Cynthia Perettie | Global Hematology Franchise Head

David Traub | Lifecycle Leader anti-CD20 Franchise

Pharmaceuticals Division

Roche Pharma Day 2015

Hematology franchise overview

DLBCL FL CLL

AML/MDS MM Hemophilia

40% of DLBCL patients

relapse and succumb

to their disease

FL Still no cure, many

patients experience

multiple relapses

before succumbing

to their disease

CLL

Still no cure, many

patients achieve

incomplete responses

and require chronic

treatment, many

experience multiple

relapses

AML/MDS

SOC in AML has made

little progress in

decades, we believe

combinations will

significantly improve

outcomes for patients

MM

Highly variable disease

with driver mutations,

current SOC (PI and IMIDs)

associated with significant

side effects, combinations

with targeted therapies will

advance SOC

Hemophilia Existing therapies

are hampered by

burden on therapy

and compliance

Hematology indications still represent large

unmet need

2

Phase I Phase II Phase III Registration Approved

MabThera SC

Gazyva Type II anti-CD20

venetoclax

idasanutlin

polatuzumab

atezolizumab

NHL combos

AML doublets

4 early assets,

incl. CD20/CD3

ACE910

Roche hematology – expanding within and

beyond NHL/CLL

ADC: Antibody-drug Conjugate *Co-development molecule with Abbvie

CLL*

NHL MM

NHL MDS MM

NHL

AML

Hemophilia

Heme indications

3

NHL

CLL

CLL

NHL

AML

NHL NHL

CLL

AML/MDS

MM

HEMOPHILIA

CLL

AML/MDS

MM

HEMOPHILIA

AML

NHL

MabThera SC

NHL launch ongoing, strong uptake in most markets

4

• First EU launches in 2014, ongoing or imminent in further countries

• Encouraging initial uptake in majority of markets, comparable to Herceptin SC

• Slower conversion in countries with strong incentives to use IV (Germany) or

limited reimbursement (UK)

Advancing the standard of care in NHL & CLL

Gazyva: Designed to be the superior aCD20

5

In collaboration with Biogen Idec

CHOP=Cyclophosphamide, Doxorubicin, Vincristine and Prednisone; CVP=Cyclophosphamide, Vincristine and Prednisolone

CLL 11 Ph III 1L Chronic Lymphocytic Leukemia (CLL)

Launched in Q4 2013

Gazyva + chlorambucil

Rituxan + chlorambucil

chlorambucil

GOYA Ph III 1L Diffuse Large B-cell Lymphoma (DLBCL)

Data expected 2016

Gazyva + CHOP

Rituxan + CHOP

GADOLIN

Ph III R/R Indolent NHL (iNHL)

Filed Q3 2015

INDUCTION

bendamustine

MAINTENANCE

Gazyva q2mo x 2 years

Gazyva + bendamustine CR, PR,SD

GALLIUM Ph III 1L Indolent NHL (iNHL)

Data expected 2017

INDUCTION

Rituxan + CHOP or Rituxan or Rituxan + bendamustine

MAINTENANCE

Gazyva q2mo x 2 years

Gazyva + CHOP or Gazyva + CVP or Gazyva + bendamustine

CR, PR,SD

Rituxan q2mo x 2 years

1L CLL n=781

Front-line DLBCL

(aggressive NHL) n=1418

Rituxan-refractory iNHL

n=411

1L iNHL n=1407

IRF-Assessed PFS MabThera-refractory iNHL (n=396)

B – median PFS 14.9 mos

PFS HR 0.55,

p=0.00011

Gazyva+B

median PFS not reached (Inv-PFS of 30 mos)

GADOLIN

Strong data for GAZYVA in refractory iNHL

6

Gazvya provides

substantial benefit in

iNHL patients who did

not achieve adequate

disease control from a

previous MabThera-

based regimen

FDA Priority Review

granted (10/24/2015)

B = bendamustine

Un-classified ABC GCB

~15% ~55% ~30%

~50%

~50%

Lenalidomide

(RELEVANCE)

Ibrutinib

(PHOENIX)

Gazyva/Polatuzumab

(GOYA)

1L DLBCL

GOYA to include data across cell of origin subtypes

7

Segment % of

incidence

Median OS

[months]

All Comers 100% >60

GCB 55% >60

ABC** 30% 30-40

Double Positive 18-33%

(46% of ABC) 24

Double-Hit 5-10% 12

** worse outcomes in ABC may be driven by higher proportion

of double positive patients

Source: Roche internal data presented during REFORCE F2F Feb-2015

* 46% of ABC patients are double positive (Hu S et l. Blood, 2013)

REFERENCES

• Johnson N et al, JCO 2012

• Hu S et al, Blood 2013

• MAIN, GATHER data

• Iqbal J et al. JCO, 2006

• Iqbal J et al. Clin Can Res 2011

• Davis et al. Nature 2010

• Haberman T et al, JCO 2006

• Thieblemont C et al. JCO 2011

Elevated bcl-2

Double Positive

Bcl-2 and myc*

Double Hit

Bcl-2

and myc

Development vision: Raising the bar for curative

therapies in NHL

Pursue compelling

combinations

with internal and

external molecules

MabThera or

GAZYVA

+ +

polatuzumab

NME ADC

Eliminate or

replace

with ADC

venetoclax

atezolizumab

Add a targeted

agent

Anti CD20 Chemo Biologic modifier

CD20/CD3

TCB

8

Drugs Disease Status

Doublet Anti-CD20 + venetoclax FL ongoing

Doublet Anti-CD20 + atezolizumab FL/DLBCL ongoing

Doublet Anti-CD20 + idasanutlin FL/DLBCL FPI 2015

Doublet Anti-CD20 + polatuzumab vedotin FL/DLBCL ongoing

Doublet + Chemo Anti-CD20 + venetoclax + CHOP DLBCL ongoing

Doublet + Chemo Anti-CD20+ venetoclax + bendamustine FL ongoing

Doublet + Chemo Anti-CD20 + polatuzumab vedotin + CHP DLBCL ongoing

Doublet + Chemo Anti-CD20 + polatuzumab vedotin + bendamustine FL ongoing

Doublet + Chemo Anti-CD20 + atezolizumab + CHOP DLBCL FPI 2015

Doublet + Chemo Anti-CD20 + atezolizumab + bendamustine FL/DLBCL FPI 2015

Triplet Anti-CD20 + atezolizumab + lenalidomide FL/DLBCL FPI 2015

Triplet Anti-CD20 + atezolizumab + polatuzumab vedotin FL/DLBCL FPI 2016

Triplet Anti-CD20 + polatuzumab vedotin + venetoclax FL/DLBCL FPI 2015

Triplet Anti-CD20 + polatuzumab vedotin + lenalidomide FL/DLBCL FPI 2015

Phase Ib/II studies in NHL

14 unique combinations

9

10

Development plan: Venetoclax

A new cornerstone of the hematology franchise

Compound Combination Indication P 1 P 2 P 3

CLL

venetoclax* +Rituxan MURANO R/R CLL

venetoclax +Gazyva CLL14 1L CLL

venetoclax Monotherapy R/R CLL 17pdel

venetoclax Monotherapy after ibrutinib/idelalisib tx R/R CLL

venetoclax +Rituxan R/R CLL and SLL

NH

L

venetoclax +Rituxan +/- B

CONTRALTO R/R FL (iNHL)

venetoclax +Rituxan/Gazyva+chemo

CAVALLI 1L aNHL

venetoclax + Rituxan + B R/R NHL

MM

venetoclax +bortezomib+dexamethasone R/R MM

AM

L

venetoclax + hypomethylating agents

+ LDAC AML

*venetoclax (Bcl2 inhibitor) in collaboration with AbbVie

B = bendamustine

LDAC = low dose Ara C

Filing Q4 ’15

MRD as prognostic factor: CLL8 study MRD (Minimal Residual Disease) detection

(illustrative)

MRD negative status as surrogate end-point for

long-term remission and/or cure

11

Peripheral

blood

Rela

tive

fre

quency

of

leukem

ic c

ells

Follow-up time

Early relapse Late relapse

Induction Maintenance

‘Cure’

Immunophenotypic

and PCR detection

limit

Cytomorphology

detection limit

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

Bone

marrow

MRD level

<10-4

≥10-4 to <10-2

≥10-2

CLL: Two different treatment paradigms

12

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

CLL: Two different treatment paradigms

13

Venetoclax1 R-

Venetoclax8

Gazyva-

bendamustine7

Gazyva-

chlorambucil2 R-chlorambucil2 R-FC3 Ibrutinib4 Idelalisib5 R-Benda-

Ibrutinib6

Line R/R R/R 1L 1L 1L 1L 1L R/R R/R R/R

N 78 49 158 238 233 408 31 61 54 30

ORR 77% 86% 78.5% 75.5% 65.9% 90% 71% 67% 56% 90%

CR 23% CR/CRi 41% CR/CRi 32.3% 22.2%

CR/CRi

8.3%

CR/CRi 44% 10 % 3% 4% 10%

MRD-

negative

BM: 55%

(6/11)*

BM: 75%

(15/20)

53% (ITT)

PB: 58.9%

BM: 27.8%

(ITT)

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 patients with a CR who have been tested

References:

1. John Seymour, EHA 2014

2. Goede et al. J Clin Oncol 2013; 31:suppl; abstr 7004 (presentation update)

3. Böttcher 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

7. Stilgenbauer et al., ASH 2015 (GREEN subgroup analysis)

8. Ma Shuo et al., ASH 2015 (abstract 80273)

Bypassing agent market ($2.1bn)† FVIII market ($6.1bn in 2012)†

Hemophilia A: ACE910 addressing major

medical need in highly focused market

14 †Company reported sales ‡EvaluatePharma consensus analyst estimates

$5.3 bn $5.5 bn $6.0 bn $6.1 bn

$8.4 bn

2009 2010 2011 2012 2018

Others Recombinate

Hemofil M Helixate

ReFacto AF/Xyntha Humate P

6%

‡

$1.7 bn $1.9 bn

$2.1 bn $2.1 bn

$2.6 bn

2009 2010 2011 2012 2018

FEIBA VH

NovoSeven

3%

‡

• Current FVIII treatments

− Limited half-life of only 8-12 hrs

− Frequent IV injections

− Induce neutralizing antibodies, which

inhibit their function

• Current bypassing treatments

− Much shorter half-life of ~4-6 hrs.

− Multiple frequent IV infusions

− Long infusion times (30+mins) for FEIBA

− Unstable efficacy compared to FVIII

Development plan: ACE910

Changing the standard of care in hemophilia A

15

2015 2016 2017 2018

Pediatrics Inhibitor

Inhibitor Non-interventional

Inhibitor (≥12 yrs)

Weight based QW dosing

(Q4W dosing study planned)

Non-inhibitor (≥12 yrs)

Weight based QW and Q2W dosing

Japanese studies

Chugai OLE

QW=weekly dosing; Q2W= dosing every 2 weeks; Q4W=monthly dosing; PK=pharmacokinetic study; OLE=open label extension

Phase II Phase III Phase I Patient transfer

Roche data highlights at ASH 2015

Gazyva combinations

• Rituxan refractory NHL: Phase 3 GADOLIN update

• 1L or R/R CLL: Phase 3 GREEN subgroup analysis with bendamustine

• 1L CLL: Phase 3 CLL14 safety run-in, combo with venetoclax

Abstracts planned/submitted Abstracts planned/submitted Abstracts planned/submitted

Orlando, 5-8 Dec

Planned presentations

venetoclax

• R/R CLLp17 del: Phase 2 data presentation

venetoclax combinations

• 1L AML: Phase 1b with decitabine or azacitidine

• R/R NHL: Phase 1 + Rituxan + bendamustine

• 1L or R/R CLL: Phase 1b with Gazyva

Roche curtain raiser highlighting key abstracts on new data at ASH to be released today

16

Garret Hampton | VP, Oncology Biomarker Development

Pharmaceuticals Division

Roche Pharma Day 2015

Molecular Information

Personalized healthcare

A cornerstone of the Genentech / Roche strategy

2

Diagnostics Pharma

60% of pipeline programs are being

developed with companion diagnostics

4 out of

9 BTDs

enabled by a Dx

that identified

patients most

likely to benefit

Molecule

Actemra (Systemic sclerosis)

Venetoclax (R/R CLL 17p)

Atezolizumab (NSCLC)

ACE 910 (Hemophilia)

Esbriet (IPF)

Lucentis (DR)

Atezolizumab (Bladder)

Alectinib (ALK+ NSCLC)

Gazyva (1L CLL)

Significant advances in cancer biology

Multiple molecular subsets of disease

Unknown

MET splice site MET

Amplification

KRAS NRAS

ROS1 Fusions

KIF5B-RET

EGFR

ALK Fusions

HER2 BRAF

PIK3CA AKT1

MAP2K1

PD-L1

Expression

3

4

Molecular Information in oncology

Combination of molecular and patient data will enable change in R&D and clinical practice

✓ ︎ ✗ ✓ ︎ ✗

Smarter, more

efficient R&D

Better

patient care Patients

matched to

clinical trials

Treatment plan

selected

Molecular understanding of cancer Patient outcomes

Database &

Analytics interface

Multiple capabilities required

Comprehensive tumor analysis and longitudinal assessment

mRNA-

expression

Cell signatures,

targets

RNA

sequencing

DNA-mutation

& CNVs

Ex: EGFR, BRAF

DNA

sequencing

Protein-

expression

PDL1, other CI

targets

Multiplex

IHC

Comprehensive tumor analysis Continuous monitoring over time

Cell free tumor

DNA

Blood DNA

sequencing

Imaging

Ex: ImmunoPet

Imaging

Ex: EGFR, BRAF

5

FMI R&D collaboration

Our partnership with FMI is key to informing R&D by leveraging molecular information

6

Molecular Information

from FMI database and

GNE/Roche clinical trials

(FM1 & FM1 heme)

mRNA-

expression

Cell signatures,

targets

RNA

sequencing

DNA-mutation

& CNVs

Ex: EGFR, BRAF

DNA

sequencing

Protein-

expression

PDL1, other CI

targets

Multiplex

IHC

Comprehensive tumor analysis Continuous monitoring over time

Cell free tumor

DNA

Blood DNA

sequencing

Imaging

Ex: ImmunoPet

Imaging

Ex: EGFR, BRAF

1 3

Development of a

blood-based

molecular assays

2

Immunotherapy panel

development (DNA & RNA)

2 2

Clinical trial data

Roche database FMI clinical database

50,000+ patient data in FMI database

1

Roche / FMI database queries

Example: PIK3CA mutations in multiple cancers

7

Implementation of FMI panels in development

Focus on high-value clinical samples

Clinical trial data

Roche database FMI clinical database

Current prioritization*:

1. Trials with post-progression biopsy (with archival baseline samples)

2. Phase 3 trial** n>300

3. Phase 2 trial* n>100

4. Phase 1b combos

** Positive trial, evidence of activity or potential identification of subset / high value for

informing our pipeline (i.e., importance of disease setting / indication / treatment)

50,000+ patient data in FMI database

1

8

FMI R&D collaboration

Immunotherapy R&D collaboration

9

2

Immunotherapy panel

development (DNA & RNA)

mRNA-

expression

Cell signatures,

targets

RNA

sequencing

DNA-mutation

& CNVs

Ex: EGFR, BRAF

DNA

sequencing

Protein-

expression

PDL1, other CI

targets

Multiplex

IHC

Comprehensive tumor analysis Continuous monitoring over time

Cell free tumor

DNA

Blood DNA

sequencing

Imaging

Ex: ImmunoPet

Imaging

Ex: EGFR, BRAF

2

Checkpoint inhibitors

Most effective in “inflamed” tumors

Inflamed Non-inflamed

TILs

PD-L1 expression

CD8+ T cells

Genomic instability

Pre-existing immunity

2

10

PD-L1 IHC: Staining for TCs and ICs

Assay sensitivity critical in detecting both cell types

11

Tumor cells

(TCs)

Tumor and immune cells

(TCs and ICs)

WCLC 2015

1IMvigor 210 ECC 2015, 2POPLAR ECC 2015

e.g. NSCLC e.g. bladder

Immune cells

(ICs)

2

Patient selection enriches for benefit

PD-L1 selected lung (TC & IC) and bladder cancer (IC)

Bladder cancer: Overall survival* Lung cancer: Survival hazard ratio*

* Monotherapy data

ECC 2015

Time (months)

100

80

60

40

20

0

5 6 7 8 9 10 11 1 2 3 4 0

– IC2/3

– IC0/1

+ Censored

12

Ove

rall

Su

rviv

al

Median OS 6.7 mo (95% CI, 5.7-8.0)

Median OS Not Reached (95% CI, 7.6-NE)

0.1 1

In favor of docetaxel

0.73

1.04

0.59

0.54

0.49

Hazard Ratio

In favor of atezolizumab

0.2 1 2

TC3 or IC3

TC2/3 or IC2/3

TC1/2/3 or IC1/2/3

TC0 and IC0

ITT N=287

2

12

Bladder cancer: Overall survival

Example: Atezolizumab phase 1 data

in urothelial bladder cancer patients

100

80

60

40

20

0

-20

-40

-60

-80

-100

0 21 42 63 84 105 126 147 168 189 210 231 252 273 294

Time on study (days)

Why do these patients progress?

Why do these patients respond? C

hange in s

um

of lo

ngest dia

mete

rs

(SLD

) fr

om

baselin

e (

%)

Time (months)

100

80

60

40

20

0

5 6 7 8 9 10 11 1 2 3 4 0

– IC2/3

– IC0/1

+ Censored

12

Ove

rall

Su

rviv

al

Median OS 6.7 mo (95% CI, 5.7-8.0)

Median OS Not Reached (95% CI, 7.6-NE)

Benefit is not the same for every patient

Some patients with high expression of PD-L1 do not benefit – why?

2

13

Many types of data will be needed to inform patient care including:

Biomarkers for cancer immunotherapy

Key platforms for discovery and development

mRNA-

expression

Cell signatures,

targets

RNA

sequencing

DNA-mutation

& CNVs

Ex: EGFR, BRAF

DNA

sequencing

Protein-

expression

PDL1, other CI

targets

IHC

Cell free tumor

DNA

Blood DNA

sequencing

Ex: EGFR, BRAF

Other Dx &

patient data

Ex: Imaging,

outcomes etc

EMRs

PDL-1 IHC and

multiplex IHC

Mutation burden

& neo-epitope

prediction

Immune cell

types and

signatures

1 2

14

Gene expression & combination hypotheses

Understanding the biology of immune cells in tumors enables combination hypotheses

−2 −1.6 −0.67 0.22 1.1 1.6 2

2 1 0 -1 -2

cbind(1:nc)

Indication

Me

lan

om

a

SC

C

NS

CL

C

RC

C

Ade

no

NS

CL

C

Bla

dde

r

TN

BC

HE

R2

+B

C

CR

C

HR

+B

C

Th17 Signature

Treg Signature

Th2 Signature

Teff Signature

B cell Signature

IB Signature

IFNg Signature

NK cell Signature

APC Signature

Myeloid Signature

1

15

Gene expression & combination hypotheses

Understanding the biology of immune cells in tumors enables combination hypotheses

16

Myeloid signature (macrophages) associated with

lack of response to atezolizumab in bladder cancer

−2 −1.6 −0.67 0.22 1.1 1.6 2

2 1 0 -1 -2

cbind(1:nc)

Indication

Me

lan

om

a

SC

C

NS

CL

C

RC

C

Ade

no

NS

CL

C

Bla

dde

r

TN

BC

HE

R2

+B

C

CR

C

HR

+B

C

Th17 Signature

Treg Signature

Th2 Signature

Teff Signature

B cell Signature

IB Signature

IFNg Signature

NK cell Signature

APC Signature

Myeloid Signature

Anti-CSF-1R

Anti-PD-L1

Tumor associated macrophages

Hypothesis: Anti-CSF-1R removes macrophages

which may enable atezolizumab activity

Myeloid signature:

IL1B, IL8, CCL2

P=0.01

PD = Progressive disease

SD = Stable disease

CR/PR = Complete/partial response

1

T cell infiltration

Cancer T cell recognition

anti-CEA/CD3 TCB

anti-CD20/CD3 TCB

anti-HER2/CD3 TCB

ImmTAC* (Immunocore)

anti-VEGF (Avastin)

anti-Ang2/VEGF (vanucizumab)

Chen and Mellman. Immunity 2013; CI=cancer immunotherapy

T cell killing

anti-PDL1 (atezolizumab)

anti-CSF-1R (emactuzumab)

anti-OX40

IDOi

IDOi* (Incyte)

CPI-444* (Corvus)

anti-TIGIT

IDO1/TDOi* (Curadev)

EGFRi (Tarceva)

ALKi (Alectinib)

BRAFi (Zelboraf)

MEKi (Cotellic)

anti-CD20 (Gazyva)

anti-HER2 (Herceptin; Kadcyla; Perjeta)

various chemotherapies

lenalidomide

rociletinib* (Clovis)

Antigen presentation

T-Vec oncolytic viruses* (Amgen)

INFa

anti-CD40

CMB305 vaccine* (Immune Design)

Priming & activation

anti-CEA-IL2v FP

anti-OX40

anti-CD27* (Celldex)

entinostat* (Syndax)

Antigen release

17

Unlocking full value of CI through combinations

Broadest industry portfolio in oncology

1

Clinical development Preclinical development

* Partnered or external

Established therapies

Schmid et al ECC 2015

Patients with a high tumor IFNg-associated gene signature derive OS

benefit from atezolizumab in NSCLC (POPLAR)

PD-L1 expression

IFN-g producing CD8+ T cells

Genomic instability

Pre-existing immunity INFLAMMED

Gene expression as a predictive biomarker

Presence of INFg-producing CD8 T-cells predicts benefit in NSCLC treated with atezolizumab

1

18

Many types of data will be needed to inform patient care including:

Biomarkers for cancer immunotherapy

Key platforms for discovery and development

mRNA-

expression

Cell signatures,

targets

RNA

sequencing

DNA-mutation

& CNVs

Ex: EGFR, BRAF

DNA

sequencing

Protein-

expression

PDL1, other CI

targets

IHC

Cell free tumor

DNA

Blood DNA

sequencing

Ex: EGFR, BRAF

Other Dx &

patient data

Ex: Imaging,

outcomes etc

EMRs

Mutation burden

& neo-epitope

prediction

Immune cell

types and

signatures

1 2

19

PFS

/ O

S

Time

High

Low

Mutation burden

# o

f m

uta

tio

ns

e.g. Lung tumors

Low

High

1

2

Tumor cell

1

Tumor cell

2

Mutation burden is clinically important

Tumors with higher numbers of mutation tend to be more sensitive to anti-PDL1 / anti-PD1

Hypothetical – partly based on: Rivzi et a l Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer,

Science, 2015; Snyder et al Genetic basis for clinical response to CTLA-4 blockade in melanoma, NEJM 2014

2

20

Conclusions

21

Personalised

healthcare

Molecular

Information

Transformational

time

Diagnostics Pharma

R&D insights

✓ ︎ ✗

Roche Pharma Day 2015

Biosimilar market in context

Fermin Ruiz de Erenchun | Global Head Biologic Strategy Team

Pharmaceuticals Division

2

Biosimilars: Ten years in the making

Regulatory environment

Summary

Biosimilars: Ten years in the making

3

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

EU pioneered the biosimilar

concept

– Six products approved, including the first mAb biosimilar (infliximab)

– Uptake did not achieve

saving expectations

WHO leading global efforts; many emerging countries implemented WHO biosimilar guidelines as a reference

US published final biosimilars guideline

– FDA pathway operating, 3 applications pending, one approval

Biosimilar entry timelines delayed (incl. Herceptin & MabThera)

Differential adoption of WHO biosimilar guidelines led to registration of Non-Comparable Biotherapeutic products (NCBs)*, driven by:

– Capacity issues at National

Regulatory Agencies

– Local economic development policies

*For definition and industry position on NCBs please refer to IFPMA Policy Statement:

http://www.ifpma.org/uploads/media/Non-comparable_Biotherapeutic_Products__English__01.pdfr

0.6 6.3

57.0

80 95

119

219

267

317

254

315

377

0

50

100

150

200

250

300

350

400

MAT Jun 2013 MAT Jun 2014 MAT Jun 2015

Sa

les in

CH

Fm

Infliximab

Somatropin

Filgrastim

Epo

Current biosimilar trends

So far, sales have not achieved initial expectations

4

MAT 870 CHFm (June 2015) (CAGR 25.5%)

*Excludes US as no biosimilars have been approved in the US so far (Omnitrope was approved under the 505(b) pathway)

IMS Health; MAT=moving annual total

Generics vs biosimilars

Clear divide in uptake; complex market drivers

0%

20%

40%

60%

80%

100%

Year 0 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6

5

Market share

Zyprexa (Eli Lilly)

Diovan (Novartis)

Filgrastim

EPO

Somatropin

Small molecule

Virtually disappear

Payer driven: 7 biosimilars

Efficacy visible immediately

High turnover of patients

Driven by price and patient offering

9 innovators, one biosimilar

Efficacy visible only longer term

No switching

Sources: IMS Biosimilar Dashboard, IMS & Roche analysis 1 Volume market share based on EU5 average; 2 Volume market share based on average of France & Germany EPO; 3 Data based on % remaining sales in EU

1

1

2

3

3

Despite 10 years of experience in the EU,

uptake of biosimilars differs across countries

6

Bio

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Reference: Assessing biosimilar uptake and competition in European markets. Report by the IMS Institute for Healthcare Informatics.

HGH=human growth hormone; EPO=Erythropoietin; G-CSF=Granulocyte-colony stimulating factor

Anti-TNF market is not a good analogue for

oncology

7

Anti TNF

Other

biologics

IV Anti-TNF

SC

Anti-TNF

Biological

products used

to treat RA, IDB

& Psoriasis

Infliximab biosimilar could expand beyond it’s accessible market and obtain market

share from Enbrel® and Humira®

Remicade®

Biosimilar accessible market

Small molecules and biologics

Not all the same

• Small molecule policies allow substituting patients only the price counts

• For biologics, European Medicine Agency (EMA) does not provide

guidance on interchangeability and substitution

• Most countries in Europe have specific policies in place to distinguish

between small molecule and biologic medicines

– Biologics must be prescribed by brand name

– Laws against substitution

– Switching remains a physician’s choice

8

Payer environment is one of multiple drivers for

biosimilar uptake

9

Drivers?

Payer environment

Therapeutic area

Innovation and change in

SoC

Physician’s support

10

Biosimilars: Ten years in the making

Regulatory environment

Summary

Biosimilar pathways

in place

Biosimilar pathways

under development

2010 2015

Establishment of biosimilar guidelines has

increased driven by WHO efforts

11

Requirements and study designs are different

for biosimilars vs innovator products

12

Aspects of

development Biosimilar Innovator product

Patient population Sensitive and homogeneous

(patients are models)

Any

Clinical design Comparative versus innovator,

normally equivalence

Superiority vs standard of care

(SoC*)

Study endpoints Sensitive, clinically validated PD

markers

Clinical outcomes data or

accepted/established

surrogates (e.g. OS and PFS)

Safety Similar safety profile to

innovator; no new findings

Acceptable benefit/risk profile

versus SoC*

Immunogenicity Similar immunogenicity profile to

innovator

Acceptable risk/benefit profile

versus SoC*

Extrapolation Possible if justified Not allowed

* In some cases SoC may not exist

How should extrapolation risk be managed?

The regulator’s perspective

13

Analytical

Non-clinical

Clinical

How should extrapolation risk be managed?

The physicians’ perspective

14

Analytical

Non-clinical

Clinical

Analytical

Clinical

Non-clinical

I would like to

see a phase III

trial for each

indication

What is the right patient population to establish

clinical similarity to Herceptin?

15

Topic Metastatic population

(advanced BC)

Neoadjuvant/Adjuvant population

(early BC)

PK Affected by patient`s status & tumor

burden

Homogeneous population can be

selected

PD Clinically validated PD marker not available

Clinical

efficacy/safety • Difficult to select homogeneous group

• Need to control and stratify for multiple

factors (e.g. prior use of chemotherapy,

performance status…)

• Population with heterogeneous

characteristics affecting final clinical

outcome

Populations less likely to be confounded by

baseline characteristics and external

factors

Immunogenicity Immune system affected by performance

status and concomitant chemotherapies

received

Immune system impaired during

chemotherapy cycles, but likely to

recover to normal status thereafter

mBC Phase III Start

Date

Regulatory

Filing

eBC Phase III Start

Date

Celltrion Q2 2010 Q1 2014

Mylan Q4 2012

Pfizer Q4 2013 Q2 2014

Samsung Q2 2014

Amgen Q4 2013

Pfizer

Samsung

2011 2012 2013 2014 2010

mBC

eBC

Initiation of

clinical trial(s)

Celltrion Mylan Pfizer

Celltrion

Amgen

The regulatory thinking is evolving

The Herceptin case

16

17

Biosimilars: Ten years in the making

Regulatory environment

Summary

Generics, biosimilars: Not all the same

18

• Small molecules: Policies allow fast penetration of generics

• Biosimilars: Countries in Europe have specific policies in place to distinguish

between small molecule and biologic medicines

– Biologics must be prescribed by brand name, laws against automatic

substitution, switching remains a physician’s choice, EMA - no guidance

on interchangeability

– After 10 years of experience in the EU, uptake of biosimilars differ heavily

across countries

• Regulatory environment: Still evolving with authorities in the process of finally

establishing frameworks; case by case decisions likely