roche ptresentation

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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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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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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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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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

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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


+ chemoDoseescalation

Doseexpansion

Anti-PDL1 q3w @selecteddose


Anti-PDL1 q2w @selecteddose


+ 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

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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

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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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71

Lampalizumab: Efficacy results III


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72

Lampalizumab: Safety results I


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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


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


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


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


frontline iNHL


DLBCL


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Doing now what patients need next

81

roche ptresentation

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