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7/22/2019 Roche ptresentation
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Roche late-stage pipeline update III
London, 1 October 2013
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2
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 existingproducts, 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 interpretedto mean that Roches earnings or earnings per share for this year or any subsequent period willnecessarily 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
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3
Roche late-stage pipeline update III
Agenda
14:30-14:35 Opening remarks
Karl Mahler, Head of Investor Relations
14:35-14:40 Introduction
Alan Hippe, CFO
14:40-15:45 Late-stage pipeline update III
Hal Barron, MD Global Development and Chief Medical Officer
15:45-16:15 Q&A
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Strong progress in non-oncology assets
4
Actemra
Immunology/
Ophthalmology
2 phase II
lebrikizumab
bitopertin
Neuroscience
ocrelizumab MS
lampalizumab2
Phase II
4 phase II
etrolizumab1
gantenerumab
1 FPI expected 1H 2014; 2 Phase III decision pending
20132009
4 phase II
Actemra
Rituxan/MabThera RA
Xolair
Lucentis
ocrelizumab RA
4 phase II
Phase III
Launched
Rituxan/MabThera RA
Xolair
Lucentis
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Innovation-driven resource allocation
Alan Hippe, Roche CFO
5
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6
Roche strategy: Focused on medically
differentiated therapies
Generics
Differentiation
MedTech
OTCPremiumfo
rinnovation
DiaPharma
Focus
Regulators:
Optimised benefit / risk ratio
Payors:
Optimised benefit / cost ratio
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Pharma market drivers and constraints
Balance of these factors will determine future growth
Major advances in science and medicine Growth and aging of world population
Increasing wealth and access (in Emerging Markets)
Patent expirations
Global economic slowdown
- Slower expansion of budgets in emerging markets- Increased pricing hurdles in developed world
7
2
1
3
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Innovation through patient stratification
Benefit for all stake holders, including the industry
Today Future
ReducedPatient pool
Higherprobabilityof success
Pricingpower
Lower
developmentcosts
Increasedmarket
share
Time tomarket
Benefit from patient stratification
8
1
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Access becoming more important
Need for tailored systems
Pack based pricing Value based pricing
Need for patient based information
Undifferentiated
$$ by vial
Today Future
Combinations
Indication based
+
Episode-of-carebased
Business challenge Moving towards value based pricing
Ensure access while rewarding value
Multiple indications and combinations
9
2
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7%
6%
5%
6%
5%
3%2%
1%
-1%
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Economies and pricing/access
Important value drivers for Pharma outlook
Example: Pharma market growth in Europe
High GDP growth: increasing pharma spend GDP challenges: austerity measures Stabilized environment?
Source: IMS
Limits to public access will
continue
Recognition and rewards for
innovation
10
3
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R&D allocation
Mix of qualitative and quantitative factors
Research & Early Development Late Stage Development
Top down Project driven
Annual budget allocation
Ensure expertise in the field
Plausibility of scientific hypotheses
Market potential
Efficient development
Probability of technical success
11
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Roche: R&D well balanced from a risk & disease
point of view
12Source: Bernstein Equity Research, Tufts University and Roche analysis
Industry average probability of success Phase I to Registration
Oncology
Virology
CNS
0% 5% 10% 15% 20% 25% 30%
Inflammation
Metabolism
Roche budgettrends
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Where science takes us
13
MabThera
Xeloda
Herceptin
Perjeta
anti-PDL1
MetMab
Kadcyla
Oncology
Avastin
BCL2i
10 phase II
GA101
Immunology/
Inflammation
2 phase II
lebrikizumab
bitopertin
Neuroscience
ocrelizumab
Strong and growing Strongly emerging Earlier stage
lampalizumab2
9 drugs launched
5 Phase III
4 drugs launched
1 Phase III
4 phase II
etrolizumab1 gantenerumab
3 Phase III
Tarceva
ZelborafErivedge
1 FPI expected 1H 2014; 2 Phase III decision pending
Launched
Phase III
Phase II
cobimetinib (MEKi)
Actemra
Rituxan/MabThera RA
Xolair
Lucentis
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Focus on innovation and growth
1
2 Growth facilitated by tailored access models
3 Leading product pipeline providing value for the future
Strategic focus on innovation and driving Personalised
Healthcare
14
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We follow the science
Hal Barron, MDGlobal Development and Chief Medical Officer
15
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Oncology drug development
Understanding of tumour biology is expanding
16
Example of melanoma
1975 1995 2010
Immunotherapy
2011
BRAF mut
2012 2013
Decarbazine
InterferonCombination
MEK mut
BRAFi+MEKi
PD1/PDL1
PDL1/PD1
combos
Immunotherapy
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Combinations
Target multiple pathways
Reduce resistance
Improve outcomes
Translating science into new medicines
requires innovation in development
17
Biology of the disease
Personalized Healthcare
Increase success rate
Improve outcome
Reduce side effects
Innovative design with
smart surrogate
end-points
pCR in early breast cancer MRD in hematology
GA lesion size in dry AMD
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Good and bad surrogate end-points
Why dont they always work?
18
True clinical
outcome
Surrogate
endpoint
True clinical
outcome
Surrogate
endpoint
Intervention
Disease
Disease
The surrogate is not in the causal pathway
of the disease process
Of several causal pathways of disease, the
intervention affects only the pathway
mediated through the surrogate
True clinical
outcome
Surrogate
endpoint
Intervention
Disease
The surrogate is not in the pathway of the
interventions effect or is insensitive to its
effect.
True clinical
outcome
Surrogate
endpoint
Intervention
Disease
The intervention has mechanisms of action
independent of the disease process
Intervention
Ann Intern Med. 1996 Oct 1;125(7):605-13
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Good surrogate end-points
19
True clinical
outcomeDisease
pCR Pathological Complete Response in early breast cancer
MRD Minimal Residual Disease in lymphomas
GA area GA area change in Geographic Atrophy
Surrogate
endpoint
Intervention
Good surrogate endpoint is in the causal pathway of the disease
Some surrogate end-points that might expedite drug development
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20
Late-stage pipeline update
Oncology
MetMAb
Phase IIINCSLC , triple neg. mBC and
mCRC
KadcylaPhase III
HER2-positive BC and gastric
cancer
obinutuzumab GA101Phase III
Hem. cancers
Bcl-2i (GDC 0199)Phase IIIHem. cancers
cobimetinib (MEKi)Phase III
melanoma
anti-PDL1Phase IIINSCLC
Immunology,ophthalmology andinfectious diseases
CNS
bitopertin
Phase IIISchizophrenia
ocrelizumabPhase III
Multiple Sclerosis
gantenerumabPhase III
Alzheimer Disease
obinutuzumab GA101
Phase IIIHem. cancers
Bcl-2i (GDC 0199)Phase III
Hem. cancers
anti-PDL1Phase III
NSCLC
KadcylaPhase IIIHER2-positive BC and
gastric cancer
lebrikizumab
Phase IIIAsthma
etrolizumabPhase III
IBD
lampalizumabPhase II
GA
mericitabine
danoprevir
Phase IIChronic Hepatitis C
lampalizumabPhase II
GA
etrolizumabPhase III
IBD
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Oncology: HER2 and Hematology franchises
Never Settle For Great 2.0 !
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Never Settle for Great 1.0
HER2 franchise
22
Herceptin
+ chemo
Lapatinib
+ chemo
Medicalvalue Kadcyla
Herceptin
+ chemo
Perjeta
Kadcyla
Perjeta
EMILIA / MARIANNE CLEOPATRA MARIANNE
Replace
Extend
Replace and extend
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TH3RESA: Kadcyla vs. physicians choice in 3L
HER2-positive BC
Kadcyla3.6 mg/kg q3w IV
Treatment ofphysicians choice
2
1KadcylaOptionalcrossover
PD
Co-primary endpoints:
PFS by Investigator OS
HER2-positive (central)
advanced BC
2 prior HER2-directed
therapies for MBCN=600
23
PD
Kadcyla in collaboration with ImmunoGen Inc.
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TH3RESA: Progression-free survival and overall
survival
Progression Free Survival (PFS)* Overall Survival (OS) - Interim
* Investigator Assessment; TPC=Treatment of Physicians Choice
198 120 62 28 13 6 1 0404 334 241 114 66 27 12 0
TPC
T-DM1
No. at risk:Time (months)
14121086420.0
0.2
0.4
0.6
0.8
1.0
0
TPC
(n=198)
T-DM1
(n=404)
Median (months) 3.3 6.2
No. of events 129 219Stratified HR=0.528
(95% CI, 0.422, 0.661) P
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TH3RESA: PFS for patients treated with
Herceptin-containing regimens
25
149 99 50 20 12 5 1 0
404 334 241 114 66 27 12 0
TPC
T-DM1
No. at risk: Time (months)
1412108642
0.0
0.2
0.4
0.6
0.8
1.0
Proportionprog
ression-free
0
TPC (H-containing)
(n=149)
T-DM1
(n=404)
Median (months) 3.2 6.2
No. of events 101 219
Stratified HR=0.558 (95% CI, 0.437, 0.771)
P
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26
HER2-positive progressive
or recurrent locally
advanced BC or previously
untreated mBC
(n=1092)Herceptin + taxane
(n=364)
Kadcyla & Perjeta
(n=364)
Kadcyla(n=364)
First-line HER2-positive mBC: MARIANNE trial
Kadcyla and Perjeta vs. standard of care
Primary end-point
Progression-free survival Recruitment started Q3 2010
Expect data H2 2014
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Neo-adjuvant HER2-positive breast cancer
Potentially completely new indication in the US
27
Early BC Neo-adjuvant
37000
~9250
~25%
Evaluating the effect of neo-adjuvant treatment
Neo-adjuvanttreatment
Pre-surgery, 4-6 cycles
Pathological complete
response, pCR
Absence of cancer cells
S
U
R
G
E
R
Y
Adjuvant treatmentPost-surgeryup to 1 year
Annual US incidence
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pCR as surrogate end-point in early breast
cancer
28
29.0%
45.8%
16.8%
24.0%
Herceptin +
docetaxel
Herceptin
& Perjeta
+ docetaxel
Herceptin
& Perjeta
Perjeta
+ docetaxel
pathologicalcompleteresponse
p = 0.0141
CTNeoBC Meta-analysis, FDA
Association of pCR with Event-free survival
(EFS) in HER2-positve BC Perjeta in neo-adjuvat setting (NEOSPHERE)
Perjeta recommended for approval in neo-adjuvant setting
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Kadcyla neo-adjuvant study
pCR as surrogate end-point
Primary
Endpoint
S
U
R
G
E
RY
HER2 positive eBC
Herceptin
+docetaxel+carboplatin
Kadcyla & Perjeta
Up to 1year6 cycles
29
Herceptin & Perjeta
+docetaxel+carboplatin
Herceptin
Kadcyla & Perjeta
Herceptin & Perjeta
Primary endpoint Pathological complete response,
pCR (ypT0N0)
Secondary endpoints
DFS, breast conservation, safety,
pCR by other definitions
FPI expected Q2 2014
Expect pCR data: end 2015
pCR
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Never Settle for Great 2.0
Hematology franchise
MabThera
BCL2
ADCs
ADC CD22
ADC CD79b
Replace
Extend
Replace and extend
CLL11 etc. Romulus
Chemo
MabThera
BCL2
ADCs
ADC CD22
ADC CD79b
Our vision
GA101 GA101
Medicalvalu
e
30
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Never Settle for Great 2.0
Hematology franchise development overview
Oncology indications:
CLL
iNHL
aNHL/DLBCL
CLL filed US/EU
Phase III rituximab ref.
NHL, 1L DLBCL and 1L
iNHL+maintenance
Phase III R/R CLL, Bcl-2
+rituximab
FPI Q1 2014
Phase II CLL (17p del)
FPI Q3 2013
Phase I GA101+Bcl-2
Bcl-2 inh +/-
anti-CD20
ADC +
anti-CD20
Obinutuzumab
(GA101)
MabThera
Rituxan
Improving the backbone
(anti-CD20)
Exploring combinations
with complementary MoA
CD20 CD22Bcl-2
CD79b
CD20
31
Phase II NHL
(FL+DLBCL)
CD22+rituximab vs.
CD79b+rituximab
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GA101 in Chronic Lymphocytic Leukemia (CLL)
CLL11: Study design
GA101: 1,000 mg days 1, 8, and 15 cycle 1; day 1 cycles 26, every 28 days
Rituximab: 375 mg/m2 day 1 cycle 1, 500 mg/m2 day 1 cycles 26, every 28 days Clb: 0.5 mg/kg day 1 and day 15 cycle 16, every 28 days
Patients with progressive disease in the Clb arm were allowed to cross over to G-Clb
R
A
N
D
O
M
I
ZE
1
:
2
:
2
Rituximab + chlorambucilx 6 cycles
GA101 + chlorambucil
x 6 cycles
Chlorambucil x 6 cycles
Previouslyuntreated CLLwith comorbidities
Total CIRS* score > 6
and/or creatinineclearance < 70 ml/min
Age 18 years
N = 780 (planned)
Stage I, n = 590
Additional 190 patients
to complete stage II
Stage II
G-Clb vs R-Clb
Stage Ia
G-Clb vs Clb
Stage Ib
R-Clb vs Clb
*Cumulative Illness Rating Scale
32
CD20
32GA101 in collaboration with Biogen Idec
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GA101 in CLL
Progression-free survival (PFS)
Type 1 error controlled through closed test procedure; p-value of the global test was
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GA101 in CLL
CLL11: Study design
GA101: 1,000 mg days 1, 8, and 15 cycle 1; day 1 cycles 26, every 28 days
Rituximab: 375 mg/m2
day 1 cycle 1, 500 mg/m2
day 1 cycles 26, every 28 days Clb: 0.5 mg/kg day 1 and day 15 cycle 16, every 28 days
Patients with progressive disease in the Clb arm were allowed to cross over to G-Clb
R
A
N
D
O
M
I
ZE
1
:
2
:
2
Rituximab + chlorambucilx 6 cycles
GA101 + chlorambucil
x 6 cycles
Chlorambucil x 6 cycles
Previouslyuntreated CLLwith comorbidities
Total CIRS* score > 6
and/or creatinineclearance < 70 ml/min
Age 18 years
N = 780 (planned)
Stage I, n = 590
Additional 190 patients
to complete stage II
Stage II
G-Clb vs R-Clb
Stage Ia
G-Clb vs Clb
Stage Ib
R-Clb vs Clb
*Cumulative Illness Rating Scale
34
CD20
34
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Never Settle for Great!
Stage two results for GA101 in CLL11
35
GA101 plus chlorambucil was superior to MabThera/Rituxan pluschlorambucil in helping people with previously untreated chronic
lymphocytic leukemia live longer without their disease worsening (7/24/13)
To be presented at the American Society of Hematologys 55th AnnualMeeting in December, 2013
35
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GA101 in Non Hodgkins Lymphoma
Multiple Head-to-head phase III trials vs MabThera
36
GA101q2mo x 2 years
Bendamustinex 6 cycles
CR, PR,
SDGA101
+ bendamustinex 6 cyclesMabThera-refractory
iNHL
(n=360)
Induction Maintenance
MabThera x 8 cycles +CHOP x 6 or 8
GA101 x 8 cycles +CHOP x 6 or 8
Previously untreatedDLBCL
(n=1,400)
MabTheraq2mo x 2 years
GA101q2mo x 2 years
MabThera x 8 cycles + CHOP x 6 orMabThera x 8 cycles + CVP x 8 orMabThera x 6 cycles + benda. x 6
CR, PR
GA101 x 8 cycles + CHOP x 6 orGA101 x 8 cycles + CVP x 8 orGA101 x 6 cycles + benda. x 6
First-line iNHL
(n=1,400)
Induction Maintenance
GADOLIN study
GOYA study
GALLIUM study
Primary end-point: PFSExpect data: 2015
Primary end-point:PFS
Expect data: 2015
Primary end-point: PFS
Expect data: 2017
36
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Phase I in CLL (n=55) Blood
Lymph nodes
Bone marrow
May-2012
Partial response ongoing >1 year
Jan-2013
Bcl-2 in R/R CLL: Dose escalation phase I study
37Presented at ASCO 2013
Bcl-2 inhibitor in collaboration with AbbVie
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Bcl-2 development program in CLL
38
Phase III Relapsed/Refractory CLL
Relapsed/Refractory CLL
with 17 p deletion
GDC-0199
400 mg
Treatment
to progression
Adjunct Phase II study Relapsed/Refractory CLL with 17 p deletion
GDC-199
2 years
Rituximab + Bendamustine
X 6 cycles
Rituximab + GDC-0199
X 6 cyclesRelapsed/Refractory
CLL
Observation
Primary end-point:PFS
Primary end-point:
Overall Response RateFPI: Q2 2013
Expect data: end 2014
FPI: Q1 2014
Expect data: 2016
Phase I study Relapsed/Refractory CLL
Relapsed/Refractory
CLL
Bcl-2 dose-escalation
4 cohorts (100-400 mg)
Combination
GA101+Bcl-2
6 cycles
Single agent Bcl-2
to progression
Establish the dose of Bcl-2 and safety of the combination (Q4 2013)Activity in expansion cohorts (2H 2014)
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ADCs in hematology: Anti-CD22 and anti-CD79b
Phase I responses in multiple histologies
39
Anti-tumor responses observed by histology
Anti-CD22
Anti-CD79b
CD22
CD79b
39ADCs in collaboration with Seattle Genetics Presented at ICML 2013
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ADCs in hematological cancers: Anti-CD22 and
anti-CD79b
40
anti-CD22 ADC
+ rituximab
anti-CD79b ADC+ rituximab
PD
PD
NHL
(R/R FL and
2/3 line DLBCL)
N=120
anti-CD79b ADC
+ rituximab
anti-CD22 ADC+ rituximab
Primary end-point: Progression Free Survival
Expect data: 2014
ROMULUS phase II
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Improving the standard of care in Hematology
41
Objectives
Increase cure rate or extend treatment-free
remissions
Improve upon individual agents in current SOC
Add novel agents to current SOC
Anti CD20 + Chemo + Biologic modifier
Rituxan or
GA101
Eliminate or replace
with ADC
Add a targeted agent
(Bcl-2, BTKi, Pi3K, aPD-L1)
Manage/decrease toxicity
Evaluate chemo-free regimens
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MRD (Minimal Residual Disease) as surrogate
end-point for longer remission and/or cure
42
MRD as prognostic factor: CLL8 study
MRD level
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CLL market fragmented between two treatment
approaches
Short course combinations that induce
deep responses followed by long
treatment-free remissions
Chronic treatments
with agents that are
effective, safe, and convenient
MRD-negative responses
followed by long remissions
Long remissions from safe, tolerable,
chronic therapy
GDC-01991GA101-
chlorambucil2R-
chlorambucil2R-FC3 Ibrutinib4 Idelalisib5
R-Benda-
Ibrutinib6
Line R/R 1L 1L 1L 1L R/R R/R R/R
N 56 238 233 408 31 61 54 30
ORR 84% 75.5% 65.9% 90% 71% 67% 56% 90%
CR 20% CR/CRi22.2%CR/CRi
8.3%CR/CRi 44% 10% 3% 4% 10%
MRD- BM: 35-50%*PB: 31% (41/132)
BM: 17% (15/88)
PB: 2% (3/150)
BM: 3% (2/72)
PB: 63%
(90/143)Not reported Not reported Not reported
MRD: minimal residual disease; R/R: relapsed/refractory; 1L: first-line; BM: bone marrow;
PB: peripheral blood* MRD tests performed in local unvalidated laboratories in a small number of patients; in patientswith a CR who have been tested
MRD rates in CLL
References:
1 . John Seymour, iwCLL 2013
2. Goede et al.J Clin Oncol2013; 31:suppl; abstr 7004 (presentation update)
3. Bttcher et al.J Clin Oncol2012 ;30:980-9884. Byrd et al. Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 189
5. Flinn et al. Hematol Oncol2013; 31 (Suppl. 1): Abstract 2976. Brown et al. Haematologica 2012; 97(s1) : Abstract 0543
43
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Anti-PDL1
Immunotherapy
44
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Anti-PDL1 overview
45
NSCLC
Melanoma
RCC
Combo w Avastin
Solid tumours
Combo w Zelboraf
Melanoma
Multiple combos start
2H13/1H14
Potential for
better safety
Potential for
personalized
approach
Potential for
longer response
Differentiation Development
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MPDL3280A Phase Ia: Efficacy Summary
46
Single Agent
RECIST 1.1
Response Rate
(ORRa)
SD of 24
Weeks or
Longer
24-Week
PFS Rate
Overall population
(N = 175)21% 19% 42%
NSCLC
(n = 53) 23% 17% 45%
Non-squamous
(n = 42)21% 17% 44%
Squamous
(n = 11) 27% 18% 46%
a ORR includes investigator-assessed unconfirmed and confirmed PR.
6 patients that did not have a post-baseline scan were included as non-responders.Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013. Soria et al, ECCO 2013
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MPDL3280A Phase Ia in NSCLC: Best response
by PD-L1 IHC Status
47
Diagnostic Populationa
(n = 53)
ORRb
% (n/n)
PD Rate
% (n/n)
IHC 3 83% (5/6) 17% (1/6)
IHC 2 and 3 46% (6/13) 23% (3/13)
IHC 1/2/3 31% (8/26) 38% (10/26)
All Patientsc 23% (12/53) 40% (21/53)
a IHC 3: 10% tumor immune cells positive for PD-L1 (IC+); IHC 2 and 3: 5% tumor immune cells positive for PD-L1 (IC+); IHC 1/2/3:1% tumor immune cells positive for PD-L1 (IC+); IHC 0/1/2/3: all patients with evaluable PD-L1 tumor IC status.b ORR includes investigator-assessed unconfirmed and confirmed PR.c All patients includes patients with IHC 0/1/2/3 and 7 patients have an unknown diagnostic status.Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013. Soria et al, ECCO 2013
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0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84
On study, on treatment
Treatment discontinued
First response
First PD
On study, post treatment
Ongoing response
Duration of Treatment and Response
Time (Weeks)
Histology IHC
Nonsquamous IHC 0
Squamous IHC 3
Nonsquamous IHC 0
Nonsquamous IHC 1
Nonsquamous IHC 0
Squamous IHC 2
Nonsquamous IHC 3
Squamous IHC 3
Nonsquamous IHC 3
Nonsquamous IHC 0
Nonsquamous IHC 3
Nonsquamous IHC 1
a Patient experiencing ongoing benefit per investigator.
Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013.
Duration of treatment in responders
Sustained response in majority of responders
48
a
Soria et al, ECCO 2013
A i PDL1 D l NSCLC
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Anti-PDL1 Development: NSCLC
Metastatic
NSCLC (2/3L)
Docetaxel75 mg/m2 IV Q3 wk
Anti-PDL1
1200 mg IV Q3 wk
OAK Study : Phase III 2/3L mNSCLC
Primary end-point:
Overall Survival
Expect FPI: Q1 2014
FIR Study: Phase II Dx-positive advanced mNSCLC
PDL1 positive NSCLC Anti-PDL1 1200 mg IVQ3 weeks Primary end-point:
Overall Response Rate
Ongoing
Metastatic
NSCLC (2/3L)
Docetaxel75 mg/m2 IV Q3 wk
Anti-PDL11200 mg IV Q3 wk
POPLAR Study : Phase II 2/3L mNSCLC
Ongoing
Primary end-point:Overall Survival
49
A ti PDL1 i bi ti ith A ti
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Anti-PDL1 in combination with Avastin
50
0
500
1000
1500
2000
0 10 20 30 40 50
TumorVolum
e,mm
3
Day
Anti-VEGF combination:
preclinical data
a-VEGF
a-PD-L1
a-PD-L1 + a-VEGF
Control
Cloudman melanoma
Arm A (n=6)
Anti-PDL1 q3w
Bevacizumab 15mg/kg q3w
Arm B (n=6)Anti-PDL1 q2w
Bevacizumab 10mg/kg q2w
+ chemoDoseescalation
Doseexpansion
Anti-PDL1 q3w @selecteddose
Bevacizumab 15mg/kg q3w
Anti-PDL1 q2w @selecteddose
Bevacizumab 10mg/kg q2w
+ chemo
Combination of anti-PDL1 and Avastin
(Study GP28328, solid tumors)
T ll di t d th ti M lti l
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T cell-directed therapeutics: Multiple
possibilities
Clinical
validationSafety issues
Pros: Stimulate Teffand inhibit Treg production (or activity), CTLA4 - possibly PD1 - areclinically validated
Cons: Can amplify auto-reactive T cell responses, disregulate T cell proliferation & cytokine
production
51Nature. 2011 Dec 21;480(7378):480-9
Novel molecules in cancer immunotherapy:
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Novel molecules in cancer immunotherapy:
Preliminary pre-clinical moleculesPreliminary pre-clinical
data: NME1 + anti-PD-L1
Co-blockade induces tumorrejection and creates resistant
to tumor re-challenge
Preliminary pre-clinical
data: NME2
Tumor volume reduction seenin pre-clinical models with
NME2
Median tumor volume (mm3)
52Internal data
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Etrolizumab
Anti-7 Integrin in Inflammatory Bowel Disease
53
Inflammatory Bowel Disease (IBD) overview
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Inflammatory Bowel Disease (IBD) overview
Two distinct diseases with high unmet medical need
54
Ulcerative colitis Crohns disease
Age of onset 20-30 yrs
Continuous mucosal distal
disease
Confined to sigmoid/colon
Bloody, frequent bowelmovements
Progressive over time
Age of onset 15-30 yrs
Patchy transmural disease
Most common in ileum
and ascending colon
Abdominal pain, diarrhea,vomiting, weight loss
Fistulae and strictures
Medical need
Higher sustained remission rates Decreased risk of severe infections Avoidance of surgery and hospitalizations
Inflammatory Bowel Disease (IBD)
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Inflammatory Bowel Disease (IBD)
Epidemiology and current treatment options
55
0
100
200
300
400
500
600
700
800
US 5EU US 5EU
MildModerate-Severe
Ulcerative colitis Crohns disease
Prevalenc
e(000)
5EU=UK, Germany, France, Italy, Spain
Epidemiology Current treatment options
Surgeryanti-TNFs
cyclosporine
anti-TNFs
Immunosuppressants(azathioprine, 6-MP)
5-amniosalicylates (5-ASAs)Antibiotics, Alternative therapiesMild
Moderate
Severe
Etrolizumab: Gut-selective anti-7 integrin with
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Etrolizumab: Gut selective anti 7 integrin with
dual mode of action and no expected CNS effect
Lamina propria venule
47
MAdCAM-1
VCAM-141
E7
E-cadherin
Intra-epitheliallymphocyte retention
Gut epithelium
Leukocyte trafficking
Etrolizumab: Anti-7
Blocks leukocyte trafficking
andlymphocyte retention
1 2
Vedolizumab: Anti-47
a. Blocks leukocyte trafficking only
No apparent effect on CNS
a
Natalizumab (Tysabri): Anti-4
a. Blocks leukocyte trafficking onlyb. Affects trafficking to CNS, associated with PML
a
b
56
Evaluating efficacy in Ulcerative Colitis
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Sustainedremission
Inductionof
remission
Evaluating efficacy in Ulcerative Colitis
Importance of induction and sustainability of remission
57
Week 6 8 10
Induction treatment Maintenance treatment
%patientsinre
mission
End-point I End-point II
Illustrative
1 year from induction
* Most trial designs utilize randomized withdrawal design to assess maintenance of remission.
Etrolizumab phase II study in Ulcerative Colitis
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Etrolizumab phase II study in Ulcerative Colitis
Compelling remission rates
58
0.0% 0.0% 0.0%
8 (20.5%)
7 (43.8%)
1(4.5%)
10.3%
25.0%
4.0%
5 (10.6%)
All-comers TNF-naive TNF-IR
Placebo
Etrolizumab 100mg
Etrolizumab 300mg+LD
n=41 n=39 n=15 n=16 n=12 n=25 n=22 n=25n=39
Clinical remission by MCS, Week 10
n=47
TNF-IR patients without
response at 10 weeks
continued etrolizumab
treatment to 14 weeks *
TNF-IR remitters
at week 10 or 14
MCS=Mayo Clinic Score, using central endoscopy reading; * 14 week remission as assessed by partial MCS
Etrolizumab among highest placebo-corrected
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Etrolizumab among highest placebo corrected
remissions for TNF-nave patients
14.9%
11.0%
6.6%
10.0%
38.8%
21.3% 23.3%
48.0%
Remicade
8 weeks
Humira
8 weeks
vedolizumab
6 weeks
tofacitinib
TNF nave/IR
8 weeks
PlaceboActive
Remicade ACT1 (Rutgeerts NEJM 05), Humira ULTRA2 (Sandborn GE12), Vedolizumab DDW 12,Tofacitinib (Sandborn NEJM 12), Etrolizumab (ENCALYPTUS);
59
23.9% 38%
10.3%16.7%
etrolizumab
10 weeks
43.8%
0.0%
43.8%
Etrolizumab
(Only program to use central
endoscopy reading)
%achievingclinicalremission
25%
100
mg300
mg
Anti-integrins may sustain remission better than
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Anti integrins may sustain remission better than
TNF-inhibitors: Learning from in-class compounds
60
14.9%
6.6%
11.0%
6.2%
38.8%
19.8% 21.3%
10.7%
36.0%
24.0%
Week 8 Sustained
week 54
Week 8 Sustained
week 52
Week 6 Sustained
week 52
Placebo
Active
Remicade Humira VedolizumabTNF-Naive & TNF-IR
-50%
-50%
-33%
E7 may predict remission in TNF-naive
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0%
0/5
0%
0/8
19%
3/16
64%
7/11
0%
20%
40%
60%
80%
E low E high
E7 may predict remission in TNF naive
patients: Potential for PHC approach
61
45% 35%
Note: ~10% and 40% of patients were missing qPCR and IHC data, respectively
E by qPCR E by IHC
Remission at 10 weeks
0%
0/1
0%
0/7
25%
2/8
60%
6/10
0%
20%
40%
60%
80%
E low E high
Placebo Pooled Etrolizumab
Potential for better efficacy in Crohns Disease
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y
Higher concentration of E in small bowel,
often involved in Crohns Disease
62
E+ cells in gut mucosa
Small bowel, often involved in Crohns Disease
Jejunum
Ileum
Phase III outlook
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63
Best-in-disease in Inflammatory Bowel Disease
>3000 patients program
First subcutaneous gut-selective anti-integrin
Better safety profile with reduced risk of severe infection ormalignancy
PHC through E expression as potential companion
diagnostics
Further details after discussions with healthcare authorities
FPI 1H 2014. Expect first data 2018
Ulcerative Colitis Crohns disease
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Lampalizumab
Anti-factor D in Geographic Atrophy
64
Age-related macular degeneration (AMD)
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Progression of the disease
65
Normal retinaEarly or intermediate
dry AMD
Geographic atrophy
Neovascular AMDNat Rev Immunol. 2013 Jun;13(6):438-51
Clinical spectrum of AMD
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Early AMD Intermediate AMD
Geographic Atrophy
fovea-
threatening
fovea-
involved
Wet AMD
Advanced AMD
Initially, visual acuity minimally affected; signs are
anatomic (drusen and pigmentary changes) with
symptoms of visual function impairment (e.g, dark
adaptation, contrast sensitivity)
non fovea-
threatening
Arch Ophthalmol 2001;119:1417-1436 66
Epidemiology and current treatment options for
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Geographic Atrophy
67
Prevalence of Geographic Atrophy Current treatment options
No treatments that showed
improvement or disease slowdown
High-dose antioxidant vitamins and
zinc often recommended
0
0.5
1
1.5
US 5 EU
millio
ns
Rudnicka at al. Ophthalmology. Mar 2012;119(3):571-580.
Lampalizumab (anti-factor D): Selective inhibitor
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of the alternative complement pathway
Molecule Fab of a humanized monoclonal
antibody
Targets complement factor D of thealternative pathway
Target
Complement factor D is a rate-
limiting enzyme in the alternative
pathway and present in relatively
low abundance
C3a
C3b
C5b
C5a
C5
C3b
C3b
C3b
Bb
Bb
Classical pathway
MBL pathway
C3b
C4b
C2a
C4b
C2a
C3
Alternative pathway
fB
fD
fB
fD
fH
fH
Inflammation
MAC
Inflammation
Amplification
MAC=Membrane Attack Complex; MBL=mannose-binding lectin
C1q
AFD
AFD
68
MAHALO Phase II study
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Month 18
Phase IbOpen-label safety run-In
(N=14)
Phase II (N=129)*
Randomized 1:2:1:2
Safety follow-up period or Open-label extension study
Lampalizumab10 mg, every 2 mths
N=44
Lampalizumab10 mg, monthly
N=43
ShamMonthly
N=21
ShamEvery 2 mths
N=21
*N = 123 for pre-specified modified intent-to-treat population, which is the primary efficacy analysis population.
Mean change in GA area from
baseline to Month 18 assessed
by fundus autofluorescence
(FAF)
Holz FG et al.Am J Ophthalmol.
2007;143:463-72
Study design Primary Endpoint
69
Lampalizumab: Efficacy results I
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Data embargoed for printing until the publication in a scientific/medical journal
70
Lampalizumab: Efficacy results II
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Data embargoed for printing until the publication in a scientific/medical journal
71
Lampalizumab: Efficacy results III
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Data embargoed for printing until the publication in a scientific/medical journal
72
Lampalizumab: Safety results I
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Data embargoed for printing until the publication in a scientific/medical journal
73
AMD risk has a strong genetic component
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19 confirmed loci in
pathways related to:
Complement
Lipid metabolism
Angiogenesis
Apoptosis
Extracellular matrix
Fritsche, et al. Nat Gen 2013 45(4):433-9
Identifying patients that benefit the most
Genetic factors account for ~55% of total variability in disease risk
Lifetime AMD risk for individual of affected family member 50% compared to 12% for relatives
of controls
Strong biological rationale for lampalizumab biomarker
To be presented at AAO, November 16-19
74
Further development: Learning from the natural
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history of the disease I
75
Challenges
Slow progressing disease
No formal regulatory guidelines on end-points
Medical need
No approved treatment options
GA associated with visual loss
For all levels of baseline total atrophy, there
was significant enlargement of atrophy over
time, with only six eyes (7%) not
demonstrating significant growth.
GA area progression over time*
*Ophthalmology. 1999 Sep;106(9):1768-79; DA=Macular Photocoagulation Study disc areas
Further development: Learning from the natural
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history of the disease II
76
Challenges
Slow progressing disease
No formal regulatory guidelines on end-points
Medical need
No approved treatment options
GA associated with visual loss
Mean BCVA of 63.6 ETDRS letters
(approx. 20/50) one year prior to
diagnosis of central GA
22-letter decrease by year 5 (BCVA of
41.9 letters, approx. 20/160) over 6
years
*AREDS Report Number 26, Archives of Ophthalmology 2009, 127:1168-74
Visual Acuity over time in patients with central GA*
~20/50
Time, y
Phase III study design to be discussed with healthcare authorities
Development
of central GA
Smart development: Similarities between
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early BC and Geographic Atrophy
77
Early Breast Cancer Geographic Atrophy
High unmet medical need with no approved treatments
Slow progressing disease
Long survival Slow decline in visual function
Potentially long clinical trials
Biological rationale for surrogate end-point
GA area change pCR
Perjeta&Herceptin: Approved for
neoadjuvant HER2+ BC based on pCR
Lampalizumab: Phase III design to be
discussed with healthcare authorities
Summary: Successful 2013
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78
Regulatory
achievements
Late-stage
read-outs
Positiveproof-of-concept
US approvals: Kadcyla, Avastin TML, Tarceva EGFR+ NSCLC,
Lucentis (HARBOR)
EU approvals: Perjeta, Avastin TML, Erivedge, Herceptin SC Positive opinions: Kadcyla (EU), Perjeta neoadjuvant (US)
GA101 in CLL
Xolairin Chronic idiopathic urticaria
Avastin in GBM, Cervical cancer
Anti-PDL1 in solid tumours
Bcl-2 inh in hematology
Lampalizumab in dry AMD
Etrolizumab in Inflammatory Bowel Disease
2011 to present: Strong pipeline progression
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20132012
29 successful late-stage trials
2011
Avastin+
pemetrexedAVAPERL
TarcevaEURTAC
MetMAbNSCLC
Avastin+
HerceptinAVEREL
ZelborafBRIM 3
lebrikizumabMILLY
LucentisRIDE
KadcylaPhase II
PerjetaCLEOPATRA
Avastin OCOCEANS
LucentisRISE
ErivedgeERIVANCE
LucentisHARBOR
GA101GAUSS
ActemraACT-Ray
Herceptin scHANNAH
dalcetrapibdal-OUTCOMES
AvastinAURELIA
ActemraADACTA
MabThera SCSABRINA
AvastinBEATRICE
ActemraSUMMACTA
AvastinAVAGLIO
KadcylaEMILIA
ActemraBREVACTA
XolairASTERIA
ActemraFUNCTION
ObinutuzumabCLL-11
ActemraCHERISH
Positive trials New Molecular Entity
XolairGLACIAL
aleglitazarAleCardio
AvastinTML
KadcylaTH3RESA
HerceptinHERA2
ActemraBUILDER I/II
MetMAbTNBC
AvastinCervical
79
NME submissions and their additional indications
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Projects currently in phase 2 and 3
80
Unless stated otherwise, submissions are planned to occur in US and EU.
indicates a submission which has occurred with regulatory action pending
# negative symptoms and sub-optimal control
Neuroscience
Ophthalmology
NME
Oncology
Immunology
Infectious Diseases
CardioMetabolism
bitopertin (RG1678)
schizophrenia#
obinutuzumab (GA101)
CLL
onartuzumab (MetMAb)
mNSCLC, 2nd/3rd line
ocrelizumab (RG1594)
PPMS and RMS
obinutuzumab (GA101)
iNHL relapsed
Status as of June 30, 2013
cobimetinib (MEK inh)(RG7421) combo Zelboraf
met melanoma
mericitabine (RG7128)HCV
danoprevir (RG7227)
HCV
pictilisib (RG7321)PI3 kin inh solid tumors
setrobuvir (RG7790)
HCV
mGlu5 NAM (RG7090)
depression
inclacumab (RG1512)
ACS/CVD
crenezumab (RG7412)
Alzheimers
gantenerumab (RG1450)
Alzheimers
MAO-B inh (RG1577)Alzheimers
mGlu2 NAM (RG1578)
depression
PI3K/mTOR inh (RG7422)solid & hem tumors
HER3/EGFR MAb (RG7597)m. epithelial tumors
glypican-3 MAb (RG7686)liver cancer
quilizumab (RG7449)
asthma
lampalizumabanti-factor D Fab (RG7417)
geographic atrophy
lebrikizumab (RG3637)
asthma
etrolizumab (RG7413)
ulcerative colitis
bitopertin (RG1678)
obsessive compulsive dis.
2013 2014 2015 2016 and beyond
(RG7667)
CMV
oral octreotide (RG3806)
acromegaly
CD22 ADC (RG7593)CD79b ADC (RG7596)
heme tumors
parsatuzumab (RG7414)EGFL7 Mab solid tumors
ALK inhibitor (RG7853)
NSCLC
PD-L1 MAb (RG7446)solid tumors
Bcl-2 inh (RG7601)
CLL and NHL
onartuzumab (MetMAb)
gastric cancer & other AIs
obinutuzumab (GA101)
frontline iNHL
obinutuzumab (GA101)
DLBCL
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Doing now what patients need next
81