Roche Committedto Innovation

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RocheCommitted to Innovation

Jean-Jacques Garaud, M.D.|Global Head of pharma. Research & Exploratory DevelopmentRoche Pharmaceuticals

2010 Citi Investment Research Global Health Care Conference

May 26, 2010, New York

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Roche: Focused on medically differentiated therapies

Generics

Differentiation

Focus

MedTech

OTC

Value

DiaPharma

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Unique diversity of approaches

Autonomous centers

GenentechR&ED*

Diversity Scale, Reach, Speed

“Federation” of >150 partners

* R&ED = Research & Early Development

RocheR&ED* Research

Early Dev.

Worldwideexecution

Roche Dx

Chugai

Global Product Development

Manufacturing

Commercialisation

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Roche pharma Research & Early Development Legacy

Six transitions to late-stage over 2007-2009

GA101

Aleglitazar

Taspoglutide

B-RAF antagonist

Gly T-1 inhibitor

Dalcetrapib

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The pRED mission

Science and patients: our focus, our passion

Deepen understanding of disease biology and the molecular basis of heterogeneity of diseases

Leverage technologies and capabilities to develop new compounds to Lifecycle Investment Point (LIP)

Deliver on individual patient needs through the implementation of PHC strategies

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Three critical steps for innovation in drug discovery and early development

We know what to target

(Understanding disease, new pathways, Biomarkers, PHC)

We have a powerful multiplier

(Therapeutic Modalities)

World-Class skills inTranslational Medicine

(PoM and PoC)

Small Molecules

Therapeutic Proteins

RNA Interference

Therapeutic stem cells

Peptides

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Strong progress in small molecule discovery

Attrition for safety reasons dramatically reduced

% of projects terminated for safety reasons

Phase 0 Phase 1

Industry-leading safety based attrition rates in Phase 0 and 1

Outstanding medicinal chemistry capabilities

+

Source: internal analysis

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MDM2 antagonist (RG7112) induces apoptosis

Nutlins: a novel approach to cancer therapy

• p53 is a major tumor suppressor protein that induces apoptosis in tumors

– MDM2 naturally inhibits the activity of p53

– Nutlins prevent MDM2 from inactivating p53

• Nutlins represent a breakthrough in cancer drug research

– small molecule that specifically blocks the interaction between the two proteins

• Roche is the leader in the field

Xenografts model results

• RG7112 currently in late Phase 1

• Companion diagnostics in co-development with Diagnostics (p53 chip & MDM2 expression)

L Vassilev et al. (2004) Science, 303, 844-848; L Vassilev (2006) Trends in Molecular Medicine 13, 1 23-31; Rosisnki, J., etal., Proc. Natl. Acad. Sci. 103 1888-93 (2006); Xia M., etal., Cell Cycle 7 1604-12 (2008); Huang B, etal., Mol Cancer Res. 2009 Sep;7(9):1497-509.

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Enhancing antibody performance

NK

or MØØØØ

Bi-specific antibodybinds to two different targetsand enhances specificity

Antibody inhibits or activates signaling

Naked Antibodies

bi-specific Antibodies

Bi-specific antibodybinds to two different targets in different cells

bi-specific Antibodiesdrugdrug

drugdrug

Antibody recruits immune effectorcell and induces cytotoxicity

ADCC enhanced Antibody

Antibody specifiesdelivery of drug

Armed Antibodies

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T-DM1

HER2 suppression meets cytotoxic potency

• A novel anti-cancer agent

– Herceptin’s biologic activity

– Targeted intracellular delivery of a potent cell-killing agent, DM1

• Unprecedented efficacy inheavily pre-treated HER2+ mBC

– 33% ORR

• Single agent data indicates better tolerability than standard chemotherapy-containing regimens

In collaboration with ImmunoGen

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T-DM1

Changing paradigm in a broad clinical program

HER2-positive Metastatic Breast Cancer

Third-line

Treatment

Second-line

Treatment

First-line

Treatment

First-line

Treatment

Phase IIPhase III

EMILIA

Randomised

Phase II

Preparing for

Phase III

• Single ARM: T-DM1

• Potential US submission

2010

• ARM A: T-DM1

• ARM B: Xeloda plus lapatinib

• Potential submission 2012

• ARM A: T-DM1

• ARM B: Herceptin plus docetaxel

• ARM A: Herceptin plus taxane

• ARM B: T-DM1

• ARM C: T-DM1 plus pertuzumab

• Potential submission

beyond 2014

Phase II 1L HER2+ mBC data submitted for presentation at

ESMO 2010In collaboration with ImmunoGen

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Pertuzumab

Redefining HER2 blockade in breast cancer

• Synergistic to Herceptin

• Phase II study of pertuzumab + Herceptin

– Clinical benefit rate 50%

• Important Upcoming Data Results:

– Phase II NeoSphere ASCO 2010

– Phase III CLEOPATRA (2011)

First-line HER2-positive Metastatic Breast Cancer

Phase III CLEOPATRA

• ARM A: Herceptin and docetaxel

• ARM B: Pertuzumab plus Herceptin and docetaxel

Neoadjuvant HER2-positive Breast Cancer

Phase II NeoSphere

• ARM A: Herceptin plus docetaxel

• ARM B: Herceptin, docetaxel plus pertuzumab

• ARM C: Herceptin plus pertuzumab

• ARM D: Pertuzumab plus docetaxel

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GA101: a glycoengineered, type II anti-CD20 antibody

Enhanced ADCC and direct cell induction

GA101 in patients with relapsed/refractory CD20+B-CLL

Glycoengineered

Type II epitope

Mossner E., etal., Blood, Mar 2010 GA101 B-CLL data presented at ASH, December, 2009

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GA201

Anti-EGFR glycoengineered antibody for enhanced ADCC

• A potential breakthrough in cancer therapy

– opportunity to treat k-ras mutant tumors

• Will allow to demonstrate the utility of glycoengineering antibodies

• Roche could become the leader in ADCC–enhanced antibody therapy

GA201

Fully humanEGFR mAb

Cetuximab

-20

0

20

40

60

80

100

1500 300 60 12 2.40 0.48 0.096

Antibody Concentration (ng/ml)

AD

CC

(%

)

GA201 vs. other EGFR Abs(NK92/FcgRIIIA-158F effector cells)

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

Study day

0

20

40

60

80

100

120

Sur

viva

l %

CetuximabVehicleGA201

Superior efficacy in CRC (kRAS mut liver met model in Scid-bg mice)

Patient 1696 (kRAS WT, EGFR mut CRC): complete response

after 12 cyclesGerdes C., etal., Presentation at AACR Meeting, April 2009; Abstract 5476.Data on file, Roche

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2007 2008 2009 2010E

Late-stage pipeline continues to build up

Expanding into new therapeutic areas

Number of NMEs

2

4

10Metabolic

Oncology

Inflammation

ocrelizumab

dalcetrapib

pertuzumab

dalcetrapib

taspoglutide

Actemra

ocrelizumab

aleglitazar

dalcetrapib

taspoglutide

aleglitazar

SGLT2 inh*

CNS

taspoglutide

ocrelizumab

GlyT-1 inh

ocrelizumab MS*

pertuzumab

T-DM1

Hedgehog inh

BRAF inhibitor

RG7159 (CLL)

GlyT-1 inh

pertuzumab

BRAF inhibitor

T-DM1

Hedgehog inh

RG7159 (CLL, NHL)

up to 13

lebrikizumab *

HCV pol inh *

Virology

* LIP or phase III decision pending

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Metabolism/CV: High Unmet Need Remains

> 65% of CV events not prevented despite wide use of statins

Major clinical trials aimed at reducing cardiovascular risk

0%

20%

40%

60%

80%

100%

4S Lipid Care HPS WOSCOP AFCAPS/TexCAPS

TNT

% event not prevented % event prevented

4S, The Lancet, 1994 - Lipid, NEJM, 1998 - Care, NEJM, 1996 - HPS, The Lancet, 2002WOSCOP, NEJM, 1999 - AFCAPS/TexCAPS, JAMA, 1998 - TNT, NEJM, 2005

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HDL-C, mg/dL

(mmol/L)

FRAMINGHAM: Low HDL-C is an independent factor of CAD risk even when LDL-C is low

CAD Risk After 4 Years

a

85 (2.2)65 (1.7)

45 (1.2)25 (0.7)

100 (2.6) 160 (4.1) 220 (5.7)

LDL-C, mg/dL (mmol/L)

0

1

2

3

• HDL-C is inversely correlated with CAD risk

• Correlation is independent of LDL-C

aMen aged 50–70

Castelli. Can J Cardiol. 1988;4(suppl A):5A–10A.CAD: coronary artery disease, HDL-C: high densitiy lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol

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LIVER

PERIPHERAL TISSUEBile Excretion

Reverse

Cholesterol Transport

LDL

PLASMA

Cholesterol Efflux

CETP Athero-sclerosis

HDL removes cholesterol from atherosclerotic plaque

CETP inhibition: next breakthrough in CV risk reduction?

Hypothesis tested with CETP inhibition

• Increases HDL

• Promotes cholesterol efflux from macrophages in atherosclerotic plaque

• Promotes reverse cholesterol transport

Cardiovascular Morbidity and Mortality benefits

HDL

?

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dalHDL

torcetrapib

CETP

HDL

• Dalcetrapib binds to CETP, inducing aconformational change of CETP1

• HDL generated is of normal composition

• Torcetrapib binding to CETP results in a highaffinity complex of torcetrapib, HDL and CETP2,3,4

• HDL generated is different from physiological

1 Okamoto et al. Nature. 2000;406:203–207; 2Niesor et al. Atheroslerosis. 2008;199:231;3 Clark et al. J. Lipid Res. 2006;47:537–552; 4Barter et al. N Engl J Med. 2007;357:2109–2122.

Dalcetrapib and torcetrapib

Different mechanisms of CETP inhibition

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• Patients with acute coronary syndrome and diabetes: at highest risk of recurring CV events

• Patients with ACS and diabetes are characterized by atherogenic dyslipidemia:

– Triglycerides ↑

– HDL ↓

– small, dense LDL ↑

– Apo-B ↑

RR=1.99 (1.52 -2.60)

RR=1.71 (1.44 - 2.04)

RR=1.00

RR=2.88 (2.37– 3.49)

Event rate

6 9 153 18 2112 24

Diabetes/CVD (n = 1148)

No Diabetes/CVD (n = 3503)

Diabetes/No CVD (n = 569)

No Diabetes/No CVD (n = 2796)

6 9 153 18 2112 24

Months

0.00

0.05

0.10

0.15

0.20

0.25

The true unmet medical need in type 2 diabetes is cardiovascular risk reduction

Malmberg K et al. Circulation 2000;102:1014-1019; Results of the OASIS(Organisation to Assess Strategies for Ischemic Syndromes) Registry

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Aleglitazar: Significant dose-dependent reduction in HbA1c and improvements in lipid profiles

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

LS m

ean

(SE

) ab

solu

te c

hang

e fr

om b

asel

ine

HbA

1c (

%)

Placebo

50 μg 150 μg 300 μg 600 μg

Aleglitazar Pioglitazone

45 mg

p<0.0001

p=0.048

P values vs. placebo.

p<0.0001p<0.0001

p<0.0001

Placebo

50 μg 150 μg 300 μg 600 μg

Aleglitazar Pioglitazone

45 mg

LS m

ean

(SE

) pe

rcen

t cha

nge

from

bas

elin

e tr

igly

cerid

es

p=0.0007

P<0.0001

p=0.006

P<0.0001P<0.0001-50

-40

-30

-20

-10

0

10

20

LS m

ean

(SE

) pe

rcen

t cha

nge

from

bas

elin

e H

DL-

C

p=0.001

p=0.031

p<0.0001

Placebo

50 μg 150 μg 300 μg 600 μg

Aleglitazar Pioglitazone

45 mg

p<0.0001 p<0.0001

0

5

10

15

20

25

30

Triglycerides HDL-C

LDL-C HbA1c

Robert R Henry, et al., Lancet 2009:374:126-35 all P values vs. placebo

-25

-20

-15

-10

-5

0

5

10

LS m

ean

(SE

) pe

rcen

t cha

nge

from

bas

elin

e LD

L-C

p=0.08

p=0.003p=0.012

p<0.0001

p=0.96

Placebo

50 ?g 150 ? g 300 ?g 600 ? g

Aleglitazar Pioglitazone

45 mg

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Patients

• Type 2 diabetes (known and recently diagnosed)

• Hospitalized for acute coronary syndrome

Primary endpoint• Composite endpoint of reduction in cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke (MACE)

Design

• Double-blind, placebo-controlled study on top of standard of care

• Treatment duration: At least 2.5 years

• N = 6,000

Treatment periodScreening/ placebo run-in period

Follow-up period

At least 2.5 years 4 weeks

Aleglitazar 150 µg or placebo

Standard of care (diabetes and other cardiovascular risk factors)

Aleglitazar development in patients with high CV risk

Phase III CV outcomes study: recruitment started Q1 2010

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Schizophrenia, a devastating disease

The clock stops when schizophrenia starts

• Average life expectancy ~20 years shorter

– Attributed to suicide andcardiovascular co-morbidities

• Patient faced with invalidility

– Loss of job, hobbies, friends

– Heavily dependent on support

– Poor insurance coverage in the US

• High burden for caregivers

– Isolation

– Loss of previous life, often job

– Depression and stress

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Features of schizophrenia syndrome

Heterogeneity requires specific treatment of symptoms

Social Dysfunction• Work

• Interpersonal relationships

• Self-care

Positive Symptoms

• Delusions

• Hallucinations

• Disorganized speech

• Catatonia

Primary Negative Symptoms

• Affective flattening

• Alogia

• Avolition

• Anhedonia

• Social withdrawal

Cognitive Deficits

• Attention

• Memory

• Executive functions(eg, abstraction)

Comorbid Substance Abuse

Mood Symptoms

• Depression

• Hopelessness

• Suicidality

• Anxiety

• Agitation

• Hostility

• InsomniaMaguire GA. Am J Health-Syst Pharm. 2002;59:S4-S11.

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GlyT-1 inh. phase II data in schizophreniaPrimary endpoint: PANSS negative symptom factor score

-7

-6

-5

-4

-3

-2

-1

0

Placebo GlyT-1

-5.11

-6.45

�� ��Im

provement

ITT Population

-7

-6

-5

-4

-3

-2

-1

0

Placebo GlyT-1

-4.86

-6.50 *

�� ��Im

provement

p < 0.05

Per-Protocol Population

Three doses were tested in Phase II – data shown is for the most effective dose

p = 0.07

Change from Baseline at Week 8

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Strong late-stage portfolio of NMEs

Limited risk due to rigorous proof of concept studies

Probability of technical success

Peak sales

CHF 2 bn

0% 50% 100%

aleglitazarocrelizumab MS*

GlyT-1 inhGA101

pertuzumabtaspoglutide

T-DM1

BRAF inh (Melanoma)Hedgehog inh (BCC)

CHF 5 bn

dalcetrapib

T-DM1 (early launch)

* Phase III “go/no go” decision pending

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Changing the practice of medicine!

Improve outcomes in cardiovascular disease (taspoglutide, aleglitazar, dalcetrapib)

New therapies for Schizophrenia and MS (GlyT-1 inh. and ocrelizumab)

Better therapies for cancer (antibody drug conjugates, glycoengineered Abs-GA101, pertuzumab, BRAF and hedgehog inhibitors)

Prevent blindness with Lucentis(AMD, RVO and DME)

Launch at least 6 new products (NMEs) by end 201435 Line extensions of existing products could be filed by end 2014

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