De-Risking the Phase II to Phase III Advancement Decision: Sound Science, Critical Thinking and...

De-Risking the Phase II to Phase III

Advancement Decision:

Sound Science, Critical Thinking

and Weighing Time versus Cost

June 28, 2011

Speakers & Topics

Lisa Natanson

Senior Analyst

Deloitte Recap LLC

David Stump

Executive Vice President, R&D

Human Genome Sciences, Inc.

John Orwin

Chief Executive Officer

Affymax, Inc.

Panel Session

What Can We Learn From the Data

About Late-Stage Drug Development

Failures?

BenlystaTM Case Study

Killing the Vampire:

Anti-IGF1R Phase III Go/No-Go

Recommendation

Q&A

2

What Can We Learn

From the Data About Late-Stage Drug

Development Failures?

Lisa Natanson

Senior Analyst, Deloitte Recap LLC

An approved product that…

• Improves survival and quality of

life for patients

• Provides return on investment for

companies and stockholders

Success

A terminated product that…

• Fails at Phase III or Filing after

years of development, providing no

benefit to patients

• Provides no return on investment

for companies and stockholders

Late-Stage Failure

4

“Companies that are good at drug development have always recognized that Phase II is the critical place to weed out drugs that don’t have a good future in terms of safety or efficacy.”

John Jenkins, M.D., F.C.C.P.Director, Office of New Drugs

Food and Drug Administration-- Signals magazine, November 2003

5

587

Ongoing

Compounds

152

Marketed

Compounds

160 Fast Track Indications

308 Orphan Indications

523

Terminated

Compounds 41% 47%

12%

Data Source: 190 Leading Biotechnology Companies

60% Small Molecules

40% Large Molecules

DATA SOURCES: Securities and Exchange Commission filings, clinical trial registries, U.S. and E.U. regulatory agency

briefing documents, refereed journal articles, scientific and medical meeting abstracts, corporate press releases and investor

presentations, university and governmental medical research institute websites, as well as other public, primary data sources.

23 June 20116

Approved

Compounds

152

117

--

--

74

70

64

Terminated

Compounds

523

450

74

56

44

39

33

1. Compound was developed by RBI company(1)

2. Compound’s origin was In-House

3. For Terminated Compounds:

• Phase at Termination was Phase III or Filing

• Documented Reason for Termination was

“Lack of Activity or Efficacy” or “Safety”

4. Compound reached final clinical outcome between

January 1, 2000 and May 31, 2011

5. Vaccines, imaging agents, devices, and 505(b)(2)

NDAs excluded

6. Complete and verifiable data for all Phase II and

Phase III trials conducted*

* Missing data for 15% (6/39) of Terminated compounds and 9% (6/70) of Approved compounds.

(1) RBI = Recap BioPortfolio Index (n=190 companies)

Compound Data Set (n=97)

23 June 20117

33 Compounds

Terminated at

Phase III or Filing

64 Compounds

Approved by FDA

versus

January 1, 2000 - May 31, 2011

Compound Data Set (n=97)

8

SuccessLate-Stage Failure

23 June 2011

9

Methodology for Comparing Phase II Programs

Phase II program metrics reported contain only trials ongoing

and/or completed prior to the Phase III trial start date or

announced advancement decision. Phase II trials initiated

and conducted after the pivotal trial(s) start date but prior to

regulatory filings were not counted since they did not inform

the advancement decision.

Phase I/II trials were counted as Phase II trials and Phase II/III

trials were counted as Phase III trials.

Median Metrics of Phase II Clinical ProgramsJanuary 1, 2000 - May 31, 2011

23 June 201110

MetricTerminated

At Phase III or Filing(n=33)

Trials1.0 [Range: 0-4]

[Mean: 1.18, SD 0.73]

Patients69 [Range: 0-949]

[Mean: 169.5, SD 225.7]Data Source: Deloitte Recap LLC

Median Metrics of Phase II Clinical Programs

MetricTerminated


Approved by FDA(n=64)


[Mean: 1.18, SD 0.73]

2.0 [Range: 0-6]

[Mean: 1.97, SD 1.15]


[Mean: 169.5, SD 225.7]

171 [Range: 0-4,121]

[Mean: 302.4, SD 547.1]

January 1, 2000 - May 31, 2011

23 June 201111

Data Source: Deloitte Recap LLC


23 June 201112

MetricTerminated



p-Value[Wilcoxon]


[Mean: 1.18, SD 0.73]

2.0 [Range: 0-6]

[Mean: 1.97, SD 1.15]0.0002


[Mean: 169.5, SD 225.7]

171 [Range: 0-4,121]

[Mean: 302.4, SD 547.1]0.03


13



MetricTerminated



p-Value[Wilcoxon]


[Mean: 1.18, SD 0.73]

2.0 [Range: 0-6]

[Mean: 1.97, SD 1.15]0.0002


[Mean: 169.5, SD 225.7]

171 [Range: 0-4,121]

[Mean: 302.4, SD 547.1]0.03

39 Trials

5,592 Patients

126 Trials

19,354 Patients

23 June 2011

14



MetricTerminated



p-Value[Wilcoxon]


[Mean: 1.18, SD 0.73]

2.0 [Range: 0-6]

[Mean: 1.97, SD 1.15]0.0002


[Mean: 169.5, SD 225.7]

171 [Range: 0-4,121]

[Mean: 302.4, SD 547.1]0.03

Successful programs invested more in Phase II trials.

23 June 2011

IQR = Inter-Quartile Range (where 50% of the data reside).



23 June 201115

MetricTerminated

At Phase III or Filing (n=33)

ApprovedBy FDA(n=64)

Patients EnrolledPer Phase II Program

69IQR: 33-210

171IQR: 65-380

Observation: The ratio of median patients enrolled from Phase II to Phase III was 1 to 12 versus a ratio for approved products of 1 to 4.


Median Metrics of Phase III Clinical ProgramsJanuary 1, 2000 - May 31, 2011

23 June 201116

MetricTerminated




69IQR: 33-210

171IQR: 65-380

Patients Enrolled Per Phase III Program

821IQR: 433-1,425

697IQR: 220-1,284




Median Metrics of Phase III Clinical ProgramsJanuary 1, 2000 - May 31, 2011

MetricTerminated




69IQR: 33-210

171IQR: 65-380

Patients Enrolled Per Phase III Program

821IQR: 433-1,425

697IQR: 220-1,284

23 June 201117

Unsuccessful programs invested more in Phase III trials.

Phase II Trial Conduct PatternsJanuary 1, 2000 - May 31, 2011

CompoundSet

0Phase II Trials

1Phase II Trial

2 or MorePhase II Trials

Terminated at Phase III or

Filing(n=33)

9%(3/33)

70%(23/33)

21%(7/33)

Approved by FDA

(n=64)

2%(1/64)

41%(26/64)

58%(37/64)


1823 June 2011

Phase II Trial Conduct PatternsJanuary 1, 2000 - May 31, 2011

CompoundSet

0Phase II Trials

1Phase II Trial

2 or MorePhase II Trials


Filing(n=33)

9%(3/33)

70%(23/33)

21%(7/33)

Approved by FDA

(n=64)

2%(1/64)

41%(26/64)

58%(37/64)


1923 June 2011

Advancement Decisions Based on One Phase II TrialDoes Quality of Efficacy Evidence Correlate with Risk?

CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

23 compounds advanced on data

from a single trial.

26 compounds advanced on data

from a single trial.

Question: Can we learn anything

from looking at the Phase II trial

results informing these

advancement decisions?


2023 June 2011

Higher Risk Evidence

Advancement Decisions Based on One Phase II TrialEfficacy Evidence and Risk

CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

21


23 June 2011

61% (14/23)

Phase II Trial Result CategoriesBased on Design Rigor & Prospectively Defined Primary Endpoint

Negative or Neutral Efficacy Signals

No Statistically Significant Effect Controlled, randomized trial. Experimental agent loses on the prospectively defined Primary Endpoint and p-value does not reach significance at the prespecified level.

Minimal Biologic Activity Uncontrolled trial (includes historical control) that showed very modest activity.

Evidence of Biologic Activity –Non Orphan Disease

Uncontrolled trial (i.e., no active, placebo, standard of care or historical control arm) that showed activity – in a non-Orphan disease indication.

Well Tolerated Safety is Primary Endpoint, even though it is a Phase II trial.

22



CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

23


23 June 2011

61% (14/23)

39% (9/23)

Lower Risk Evidence

Phase II Trial Result CategoriesBased on Design Rigor & Prospectively Defined Primary Endpoint

Statistically Significant Benefit Controlled, randomized trial. Experimental agent wins on the prospectively defined Primary Endpoint at the prespecified level of statistical significance (including any corrections for multiple comparisons).

Evidence of Biologic Activity –Orphan Disease

Uncontrolled trial (i.e., no active, placebo, standard of care or historical control arm) that showed activity – in an Orphan disease indication.

Equivalent to Approved Agent Controlled, randomized trial with non-inferiority as Primary Endpoint.

Superior to Approved Agent Controlled, randomized non-inferiority & equivalency trials that have a prespecified superiority analysis.

Positive Efficacy Signals

24

Lower Risk Evidence


CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

61%

39%

25


23 June 2011


Lower Risk Evidence


CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

61%

26


23 June 2011


19% (5/26)

27


CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

39%


23 June 2011

81% (21/26)

Lower Risk Evidence


CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

61%

39%

19%

81%

28


23 June 2011


Lower Risk Evidence

To emulate successful

drugs, Phase II

advancement decisions

made on the basis of

Higher Risk evidence

from a single trial should

occur infrequently (about

1 in 5 decisions)


CompoundSet

1Phase II Trial


Filing(n=33)

70%(23/33)

Approved by FDA

(n=64)

41%(26/64)

61%

39%

19%

81%

29


23 June 2011


Lower Risk Evidence

88%

45%

Approved By FDA

(n=64)

Terminated at Phase III

or Filing

(n=33)

Changing Endpoints Between Phase II and Phase IIIPercent of Compounds that Switched Primary Efficacy Endpoint


3023 June 2011

Compound Characteristics: Therapeutic AreasTAs with Balance or Minor Imbalance Between Groups


Therapeutic AreaTerminated


ApprovedBy FDA*(n=64)

Cancer 24% (8/33) 20% (13/64)

Cardiovascular 6% (2/33) 5% (3/64)

Infectious Disease 15% (5/33) 17% (11/64)

Miscellaneous* 12% (4/33) 19% (12/64)

Neuroscience 24% (8/33) 3% (2/64)

Gastrointestinal 15% (5/33) 2% (1/64)

* Includes: Dental/Oral, Dermatologic, Genitourinary, Respiratory, Transplantation, Ophthalmic and Other.

3123 June 2011

Compound Characteristics: Therapeutic AreasTAs with Major Imbalance Between Groups

Therapeutic AreaTerminated


ApprovedBy FDA*(n=64)

Endocrine/Metabolic 3% (1/33) 14% (9/64)

Hematologic 0% (0/33) 8% (5/64)

Autoimmune/Inflammatory

0% (0/33) 13% (8/64)


Observation: When we removed all compounds (n=23) representing these three Therapeutic Areas from both data sets, results for Phase II and Phase III program

conduct remained essentially unchanged.

3223 June 2011

Compound Characteristics: MiscellaneousBalance Between Groups of Other Relevant Factors

CompoundCharacteristic

TerminatedAt Phase III or Filing

(n=33)


Fast Track 39% (13/33) 46% (30/64)

Orphan Drug 33% (11/33) 36% (23/64)

Development Partner 48% (16/33) 56% (36/64)

Large Molecules 33% (11/33) 52% (33/64)

Mean Time to “Final” Outcome

7.4 years 6.9 years*

* For approved drugs, 58% (37/64) received Priority Review and 42% (27/64) could be considered First-in-Class.


3323 June 2011

~80% of Phase II programs for failed drugs involved 1

or no Phase II trials

~90% of failed drugs used a different primary endpoint

in Phase III than was tested in Phase II

Phase III advancement on the basis of a single Phase

II trial was based on higher risk (weaker efficacy) data

about 2/3 of the time for failed drugs

Phase II Risk Factors

3423 June 2011

Program Characteristics of 33 Products That Terminated Late

35

~2/3 of approved compounds conducted 2 or more

Phase II trials prior to Phase III advancement decision

Phase II programs of approved drugs were 2.5 times

larger than those for failed drugs

A majority of approved drugs used the same primary

endpoint in Phase II and III

Phase III advancement on the basis of a single Phase II

trial was based on lower risk (stronger efficacy) data

~80% of the time for approved drugs

Phase II Risk MitigationProgram Characteristics of 64 FDA-Approved Products

23 June 2011

Derisking the Phase II to Phase III

Advancement Decision

Case Study: Belimumab

David C. Stump, MD



June 28, 2011

BLyS: Mechanism of Action

B cell

Antigens present

in the periphery

Monocytes, activated by

antigen, express

membrane bound BLyS

B cell survival,

differentiation, & antibody

formation

BLyS is cleaved to

active, soluble form

37

Rationale for BLyS Antagonists in SLE

• Mouse data links BLyS and autoimmune disease

• Transgenic models over-expressing BLyS have autoimmune/SLE-like phenotype

• Genetic models of autoimmune disease have elevated levels of circulating BLyS

• Soluble BLyS receptors administered in an animal model of SLE ameliorates

disease progression and improves survival

• BLyS antagonists inhibit BLyS effects in mice

• Human BLyS administration results in increased spleen weight, B220+/ThB+ splenic

B cell numbers and serum IgA

• BLyS antagonists selectively inhibit these BLyS-induced effects

38

Autoimmune Patients Display Elevated Serum

BLyS Concentrations

LLOQ

Normal SLE RA MS T1 Diabetes0

1

2

3

4

5

LLOQ

6

9

12

15

Disease

BL

yS

(n

g/m

L)

39

BLyS Observational SLE Study

There is a strong association between SLE disease activity, the presence of anti-

dsDNA and BLyS levels in SLE patients.

*Petri M et al. A&R 2008;58(8)2453-9.

40

By Binding to BLyS, Belimumab Inhibits

B-cell Survival, May Induce Apoptosis

Do RKG et al. J Exp Med. 2000;192:953-964; Ammana et al. J Immunol. 2003;170:4593-4600.

= Belimumab

Autoreactive B-cell apoptosis

= BLyS = TACI, BCMA, BAFF-R

Autoreactive B-cell survival

Belimumab Binds BLySAutoimmune Disease

41

Belimumab Clinical Studies in SLE*

Phase Population # Treated Duration of Rx (Dose)

1 SLE with stable disease for at least 2

mos. prior to screening

57 21 days (1, 4, 10, or 20 mg/kg; 1

IV or 2 IV, 21 days apart

2 Active SLE defined as SS ≥ 4 at

screening, stable SLE treatment, & hx

of autoantibodies

449 76 wks. (1, 4, 10 mg/kg IV; 52-

wk placebo-controlled treatment

phase and 24 wk extension)

3 Active SLE defined as SS ≥ 6, stable

SLE treatment, and +ANA/dsDNA at

two independent timepts

819 76 wks. (1 or 10 mg/kg IV

placebo controlled); primary

endpoint at 52-wks

3 Active SLE defined as SS ≥ 6, stable

SLE treatment, and + ANA/dsDNA at

two independent timepts

865 52 wks. (1 or 10 mg/kg IV,

placebo controlled)

*Excludes Continuation Clinical Trials

42

Phase 2 SLE Trial Design

• Efficacy assessments • SELENA-SLEDAI (SS), SLE Flare Index (SFI), PGA, BILAG Classic 2000

• Every 4-8 weeks in first 52 weeks & extension; every 8-16 weeks in continuation

• Safety assessments• Adverse events recorded every visit. Safety labs every 4 weeks in first 52 weeks;

every 8 weeks in extension & continuation

* All treatments included standard of care PGA = Physician’s Global Assessment. BILAG = British Isles Lupus Assessment Group

43% (193/449) remained on treatment as of 28 Dec. 2010

1,632 Cumulative Patient-years

43

Lessons Learned from the Belimumab Phase 2

SLE Study

• Did not meet co-primary endpoints of:

• % reduction of SELENA SLEDAI score at week 24

• time to first SLE flare over 52 weeks

• Presumption of 65-70% annual flare rate too low in moderate-severe

SLE patients

• Early reductions in B-cell subsets and improved PGA responses

required time to translate into decreased SLE disease activity as

measured by the SELENA-SLEDAI

• Serologically active (ANA≥1:80 and/or anti-dsDNA ≥30 IU/mL) patients

at entry were more responsive to BLyS-specific inhibitor therapy

• Permitting changes in prednisone and immunosuppressive

medications confounded SLE disease activity assessments

44

Lessons Learned from the Belimumab Phase 2

SLE Study• Limitations and strengths of BILAG and SELENA SLEDAI (SS)

disease activity scales were identified:• Using the same scale to show improvement and worsening

• Population-based disease activity more difficult to interpret than individual responders

• Wanted unambiguous measure of stable improvement in disease activity

• SS is a better measure of sustained overall improvement

• BILAG highly variable measure of improvement

• BILAG B flares could easily be triggered

• BILAG is a better measure of organ specific worsening

45

Rationale for Novel Composite Endpoint in SLE

• FDA had recommended that results of clinical trials be analyzed to verify that improved SLE disease activity score translates into a clinical benefit for the patient1

• Improvement in disease activity should not be accompanied by worsening in other disease manifestations

• SELENA SLEDAI (SS) tracks complete elimination, but not partial changes. Has 24 items.

• Clinical response on SS defined as ≥4-point decrease2

• BILAG measures changes in disease activity in individual organ systems

• BILAG A or 2 BILAG B flares represent increased activity sufficient to require a therapeutic alteration (e.g., steroid or immunosuppressant); triggered by physician’s ―intent to treat‖

• PGA is semi-quantitative and sensitive to patient’s overall condition• No worsening defined as <0.3-unit (≈10%) increase on visual analog scale

1. FDA. Draft Guidance for Industry: Systemic Lupus Erythematosus — Developing Drugs for Treatment. Released March 16, 2005;

2. Gladman DD, et al. J Rheumatol. 2000;27:377-379.

46

≥ 4 point improvement in SELENA SLEDAI score

AND

No new BILAG A or 2 BILAG B organ domain flares

AND

No worsening in Physician’s Global Assessment

(<0.3 point increase)

Novel SLE Responder Index

47

Difference in Phase 3 BLISS Trials Compared to

the Phase 2 SLE Trial Design• Created a novel evidence-based SLE responder index (SRI) as the

primary endpoint at Week 52

• Only enrolled autoantibody positive (ANA≥1:80 and/or anti-dsDNA ≥30 IU/mL) at baseline as these patients were more responsive to belimumab therapy in Ph 2

• Ensures improvement is disease activity and is not accompanied by worsening in specific organ systems or in the patient’s condition overall

• Increased the sample size ~3-fold for 90% power

• Global input on trial design and background standard of care therapies allowed participation of patients from different regions of the world

48

Difference in Phase 3 BLISS Trials Compared to

the Phase 2 SLE Trial Design• Strict entry criteria to identify SLE patients with moderate to severe

disease activity • Increased minimum entry SS score from 4 to 6

• Stable standard of care medications 1-6 months before study initiation

• Controlled concomitant use of standard of care therapies during the trial that could impact SLE disease activity assessments

• Extensive training of SLE disease activity scales (SELENA SLEDAI and BILAG )

• Automatic edits programmed in eCRF for SLE disease activity scales and cross-checking

49

BLISS Phase 3 Clinical Trial Program

1,684 patients from 223 centers in 31 countries

865 (BLISS-52) and 819 (BLISS-76) patients

US

Puerto Rico

Canada

Mexico

Costa Rica

Argentina

Brazil

Chile

Colombia

Peru

Austria

Belgium

Czech Republic

France

Germany

Israel

Italy

The Netherlands

Poland

Romania/Romania

Russia

Slovakia

Spain

Sweden

UK

Australia

Hong Kong

India

Korea

The Philippines

TaiwanBLISS-52

BLISS-76

50

BLISS-52 Study Design

R

A

N

D

O

M

I

Z

E

Belimumab 1 mg/kg

+ Standard of Care

Placebo

+ Standard of Care

Belimumab 10 mg/kg

+ Standard of Care

865 subjects with active SLE

SELENA-SLEDAI ≥ 6

Serologically active (ANA ≥ 1:80 and/ or anti-dsDNA ≥ 30 IU/mL)

Stable standard of care therapy >30 days

No active severe lupus nephritis or CNS lupus

Progressive restrictions on concurrent medications (weeks 16, 24 and 44)

51

BLISS-52: Primary Response at Week 52

52

819 subjects with active SLE

SELENA-SLEDAI ≥ 6

Serologically active (ANA ≥ 1:80 and/ or anti-dsDNA ≥ 30 IU/mL)

Stable standard of care therapy >30 days

No active severe lupus nephritis or CNS lupus

Progressive restrictions on concurrent medications (weeks 16, 24 and 44)

BLISS-76 Study Design

R

A

N

D

O

M

I

Z

E

Belimumab 1 mg/kg

+ Standard of Care

Placebo

+ Standard of Care

Belimumab 10 mg/kg

+ Standard of Care

53

BLISS-76 Primary Efficacy Endpoint at Week 52

Belimumab

54

Efficacy Conclusions: Primary Endpoint

• Belimumab 10 mg/kg met primary endpoint in both trials

• Greater duration of response

• Robust in sensitivity analyses

• Greater benefit at higher thresholds (SRI ≥5)

• At Weeks 52 and 76

• Multivariate analyses

• No heterogeneity of effect by study, region or race

• Further study of black patients needed

• Identified potential predictors of greater response

• Higher SELENA SLEDAI, low complement, steroid use

55

Safety Summary

• Overall adverse event rates similar to placebo

• With wide range of standard therapies

• Numerically more deaths reported than placebo; rates and

causes of death consistent with SLE

• Increased rate of infusion reactions

• Majority mild to moderate; manageable

• Serious infection rates similar to placebo

• No increase in malignancies

56

So What’s One to Do?

• Thoroughly understand target biology and pathophysiology

• Define relationship of target to manifestations of disease

• Effective phase 2 strategy

• Do not skip it

• Consider it exploratory rather than pivotal

• Learn from it

57

So What’s One to Do?

• Effective phase 3 strategy

• Apply phase 2 learnings

• Understand and manage risks from BOTH noise of implementation and natural

variability of disease

• Adequately power studies

• Do not fear going global

58

Derisking the Phase II to Phase III

Advancement Decision

Case Study: Belimumab

David C. Stump, MD



June 28, 2011

Killing the Vampire

Anti-IGF1R Phase III Go/No-Go

Recommendation

John Orwin

Chief Executive Officer

Affymax

Anti-IGF1R Phase III Go / No Go Decision

• IGF1R was a target of high scientific and commercial interest market

• IGF1R highly expressed in several highly prevalent tumor types

• Appeared combinable with other targeted and cytotoxic therapies

• Genentech portfolio planning set a high bar

• 1st in class or best in class

• Competition with other high value projects

• Highly sophisticated market planning models

• Patient-based, tumor-specific incidence and prevalence based models

• Captured order and angle of entry

• An undifferentiated, late to market product would not meet the hurdle –

but how to convince the enthusiastic scientists?

61

Competitive Landscape anti-IGF1R Class, April 25, 2007

Preclinical Phase I Phase II Phase III Launched

Merck/PierreFabre

h7C10/F50035

Schering-Plough

19D12

BMSBMS-695,735BMS-544,417BMS-536,924

GSKGSK-665,602GSK-621,659

NovartisNOV-AEW-541NOV-ADW-742

ImmunoGen/Sanofi

EM-164/AVE1642

IGF1R Antibody

IGF1R TKI

Imclone

IMC-A12

Genentech

10H5

OSI

OSI-906 (QPIP)

Biogen/IDEC

BIIB-022

Amgen

AMG 479

Roche

R1507

Pfizer

CP-751,871

Exelixis

XL-228

Merck

MK-0646

CRC

Insmed

INSM-18

Prostate

AbbottA928605

62

Predicted anti-IGF1R Launches:

10H5 Will Launch More than 2 Years After Leader

2009 20132010 2011 2012 2014

Pfizer

ImClone

Merck

Roche Sarc (no AA)

Timelines based on generic PPC-approved assumptions for approval, and Ph II/III unless accelerated approval expected (AA)

2L NSCLC

mBC, HRPC

1L NSCLC

2LCRC

2L NSCLC

2L NSCLC

RR mBC, Sarc, HNC, 2L HCC

Sarc (AA)

GNE: 2L NSCLC FPI LaunchLPO BLA

2L CRC, Prostate

*2L NSCLC

1

2

NSCLC

Launch

Order

3

4

Amgen

Schering Plough Sarc (no AA)

Sarc (AA)

Sarc (no AA)

mBC Panc

Sarc (AA)

2LCRC

*Assumed – not publicly disclosed

63

Anti-IGF1R Class is a Commodity

• Current data suggests that anti-IGF1R class is undifferentiated• No clear path to demonstrate best in class for10H5

• No dosing nor safety advantage over competitors

• All mAbs predicted to have similar PTS to launch

• None have IP advantage

• Therefore, market order entry will dictate resulting market share

• First mover advantage is often retained in oncology markets without clear

advantages of follow on products

64

Pfizer Gains First-Mover Advantage in Undifferentiated Market

Key Drivers and Barriers of Class Penetration

Strong efficacy improvement over Tarceva expected

High degree of combinability with chemo and other targeted agents due to clean safety profile

Combination with anti-angiogenics less likely

Large class due to 5+ aIGF1R agents in late stage development

Greater use of biomarker tests lead to fragmented market

Slide 65 2/29/2008

Pfizer

ImClone

Merck

All Other aIGF1Rs*

GNE

0%

10%

20%

30%

40%

50%

60%

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

aIG

F1R

Net

Usag

e in

2L

NS

CL

C

GNE captures 10% market share as 4th entrant in 2L NSCLC

65

Strategies Explored to Maximize the Value of 10H5

Independent

Value for

10H5

Incremental

Value to

Portfolio

Maximize

Speed to

Market

Maximize

Market

Share

– Order of market entry is a critical driver of revenue assumptions

– Line extensions may provide additive value

Combo

Augments

Efficacy

– Combinations with pipeline products may be innovative

66

Attempt Earlier Launch to Gain Greater Market Share2009 20132010 2011 2012 2014

Pfizer

ImClone

Merck

Roche Sarc (no AA)

Timelines based on generic PPC-approved assumptions for approval, and Ph II/III unless accelerated approval expected (AA)

2L NSCLC

mBC, HRPC

1L NSCLC

2LCRC

2L NSCLC

2L NSCLC

RR mBC, Sarc, HNC, 2L HCC

Sarc (AA)

GNE: FPI

2L CRC, Prostate

*2L NSCLC

Amgen

Schering Plough Sarc (no AA)

Sarc (AA)

Sarc (no AA)

mBC Panc

Sarc (AA)

2LCRC

*Assumed – not publicly disclosed

2L NSCLC Launch

Target launch

window

67

No Fast to Market Strategies Could Launch Within

Target Timeframe

2L HR

PrCa

Melanoma (w/Mek, Avastin)

RCC w/VEGF

Ref OvCa

HCCw/nex

HNSCC w/EGFR

Pancreaticw/EGFR

Science

Speed

Portfolio/

Pipeline

Ewing’s

Sarcoma

Sarcoma

NSCLC

MBC

HSPrC

CRC

HCC (w/A+T)

Neuroendocrine

1L HRPrC

RCC w/mTOR

No current IGF1R trials

OvCa w/pert, AVF

Melanoma (w/DTIC)

SCLC

68

Large Markets Crowded by Anti-IGF1R Competitors

NSCLC Breast CRC Pros Sarc Panc HCC HNC Other

Pfizer2L 2011

1L 2012

2013 2013 2013 TBD

Amgen2013 2012 2012

Imclone/NCI2013 2013 2012 2013 2013 2013 2013 2013

Merck2013 2012 2013

Roche2010

(AA)

Schering-Plough

2012 2011

(AA)

InsmedTBD

• Unlikely that 10H5 will enter market early in big indications, thereby

constraining market value

Ph 1

Ph 2

Ph 3

69

Anti-IGF1R Phase 3 Decision

• Commercial recommendation was not to advance 10H5

• Numerous approached explored to differentiate product but were

unconvincing

• Different antibody

• Unique combinations with proprietary, earlier stage molecules

• Many fast-to-market development options were considered

• Rare, high unmet need tumor types

• Strategic value was considered – but was owning the product the only

or best way to release the combination potential?

• The product was discontinued prior to phase 3 start

• The class later was largely abandoned when products failed in late

stage phase 2 and phase 3 trials

70

Anti-IGF1R Lessons Learned

• Models are valuable when they are used to help inform decisions

rather than support a given decision

• Decision rules are valuable but only if they are followed – discipline is

required

• Commercial risk must be considered along with scientific and technical

risk

• Great momentum exists for projects in motion

• Even for companies with a high hurdle and competing opportunity set

• Great care and tenacity are required when killing a vampire!

71

De-Risking the Phase II to Phase III

Advancement Decision:

Sound Science, Critical Thinking

and Weighing Time versus Cost

June 28, 2011

Q&A

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