Jean-Jacques Garaud, MD Global Head Pharma ... - Roche

Clinical Development at Roche: Driving the paradigm shift
Jean-Jacques Garaud, MD
Global Head Pharma Development, Chief Medical Officer Roche
UBS Global Life Science Conference, New York, September 22, 2008

This presentation contains certain forward-looking statements. These forward-looking statements
may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’,
‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy,
goals, plans or intentions. Various factors may cause actual results to differ materially in the future
from those reflected in forward-looking statements contained in this presentation, among others:
1 pricing and product initiatives of competitors;
2 legislative and regulatory developments and economic conditions;
3 delay or inability in obtaining regulatory approvals or bringing products to market;
4 fluctuations in currency exchange rates and general financial market conditions;
5 uncertainties in the discovery, development or marketing of new products or new uses of existing products,
including without limitation negative results of clinical trials or research projects, unexpected side-effects of
pipeline or marketed products;
6 increased government pricing pressures;
7 interruptions in production
8 loss of or inability to obtain adequate protection for intellectual property rights;
9 litigation;
10 loss of key executives or other employees; and
11 adverse publicity and news coverage.
Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean
that Roche’s earnings or earnings per share for this year or any subsequent period will necessarily match or
exceed the historical published earnings or earnings per share of Roche.
For marketed products discussed in this presentation, please see full prescribing information on our website –
www.roche.com
All mentioned trademarks are legally protected
2

Our new R&D model: Paradigm changes
Genentech offer – Development perspective
Franchises and assets
Summary
3

New R&D model
Innovation truly at its core
Translational Medicine
Customized /original design
System Biology
Understanding complexity
Innovation
Modeling and Simulation
Driving decision-making
process
Biomarkers
Relevant tools
4

Biomarkers
A central element throughout the life cycle of a medicine
• Biomarkers are critical for translational medicine,
exploratory and confirmatory development strategies
- Improved decision making in R&D (e.g. tools
for profiling targets, compounds, PD Markers)
- Understanding pathways and mechanisms
(e.g. pt. subpopulations, optimized patient
stratification)
- Drivers for pharmacodiagnostic development
e.g. increased benefit/risk ratio, companion
diagnostics)
• Biomarkers are a central element throughout the
lifecycle of a medicine from target ID to market
5

Development does never stop
Continuous with integration of biomarkers across development
More Internal
Innovation
Research Development Marketing
Discovery
Phase
Exploratory Phase
Biomarker Development
Learning (reducing uncertainty)
Clinical Research & Exploratory Development
PoC
Modeling & Simulation
Confirmatory Phase
Confirming
Clinical Development
Biostatistics
Co-Develop with Diagnostics
Biomathematics
6

Our new R&D model: Paradigm changes
Genentech offer – Development perspective
Franchises and assets
Summary
7

Key objectives of combining Genentech and Roche
…building a leading organization
Research and Early
Development
Late
Development
Manufacturing
Commercial
Admin &
other
Enhance innovation
• Allow diversity of
approaches in research
• Encourage sharing of IP,
technologies, networks etc.
• Post 2015 partnership
Improve operational efficiency
• Reduce complexity
• Eliminate duplications
• Leverage combined scale in the
US and globally
8

Enhance innovation
…by maintaining diversity of approaches
Genentech:
• Keep Founders Research Center independent
Oncology
Inflammation
Inflammation CNS
+ …
Oncology
Inflammation
Inflammation CNS
Virology*
Metabolism
Roche:
• Keep existing Disease Biology Area (DBA)
model
• Transfer Palo Alto activities:
• Virology DBA to South San Francisco
• Inflammation DBA to Nutley
• No changes outside the US
* Located on Genentech site in South San Francisco
9

Our new R&D model: Paradigm changes
Genentech offer – Development perspective
Franchises and assets
Summary
10

Roche Pharma pipeline overview
Focused on five Disease Biology Areas
Oncology
Xeloda
MabThera
Herceptin
Avastin
Tarceva
Pertuzumab
T-DM1
R1507 (IGF-1R mAb)
Apomab
Apo2L/TRAIL
Anti-CD40 mAb
Hedgehog antagonist
18 phase I compounds
On Hand
RA/Inflammation
MabThera
Actemra
R1594 ocrelizumab
R667 RARg
9 phase I compounds
Metabolic
R1658 CETP Inh.
R1583 GLP-1
R1439 dual PPAR
9 phase I compounds
Promising Late
Stage
Virology
Pegasys
Tamiflu
R3484 HPV16
R1626 HCV pol. Inh.
R7128 HCV pol. Inh.
R7227 HCV prot. inh.
Emerging
Mid-Term
CNS
ocrelizumab RRMS
R1678 Schizophrenia
R3487 Alzheimer’s
3 phase I compounds
Early
Stage
11

Key drivers for long term development in place
Develop the short term drivers while not ‘leaving ‘ the others
Inherent development risk
Low High
ILLUSTRATIVE
Oncology
Inflammation
existing
Earlier Phases
Maturity of portfolio
Virology
CNS
Metabolic
12

Major Roche-managed oncology submissions
Industry-leading oncology pipeline
Avastin
mBC + standard chem (EU)
Herceptin
gastric Ca (EU)
Phase 3
Avastin
mBC + docetaxel (EU)
Avastin
glioblastoma 2nd line (EU)
MabThera
CLL (EU)
Tarceva
NSCLC 1 st line maint (EU)
Tarceva + Avastin
NSCLC 1 st line maint (EU)
Xeloda
adj BC
Avastin
adj CC (EU)
Avastin
gastric Ca metastatic (EU)
Avastin
ovarian Ca (EU)
Avastin
prostate Ca (EU)
Avastin+Herceptin
mBC 1st line (EU)
MabThera
iNHL maint 1 st line (EU)
Avastin
HER2- adj BC (EU)
Avastin
adj mBC Her 2+(EU)
Avastin
adj NSCLC (EU)
Tarceva+Avastin
NSCLC 2nd line (EU)
Xeloda
adj CC combo oxaliplatin
Xeloda+Avastin
adj CC (EU)
pertuzumab (R1273)
HER 2+ mBC (EU)
MabThera+Avastin
aggressive NHL (EU)
Tarceva
adj NSCLC (EU)
2008 2009 2010 2011 post 2011
Phase 2
Avastin
glioblastoma 1st line (EU)
Avastin
NSCLC squamous (EU)
IGF-1R inh huMAb(R1507)
Ewing’s sarcoma
pertuzumab (R1273)
early BC (EU)
Tarceva+Avastin
NSCLC 1 st line (EU)
TDM1 (R3502)
mBC (EU)
Status as of June 30, 2008
Unless stated otherwise, submissions will occur in US and EU
13

Avastin still early in its journey
Realising full potential across tumour types
Tumour
Early/adjuvant
(Potential for cure)
Advanced/metastatic
(Extending life)
1 st -line of treatment 2 nd -line of treatment
Colon,
colorectal
Phase III
(AVANT, NSABP C-08)
Launched
[EU, US, JP; broad label in 1st and subsequent lines]
Lung
(NSCLC)
Phase III
(E1505)
Launched
[EU majority of chemos,
US carboplatin/paclitaxel]
Phase III
(BETA Lung w/Tarceva)
Breast
(HER2-)
Phase III
(BEATRICE, E5103)
Launched [EU, US w/paclitaxel]
Phase III (RIBBON-1)
Phase III
(RIBBON-2, incl. w/Xeloda)
Breast
(HER2+)
Phase III
(BETH w/Herceptin)
Phase III
(AVEREL w/Herceptin)
–
Kidney
(RCC)
–
Launched
[EU; with interferon]
Avastin also tested in gastric, ovarian and prostate cancer, aNHL, and brain (GBM)
14
(Trial names) [Approval status]. More trials are ongoing than listed above.

Avastin and cetuximab in combination with
irinotecan-based regimen
Study Regimen PFS
Study arm
Crystal Folfiri +/- Cetuximab
PFS
control
Benefit
(detriment)
ITT 8.9 8.0 0.9 0.85 0.0479
K-Ras WT 9.9 8.7 1.2 0.68 0.0167
K-Ras mut 7.6 8.1 -0.5 1.07 0.75
AVF 2107
IFL +/- Avastin
ITT 10.6 6.2 4.4 0.54 0.001
K-Ras WT 13.5 7.4 6.1 0.44 0.0001
K-Ras mut 9.3 5.5 3.8 0.41 0.0008
HR
p
15

Avastin in 1st line mCRC: the only biologic with
significant survival benefit
Study Regimen OS
Study arm
Crystal Folfiri +/- Cetuximab
OS
control
Benefit
(detriment)
ITT 19.9 18.6 1.3 0.93 0.30
K-Ras WT 24.9 21.0 3.9 0.84 0.22
AVF 2107
IFL+/-Avastin
ITT 20.3 15.6 4.7 0.66

Avastin and cetuximab in combination with
oxaliplatin-based regimen
Study Regimen PFS
Study arm
Opus Folfox +/- Cetuximab
PFS
control
Benefit
(detriment)
ITT 7.2 7.2 0 0.93 0.62
K-RAS WT 7.7 7.2 0.5 0.57 0.016
K-Ras mut 5.5 8.6 -3.1 1.83 0.019
Cairo 2
Xelox-Avastin +/- Cetuximab
ITT 9.6 10.7 -1.1 1.21 0.018
K-Ras WT 10.1 10.7 -0.6 na 0.1
K-Ras mut 8.6 12.5 -3.9 na 0.043
HR
p
17

Avastin in Refractory Glioblastoma Multiforme (GBM)
High unmet medical need
Lesion
Screening Week 12 Week 24
• Incident Primary Brain Tumors population in line with mRCC
– 20,000 incident patients in top 5 EU countries (mRCC: 17,000)
• Phase II data demonstrated encouraging six-month PFS and ORR in patients with relapsed
GBM, exceeding historical estimates of 15%
• Avastin in relapsed GBM ph. II data on track to be filed by end 2008
• Phase III in first-line Glioblastoma in preparation
T. F. Cloughesy et al., ASCO 2008, abstract 2010b (Monday)
18

Attacking the HER2 pathway from multiple angles
Pertuzumab and Trastuzumab-DM1 moving forward
Herceptin
Pertuzumab
Trastuzumab-DM1
Mechanism
Specifically targeting
HER2
Inhibits HER2-mediated
signalling
First in class HER
dimerization inhibitor
Inhibits multiple HERmediated
pathways
Binds to HER2 and
delivers intracellularly
a potent cytotoxic
agent in a targeted
manner
Phase of
development
Approved for adjuvant
and mBC (HER2+)
Phase III in 1st line
mBC (CLEOPATRA)
FPI Q1 2008
Phase II FPI Q3 2007
Efficacy data
Survival benefit
In adjuvant and
metastatic
HER2+ BC
Ph. II data at ASCO ‘08
ORR: 24%
Clinical benefit rate:
50%
Promising phase I
data at ASCO 2008
Clinical benefit rate:
53%
Newsflow
Unprecedented benefit
– standard of care
Phase III in 1st line
mBC ongoing
First ph.II data at
ASCO BC 2008
19

Exciting mid- and early-stage opportunities in oncology
IGF1-R Inhibitor – Impressive early results
Potential broad use in cancer therapy
3rd generation anti-CD20
Potential for improvement over MabThera
Increased direct cell death
Increased ADCC
Lower CDC
Restaging Week 6
Unique Features: Selective to IGF pathway
which is a key factor in tumor growth
Drivers of Value: IGF pathway linked to many
tumor types
Phase I in NHL
Unique Features: fully humanized MAb
recognizing type II CD 20 epitope
Drivers of Value: superior to rituximab in vitro
and in pre-clinical models
Phase II ongoing
Phase I data at ASH
ADCC= (antibody dependent cell-mediated cytotoxicity); CDC= (complement dependent cytotoxicity)
20

Implementing biomarker strategy for all pipeline drugs
Oncology leads the way
Ph I / II
Ph III / Market
IGF-1R mAb
(R1507)
• Range of candidate
markers
Herceptin
• HER2 expression
• HER2 gene amplification
MDM2 antag
(R7112)
• P53 wild-type
Avastin
• Range of candidate
markers for investigation
PLX4032
(R7204)
T-DM1
(R3502)
• BRAF V600E gene
mutation
• HER2 expression
•HER2gene
amplification
Pertuzumab
Tarceva
• Range of candidate
markers for investigation
• EGFR expression (IHC)
• EGFR gene copy # (FISH)
•EGFRmutations
• KRAS mutations
Prospectively assessing opportunities
for patient selection
Identifying patients who have an improved
clinical benefit to launched drugs
21

Oncology: Major newsflow expected in H2 2008
MabThera in relapsed CLL: REACH
Randomized ph. III, 552 patients
Fludarabine+cyclophosphamide
+/-MabThera
Avastin in 1st line mBC: RIBBON-1
Phase III study, 1200 patients, 2 analyses:
Anthracycline-/taxane-based +/- Avastin,
and Xeloda +/- Avastin
Expect data H2 ‘08
Expect topline data H2 ‘08
Tarceva+Avastin in 2nd line NSCLC:
BETA lung
Tarceva+/-Avastin
Enrollment completed Q2 ’08
Potentially label-enabling for Avastin
Expect topline data H2 ‘08
Tarceva 1st line maintenance NSCLC:
SATURN
4 chemo cycles followed by T vs. placebo
Enrollment completed Q2 ‘08
Potentially label-enabling for Tarceva
Expect topline data H2 ‘08
22

Key drivers for long term development in place
Develop the short term drivers while not ‘leaving ‘ the others
Inherent development risk
Low High
ILLUSTRATIVE
Oncology
Inflammation
existing
Earlier Phases
Maturity of portfolio
Virology
CNS
Metabolic
23

Rheumatoid Arthritis: Not all patients respond to
current therapy
Gold standard therapy
anti-TNF + MTX
% ACR70 Responders
Unmet Medical Need
Only 1 of 3 patients receives
significant benefit
anti-TNF + MTX
anti-TNF alone
ACR 70=70% Improvement in:
MTX alone
Disease activity – patient
Disease activity – physician
Patient assessment of Pain
Physical disability
Acute phase reactants – CRP,ESR
24

Actemra: The first IL-6 receptor inhibitor
Unprecedented level of remission in moderate to severe
patients with RA
mIL-6R
Tocilizumab
gp130
mIL-6R
• Largest clinical programme of any biologic for RA
• Consistently high & durable remission rates - across
different disease stages
• Rapid treatment response - as early as 2 weeks
New data presented at EULAR 2008:
• RADIATE: Rapid and significant improvements in
patients who have failed up to 3 anti-TNF inhibitors 1
• AMBITION: Only biologic to have demonstrated
superiority vs. methotrexate as monotherapy 2
Filed in US & EU Nov ‘07 (RA)
Approved in Japan Apr ‘08 (RA, sJIA, pJIA)
1 Emery et al., EULAR 2008, Abstract OP-0251 2 Jones et al., EULAR 2008, Abstract OP-0131
25

Key drivers for long term development in place
Develop the short term drivers while not ‘leaving ‘ the others
Inherent development risk
Low High
ILLUSTRATIVE
Oncology
Inflammation
existing
Earlier Phases
Maturity of portfolio
Virology
CNS
Metabolic
26

CETP Inhibitor
R1658 is a unique CETPi
• In contrast to the majority of other CETPi, R1658 has a different chemical backbone to
Torcetrapib
• In patients treated with R1658, HDL is of normal composition
• In pre-clinical models and in clinical trials up to phase II, data showed that R1658 at
therapeutic doses had a similar safety profile to placebo, including effects on blood
pressure and RAAS activation
R1658 (Dalcetrapib)
Torcetrapib
F
F
F
F
H
N
S
O
F
F
F
O
O
N
F
O
F
N
O
O
27

Relationship Between Changes in
LDL-C and HDL-C Levels and CHD Risk
1% decrease
in LDL-C reduces
CHD risk by 1%
1% increase
in HDL-C reduces
CHD risk by 1%
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001.
Large mortality and morbidity study running
• Only true evaluation of the CV benefits of raising HDL-C by CETPi
• R1658 is being investigated to reduce CV risk on top of current recommended standard of
care for CV risk factors
• Currently the only route to approval of CETPi
28

Taspoglutide: investigational once-weekly GLP-1 analogue
for the treatment of type-II diabetes
• Significantly reduces blood glucose over only eight weeks
• Provides substantial weight loss in a dose-response fashion
• Additional titration study confirmed the safety and tolerability of taspoglutide
• Efficacy, safety and tolerability profile encouraging
• Phase III recruitment started in Q3 2008
Taspoglutide (R1583) has the potential
to be the first once weekly, long-acting human GLP-1 analogue
29

Key drivers for long term development in place
Develop the short term drivers while not ‘leaving ‘ the others
Inherent development risk
Low High
ILLUSTRATIVE
Oncology
Inflammation
existing
Earlier Phases
Maturity of portfolio
Virology
CNS
Metabolic
30

CD20 targeting: new treatment strategy for MS
Very promising signals from Phase II with rituximab
• Total cumulative mean number of
gadolinium lesions was reduced by 91
%, p

Our new R&D model: Paradigm changes
Genentech offer – Development perspective
Franchises and assets
Summary
32

Roche R&D opportunities in summary
• Innovation-driven business focused on differentiated products that add medical
value
• Network approach to foster innovation and build on our core business
• Leverage combination of Pharmaceuticals and Diagnostics in-house to develop
more targeted treatment options (personalised healthcare)
• Numerous short- and mid-term drivers of growth with low development risk
• Broad pipeline for long-term sustainable growth
Our unique strategy provides Roche
with a competitive edge for sustainable outperformance
33

We Innovate Healthcare
34

Avastin’s position as standard of care in first-line
mCRC and mNSCLC remains unchallenged
Avastin in 1st line and 2nd line mCRC: the only biologic with significant survival benefit
• Avastin: only biologic with a statistically significant overall survival (OS) benefit in 1st line and
2nd line mCRC
• Avastin: only biologic offering a progression-free survival (PFS) benefit regardless of
mutations in K-Ras gene
• Avastin: only biologic with a statistically significant OS benefit in K-Ras wild-type patients
Avastin remains the best option for the majority of patients with mNSCLC
• E2100 and AVAIL: Robustness and consistency of data across endpoints in two phase III
studies
• The longest median overall survival in first-line non-squamous mNSCLC
• ARIES and SAiL data presented at ASCO ‘08 further establish safety / tolerability and broad
applicability for non-squamous mNSCLC
35

Avastin in 2nd line mCRC: the only biologic with
significant survival benefit
Study Regimen OS
Study arm
Epic Irinotecan +/- Cetuximab
OS
control
Benefit
(detriment)
ITT 10.71 9.99 0.7 0.98 0.712
K-Ras WT 10.94 11.56 -0.6 1.28 na
E 3200
FOLFOX+/-Avastin
ITT 12.9 10.8 2.1 0.75 0.001
HR
p
36