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Roche late-stage pipeline update III

London, 1 October 2013

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 2 3 4 5 6 7 8 9 10 11 pricing and product initiatives of competitors; legislative and regulatory developments and economic conditions; delay or inability in obtaining regulatory approvals or bringing products to market; fluctuations in currency exchange rates and general financial market conditions; 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; increased government pricing pressures; interruptions in production; loss of or inability to obtain adequate protection for intellectual property rights; litigation; loss of key executives or other employees; and 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 Roches 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

Roche late-stage pipeline update III

Agenda

14:30-14:35 14:35-14:40 14:40-15:45 15:45-16:15

Opening remarks Karl Mahler, Head of Investor Relations Introduction Alan Hippe, CFO Late-stage pipeline update III Hal Barron, MD Global Development and Chief Medical Officer Q&A

Strong progress in non-oncology assets


2009 2013
Xolair Lucentis Rituxan/MabThera RA Actemra bitopertin ocrelizumab MS gantenerumab lebrikizumab etrolizumab1 lampalizumab2 2 phase II 4 phase II Immunology/ Ophthalmology Neuroscience

Launched

Xolair Lucentis Rituxan/MabThera RA

Phase III

ocrelizumab RA Actemra 4 phase II

Phase II

4 phase II

4
1

FPI expected 1H 2014; 2 Phase III decision pending

Innovation-driven resource allocation

Alan Hippe, Roche CFO

Roche strategy: Focused on medically differentiated therapies

Premium for innovation

Pharma

Dia

Regulators:
Optimised benefit / risk ratio

Focus

Payors:
Optimised benefit / cost ratio

MedTech Generics OTC

Differentiation

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) 2 1

Patent expirations Global economic slowdown 3 - Slower expansion of budgets in emerging markets - Increased pricing hurdles in developed world

Innovation through patient stratification

Benefit for all stake holders, including the industry


Today Benefit from patient stratification Future

Increased market share Reduced Patient pool Time to market Lower development costs Higher probability of success Pricing power

Access becoming more important



Moving towards value based pricing Ensure access while rewarding value Multiple indications and combinations

Need for tailored systems


Business challenge

Today Pack based pricing Value based pricing


Episode-of-care based

Future

Undifferentiated $$ by vial

Combinations

Indication based

Need for patient based information

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? Limits to public access will continue

7% 6% 5% 6% 5%

Recognition and rewards for innovation


3% 2% 1%

-1%
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Source: IMS

10

R&D allocation

Mix of qualitative and quantitative factors

Research & Early Development

Late Stage Development

Top down
Annual budget allocation Ensure expertise in the field Plausibility of scientific hypotheses

Project driven
Market potential Efficient development Probability of technical success

11

Roche: R&D well balanced from a risk & disease point of view

Roche budget trends

Oncology

Metabolism CNS Inflammation Virology

0%

5%

10%

15%

20%

25%

30%

Industry average probability of success Phase I to Registration

12
Source: Bernstein Equity Research, Tufts University and Roche analysis

Where science takes us


Oncology
9 drugs launched 5 Phase III
Avastin MabThera Herceptin Xeloda Tarceva Zelboraf Erivedge Perjeta Kadcyla MetMab anti-PDL1 BCL2i GA101 cobimetinib (MEKi) 10 phase II

Immunology/ Inflammation
4 drugs launched 1 Phase III

Neuroscience
3 Phase III

Launched

Xolair Lucentis Rituxan/MabThera RA Actemra

Phase III

lebrikizumab etrolizumab1 lampalizumab2 2 phase II

bitopertin ocrelizumab gantenerumab 4 phase II

Phase II

Strong and growing


1

Strongly emerging

Earlier stage 13

FPI expected 1H 2014; 2 Phase III decision pending

Focus on innovation and growth

Strategic focus on innovation and driving Personalised Healthcare

Growth facilitated by tailored access models

Leading product pipeline providing value for the future

14

We follow the science

Hal Barron, MD Global Development and Chief Medical Officer

15

Oncology drug development

Understanding of tumour biology is expanding


Example of melanoma

Interferon 1975 1995

BRAF mut

BRAFi+MEKi

Combination

PDL1/PD1 combos

2010 2011 2012 2013 MEK mut

Decarbazine

PD1/PDL1
Immunotherapy

Immunotherapy

16

Translating science into new medicines requires innovation in development


Biology of the disease

Personalized Healthcare

Combinations

Innovative design with smart surrogate end-points

Increase success rate Improve outcome Reduce side effects

Target multiple pathways Reduce resistance Improve outcomes

pCR in early breast cancer MRD in hematology GA lesion size in dry AMD

17

Good and bad surrogate end-points

Why dont they always work?


Intervention

Disease

Surrogate endpoint

True clinical outcome

The surrogate is not in the causal pathway of the disease process

Intervention

Disease

Surrogate endpoint

True clinical outcome

The intervention has mechanisms of action independent of the disease process The surrogate is not in the pathway of the interventions effect or is insensitive to its effect. Of several causal pathways of disease, the intervention affects only the pathway mediated through the surrogate 18

Intervention

Disease
Intervention

Surrogate endpoint

True clinical outcome

Disease

Surrogate endpoint

True clinical outcome

Ann Intern Med. 1996 Oct 1;125(7):605-13

Good surrogate end-points

Good surrogate endpoint is in the causal pathway of the disease


Intervention

Disease

Surrogate endpoint

True clinical outcome

Some surrogate end-points that might expedite drug development pCR Pathological Complete Response in early breast cancer MRD Minimal Residual Disease in lymphomas GA area GA area change in Geographic Atrophy
19

Late-stage pipeline update


Oncology
Immunology, ophthalmology and infectious diseases
lebrikizumab
Phase III Asthma

CNS
bitopertin
Phase III Schizophrenia

Kadcyla Phase III

MetMAb

NCSLC , triple neg. mBC and Phase III mCRC HER2-positive BC and Kadcyla gastric cancer

Phase III HER2-positive BC and gastric cancer obinutuzumab GA101

etrolizumab Phase III


IBD Phase

etrolizumab

ocrelizumab
Phase III Multiple Sclerosis

III

Phase III obinutuzumab GA101


Phase III Hem. cancers Hem. cancers Bcl-2iBcl-2i (GDC 0199) (GDC 0199)
Phase III Phase III Hem. cancers Hem. cancers

IBD

lampalizumab

gantenerumab
Phase III Alzheimer Disease

Phase II GA lampalizumab

cobimetinib (MEKi)

Phase II mericitabine GA danoprevir


Phase II Chronic Hepatitis C

Phase III melanoma anti-PDL1 Phase IIIanti-PDL1


III NSCLCPhase NSCLC

20

Oncology: HER2 and Hematology franchises

Never Settle For Great 2.0 !

Never Settle for Great 1.0

HER2 franchise
Extend Replace
Perjeta

Replace and extend

Perjeta

Medical value

Kadcyla Herceptin + chemo Lapatinib + chemo Herceptin + chemo

Kadcyla

EMILIA / MARIANNE

CLEOPATRA

MARIANNE

22

TH3RESA: Kadcyla vs. physicians choice in 3L HER2-positive BC

Kadcyla
HER2-positive (central) advanced BC 2 prior HER2-directed therapies for MBC N=600
3.6 mg/kg q3w IV

PD

2 1
Treatment of physicians choice

PD

Kadcyla
Optional crossover

Co-primary endpoints: PFS by Investigator OS


Kadcyla in collaboration with ImmunoGen Inc.

23

TH3RESA: Progression-free survival and overall survival

Progression Free Survival (PFS)*


1.0 0.8 0.6 0.4 0.2 0.0

Overall Survival (OS) - Interim


Observed 21% of targeted events
1.0 0.8 0.6 0.4 0.2 0.0

TPC T-DM1 (n=198) (n=404) Median (months) 3.3 6.2 No. of events 129 219 Stratified HR=0.528 (95% CI, 0.422, 0.661) P<0.0001

Median (months) No. of events

TPC (n=198) 14.9 44

T-DM1 (n=404) NE 61

Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034 0


198 404

2
120 334

4
62 241

No. at risk: TPC 198 T-DM1 404

6 8 Time (months)
28 114 13 66

10
6 27

12
1 12

14
0 0

2
169 381

4
125 316

6
80 207

8 10 Time (months)
51 127 30 65

12
9 30

14
3 7

16
0 0

* Investigator Assessment; TPC=Treatment of Physicians Choice

24
Presented at ECC 2013

TH3RESA: PFS for patients treated with Herceptin-containing regimens

1.0

Proportion progression-free

0.8

TPC (H-containing) T-DM1 (n=149) (n=404) Median (months) 3.2 6.2 No. of events 101 219 Stratified HR=0.558 (95% CI, 0.437, 0.771) P<0.0001

0.6

0.4

0.2

0.0 0
No. at risk: TPC 149 T-DM1 404

2
99 334

4
50 241

6
20 114

10
5 27

12
1 12

14
0 0

Time (months)
12 66

25
Presented at ECC 2013

First-line HER2-positive mBC: MARIANNE trial

Kadcyla and Perjeta vs. standard of care


Kadcyla & Perjeta (n=364) Kadcyla (n=364) Herceptin + taxane (n=364)

HER2-positive progressive or recurrent locally advanced BC or previously untreated mBC (n=1092)

Primary end-point Progression-free survival

Recruitment started Q3 2010 Expect data H2 2014

26

Neo-adjuvant HER2-positive breast cancer

Potentially completely new indication in the US


Annual US incidence
37000 Neo-adjuvant treatment Pre-surgery, 4-6 cycles

Evaluating the effect of neo-adjuvant treatment

~9250

S U R G E R Y

Adjuvant treatment Post-surgery up to 1 year

~25% Early BC Neo-adjuvant


Pathological complete response, pCR Absence of cancer cells

27

pCR as surrogate end-point in early breast cancer


Association of pCR with Event-free survival (EFS) in HER2-positve BC Perjeta in neo-adjuvat setting (NEOSPHERE)
p = 0.0141 45.8%

pathological complete response

29.0% 24.0% 16.8%

CTNeoBC Meta-analysis, FDA

Herceptin + Herceptin Herceptin Perjeta docetaxel & Perjeta & Perjeta + docetaxel + docetaxel

Perjeta recommended for approval in neo-adjuvant setting

28

Kadcyla neo-adjuvant study

pCR as surrogate end-point


6 cycles
Herceptin +docetaxel+carboplatin
S U R G E R Y

Primary Endpoint

Up to 1year
Herceptin

HER2 positive eBC

Herceptin & Perjeta +docetaxel+carboplatin Kadcyla & Perjeta

pCR

Herceptin & Perjeta Kadcyla & Perjeta

Primary endpoint Pathological complete response, pCR (ypT0N0) DFS, breast conservation, safety, pCR by other definitions

Secondary endpoints

FPI expected Q2 2014 Expect pCR data: end 2015 29

Never Settle for Great 2.0

Hematology franchise
Extend Replace

Replace and extend

BCL2 ADCs
ADC CD22 ADC CD79b

BCL2 ADCs
ADC CD22

Medical value

GA101 Chemo

ADC CD79b

GA101

MabThera

MabThera

CLL11 etc.

Romulus

Our vision

30

Never Settle for Great 2.0

Hematology franchise development overview


Exploring combinations with complementary MoA

Improving the backbone (anti-CD20)

ADC + anti-CD20 Bcl-2 inh +/anti-CD20


Phase III R/R CLL, Bcl-2 +rituximab FPI Q1 2014 Phase II CLL (17p del) FPI Q3 2013 Phase I GA101+Bcl-2

Obinutuzumab (GA101) MabThera Rituxan


CLL filed US/EU
Oncology indications: CLL iNHL aNHL/DLBCL

Phase II NHL (FL+DLBCL) CD22+rituximab vs. CD79b+rituximab

Phase III rituximab ref. NHL, 1L DLBCL and 1L iNHL+maintenance

CD79b

CD20

CD20

Bcl-2

CD22

31

GA101 in Chronic Lymphocytic Leukemia (CLL)

CLL11: Study design


Stage I, n = 590

CD20

Additional 190 patients to complete stage II

Previously untreated CLL with comorbidities


Total CIRS* score > 6 and/or creatinine clearance < 70 ml/min Age 18 years N = 780 (planned)

R A N D O M I Z E 1 : 2 : 2

Chlorambucil x 6 cycles

Stage Ia G-Clb vs Clb Stage Ib R-Clb vs Clb Stage II G-Clb vs R-Clb

GA101 + chlorambucil x 6 cycles

Rituximab + chlorambucil x 6 cycles

*Cumulative Illness Rating Scale

32

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

GA101 in collaboration with Biogen Idec

32

GA101 in CLL

Progression-free survival (PFS)


Stage Ia
1.0 0.9 G-Clb: Median 23.0 mo* 1-year PFS 84% 1.0 0.9 0.8 0.7 0.6 0.5 Clb: Median 10.9 mo 1-year PFS 27% 0.4 0.3 Stratified HR: 0.14
95% CI: 0.090.21 p < 0.0001 (log-rank)

CD20
Stage Ib
R-Clb: Median 15.7 mo 1-year PFS 63%

Progression-free survival

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3


99 213 82 207

Clb: Median 10.8 mo 1-year PFS 27%

0.2 0.1 0.0

Stratified HR: 0.32


95% CI: 0.240.44 p < 0.0001 (log-rank)

6
47 152

9
18 117

12
5 75 3 40

15
0 15

18
0 2

21
0 0

24

27
Clb

n at risk
Clb 118

0
118 101 225

3
85 215

6
49 148

9
19 95

12
6 63 3 28

15
0 11

18
0 3

21
0 0

24

27

G-Clb 238

R-Clb 233

33

Type 1 error controlled through closed test procedure; p-value of the global test was <.0001. * In the G-Clb arm < 10% of patients had reached the median at cutoff; therefore, in contrast to the Clb arm the G-Clb median PFS could not be reliably estimated due to the few patients at risk at time of G-Clb median. Independent Review Committee (IRC) - assessed PFS was consistent with investigator-assessed PFS

33
Presented at ASCO 2013

GA101 in CLL

CLL11: Study design


Stage I, n = 590

CD20

Additional 190 patients to complete stage II

Previously untreated CLL with comorbidities


Total CIRS* score > 6 and/or creatinine clearance < 70 ml/min Age 18 years N = 780 (planned)

R A N D O M I Z E 1 : 2 : 2

Chlorambucil x 6 cycles

Stage Ia G-Clb vs Clb Stage Ib R-Clb vs Clb Stage II G-Clb vs R-Clb

GA101 + chlorambucil x 6 cycles

Rituximab + chlorambucil x 6 cycles

*Cumulative Illness Rating Scale

34

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

34

Never Settle for Great!

Stage two results for GA101 in CLL11

GA101 plus chlorambucil was superior to MabThera/Rituxan plus chlorambucil 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 Annual Meeting in December, 2013

35

35

GA101 in Non Hodgkins Lymphoma

Multiple Head-to-head phase III trials vs MabThera


GADOLIN study Induction
GA101 + bendamustine x 6 cycles Bendamustine x 6 cycles
CR, PR, SD

Maintenance
GA101 q2mo x 2 years

MabThera-refractory iNHL (n=360)

Primary end-point: PFS Expect data: 2015

GOYA study
Previously untreated DLBCL (n=1,400)

GA101 x 8 cycles + CHOP x 6 or 8 MabThera x 8 cycles + CHOP x 6 or 8

Primary end-point: PFS Expect data: 2015

GALLIUM study

Induction
GA101 x 8 cycles + CHOP x 6 or GA101 x 8 cycles + CVP x 8 or GA101 x 6 cycles + benda. x 6 First-line iNHL (n=1,400) MabThera x 8 cycles + CHOP x 6 or MabThera x 8 cycles + CVP x 8 or MabThera x 6 cycles + benda. x 6
CR, PR

Maintenance
GA101 q2mo x 2 years

Primary end-point: PFS Expect data: 2017


MabThera q2mo x 2 years

36

36

Bcl-2 in R/R CLL: Dose escalation phase I study


Phase I in CLL (n=55)
May-2012 Jan-2013 Blood

Lymph nodes

Partial response ongoing >1 year

Bone marrow

Bcl-2 inhibitor in collaboration with AbbVie

37
Presented at ASCO 2013

Bcl-2 development program in CLL


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)

Adjunct Phase II study Relapsed/Refractory CLL with 17 p deletion


Relapsed/Refractory CLL with 17 p deletion

GDC-0199 400 mg

Treatment to progression

Primary end-point: Overall Response Rate FPI: Q2 2013 Expect data: end 2014

Phase III Relapsed/Refractory CLL


Rituximab + GDC-0199 X 6 cycles Rituximab + Bendamustine X 6 cycles GDC-199 2 years Observation

Primary end-point: PFS FPI: Q1 2014 Expect data: 2016

Relapsed/Refractory CLL

38

ADCs in hematology: Anti-CD22 and anti-CD79b

Phase I responses in multiple histologies


Anti-tumor responses observed by histology

Anti-CD22
CD22

Anti-CD79b
CD79b

39

39
Presented at ICML 2013

ADCs in collaboration with Seattle Genetics

ADCs in hematological cancers: Anti-CD22 and anti-CD79b


ROMULUS phase II
anti-CD22 ADC + rituximab PD anti-CD79b ADC + rituximab

NHL (R/R FL and 2/3 line DLBCL) N=120

anti-CD79b ADC + rituximab

PD

anti-CD22 ADC + rituximab

Primary end-point: Progression Free Survival Expect data: 2014

40

Improving the standard of care in Hematology

Anti CD20 + Chemo + Biologic modifier


Rituxan or GA101 Eliminate or replace with ADC Add a targeted agent (Bcl-2, BTKi, Pi3K, aPD-L1)

Objectives Increase cure rate or extend treatment-free remissions Improve upon individual agents in current SOC Add novel agents to current SOC 41 Manage/decrease toxicity Evaluate chemo-free regimens

MRD (Minimal Residual Disease) as surrogate end-point for longer remission and/or cure
MRD detection MRD as prognostic factor: CLL8 study
Peripheral blood Relative frequency of leukemic cells Early relapse Late relapse
MRD level <10-4 10-4 to <10-2 10-2

Cytomorphology detection limit

Immunophenotypic and PCR detection limit

Bone marrow

Cure

Induction

Maintenance Follow-up time

42
J Clin Oncol. 2012 Mar 20;30(9):980-8

CLL market fragmented between two treatment approaches


Short course combinations that induce deep responses followed by long treatment-free remissions MRD-negative responses followed by long remissions MRD rates in CLL
GDC-01991
Line N ORR CR MRDR/R 56 84% 20% CR/CRi BM: 35-50%*

Chronic treatments with agents that are effective, safe, and convenient Long remissions from safe, tolerable, chronic therapy

GA101chlorambucil2
1L 238 75.5% 22.2% CR/CRi PB: 31% (41/132) BM: 17% (15/88)

Rchlorambucil2
1L 233 65.9% 8.3% CR/CRi PB: 2% (3/150) BM: 3% (2/72)

R-FC3
1L 408 90% 44% PB: 63% (90/143)

Ibrutinib4
1L 31 71% 10% R/R 61 67% 3%

Idelalisib5
R/R 54 56% 4% Not reported

R-BendaIbrutinib6
R/R 30 90% 10% 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 patients with a CR who have been tested

References: 1. John Seymour, iwCLL 2013 2. Goede et al. J Clin Oncol 2013; 31:suppl; abstr 7004 (presentation update) 3. Bttcher et al. J Clin Oncol 2012 ;30:980-988 4. Byrd et al. Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 189 5. Flinn et al. Hematol Oncol 2013; 31 (Suppl. 1): Abstract 297 6. Brown et al. Haematologica 2012; 97(s1) : Abstract 0543

43

Anti-PDL1

Immunotherapy

44

Anti-PDL1 overview
Differentiation
NSCLC Potential for better safety Melanoma RCC Potential for personalized approach Combo w Avastin Solid tumours Combo w Zelboraf Melanoma Multiple combos start 2H13/1H14

Development

Potential for longer response

45

MPDL3280A Phase Ia: Efficacy Summary


Single Agent RECIST 1.1 Response Rate (ORRa) Overall population (N = 175) NSCLC (n = 53) Non-squamous (n = 42) Squamous (n = 11) SD of 24 Weeks or Longer

24-Week PFS Rate

21% 23% 21% 27%

19% 17% 17% 18%

42% 45% 44% 46%

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.
a

Soria et al, ECCO 2013

46

MPDL3280A Phase Ia in NSCLC: Best response by PD-L1 IHC Status


Diagnostic Populationa
(n = 53)

ORRb
% (n/n)

PD Rate
% (n/n)

IHC 3 IHC 2 and 3 IHC 1/2/3 All Patientsc

83% (5/6) 46% (6/13) 31% (8/26) 23% (12/53)

17% (1/6) 23% (3/13) 38% (10/26) 40% (21/53)

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. Soria et al, ECCO 2013 Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013.
a

47

Duration of treatment in responders

Sustained response in majority of responders


Histology IHC

Duration of Treatment and Response

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
0 3
a

On study, on treatment On study, post treatment

Treatment discontinued Ongoing response First response First PD

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

Patient experiencing ongoing benefit per investigator. Time (Weeks) Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013.

Soria et al, ECCO 2013

48

Anti-PDL1 Development: NSCLC


FIR Study: Phase II Dx-positive advanced mNSCLC PDL1 positive NSCLC
Anti-PDL1 1200 mg IV Q3 weeks

Ongoing Primary end-point: Overall Response Rate

POPLAR Study: Phase II 2/3L mNSCLC


Metastatic NSCLC (2/3L)
Docetaxel 75 mg/m2 IV Q3 wk Anti-PDL1 1200 mg IV Q3 wk

Ongoing Primary end-point: Overall Survival

OAK Study: Phase III 2/3L mNSCLC


Metastatic NSCLC (2/3L)
Docetaxel 75 mg/m2 IV Q3 wk Anti-PDL1 1200 mg IV Q3 wk

Expect FPI: Q1 2014 Primary end-point: Overall Survival 49

Anti-PDL1 in combination with Avastin


Anti-VEGF combination: preclinical data
Cloudman melanoma a-PD-L1
1500 Tumor Volume, mm
3

Combination of anti-PDL1 and Avastin (Study GP28328, solid tumors)


Dose escalation

2000

Arm A (n=6)
Anti-PDL1 q3w Bevacizumab 15mg/kg q3w

Arm B (n=6)
Anti-PDL1 q2w Bevacizumab 10mg/kg q2w + chemo

Control

a-VEGF

Dose expansion

1000

500

a-PD-L1 + a-VEGF

Anti-PDL1 q3w @selected dose Bevacizumab 15mg/kg q3w

Anti-PDL1 q2w @selected dose Bevacizumab 10mg/kg q2w + chemo

0 0 10 20 Day 30 40 50

50

T cell-directed therapeutics: Multiple possibilities


Safety issues Clinical validation

Pros: Stimulate Teff and inhibit Treg production (or activity), CTLA4 - possibly PD1 - are clinically validated Cons: Can amplify auto-reactive T cell responses, disregulate T cell proliferation & cytokine production 51

Nature. 2011 Dec 21;480(7378):480-9

Novel molecules in cancer immunotherapy: Preliminary pre-clinical molecules


Preliminary pre-clinical data: NME1 + anti-PD-L1
Co-blockade induces tumor rejection and creates resistant to tumor re-challenge
Median tumor volume (mm3)

Preliminary pre-clinical data: NME2


Tumor volume reduction seen in pre-clinical models with NME2

Internal data

52

Etrolizumab

Anti-7 Integrin in Inflammatory Bowel Disease

53

Inflammatory Bowel Disease (IBD) overview

Two distinct diseases with high unmet medical need


Ulcerative colitis
Age of onset 20-30 yrs Continuous mucosal distal disease Confined to sigmoid/colon Bloody, frequent bowel movements Progressive over time

Crohns disease
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
54

Inflammatory Bowel Disease (IBD)

Epidemiology and current treatment options


Epidemiology
800 700 600

Current treatment options


Mild Moderate-Severe

Severe

Prevalence (000)

500 400 300 200 100 0

Surgery anti-TNFs cyclosporine anti-TNFs Immunosuppressants (azathioprine, 6-MP)

Moderate

Mild
US 5EU US 5EU

5-amniosalicylates (5-ASAs) Antibiotics, Alternative therapies

Ulcerative colitis

Crohns disease 55

5EU=UK, Germany, France, Italy, Spain

Etrolizumab: Gut-selective anti-7 integrin with dual mode of action and no expected CNS effect
Etrolizumab: Anti-7
Blocks leukocyte trafficking and lymphocyte retention Intra-epithelial lymphocyte retention
E7 E-cadherin

Vedolizumab: Anti-47
a. Blocks leukocyte trafficking only No apparent effect on CNS

a Leukocyte trafficking
MAdCAM-1 47

a b
Lamina propria venule

41

VCAM-1

Gut epithelium

Natalizumab (Tysabri): Anti-4


a. Blocks leukocyte trafficking only b. Affects trafficking to CNS, associated with PML

56

Evaluating efficacy in Ulcerative Colitis

Importance of induction and sustainability of remission


Illustrative Induction treatment Maintenance treatment

Week

10

1 year from induction

Induction of remission
% patients in remission

Sustained remission

End-point I

End-point II

* Most trial designs utilize randomized withdrawal design to assess maintenance of remission.

57

Etrolizumab phase II study in Ulcerative Colitis

Compelling remission rates


Clinical remission by MCS, Week 10
7 (43.8%)

Placebo Etrolizumab 100mg Etrolizumab 300mg+LD

25.0% 8 (20.5%) TNF-IR patients without response at 10 weeks continued etrolizumab treatment to 14 weeks *

10.3% 1(4.5%) 4.0% 0.0%


n=41 n=39

5 (10.6%)

0.0%
n=39 n=15 n=16 n=12

0.0%
n=25 n=22 n=25

All-comers

TNF-naive

TNF-IR

n=47

TNF-IR remitters at week 10 or 14

58
MCS=Mayo Clinic Score, using central endoscopy reading; * 14 week remission as assessed by partial MCS

Etrolizumab among highest placebo-corrected remissions for TNF-nave patients


Etrolizumab (Only program to use central endoscopy reading)
43.8%

48.0%

% achieving clinical remission

Placebo Active 38.8%

23.9%
21.3% 14.9% 23.3%

38% 43.8%

25%

10.3%
11.0%

16.7%
10.0% 6.6% 0.0% 100 mg 300 mg

Remicade 8 weeks

Humira 8 weeks

vedolizumab 6 weeks

tofacitinib TNF nave/IR 8 weeks

etrolizumab 10 weeks

Remicade ACT1 (Rutgeerts NEJM 05), Humira ULTRA2 (Sandborn GE12), Vedolizumab DDW 12, Tofacitinib (Sandborn NEJM 12), Etrolizumab (ENCALYPTUS);

59

Anti-integrins may sustain remission better than TNF-inhibitors: Learning from in-class compounds
Remicade
38.8% Placebo Active 36.0%

Humira

Vedolizumab
TNF-Naive & TNF-IR

-50%

-33%
24.0%

19.8% 14.9%

21.3%

-50%
11.0% 10.7% 6.2%

6.6%

Week 8

Sustained week 54

Week 8

Sustained week 52

Week 6

Sustained week 52

60

E7 may predict remission in TNF-naive patients: Potential for PHC approach


Remission at 10 weeks

80%
64% 7/11

80%

60%

45%

60%

35%

60% 6/10

40%
19% 3/16 0% 0/5 0% 0/8

40%

25% 2/8

20%

20%
0% 0/1 0% 0/7

0%

0%

E low

E high

E low E by IHC

E high

E by qPCR
Placebo

Pooled Etrolizumab

61

Note: ~10% and 40% of patients were missing qPCR and IHC data, respectively

Potential for better efficacy in Crohns Disease


Higher concentration of E in small bowel, often involved in Crohns Disease

E+ cells in gut mucosa

Jejunum

Ileum

Small bowel, often involved in Crohns Disease

62

Phase III outlook


Best-in-disease in Inflammatory Bowel Disease >3000 patients program Ulcerative Colitis Crohns disease

First subcutaneous gut-selective anti-integrin Better safety profile with reduced risk of severe infection or malignancy PHC through E expression as potential companion diagnostics Further details after discussions with healthcare authorities FPI 1H 2014. Expect first data 2018

63

Lampalizumab

Anti-factor D in Geographic Atrophy

64

Age-related macular degeneration (AMD)

Progression of the disease


Geographic atrophy Normal retina Early or intermediate dry AMD

Nat Rev Immunol. 2013 Jun;13(6):438-51

Neovascular AMD

65

Clinical spectrum of AMD


Advanced AMD
Geographic Atrophy

Early AMD

Intermediate AMD

non foveathreatening

foveathreatening

foveainvolved

Initially, visual acuity minimally affected; signs are anatomic (drusen and pigmentary changes) with symptoms of visual function impairment (e.g, dark adaptation, contrast sensitivity)

Wet AMD

66
Arch Ophthalmol 2001;119:1417-1436

Epidemiology and current treatment options for Geographic Atrophy


Prevalence of Geographic Atrophy 1.5 No treatments that showed improvement or disease slowdown millions 1 High-dose antioxidant vitamins and zinc often recommended Current treatment options

0.5

0 US 5 EU
67

Rudnicka at al. Ophthalmology. Mar 2012;119(3):571-580.

Lampalizumab (anti-factor D): Selective inhibitor of the alternative complement pathway


Classical pathway
C1q MBL pathway

Alternative pathway
C3

fD Amplification C3a Bb fH C5 C5a


AFD

fB

Inflammation
C3b

C2a C4b

C3b

Molecule Fab of a humanized monoclonal antibody Targets complement factor D of the alternative pathway Target Complement factor D is a ratelimiting enzyme in the alternative pathway and present in relatively low abundance

Inflammation MAC

C2a C3b C4b C3b C3b

Bb fH

AFD

fB fD

C5b

68
MAC=Membrane Attack Complex; MBL=mannose-binding lectin

MAHALO Phase II study

Study design
Phase Ib Open-label safety run-In (N=14) Phase II (N=129)* Randomized 1:2:1:2

Primary Endpoint
Mean change in GA area from baseline to Month 18 assessed by fundus autofluorescence (FAF)

Sham
Monthly N=21

Lampalizumab
10 mg, monthly N=43

Sham
Every 2 mths N=21

Lampalizumab
10 mg, every 2 mths N=44

Holz FG et al. Am J Ophthalmol. 2007;143:463-72

Month 18 Safety follow-up period or Open-label extension study

69
*N = 123 for pre-specified modified intent-to-treat population, which is the primary efficacy analysis population.

Lampalizumab: Efficacy results I

Data embargoed for printing until the publication in a scientific/medical journal

70

Lampalizumab: Efficacy results II

Data embargoed for printing until the publication in a scientific/medical journal

71

Lampalizumab: Efficacy results III

Data embargoed for printing until the publication in a scientific/medical journal

72

Lampalizumab: Safety results I

Data embargoed for printing until the publication in a scientific/medical journal

73

AMD risk has a strong genetic component

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 19 confirmed loci in pathways related to: Complement Lipid metabolism Angiogenesis Apoptosis Extracellular matrix

Strong biological rationale for lampalizumab biomarker To be presented at AAO, November 16-19
Fritsche, et al. Nat Gen 2013 45(4):433-9

74

Further development: Learning from the natural history of the disease I


Challenges Slow progressing disease No formal regulatory guidelines on end-points Medical need No approved treatment options GA associated with visual loss

GA area progression over time*

For all levels of baseline total atrophy, there was significant enlargement of atrophy over time, with only six eyes (7%) not demonstrating significant growth.

*Ophthalmology. 1999 Sep;106(9):1768-79; DA=Macular Photocoagulation Study disc areas

75

Further development: Learning from the natural history of the disease II


Challenges Slow progressing disease No formal regulatory guidelines on end-points Medical need No approved treatment options GA associated with visual loss

Visual Acuity over time in patients with central GA*


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
~20/50

Development of central GA
Time, y

Phase III study design to be discussed with healthcare authorities


*AREDS Report Number 26, Archives of Ophthalmology 2009, 127:1168-74

76

Smart development: Similarities between early BC and Geographic Atrophy

Early Breast Cancer

Geographic Atrophy

Slow progressing disease Long survival Slow decline in visual function High unmet medical need with no approved treatments Potentially long clinical trials Biological rationale for surrogate end-point pCR
Perjeta&Herceptin: Approved for neoadjuvant HER2+ BC based on pCR

GA area change
Lampalizumab: Phase III design to be discussed with healthcare authorities 77

Summary: Successful 2013

Regulatory achievements

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 Xolair in Chronic idiopathic urticaria Avastin in GBM, Cervical cancer Anti-PDL1 in solid tumours

Late-stage read-outs

Positive proof-of-concept

Bcl-2 inh in hematology Lampalizumab in dry AMD Etrolizumab in Inflammatory Bowel Disease 78

2011 to present: Strong pipeline progression

29 successful late-stage trials


Zelboraf BRIM 3 Erivedge ERIVANCE MetMAb NSCLC Herceptin sc HANNAH Lucentis HARBOR Avastin TML dalcetrapib dal-OUTCOMES Herceptin HERA2 Avastin Cervical aleglitazar AleCardio

Avastin OC OCEANS

Actemra ACT-Ray

Perjeta CLEOPATRA

Actemra BUILDER I/II

Actemra CHERISH

MabThera SC SABRINA

Actemra BREVACTA

Avastin AVAGLIO

Obinutuzumab CLL-11

2011

2012

2013

Tarceva EURTAC

Lucentis RISE

Kadcyla Phase II

Avastin+ pemetrexed AVAPERL

Avastin+ Herceptin AVEREL

Actemra ADACTA

Kadcyla EMILIA

Xolair ASTERIA

Actemra SUMMACTA

MetMAb TNBC

Kadcyla TH3RESA

Lucentis RIDE

lebrikizumab MILLY

GA101 GAUSS

Avastin AURELIA

Avastin BEATRICE

Actemra FUNCTION

Xolair GLACIAL

Positive trials

New Molecular Entity

79

NME submissions and their additional indications

Projects currently in phase 2 and 3


onartuzumab (MetMAb) gastric cancer & other AIs obinutuzumab (GA101) frontline iNHL Bcl-2 inh (RG7601) CLL and NHL
PI3 kin inh solid tumors

obinutuzumab (GA101) DLBCL lebrikizumab (RG3637) asthma etrolizumab (RG7413) ulcerative colitis quilizumab (RG7449) asthma mericitabine (RG7128) HCV danoprevir (RG7227) HCV (RG7667) CMV setrobuvir (RG7790) HCV inclacumab (RG1512) ACS/CVD bitopertin (RG1678) obsessive compulsive dis. gantenerumab (RG1450) Alzheimers MAO-B inh (RG1577) Alzheimers mGlu2 NAM (RG1578) depression mGlu5 NAM (RG7090) depression crenezumab (RG7412) Alzheimers
anti-factor D Fab (RG7417)

pictilisib (RG7321)

parsatuzumab (RG7414) EGFL7 Mab solid tumors PI3K/mTOR inh (RG7422) solid & hem tumors PD-L1 MAb (RG7446) solid tumors CD22 ADC (RG7593) CD79b ADC (RG7596) heme tumors onartuzumab (MetMAb) mNSCLC, 2nd/3rd line
(RG7421) combo Zelboraf met melanoma

obinutuzumab (GA101) iNHL relapsed ocrelizumab (RG1594) PPMS and RMS bitopertin (RG1678) schizophrenia#

HER3/EGFR MAb (RG7597) m. epithelial tumors glypican-3 MAb (RG7686) liver cancer ALK inhibitor (RG7853) NSCLC

cobimetinib (MEK inh)

obinutuzumab (GA101) CLL

oral octreotide (RG3806) acromegaly

lampalizumab

geographic atrophy

2013

2014

2015

2016 and beyond


Oncology Immunology Infectious Diseases CardioMetabolism Neuroscience Ophthalmology NME

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

80

Status as of June 30, 2013

Doing now what patients need next

81