 Reduced release and stability testing

13 Platform CMC package

14 Molecular Assessment

15 Streamlined formulation development

16 Streamlined DP tech transfer and manufacture

…And how did we do it?

16

Standing Offer Updates - Summary 10.28.13 updated summary 12-5-13.pptx

Extensive review of standard

mAb offer Identifies key

opportunity “buckets”

Risk analysis, time and cost

implications and

understanding

interdependencies

Opportunity Bucket #5: Modular Viral Clearance

• Description

– Modular viral clearance package to support regulatory

requirements; product specific studies in late stage

– Cost, material, and FTE savings

• Justification

– proven viral clearance capabilities of unit operations

• Risks

– Regulatory acceptance of strategy

Decision: opportunity pursued in LCLV Option (US)

Opportunity Bucket #10: NO DS Formal Stability

• Description

– There will be no DS stability program

– Cost, material, and FTE savings

– Reduce complexity by eliminating activity that adds no value

• Justification

– All DS will be filled into DP, no long-term storage

– Molecular assessment includes stability in formulation, to provide confidence for

short term storage/temp excursions

– Product quality controlled at DP release and stability testing

• Risks

– Business risk: molecular assessment not predictive, GMP DS is unstable over a

few months at -20 oC and fails DP release

– Regulatory Acceptance

Decision: opportunity pursued in LCLV Option

Opportunity Bucket #7: No Bioassay

Development

• Description

– Bioassay will be transferred from Discovery, performed on Toxicology material and DP

as characterization assay only; full development/incorporation in specs in later stage

– Activities eliminated: method development and qualification; bioassay in release and

stability testing

• Justification

– Discovery bioassay (with proper guidance in Molecular Assessment) is scientifically

appropriate to demonstrate biological activity

– Bioassays typically less stability-indicating than biochemical assays

• Risks

– Regulatory acceptance

Decision: opportunity not pursued in LCLV Option

Apr May Jun Jul Aug Sep Oct Nov Dec

2012 Q3 Q4

Candidate

Selection Molecular Assessment

Implementation of First LCLV Project

1.32

1.27

1.34

1.31 > 5%

HMW mA

U

time

SSI 12 day

culture

ProA

60min pH 3.5

Hold

TMAE

Viral filtration

UF/DF

Analytical

SEC

>

LCLV Criterion: < 5% HMW in ProA Pool

< Go

No-Go

Production in CHO SSI

0

5

10

15

20

25

30

35

40

45

50

0 50 100 150 200

Vis

cosi

ty (c

P)

Concentration (mg/mL)

1.27 1.31 1.32

1.33 1.34

Viscosity

0

10

20

30

40

50

1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34

% a

gg

reg

ate

115-157mg/ml aggregation in

His-Sucrose platform buffer

Tech Transfer

Start

Oct Nov Dec Jan Feb Mar Apr May Jun

2012 2014 Q4 Q1 Q2

Jul Aug Sep

Q3

GMP DS

Mfg

GMP

DP

Mfg

Tox Manufacture Tox

Material

Available

Candidate

Selection

Tech Transfer to New CMO

Oct Nov Dec

Q4

IND

Submission

(Nov 8)

Pre-IND

Telecon

FIH

(Dec 17)

Pre-IND

Briefing Doc

Implementation of First LCLV Project

Pre-IND and IND Experience

Modular Viral Clearance

• In Pre-IND briefing document, proposed filing modular retroviral

clearance data in a DMF for use across Pfizer phase I/II mAbs

• Viral clearance data using bracketed approach (8 mAbs)

– Overall clearance of > 16.4 LRV demonstrated for MuLV

• FDA agreed that DMF is appropriate approach

No formal DS stability when all DS is converted to DP

• IND included 3 month hold data only

Reduced DS Testing

• 5 assays removed from standard DS spec (redundant to DP testing)

• FDA agreed that proposed limited assays were reasonable (Concentration,

SE-HPLC, identity, bioburden, endotoxin), recommended bioassay

Overall positive FDA feedback on LCLV elements

• No CMC questions on the IND

Next Steps

• Implement and improve LCLV on additional programs

• Explore LCLV implementation ex-US

– Modular viral clearance approach

– Release and stability strategies

• Integrate some of the LCLV elements into standard mAb

development paradigm

• Beyond LCLV—speed, throughput, flexibility and cost

• Molecular Design and Molecular Assessment

– Design and Select for stable, well-behaved mAbs in addition to

biological activity

– Development of predictive tools

Summary

• CMC Development has a significant role in changing current

BioTx clinical development model

• Platform knowledge in mAb development can be leveraged to

improve efficiency without compromising quality

• Partnerships with project teams, CMOs, and regulatory

agencies are necessary to affect positive change

Acknowledgments

Marta Czupryn

Steffanie Pluschkell

Robert Repetto

Sa Ho

Kristin Murray

Tom Crowley

Tom Greenwood

Maeve Donegan

Bernie Huyghe

Bob Faneuff

Monica Purcell

Ling Gu

Concepcion Kafka

Bob Kitchen

Janelle Lavoie

Lisa Marzilli

Jim Mercer

Joe McLaughlin Gerry Boushelle

Karen Cook

Jon Coffman

Paula Miller

Martin Allen

Rob Dufield

Freddie Fowlkes

Derek Gates

Jackie Moxham

Nick Warne

Laura Lin

Tao He

Mark Krebs

Backup Slides

Cost of Development for ‘Standard’ mAb Adjusted for

Attrition

$-

$50,000,000

$100,000,000

$150,000,000

$200,000,000

$250,000,000

$300,000,000

$-

$2,000,000

$4,000,000

$6,000,000

$8,000,000

$10,000,000

$12,000,000

$14,000,000

$16,000,000

0 1 2 3 4 5 6 7 8 9

Inte

grated P

roje

ct Co

stDe

velo

mp

en

t F

TE C

ost

Years

FTE Cost

FTE cost (Adjusted for attrition)

Total Cost

Total Cost (Adjusted for attrition)

FIH -Start Candidate

Selection

Ph. IIb

start Ph. III

start

BLA

sub. Launch