Scientific Excellence Transforming
Medical Treatment
Genentech Research and Early Development as
an Experiment in R&D Productivity
Karl Mahler - Head of Investor Relations
Sean Bohen - Senior Vice President, Genentech Early Development
© 2012, Genentech / Proprietary information — Please do not copy, distribute or use without prior written consent
Roche Group
2
An innovation network
Academia &
industry
Independent centers for research
and early development
Over 150
partners
gRED
Global Product
Development
pRED
Manufacturing
Chugai
Roche Diagnostics
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Worldwide execution
Commercialisation
R&D productivity of Pharma industry
3
Output relatively flat, while R&D costs have increased
Industry R&D spend (US$ bn)
# NMEs approved
60
55
50
50
45
40
40
35
# New Molecular Entities (NMEs)
(lagging 5 year average)
30
30
25
20
20
15
10
10
5
R&D spend
0
0
70
72
74
76
78
80
82
84
86
88
90
92
94
96
98
00
02
04
06
08
10
Notes: R&D spend figures may not include overhead components as reported in company annual reports
Source:. NME data for 1966-1971 from Peltzman, S. (1973) J. of Political Economy 81, no. 5: 1049–91. NME data for 1972-1979 as reported in Hutt, P.B.
(1982) Health Affairs 1(2) 6-24. NME Data for 1980-2007 from Parexel’s Pharma R&D Statistical Sourcebook 2009/2010, FDA, and PhRMA. Industry R&D
spend data from PhRMA Annual Membership Survey, 2008 and Parexel 2009/2010
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Excellence in science leveraged to reduce attrition
Industry success rate 2005-2009
Research Phase 0
Phase 1
Phase 2
Phase 3 Registration
Launch
• Understanding of disease biology
Probability
of success
-
64%
48%
Industry:
Roche:
25%
67%
83%
ð
4%
4%
9%
• Leveraging Personalized Healthcare stratify patient population early on
• Rigorous decision making –
transition only most promising projects
Major decision points
Source: Industry success rates - Linda Martin, KMR, Bernstein R&D conference 2011, Roche – publicly available data, BCG analysis
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R&D allocation: qualitative and quantitative factors
Late Stage Development
Research & Early Development
Top down
Late Stage Development
Project driven
• Annual budget allocation
• Unmet medical need
• Number of phase II transitions
• Market potential
• Efficient development
• Probability of technical success
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Personalized Healthcare: benefit for all
Today
6
Benefit from patient stratification
Future
Time to
market
Faster
penetration
Reduced
Patient pool
Lower
development
costs
Increased
market
share
Price
increase
/stability
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Genentech’s legacy
7
Founded in 1976 by professor Herb Boyer
and entrepreneur Bob Swanson based on
the idea of using recombinant DNA
technology to create therapeutic proteins –
novel and unproven technology at the time
“I also wanted to bring in scientists that were outstanding and have them
have an opportunity to establish their own reputation, get their own
recognition. So we tried to set up an atmosphere which would take the
best from industry and the best from the academic community, and put
them together” – Herb Boyer, Boyer oral history, 1994, 87
Genentech – Genetic engineering technology
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Cultivating Scientific Excellence: awards and recognitions
Richard Scheller, Ph.D.
Kavil Prize in Neuroscience, 2010
Art Levinson, Ph.D.
Foti Award, 2011
Apple Chairman of the board, 2011
Ira Mellman, Ph.D.
National Academy of Sciences
Membership, 2011
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Napoleon Ferrara, Ph.D.
Dr. Paul Janssen Award for
Biomedical Research, 2011
Vishva Dixit, M.D.
American Academy of Arts &
Sciences membership, 2011
Robert Gentleman, Ph.D.
American Statistical Association,
Statistical computing and graphics
award, 2010
8
gRED Exploratory Clinical Development and Development Sciences:
The People
Scientific expertise to translate research data
into development plans appropriate for each NME
Oncology and ITGR ECD
Education
Disease Expertise
23 Oncologists or Heme/Onc
1
Pulmonologist
1
Rheumatologist
18 MD, PhD
2
Cardiologists
1
MD, MPH, MS
2
Allergy/Immunology
1
MD, MS
2
Infectious Disease
17 MD
2
Neurologist
12 PhD
1
Ophthalmologist
1
Psychiatrist
1
Endocrinologist
1
Clinical Pharmacologist
Development Sciences: 130 doctorates and 34 Masters degrees in a group of 370 people
ITGR – Immunology, Tissue Growth and Repair; ECD – Early Clinical Development
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9
Genentech publications and patents: an external measure of
Scientific Excellence
10
Genentech publications
600
Total
120
Cell, Science, Nature
479
500
400
243 235
303
280 284 289 272 288
253
100
16
3
41
7
63
8
90 100
16
16
80
306
285 291 292
248
222
183
200
0
406
376
300
100
204
165
133
60
205 205
180 193 166
40
114
20
22
19
29
16
22
12
12
10
16
11
12
8
7
7
6
10
4
3
4
9
4
9
10
7
11
17
12
1
0
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012
12 papers were published in Cell, Science and
Nature in 2011
US patents issued to Genentech in the last 10
years
275
300
221
200
100
137
70
76
74
67
70
1
2
3
4
5
85
123
79
0
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7
8
9
10
11
gRED Portfolio governance
11
Research Review Committee (RRC)
• Sponsor: Richard Scheller, Ph.D.
• Alternate Chairs:
Early Stage Portfolio Committee (ESPC)
• Sponsor: Richard Scheller, Ph.D.
• Alternate Chairs:
• Andy Chan, M.D., Ph.D.
• Ira Mellman, Ph.D.
Decision
Points
Phase
• Sean Bohen, M.D., Ph.D.
• Mike Varney, Ph.D.
ESR
LSR
ED
ED
Phase 1
Phase 2
LIP
Go
Go
Ready
Go
Go
Go
ready
Phase 1
Phase 2
Discovery
Early Stage
Late Stage
Early
Research
Research
Research
Development
Governance
ESPC
LSPC / CEC
DRC
Late Stage
DRC
Test diagnostic hypothesis
Stratify/
validate
RRC
Scientific
review
Diagnostics
Formulate diagnostic hypothesis
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Phase 3
Our approach to drug development
Understanding disease biology is key
Homogeneous diseases
• Defined underlying molecular defects manifesting in a unique set of symptoms
• Example: Erivedge in Basal Cell Carcinoma (BCC)
Heterogeneous diseases
• The majority of diseases caused by multiple defects that manifest as similar
clinical syndromes. Currently, we classify and attempt to treat them as a single,
homogeneous disease
• Example: Lebrikizumab in Asthma
We strive to characterize the dominant causal factors in subsets of a heterogeneous
disease and tailor the treatment to this well-defined subset
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12
Our approach to drug development
Develop best in disease treatments
• Decisions are guided by a “Best in Disease” Target Product Profile
• Design early clinical studies with ambitious endpoints – efficacy can often
be assessed early with a high bar
• For the heterogeneous diseases, Phase 2 studies are designed to show
remarkable efficacy in a target subpopulation – this sometimes requires
larger trials
• Technical review of new internal and external data occurs throughout the
development process to identify potential issues, reassess probability of
success, and modify the development strategy as appropriate
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Our approach to drug discovery
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Understanding disease biology
Homogeneous disease – Basal Cell Carcinoma
Cause: 90% of all BCCs have abnormal hedgehog pathway signaling
Week 16 - no BCC on biopsy
Baseline
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Week 8
Week 20
Our approach to drug discovery
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Understanding disease biology
Heterogeneous disease - Asthma
Histology
Bronchoalveolar
lavage
cell counts
Transcriptome
of epithelial
brushings
Transcriptome
of bronchial
biopsies
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Identification of two distinct asthma subgroups
IL-13 induced genes in epithelial brushings
asthmatics
May be responsive
to lebrikizumab (anti-IL13)
asthmatics & controls
May NOT be responsive to
lebrikizumab (anti-IL13)
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Subpopulation of patients derives significantly better benefit from
treatment
Results of the proof-of-concept Phase 2 study*
PERIOSTIN HIGH SUBJECTS ONLY
PERIOSTIN LOW SUBJECTS ONLY
Time (Weeks)
Time (Weeks)
% Change FEV1
ALL EFFICACY EVALUABLE SUBJECTS
Time (Weeks)
Relative Mean FEV1 change at week 12
Total ITT
population
Periostin High
Periostin
Low
Placebo
4.3%
5.8%
3.5%
Lebrikizumab
9.8%
14.0%
5.1%
5.5%
(p=0.02)
8.2%
(p=0.03)
1.6%
(p=0.61)
Difference
Incorporation of the diagnostic hypothesis doubled the number of projects
transitioning to the late stage development in the past 3 years
*Corren et al. NEJM, 2011
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75% of gRED molecules are being developed with companion
diagnostics (CDx)
Early Development
Phase 1
Phase 2
NME 1
AKT Inhibitor (GDC-0068)
Anti-EGFL7
NME 2
Anti-PD-L1 MAb
PI3K Inhibitor (GDC-0941)
NME 3
Anti-HER3/EGFR DAF
PI3K/mTOR (GDC-0980)
NME 4
MEK Inhibitor (GDC-0623)
Rontalizumab (Anti-INF alpha)
NME 5
MEK Inhibitor (GDC-0973)
Anti-LT alpha
Bcl-2 Inhibitor (GDC-0199)
Anti-M1 prime
ChK1 Inhibitor (GDC-0425)
Etrolizumab (rhuMAb beta 7)
PI3K Inhibitor (GDC-0032)
Anti-factor D
NME 6
Crenezumab (Anti-Abeta)
Anti-CD22 vcMMAE ADC
Anti-oxLDL
NME 7 ADC
NME 8 ADC
NME 9 ADC
NME 10 ADC
NME 11 ADC
NME 12 ADC
NME 13 ADC
Anti-IL-17 MAb
NME 12
NME 13
Status as of March 31, 2012
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Project with CDx
Project without CDx
RTD - Roche Tissue Diagnostics/Ventana
RMD - Roche Molecular Diagnostics
RPD - Roche Professional Diagnostics
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ADCs: New generation of anti-cancer drugs building on T-DM1
Phase 2 study TDM4450g: T-DM1 vs. Herceptin +
docetaxel in HER2+ breast cancer*
T-DM1 significantly improves PFS
Proportion progression-free
Antibody
targeted to
tumor antigen
Linker stable
in circulation
Very potent
Chemotherapeutic
drug
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Median Hazard Log-rank
PFS, mos ratio P value
1.0
T+D
0.8
T-DM1
9.2
14.2
0.594
0.0353
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
18
Duration of objective response (months)
Greater therapeutic window
Chemo
ADCs
Phase 3 study EMILIA: T-DM1 vs. Xeloda + lapatinib in
HER2+ breast cancer
• First randomized Phase 3 trial to demonstrate efficacy of
T-DM1 in significantly extending PFS in breast cancer
Toxic dose
• Data submitted for presentation at ASCO 2012
• Provides a proof-of concept for our extensive ADC
portfolio
*Hurvitz SA, et al. Abstract 5.001. ESMO 2011
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gRED Development Portfolio: 35 molecules from Early Development
to Phase 2
Early Development
Phase 1
Phase 2
NME 1
AKT Inhibitor (GDC-0068)
Anti-EGFL7
NME 2
Anti-PD-L1 MAb
PI3K Inhibitor (GDC-0941)
NME 3
Anti-HER3/EGFR DAF
PI3K/mTOR (GDC-0980)
NME 4
MEK Inhibitor (GDC-0623)
Rontalizumab (Anti-INF alpha)
NME 5
MEK Inhibitor (GDC-0973)
Anti-LT alpha
Bcl-2 Inhibitor (GDC-0199)
Anti-M1 prime
ChK1 Inhibitor (GDC-0425)
Etrolizumab (rhuMAb beta 7)
PI3K Inhibitor (GDC-0032)
Anti-factor D
NME 6
Crenezumab (Anti-Abeta)
Anti-CD22 vcMMAE ADC
Anti-oxLDL
NME 7 ADC
NME 8 ADC
NME 9 ADC
NME 10 ADC
Oncology
Immunology
Neuroscience and Ophthalmology
NME 11 ADC
NME 12 ADC
NME 13 ADC
Anti-IL-17 MAb
NME 12
NME 13
Status as of March 31, 2012
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Metabolism
Infectious Diseases
20
Antibody drug conjugate (NME ADC)
21
Evidence of activity in ovarian cancer
• 60 year old woman with platinum-resistant ovarian cancer who progressed
through 7 prior therapies was given our novel antibody drug conjugate
• Confirmed partial response after four cycles with an overall 51% reduction
in target lesions including the disappearance of some masses
• No treatment related adverse events have been reported for this patient.
She continues to be able to work, now in the middle of cycle 10
Predose
Post cycle 2 dose
Post cycle 2 dose
Zoom
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Antibody drug conjugate (NME ADC)
Evidence of activity in ovarian cancer
Predose
Post cycle 2
dose
Predose
Post cycle 2
dose
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Summary
• gRED continues to operate on the founding principles of Genentech –
maintain an environment where talented researchers and physicians create
innovative medicines, guided by science
• We invest in understanding the heterogeneity and underlying causes of
disease to target treatments to the appropriate patients
• We set a high bar for moving forward in development and assess efficacy
early
• By incorporating a diagnostic hypothesis early in development, we increase
the success rate
• We have expanded beyond oncology and are exploring new technologies
(ADCs, bispecific antibodies, DAFs) and treatment regimens (novel
combinations) to bring more effective treatments to patients
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