p 1 tocilizumab arthritis advisory committee hoffmann-la roche inc. july 29, 2008

P 1

TocilizumabTocilizumabArthritis Advisory CommitteeArthritis Advisory Committee

Hoffmann-La Roche Inc.Hoffmann-La Roche Inc.July 29, 2008 July 29, 2008

P 2

TocilizumabTocilizumabIntroductionIntroduction

Jonathan Leff, MDJonathan Leff, MDVice President and Clinical Development Head, Vice President and Clinical Development Head,

Inflammation Disease Biology AreaInflammation Disease Biology Area

P 3

Proposed IndicationProposed Indication

ACTEMRA (tocilizumab) is indicated for:ACTEMRA (tocilizumab) is indicated for:

• Reducing signs and symptoms in adult patients with Reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who moderately to severely active rheumatoid arthritis who had an inadequate response to one or more DMARDs had an inadequate response to one or more DMARDs or TNF antagonists or in whom DMARDs are not or TNF antagonists or in whom DMARDs are not considered appropriate considered appropriate

• Can be used alone or in combination with Can be used alone or in combination with methotrexate or other DMARDs methotrexate or other DMARDs

• Should not be used in combination with other biologicsShould not be used in combination with other biologics

P 4

Dosage and AdministrationDosage and Administration

DoseDose

• 8 mg/kg intravenously once every 4 weeks8 mg/kg intravenously once every 4 weeks

General Dose AdviceGeneral Dose Advice

• 8 mg/kg is consistently more efficacious than 4 mg/kg 8 mg/kg is consistently more efficacious than 4 mg/kg in a range of RA patientsin a range of RA patients

• Reduction from 8 mg/kg to 4 mg/kg may be considered Reduction from 8 mg/kg to 4 mg/kg may be considered for management of dose related laboratory changes for management of dose related laboratory changes including elevated liver enzymes, neutropenia, and including elevated liver enzymes, neutropenia, and thrombocytopeniathrombocytopenia

• In DMARD-IR patients, 4 mg/kg may be considered In DMARD-IR patients, 4 mg/kg may be considered followed by an increase to 8 mg/kg based on clinical followed by an increase to 8 mg/kg based on clinical responseresponse

P 5

TocilizumabTocilizumab

• Humanized mAb IgG1 Humanized mAb IgG1 (MW ~150 kd)(MW ~150 kd)

• Key Features:Key Features:

– Binds soluble and Binds soluble and membrane bound IL-6R membrane bound IL-6R

– Weak/no CDC* or Weak/no CDC* or ADCC** effector ADCC** effector functions (functions (in vitroin vitro))

Heavy chain

Light chain

CDR region

*CDC: complement-dependent cytotoxicity*CDC: complement-dependent cytotoxicity**ADCC: antibody-dependent cellular cytotoxicity**ADCC: antibody-dependent cellular cytotoxicity

P 6

IL-6 is Produced by Multiple Cell Types and Is IL-6 is Produced by Multiple Cell Types and Is Associated with Numerous Biologic ActivitiesAssociated with Numerous Biologic Activities1,21,2

Monocytes/macrophages

T-cell activation

Endothelial cells Mesenchymal cells,fibroblasts/

synoviocytes

Hepatocytes

Acute-phase responseHepcidin, CRP

↓ CYP450Maturation ofmegakaryocytes

Thrombocytosis

Osteoclast activationBone resorption

B-cells

Hyper--globulinemiaAuto-antibodies (RF)

Adapted from 1 Firestein GS. Adapted from 1 Firestein GS. Nature.Nature. 2003; 423:356-361. 2003; 423:356-361. 2 Smolen JS, et al. 2 Smolen JS, et al. Nat Rev Drug DiscNat Rev Drug Disc. 2003; 2:473-488. . 2003; 2:473-488.

IL-6

P 7

IL-6 Has Numerous Articular Effects in RAIL-6 Has Numerous Articular Effects in RA1,21,2

Synoviocytes

Osteoclast activationbone resorption

Endothelial cells

VEGF

Pannus formationPannus formation

Joint destructionJoint destruction

Mediation of chronicMediation of chronicinflammationinflammation

IL-6IL-6Macrophage

T-cell

B-cell

Neutrophil

AntibodyAntibodyproductionproduction

Adapted from 1 Choy E. Adapted from 1 Choy E. Rheum Dis Clin North AmRheum Dis Clin North Am. 2004;30:405–415. . 2004;30:405–415. 2 Gabay C. 2 Gabay C. Arthritis Res Ther.Arthritis Res Ther. 2006;8(suppl 2):S3. 2006;8(suppl 2):S3.

P 8

IL-6 Mechanism of Action IL-6 Mechanism of Action Competitive Inhibition by TocilizumabCompetitive Inhibition by Tocilizumab

Signaling via the mIL-6R: Signaling via the mIL-6R: Restricted expression on hepatocytes, Restricted expression on hepatocytes,

neutrophils, subsets of T-cells neutrophils, subsets of T-cells

Trans-signaling via the sIL-6R: Trans-signaling via the sIL-6R: Expands the IL-6 responsiveness to all Expands the IL-6 responsiveness to all

cells expressing gp130 signaling complexcells expressing gp130 signaling complex

Signaling of IL-6 via Membrane Bound and Soluble ReceptorsSignaling of IL-6 via Membrane Bound and Soluble Receptors

Adapted from Rose-John S, Adapted from Rose-John S, Expert Opinion on Ther TargetsExpert Opinion on Ther Targets 2007, Vol. 11, 613-624 2007, Vol. 11, 613-624

P 9

Tocilizumab Clinical Tocilizumab Clinical PharmacologyPharmacology

Half-life (concentration-dependent): Half-life (concentration-dependent):

• 1.8 – 11.4 days at 4 mg/kg 1.8 – 11.4 days at 4 mg/kg

• 3.8 -12.9 days at 8 mg/kg 3.8 -12.9 days at 8 mg/kg

MetabolismMetabolism

• Catabolized in the reticuloendothelial system like endogenous IgGCatabolized in the reticuloendothelial system like endogenous IgG

Drug InteractionDrug Interaction

• Monitoring of drugs that are metabolized by CYPs (except 2D6) Monitoring of drugs that are metabolized by CYPs (except 2D6) with narrow therapeutic index or where the dose is individually with narrow therapeutic index or where the dose is individually adjusted is advisedadjusted is advised

4 mg/kg4 mg/kg 8 mg/kg8 mg/kg

AUCAUC28d, 28d, mgmghr/mLhr/mL 13 ± 613 ± 6 34 ± 1534 ± 15

CCmaxmax, , g/mLg/mL 88 ± 4188 ± 41 181 ± 85181 ± 85

CCminmin, , g/mLg/mL 1.47 ± 2.071.47 ± 2.07 9.52 ± 10.19.52 ± 10.1

P 10

Anti-TNF-α TherapyAnti-TNF-α Therapy

• First therapy since First therapy since MTX to dramatically MTX to dramatically improve signs and improve signs and symptomssymptoms

• Including radiographic Including radiographic responseresponse

B-Cell TherapyB-Cell Therapy

• Another mechanistic Another mechanistic option for some option for some patientspatients

Achieving Satisfactory Patient Treatment Achieving Satisfactory Patient Treatment Requires Multiple Treatment OptionsRequires Multiple Treatment Options

Early and intensive treatment with NSAIDs, methotrexate, Early and intensive treatment with NSAIDs, methotrexate, and/or traditional DMARDs with corticosteroids, and/or traditional DMARDs with corticosteroids,

helps to reduce pain and inflammationhelps to reduce pain and inflammation

There Is a Need for Therapies with New Mechanisms

Selective Modulation Selective Modulation of Co-stimulatory of Co-stimulatory

ActivationActivation

• Another mechanistic Another mechanistic option for some option for some patientspatients

P 11

Regulatory Status Regulatory Status –– Japan Japan

• Tocilizumab co-development with Chugai Tocilizumab co-development with Chugai Pharmaceutical Co., Ltd. globallyPharmaceutical Co., Ltd. globally

• Approval in Japan for treatment of adult RA, Approval in Japan for treatment of adult RA, sJIA, pJIA and Castleman’s diseasesJIA, pJIA and Castleman’s disease

– Signs and symptoms and inhibition Signs and symptoms and inhibition of progression of structural joint damageof progression of structural joint damage

– Patients treated for up to 5 years Patients treated for up to 5 years with tocilizumab with tocilizumab

P 12

• MTX InadequateMTX InadequateResponder (WA 17822)Responder (WA 17822)

• MTX Inadequate MTX Inadequate Responder – X-ray Responder – X-ray (WA17823) (WA17823)

• DMARD Inadequate DMARD Inadequate Responder (WA18063)Responder (WA18063)

Overview of Roche Clinical Overview of Roche Clinical Development ProgramDevelopment Program

• Dose-findingDose-finding– MonotherapyMonotherapy

– Combination Combination with MTXwith MTX(LRO301)(LRO301)

• WA18695 WA18695

• WA18696WA18696

• Anti-TNF Inadequate Anti-TNF Inadequate Responder (WA18062)Responder (WA18062)

• Limited or No MTX Limited or No MTX Exposure (WA 17824)Exposure (WA 17824)

Phase IIIPhase III

• sJIAsJIA

• pJIA (planned)pJIA (planned)

Phase IIPhase II Open-Label Open-Label ExtensionExtensionStudiesStudies

Other StudiesOther Studies

P 13

Tocilizumab: Roche Safety DatabaseTocilizumab: Roche Safety Database

Exposure in five pivotal DB, randomized, controlledExposure in five pivotal DB, randomized, controlledphase III studies and two long-term extensions:phase III studies and two long-term extensions:

• 3,778 pts ≥ 1 dose of TCZ (4,142 pts years)3,778 pts ≥ 1 dose of TCZ (4,142 pts years)

Exposure to TCZ: reported in patient years, first to last dose of TCZ + 28 daysExposure to TCZ: reported in patient years, first to last dose of TCZ + 28 days

8 mg/kg Exposure8 mg/kg Exposure 4 mg/kg Exposure4 mg/kg Exposure

2,792 ≥ 6-Months2,792 ≥ 6-Months

2,016 ≥ 12 months2,016 ≥ 12 months

491 ≥ 24 months491 ≥ 24 months

546 ≥ 6-Months546 ≥ 6-Months

Control TreatmentControl Treatment

979 ≥ 6-Months979 ≥ 6-Months

Robust Risk Management Plan Proposed

P 14

Presentation OutlinePresentation Outline

Introduction/Introduction/OverviewOverview Jonathan Leff, MDJonathan Leff, MD

EfficacyEfficacy Kenneth Bahrt, MDKenneth Bahrt, MD

SafetySafety Joel Krasnow, MDJoel Krasnow, MD

Risk Mitigation/ Risk Mitigation/ PharmacovigilancePharmacovigilance Philippe Van der Auwera, MD, PhDPhilippe Van der Auwera, MD, PhD

SummarySummary Kenneth Bahrt, MDKenneth Bahrt, MD

P 15

Roche DelegationRoche Delegation

PresentersPresenters

• Jonathan Leff, MD, Jonathan Leff, MD, Clinical ScienceClinical Science

• Kenneth Bahrt, MD, Kenneth Bahrt, MD, Global Medical Director, Global Medical Director, Autoimmunity (Efficacy)Autoimmunity (Efficacy)

• Joel Krasnow, MD, Joel Krasnow, MD, Clinical Science (Safety)Clinical Science (Safety)

• Philippe Van der Auwera, MDPhilippe Van der Auwera, MDGlobal Head, Drug SafetyGlobal Head, Drug Safety

RespondersResponders

• Emma Alecock, BiostatisticsEmma Alecock, Biostatistics

• Claire Davies, Clinical ScienceClaire Davies, Clinical Science

• Yamo Deniz, MD, Clinical ScienceYamo Deniz, MD, Clinical Science

• Matthew Lamb, PharmD, RegulatoryMatthew Lamb, PharmD, Regulatory

• Mark T. Marino, MD, Clinical Mark T. Marino, MD, Clinical PharmacologyPharmacology

• Osamu Okuda, PhD, Chugai Ltd. Osamu Okuda, PhD, Chugai Ltd.

• Ravi Rao, MD, PhD, Clinical ScienceRavi Rao, MD, PhD, Clinical Science

• Karen Wilcock, PhD, EpidemiologyKaren Wilcock, PhD, Epidemiology

• Michael Winter, PhD, ToxicologyMichael Winter, PhD, Toxicology

P 16

ConsultantsConsultants

Paul Watkins, MDPaul Watkins, MD

Verne S. Caviness Verne S. Caviness Distinguished Distinguished Professor of MedicineProfessor of Medicine

Hepatologist, Director, Hepatologist, Director, Translational Translational and Clinical and Clinical Sciences InstituteSciences Institute

University of University of North Carolina, North Carolina, Chapel HillChapel Hill

Naveed Sattar, MD, Naveed Sattar, MD, PhD, FRCP (Glas), PhD, FRCP (Glas), FRCPathFRCPath

Professor of Metabolic Professor of Metabolic MedicineMedicine

British Heart FoundationBritish Heart FoundationGlasgow CardiovascularGlasgow CardiovascularResearch CentreResearch Centre

University of GlasgowUniversity of Glasgow

Wayne Schwesinger, MDWayne Schwesinger, MD

Director and Chief, General Surgery B and Surgical EndoscopyThe University of Texas Health Science CenterSan Antonio, Texas

P 17

Tocilizumab: EfficacyTocilizumab: Efficacy

Kenneth Bahrt, MDKenneth Bahrt, MD

Global Medical Director, AutoimmunityGlobal Medical Director, Autoimmunity

P 18

AgendaAgenda

• Phase IIPhase II

• Phase III Efficacy OverviewPhase III Efficacy Overview

• Tocilizumab in CombinationTocilizumab in Combination

– Patients with Inadequate Response to DMARDsPatients with Inadequate Response to DMARDs

– Patients with Inadequate ResponsePatients with Inadequate Responseto Anti-TNF Therapyto Anti-TNF Therapy

• Tocilizumab MonotherapyTocilizumab Monotherapy

• ConclusionConclusion

P 19

AgendaAgenda

• Phase II Phase II







P 20

Randomization (n=359)Randomization (n=359)ScreeningScreening Treatment PeriodTreatment Period Follow-upFollow-up

00

WeekWeek

8844 1212 2020161622 66 1414FUFU

1010 1818InfusionInfusion

Primary endpointPrimary endpoint

FUFU Safety follow upSafety follow up

Phase IIPhase IILRO301 Study: DesignLRO301 Study: Design

TCZ 4 mg/kg + MTX (n=49) TCZ 4 mg/kg + MTX (n=49)

TCZ 8 mg/kg + MTX (n=50) TCZ 8 mg/kg + MTX (n=50)

TCZ 4 mg/kg (n=54) TCZ 4 mg/kg (n=54)


Placebo + MTX (n=49)Placebo + MTX (n=49)


TCZ 2 mg/kg + MTX (n=52)TCZ 2 mg/kg + MTX (n=52)

P 21

Combination – ITT PopulationCombination – ITT PopulationMonotherapy – ITT PopulationMonotherapy – ITT Population

*p<0.05, **p<0.001 TCZ vs. Placebo + MTX*p<0.05, **p<0.001 TCZ vs. Placebo + MTX

Phase II, LRO301Phase II, LRO301ACR Responses – Week 16ACR Responses – Week 16

ACR Response (%)ACR Response (%)

ACRACRPlaceboPlacebo+ MTX + MTX (n=49)(n=49)

2020 5050 7070

41

29

16

TocilizumabTocilizumab2 mg/kg2 mg/kg(n=53) (n=53)

2020 5050 7070

31

62

TocilizumabTocilizumab8 mg/kg 8 mg/kg (n=52)(n=52)

2020 5050 7070

41

16

63*

TocilizumabTocilizumab4 mg/kg4 mg/kg+ MTX + MTX (n=49)(n=49)

2020 5050 7070

37

12

63*

TocilizumabTocilizumab4 mg/kg4 mg/kg(n=54) (n=54)

2020 5050 7070

28

6

61*

TocilizumabTocilizumab2 mg/kg 2 mg/kg + MTX + MTX (n=52)(n=52)

2020 5050 7070

32

14

64*

TocilizumabTocilizumab8 mg/kg 8 mg/kg + MTX + MTX (n=50)(n=50)

2020 5050 7070

74**

53*

37*

0

10

20

30

40

50

60

70

80

P 22

Efficacy OutlineEfficacy Outline








P 23TOTALTOTALN=4211N=4211

Overview of Phase III Overview of Phase III Clinical Development Program in RAClinical Development Program in RA

Monotherapy: 6 m MTX FreeMonotherapy: 6 m MTX Free

(WA17824)(WA17824)

MTX Inadequate ResponderMTX Inadequate Responder

(WA17822)(WA17822)

MTX Inadequate ResponderMTX Inadequate Responder

(WA17823) 1 & 2 yr PJD & PF*(WA17823) 1 & 2 yr PJD & PF*

DMARD Inadequate ResponderDMARD Inadequate Responder

(WA18063)(WA18063)

Anti-TNF FailuresAnti-TNF Failures

(WA18062)(WA18062)

Reducing Reducing Signs & Signs &

Symptoms Symptoms at 6 mat 6 m

* * PJD = Prevention Joint DamagePJD = Prevention Joint DamagePF = Physical FunctionPF = Physical Function

**As of Oct 07**As of Oct 07

EligibleEligibleto Enterto Enter

N=2,715 N=2,715 (90%)(90%)

Completed Completed WK 24 on WK 24 on assigned assigned therapy = therapy =

2,398 2,398 (80%)(80%)

Entered Entered Escape = Escape = 317 (10%)317 (10%)

Ongoing Ongoing Open-Label Open-Label Extension Extension StudiesStudies(WA18695,(WA18695, WA18696) WA18696)

EnteredEnteredN=2562N=2562

Total Total WithdrawnWithdrawnN=360 (14.1%)N=360 (14.1%)

Insufficient Insufficient Efficacy**Efficacy**N=75 (2.9%)N=75 (2.9%)

AEs**AEs**N=158 (6.2%)N=158 (6.2%)

N=1,220N=1,220

N=499N=499

N=1,196N=1,196OngoingOngoing

N=623N=623

N=673N=673

P 24

Phase III Studies Phase III Studies Primary & Secondary EndpointsPrimary & Secondary Endpoints

DMARD Inadequate Responders (IR)DMARD Inadequate Responders (IR) MonotherapyMonotherapyAnti-TNF IRAnti-TNF IR

EULAR ResponseEULAR Response

SF-36 PCSSF-36 PCS

FACIT-FFACIT-F

HemoglobinHemoglobin

DAS28 < 2.6DAS28 < 2.6

DAS28DAS28

ACR ComponentsACR Components

ACR70ACR70

ACR50ACR50

ACR20ACR20

WA17824WA17824WA18062WA18062WA18063WA18063WA17823WA17823WA17822WA17822Endpoint at Week 24Endpoint at Week 24

TCZ Statistically Superior to Control. TCZ Statistically Superior to Control. Adjusted for multiplicity using pre-defined hierarchyAdjusted for multiplicity using pre-defined hierarchy

SF-36 MCSSF-36 MCS

No No Non-Inferiority Non-Inferiority

Margin Margin Pre-definedPre-defined

8 8 mg/kgmg/kg

8 8 mg/kgmg/kg

8 8 mg/kgmg/kg

88mg/kgmg/kg

88mg/kgmg/kg

XX

XX

XXXX

XX

XX

XX

XX

XX

XX

XX

XX

4 4 mg/kgmg/kg

XX

XX

XX

XX

XX

XX

XX

XX

44mg/kgmg/kg

44mg/kgmg/kg

XXXX

P 25









P 26

DMARD Inadequate Responders:DMARD Inadequate Responders:Combination StudiesCombination Studies

Double-Blind, Randomized, Placebo-ControlledDouble-Blind, Randomized, Placebo-Controlled

* ~ 50% pts on MTX alone* ~ 50% pts on MTX alone ~ 50% pts on other DMARDs alone or in combination with MTX~ 50% pts on other DMARDs alone or in combination with MTX

Pooled DMARD Inadequate RespondersPooled DMARD Inadequate Responders

WA17822WA17822N=623N=623

WA17823WA17823N=1196N=1196

WA18063WA18063N=1220N=1220

Background MedicationBackground Medication + MTX+ MTX + MTX+ MTX + DMARDs*+ DMARDs*

Tocilizumab DosesTocilizumab Doses 4, 8 mg/kg4, 8 mg/kg 4, 8 mg/kg4, 8 mg/kg 8 mg/kg8 mg/kg

ControlControl PlaceboPlacebo PlaceboPlacebo PlaceboPlacebo

Primary Endpoint Primary Endpoint (ACR 20)(ACR 20)

2424WeeksWeeks

InterimInterim24 Weeks24 Weeks 24 Weeks24 Weeks

Patient PopulationPatient Population MTX IRMTX IR MTX IRMTX IR DMARD IRDMARD IR

P 27

DMARD Inadequate Responders:DMARD Inadequate Responders: Core Study Design – Core Study Design – WA17822WA17822WA18063WA18063

MethotrexateMethotrexatecontinuedcontinued

Other DMARDsOther DMARDsstoppedstopped

ScreeningScreening6-Months 6-Months

PlaceboPlacebo

TCZ 8 mg/kgTCZ 8 mg/kg

RandomizationRandomization1:1:11:1:1

Day 1Day 1

Primary EndpointPrimary Endpoint• ACR 20ACR 20

Double-blindDouble-blind Open-label Open-label

Treated Treated

TCZ 8 mg/kgTCZ 8 mg/kgq 4 wksq 4 wks

TCZ 4 mg/kg (N=213) TCZ 4 mg/kg (N=213)

DMARDsDMARDsContinuedContinued

RandomizationRandomization2:12:1

Escape option at week 16:Escape option at week 16: TCZ 8 mg/kgTCZ 8 mg/kgIncrease dose of background DMARD or change/add background DMARDIncrease dose of background DMARD or change/add background DMARD

(N=205) (N=205)

(N=204)(N=204)

(N=803) (N=803)

(N=413)(N=413)

P 28

DMARD Inadequate Responders:DMARD Inadequate Responders: Core Study Design – WA17823Core Study Design – WA17823

Methotrexate Methotrexate continuedcontinued

Other DMARDs Other DMARDs stoppedstopped

ScreeningScreening 6-Months6-Months

Placebo (N=393)Placebo (N=393)

TCZ 8 mg/kg (N=398)TCZ 8 mg/kg (N=398)


Day 1Day 1Primary Primary EndpointEndpoint

• ACR 20ACR 20

Double-blindDouble-blind

TreatedTreated TCZ 4 mg/kg (N=399)TCZ 4 mg/kg (N=399)

24 Months24 MonthsPrimary Primary EndpointEndpoint• Structural Structural

damagedamage• Physical Physical

functionfunction

Double-blindDouble-blind Open LabelOpen Label

Primary Primary EndpointEndpoint• Structural Structural

damagedamage• Physical Physical

functionfunction

TCZ 8 mg/kg TCZ 8 mg/kg q 4 wksq 4 wks

12 Months12 Months

Escape option from week 16: TCZEscape option from week 16: TCZ

P 29

DMARD Inadequate Responders:DMARD Inadequate Responders:Baseline CharacteristicsBaseline Characteristics

ITT PopulationITT Population

WA17822*WA17822* WA17823*WA17823* WA18063*WA18063*Pooled

DMARD IR*

Female (%)Female (%) 8585 8282 8181 8282

Age, Mean, YrsAge, Mean, Yrs 5151 5353 5353 5353

Duration RA, Mean, YrsDuration RA, Mean, Yrs 7.57.5 9.39.3 9.89.8 9.39.3

RF Positive (%)RF Positive (%) 8383 8383 7878 8080

DAS28, MeanDAS28, Mean 6.86.8 6.66.6 6.76.7 6.76.7

SJC/TJC, MeanSJC/TJC, Mean 20/3220/32 17/2917/29 20/3020/30 19/3019/30

CRP, Mean, mg/dLCRP, Mean, mg/dL 2.62.6 2.32.3 2.62.6 2.52.5

HAQ, MeanHAQ, Mean 1.61.6 1.51.5 1.51.5 1.51.5

No. Prior DMARDs, MeanNo. Prior DMARDs, Mean 1.51.5 1.61.6 1.61.6 1.61.6

Oral CS/NSAIDs (%)Oral CS/NSAIDs (%) 55/6555/65 61/7161/71 51/7251/72 55/7055/70

MTX Dose, Mean, mg/WkMTX Dose, Mean, mg/Wk 14.514.5 15.415.4 14.714.7 15.015.0

* 8 mg/kg TCZ arm* 8 mg/kg TCZ arm

P 30

DMARD Inadequate Responders: DMARD Inadequate Responders: Disposition at Week 24Disposition at Week 24

All PatientsAll Patients

Number (%) of PatientsNumber (%) of Patients

Placebo Placebo + DMARD+ DMARDN=1013N=1013

4 mg/kg TCZ 4 mg/kg TCZ + MTX + MTX N=615N=615

8 mg/kg TCZ 8 mg/kg TCZ + DMARD+ DMARDN=1411N=1411

Completed 24 weeks Completed 24 weeks (inc. Escape)(inc. Escape) 915 (90)915 (90) 559 (91)559 (91) 1309 (93) 1309 (93)

EscapeEscape 263 (26)263 (26) 98 (16)98 (16) 79 (6)79 (6)

Discontinued*Discontinued* 82 (8)82 (8) 49 (8)49 (8) 98 (7)98 (7)

Adverse EventsAdverse Events 19 (2)19 (2) 29 (5)29 (5) 63 (4)63 (4)

DeathDeath 3 (<1)3 (<1) 00 2 (<1)2 (<1)

Lack of EfficacyLack of Efficacy 27(3)27(3) 3 (<1)3 (<1) 4(<1)4(<1)

Failure to ReturnFailure to Return 3 (<1)3 (<1) 2 (<1)2 (<1) 2(<1)2(<1)

Refused TreatmentRefused Treatment 22 (2)22 (2) 13 (2)13 (2) 25 (2)25 (2)

Protocol ViolationProtocol Violation 5 (<1)5 (<1) 1 1 (<1(<1)) 00

OtherOther 3 (<1)3 (<1) 1 1 (<1(<1)) 2 (<1)2 (<1)

* Excludes discontinuations on escape* Excludes discontinuations on escape

P 31

0%

10%

20%

30%

40%

50%

60%

70%

******

******

******

******

******

******

4 mg/kg4 mg/kg+ MTX+ MTXN=213N=213

PlaceboPlacebo+ MTX+ MTXN=204N=204


2020 5050 7070 2020 5050 7070 2020 5050 7070ACRACR

DMARD Inadequate Responders: DMARD Inadequate Responders: ACR20, ACR50, ACR70 Response Rates at Week 24ACR20, ACR50, ACR70 Response Rates at Week 24


WA17822, WA17823, WA18063WA17822, WA17823, WA18063

*** p<0.0001, TCZ vs. placebo +MTX or DMARD *** p<0.0001, TCZ vs. placebo +MTX or DMARD

WA17822WA17822 WA17823WA17823 WA18063WA18063



4 mgkg4 mgkg+ MTX+ MTXN=399N=399

2020 5050 7070 2020 5050 7070 2020 5050 7070

************

******

******

PlaceboPlacebo+ DMARD+ DMARD

N=413N=413

2020 5050 7070 2020 5050 7070

8 mg/kg8 mg/kg+ DMARD+ DMARD

N=803N=803

******

******

******

P 32

PlaceboPlacebo+ DMARD+ DMARD

n=322n=322

8 mg/kg8 mg/kg+ DMARD+ DMARD

n=716n=716

8 mg/kg8 mg/kg+ MTX+ MTXn=315n=315


PlaceboPlacebo+ MTX+ MTXn=212n=212



PlaceboPlacebo+ MTX+ MTXn=121n=121

WA17822WA17822 WA17823WA17823 WA18063WA18063

33.3%***

27.5%***30.2%***

3.4%

17.8%

3.8%

13.5%**

0.8%0%

10%

20%

30%

40%

** p<0.01,*** p<0.0001, TCZ vs. placebo +MTX or DMARD** p<0.01,*** p<0.0001, TCZ vs. placebo +MTX or DMARD

DMARD Inadequate Responders: DMARD Inadequate Responders: DAS28 < 2 .6 Response at Week 24DAS28 < 2 .6 Response at Week 24


WA17822, WA17823, WA18063WA17822, WA17823, WA18063

P 33 ** p<0.05 4 mg vs. 8 mg TCZ p<0.05 4 mg vs. 8 mg TCZ **** p<0.01 4 mg vs. 8 mg TCZp<0.01 4 mg vs. 8 mg TCZ

PlaceboPlacebo+ DMARD+ DMARD(N=1010)(N=1010)

4 mg/kg4 mg/kg+ MTX+ MTX

(N=612)(N=612)

8 mg/kg8 mg/kg+ DMARD+ DMARD(N=1406)(N=1406)



(N=612)(N=612)




(N=612)(N=612)


DMARD Inadequate RespondersDMARD Inadequate Responders: ACR20, : ACR20, ACR50, ACR70 Response Rates at Week 24ACR50, ACR70 Response Rates at Week 24

Pooled, ITT PopulationPooled, ITT Population

26

10

2

50

27

11

59

37

19

0

10

20

30

40

50

60

70

***

***

***

***

***

***

*** p<0.0001, TCZ Vs. placebo + DMARD*** p<0.0001, TCZ Vs. placebo + DMARD

*

**

*

(%) of ACR(%) of ACRResponders Responders

ACR ResponseACR Response

ACR20ACR20 ACR50ACR50 ACR70ACR70

P 34

AgeAge

GenderGender

RaceRace

RegionRegion

Duration of RADuration of RA

RF + or –RF + or –

PlaceboPlaceboBetterBetter

TCZ 8 mg/kgTCZ 8 mg/kgBetterBetter

(N=2416)(N=2416)All PatientsAll Patients

< 50 Years (N=874)< 50 Years (N=874)

50-64 Years (N=1142)50-64 Years (N=1142)

65-75 Years (N=352)65-75 Years (N=352)

> 75 Years (N=48)> 75 Years (N=48)

Male (N=429)Male (N=429)Female (N=1987)Female (N=1987)

Amer Indian or Alaskan Native (N=185)Amer Indian or Alaskan Native (N=185)

Asian (N=215)Asian (N=215)

Black (N=103)Black (N=103)

White (N=1732)White (N=1732)

Other (N=181)Other (N=181)

North America (N=798)North America (N=798)

South America (N=547)South America (N=547)

Europe (N=795)Europe (N=795)

Rest of World (N=276)Rest of World (N=276)

≤ ≤ 2 Years (N=482)2 Years (N=482)

> 2- ≤ 5 Years (N=490)> 2- ≤ 5 Years (N=490)

> 5 - ≤ 10 Years (N=576)> 5 - ≤ 10 Years (N=576)

> 10 Years (N=867)> 10 Years (N=867)

Positive (N=1901)Positive (N=1901)Negative (N=515)Negative (N=515)

Odds Ratio (95% CI)Odds Ratio (95% CI)

-1-1 00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515

DMARD Inadequate Responders: ACR20 Subgroup DMARD Inadequate Responders: ACR20 Subgroup Analyses at Week 24, TCZ 8 mg/kg vs. PlaceboAnalyses at Week 24, TCZ 8 mg/kg vs. Placebo


P 35

AgeAge

GenderGender

RaceRace

RegionRegion

Duration of RADuration of RA

RF + or –RF + or –

-1-1 00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515

(N=1622)(N=1622)

< 50 Years (660)< 50 Years (660)

50-64 Years (N=698)50-64 Years (N=698)

65-75 Years (N=232)65-75 Years (N=232)

> 75 Years (N=32)> 75 Years (N=32)

Male (N=278)Male (N=278)

Female (N=1344)Female (N=1344)

Amer. Indian or Alaskan Native (N=110)Amer. Indian or Alaskan Native (N=110)

Asian (N=130)Asian (N=130)

Black (N=68)Black (N=68)

White (N=1163)White (N=1163)

Other (N=151)Other (N=151)

North America (N=437)North America (N=437)

South America (N=384)South America (N=384)

Europe (N=615)Europe (N=615)

Rest of World (N=186)Rest of World (N=186)

≤ ≤ 2 Years (N=317)2 Years (N=317)

> 2 - ≤5 Years (N=337)> 2 - ≤5 Years (N=337)

> 5 - ≤ 10 Years (N=408)> 5 - ≤ 10 Years (N=408)

> 10 Years (N=560)> 10 Years (N=560)

Positive (N=1265)Positive (N=1265)

Negative (N=357)Negative (N=357)


Odds Ratio (95% CI)Odds Ratio (95% CI)

PlaceboPlaceboBetterBetter

TCZ 4 mg/kgTCZ 4 mg/kgBetterBetter

/ = Confidence Interval is too wide to display on the plot/ = Confidence Interval is too wide to display on the plot

DMARD Inadequate Responders: ACR20 Subgroup DMARD Inadequate Responders: ACR20 Subgroup Analyses at Week 24, TCZ 4 mg/kg vs. PlaceboAnalyses at Week 24, TCZ 4 mg/kg vs. Placebo


P 36

DMARD Inadequate RespondersDMARD Inadequate Responders: ACR20 Response : ACR20 Response at Week 24 by Background DMARDat Week 24 by Background DMARD


10

20

30

40

50

60

70

80

Placebo + DMARD 8 mg/kg + DMARD% ACR20% ACR20RespondersResponders

WA18063WA18063

26261515 8038031521521212333335357878456456 413413828244171716165050224224

MTXMTX Leflun-Leflun-omideomide

Sulfasal-Sulfasal-azineazine

Chloroquine/Chloroquine/Hydro-Hydro-

xychloroquinexychloroquine

Azathio-Azathio-prineprine

TwoTwoDMARDsDMARDs

3 or More3 or MoreDMARDsDMARDs

Total ITT Total ITT PopulationPopulation

N=N=

P 37

0

10

20

30

40

50

60

70

80

2 4 8 12 16 20 24

ACR50ACR20ACR70% Responders% Responders

Visit (Week)Visit (Week)

8 mg/kg + DMARD (N=1406)8 mg/kg + DMARD (N=1406)

4 mg/kg + MTX (N=612)4 mg/kg + MTX (N=612)

Placebo + DMARD (N=1010)Placebo + DMARD (N=1010)







DMARD Inadequate RespondersDMARD Inadequate Responders:: Response Over TimeResponse Over Time


P 38

0

0.5

1

1.5

2

2.5

3

0 2 4 8 12 16 20 24

CRP (mg/dL) by VisitCRP (mg/dL) by Visit ESR (mm/h) by VisitESR (mm/h) by Visit

8 mg/kg + MTX8 mg/kg + MTX


Placebo + MTXPlacebo + MTX

Mean CRPMean CRP(mg/dL)(mg/dL)

0

10

20

30

40

50

60

0 2 4 8 12 16 20 24

Mean ESRMean ESR(mm/h)(mm/h)


ULNULN

WA17822WA17822




Placebo + MTXPlacebo + MTX

DMARD Inadequate Responders:DMARD Inadequate Responders:Acute Phase Reactants by VisitAcute Phase Reactants by Visit

Safety Population Safety Population

P 39

DMARD Inadequate Responders: DMARD Inadequate Responders: Percentage Change in ACR Core Set at Week 24Percentage Change in ACR Core Set at Week 24

Pooled, ITT Population Pooled, ITT Population

-100

-80

-60

-40

-20

0

20

40

60

TJC SJC Pain Pt VAS Ph VAS HAQ CRP

Placebo +DMARD (N=1010) 4 mg/kg TCZ+MTX (N=612) 8 mg/kg TCZ+DMARD (N=1406)

Exploratory Endpoint, *** p<0.0001, TCZ vs. Placebo + DMARDExploratory Endpoint, *** p<0.0001, TCZ vs. Placebo + DMARD

****** ************

******

******

****** ****** ******

******

******************************

P 40

DMARD Inadequate RespondersDMARD Inadequate Responders:: DAS28 Responses at Week 24 DAS28 Responses at Week 24


7

32

47

0

5

10

15

20

25

30

35

40

45

50

Placebo + DMARD(n=655)

4 mg/kg TCZ + MTX(N=460)

8 mg/kg TCZ + DMARD(n=1202)

*** p<0.0001, TCZ vs. Placebo + DMARD*** p<0.0001, TCZ vs. Placebo + DMARD

PercentageResponders

DAS28 ≤ 3.2DAS28 ≤ 3.2

******

******

DAS28 < 2.6DAS28 < 2.6

3

16

31

0

5

10

15

20

25

30

35

Placebo + DMARD(n=655)

4 mg/kg TCZ + MTX(n=460)

8 mg/kg TCZ + DMARD(n=1202)

PercentageResponders

******

******

P 41

2.9

4.85.0

8.8

6.0

9.1

0123456789

10

Physical ComponentPhysical ComponentMental ComponentMental Component

MCS & PCS at Week 24MCS & PCS at Week 24

MCID

** p<0.01, *** p<0.0001, TCZ vs. Placebo + DMARD** p<0.01, *** p<0.0001, TCZ vs. Placebo + DMARD

******

************

****

PlaceboPlacebo+ DMARD+ DMARD(n=638)(n=638)

4 mg/kg4 mg/kg+ MTX+ MTX(n=435)(n=435)

8 mg/kg8 mg/kg+ DMARD+ DMARD(n=1176)(n=1176)

Mean ChangeMean Changefrom BLfrom BL

PlaceboPlacebo+ DMARD+ DMARD(n=638)(n=638)

4 mg/kg4 mg/kg+ MTX+ MTX(n=435)(n=435)

8 mg/kg8 mg/kg+ DMARD+ DMARD(n=1176)(n=1176)

DMARD Inadequate RespondersDMARD Inadequate Responders:: Mean Change from Baseline in SF-36 at Week 24Mean Change from Baseline in SF-36 at Week 24


P 42

40

58** 60***

0

10

20

30

40

50

60

70

80

90

100

4 mg/kg TCZ4 mg/kg TCZ+ MTX (N = 612)+ MTX (N = 612)

0.5

0.8

1.0

1.3

1.5

1.8

0 2 4 8 12 16 20 24

DMARD Inadequate RespondersDMARD Inadequate Responders: : Improvements in Physical FunctionImprovements in Physical Function


HAQ-DI Improved Categorical is an Exploratory Endpoint, HAQ-DI Improved Categorical is an Exploratory Endpoint,

** p<0.01, *** p<0.0001, TCZ vs. Placebo + DMARD** p<0.01, *** p<0.0001, TCZ vs. Placebo + DMARD

Visit (Week)Visit (Week) Improvement ≥ 0.3 Week 24Improvement ≥ 0.3 Week 24

8 mg/kg TCZ 8 mg/kg TCZ + DMARD (N = 1406)+ DMARD (N = 1406)

Placebo + DMARDPlacebo + DMARD(N = 1010)(N = 1010)

Mean HAQ-DIMean HAQ-DIScoreScore

%%RespondersResponders

Placebo Placebo + DMARD+ DMARD(N = 1010)(N = 1010)

4 mg/kg TCZ4 mg/kg TCZ+ MTX + MTX

(N = 612)(N = 612)

8 mg/kg TCZ 8 mg/kg TCZ + DMARD + DMARD (N = 1406)(N = 1406)

P 43

DMARD Inadequate Responders:DMARD Inadequate Responders:Long-Term Long-Term Response Over TimeResponse Over Time

110 110 110 109 108 109 111 105 104 87 67 55 19

152 153 151 150 152 152 153 138 137 123 93 69 26

164 168 167 167 166 166 168 156 156 139 104 76 31

WA17822WA17822

ACR 70ACR 70% Responders% Responders

TCZ 8 mg/kgTCZ 8 mg/kgOpen-labelOpen-label

TCZ 8 mg/kgTCZ 8 mg/kgOpen-labelOpen-label

0

10

20

30

40

50

60

70

80

90

100

8 mg/kg TCZ + MTX8 mg/kg TCZ + MTX 4 mg/kg TCZ + MTX4 mg/kg TCZ + MTX Placebo + MTXPlacebo + MTX

ACR 50ACR 50

N= 110 110 110 109 108 109 111 105 104 87 67 55 19

N= 152 153 151 150 152 152 153 138 137 123 93 69 26

N= 164 168 167 167 166 166 168 156 156 139 104 76 31

2 4 8 12 16 20 24 36 48 60 72 84 96 2 4 8 12 16 20 24 36 48 60 72 84 96

P 44

WA17823: WA17823: One Year Controlled DataOne Year Controlled Data

MTX IRMTX IR

P 45

MTX Inadequate Responders: MTX Inadequate Responders: Disposition at Week 52Disposition at Week 52



PlaceboPlacebo+ MTX+ MTX

N=392 (%)N=392 (%)

TCZ 4 mg/kg TCZ 4 mg/kg + MTX+ MTX

N=399 (%)N=399 (%)

TCZ 8 mg/kgTCZ 8 mg/kg+ MTX+ MTX

N=399 (%)N=399 (%)

Completed 52 WeeksCompleted 52 Weeks(Inc. Escape)(Inc. Escape) 334 (85)334 (85) 344 (86)344 (86) 342 (86)342 (86)

EscapeEscape 195 (50)195 (50) 95 (24)95 (24) 59 (15)59 (15)


Adverse EventsAdverse Events 10 (3)10 (3) 28 (7)28 (7) 30 (8)30 (8)

DeathDeath 1 (<1)1 (<1) 00 3 (<1)3 (<1)

Lack of EfficacyLack of Efficacy 12 (3)12 (3) 1 (<1)1 (<1) 2 (<1)2 (<1)

Failure to ReturnFailure to Return 1 (<1)1 (<1) 3 (<1)3 (<1) 00


Protocol Violation Protocol Violation 1 (<1)1 (<1) 0 0 00

OthersOthers 1 (<1)1 (<1) 2 (<1)2 (<1) 1 (<1)1 (<1)

WA17823WA17823

* Excludes discontinuations on escape* Excludes discontinuations on escape

P 46

***25%

10%

4%

47%

29%

16%

36%

20%

56%

52 52 52 52 52 52 52 52 52

***

***

***

27%

10%

2%

51%

25%

11%

56%

32%

13%

24 24 24 24 24 24 24 24 24

***

******

*** p<0.0001, TCZ vs. Placebo + MTX*** p<0.0001, TCZ vs. Placebo + MTX

WA17823WA17823

% Responders

0%

10%

20%

30%

40%

50%

60%

70%


Week:Week:

Placebo Placebo + MTX+ MTX

4 mg/kg 4 mg/kg + MTX+ MTX








MTX Inadequate Responders: ACR20, ACR50, MTX Inadequate Responders: ACR20, ACR50, ACR70 Response at Week 24 and 52ACR70 Response at Week 24 and 52


P 47

48

33***

18

47***

30

0

5

10

15

20

25

30

35

40

45

50

Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX

Week 24Week 24 Week 52Week 52 Week 24Week 24 Week 52Week 52 Week 24Week 24 Week 52Week 52

WA17823WA17823

% Patients% Patients

MTX Inadequate Responders:MTX Inadequate Responders: DAS28 < 2.6 at Week 24 and 52DAS28 < 2.6 at Week 24 and 52


*** p<0.0001, TCZ vs. Placebo + MTX*** p<0.0001, TCZ vs. Placebo + MTX

P 48

1.13

0.42

0.71

0.13**0.21**

0.34***

0.12**0.17***0.29***

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Genant Modified TotalSharp Score

Erosion Score JSN Score

Mean Change Mean Change from BLfrom BL

Placebo Placebo + MTX + MTX (n=290)(n=290)

TCZ 4 mgTCZ 4 mg+ MTX+ MTX(n=339)(n=339)








WA17823WA17823

** p<0.01, *** p<0.0001, TCZ Vs. Placebo + MTX** p<0.01, *** p<0.0001, TCZ Vs. Placebo + MTX

Genant Modified Total Sharp Score (TSS), mean at BLGenant Modified Total Sharp Score (TSS), mean at BL : : Placebo + MTX = 28.49, TCZ 4 mg/kg + MTX = 28.73, TCZ 8 mg/kg + MTX=28.81Placebo + MTX = 28.49, TCZ 4 mg/kg + MTX = 28.73, TCZ 8 mg/kg + MTX=28.81

MTX Inadequate Responders:MTX Inadequate Responders:Radiographic Scores at Week 52Radiographic Scores at Week 52

Linear Extrapolation of Missing Values – ITT PopulationLinear Extrapolation of Missing Values – ITT Population

P 49







• Tocilizumab Monotherapy Tocilizumab Monotherapy


P 50

Anti-TNF Inadequate Responders:Anti-TNF Inadequate Responders: WA18062 Study DesignWA18062 Study Design

MethotrexateMethotrexatecontinuedcontinued

Other DMARDsOther DMARDsstopped, inc. stopped, inc.

Anti-TNF washout*Anti-TNF washout*

ScreeningScreening

6-Months 6-Months

Placebo (N=160)Placebo (N=160)



Day 1Day 1


Double-blind Open-label

Treated (N=499)

TCZ 8 mg/kg TCZ 8 mg/kg q 4 wksq 4 wks

TCZ 4 mg/kg (N=164)TCZ 4 mg/kg (N=164)

Escape option at week 16: TCZ 8 mg/kgEscape option at week 16: TCZ 8 mg/kg

*Discontinued etanercept ≥ 2 wks, infliximab or adalimumab ≥ 8 wks*Discontinued etanercept ≥ 2 wks, infliximab or adalimumab ≥ 8 wks

P 51

Anti-TNF Inadequate RespondersAnti-TNF Inadequate Responders::Baseline CharacteristicsBaseline Characteristics


WA18062WA18062


4 mg/kg TCZ 4 mg/kg TCZ + MTX+ MTXN=161N=161

8 mg/kg TCZ8 mg/kg TCZ+ MTX+ MTXN=170N=170

Female (%)Female (%) 7979 8181 8484

Age, Mean, YrsAge, Mean, Yrs 5353 5151 5454

Duration RA, Mean, YrsDuration RA, Mean, Yrs 11.411.4 11.011.0 12.612.6

RF Positive (%)RF Positive (%) 7575 7373 7979

DAS28, MeanDAS28, Mean 6.86.8 6.86.8 6.86.8

SJC/TJC, MeanSJC/TJC, Mean 19/3019/30 20/3120/31 19/3219/32

CRP, Mean, mg/dLCRP, Mean, mg/dL 3.73.7 3.13.1 2.82.8

HAQ, MeanHAQ, Mean 1.71.7 1.71.7 1.71.7

No. Prior DMARDs, MeanNo. Prior DMARDs, Mean 2.12.1 2.02.0 1.91.9

Oral CS/NSAIDs (%)Oral CS/NSAIDs (%) 58/5858/58 58/6258/62 52/6252/62

MTX, Mean (mg/wk)MTX, Mean (mg/wk) 16.516.5 16.216.2 15.715.7

P 52

Anti-TNF Inadequate Responders:Anti-TNF Inadequate Responders: TNF Use Prior to StudyTNF Use Prior to Study

Safety PopulationSafety Population




Proportion (%) Pts Failed 1, 2, 3 Anti-TNFs Proportion (%) Pts Failed 1, 2, 3 Anti-TNFs Due to Inadequate Efficacy/ToxicityDue to Inadequate Efficacy/Toxicity

1 Anti-TNF (%)1 Anti-TNF (%) 4848 5050 5353

2 Anti-TNFs (%)2 Anti-TNFs (%) 4040 3737 3232

3 Anti-TNFs (%)3 Anti-TNFs (%) 1212 1212 1515

Proportion (%) Failed Due to:

Toxicity (%)Toxicity (%) 33 44 77

Inadequate efficacy (%)Inadequate efficacy (%) 8282 8080 7878

Toxicity/Efficacy (%)Toxicity/Efficacy (%) 1515 1515 1515

P 53

Anti-TNF Inadequate RespondersAnti-TNF Inadequate Responders: : Disposition at 24 WeeksDisposition at 24 Weeks




N=160* (%)N=160* (%)

4 mg/kg TCZ 4 mg/kg TCZ + MTX + MTX

N=163 (%)N=163 (%)

8 mg/kg TCZ 8 mg/kg TCZ + MTX+ MTX

N=175 (%)N=175 (%)

Completed 24 Weeks Completed 24 Weeks (inc. Escape)(inc. Escape) 127 (79)127 (79) 138 (85)138 (85) 152 (87) 152 (87)

EscapeEscape 66 (41)66 (41) 31 (19)31 (19) 20 (11)20 (11)


Adverse EventsAdverse Events 8 (5)8 (5) 10 (6)10 (6) 11(6)11(6)

DeathDeath 00 00 00

Lack of EfficacyLack of Efficacy 18 (11)18 (11) 5 (3)5 (3) 4 (2)4 (2)

Failure to ReturnFailure to Return 00 4 (2)4 (2) 1 (<1)1 (<1)


Protocol ViolationProtocol Violation 00 3 (2)3 (2) 3 (2)3 (2)

* Excludes discontinuations on Escape* Excludes discontinuations on Escape

P 54

PlaceboPlacebo+ MTX+ MTX(N=158)(N=158)

4 mg/kg4 mg/kg+ MTX+ MTX(N=161)(N=161)


****

PlaceboPlacebo+ MTX+ MTX(N=158)(N=158)



******

PlaceboPlacebo+ MTX+ MTX

(N=158)(N=158)


(N=161)(N=161)


(N=170)(N=170)

******

******

Anti-TNF Inadequate RespondersAnti-TNF Inadequate Responders: : ACR20, ACR50, ACR20, ACR50, ACR70 Response Rates at Week 24ACR70 Response Rates at Week 24


** p<0.01 *** p<0.0001, TCZ vs. Placebo + MTX** p<0.01 *** p<0.0001, TCZ vs. Placebo + MTX

10%4%

1%

30%

17%

5%

50%

29%

12%

0%

10%

20%

30%

40%

50%

60%

WA18062WA18062

Percentage (%)Percentage (%)RespondersResponders ACR20ACR20 ACR50ACR50 ACR70ACR70

P 55

0

10

20

30

40

50

Placebo + MTX (N=158) TCZ 4 mg/kg + MTX (N=161) TCZ 8 mg/kg + MTX (N=170)

Anti-TNF Inadequate RespondersAnti-TNF Inadequate Responders: : ACR20, ACR50, ACR70 ACR20, ACR50, ACR70 Response at Week 24 by Number of Previously Failed Anti-TNFsResponse at Week 24 by Number of Previously Failed Anti-TNFs


% Responders% Responders

One FailedOne FailedN=249N=249

Two FailedTwo FailedN=176N=176

Three FailedThree FailedN=62N=62


WA18062WA18062

ACR20ACR20 ACR50ACR50 ACR70ACR70 ACR20ACR20 ACR50ACR50 ACR70ACR70

P 56

2

8

30

0

5

10

15

20

25

30

35

*** p<0.0001, TCZ vs. Placebo + DMARD*** p<0.0001, TCZ vs. Placebo + DMARD

PercentagePercentageRespondersResponders

DAS28 DAS28 ≤≤ 3.2 3.2

5

15

51

0

10

20

30

40

50

60 ******

DAS28 < 2.6DAS28 < 2.6

PlaceboPlacebo+ MTX+ MTX(n=61)(n=61)

4 mg/kg TCZ4 mg/kg TCZ+ MTX+ MTX(n=105)(n=105)


WA18062WA18062

PlaceboPlacebo+ MTX+ MTX(n=61)(n=61)



PercentagePercentageRespondersResponders

******

Anti-TNF Inadequate Responders: Anti-TNF Inadequate Responders: DAS28 Response at Week 24 DAS28 Response at Week 24

ITT Population ITT Population

P 57









P 58

Monotherapy: Double-Blind, Randomized, Monotherapy: Double-Blind, Randomized, Placebo ControlledPlacebo Controlled

Phase III WA17824Phase III WA17824

N=673N=673

Background DMARDsBackground DMARDs None (Monotherapy)None (Monotherapy)

Tocilizumab Doses Tocilizumab Doses 8 mg/kg8 mg/kg

ControlControl

MTX (p.o)MTX (p.o)Weeks 0-3: 7.5 mg/wkWeeks 0-3: 7.5 mg/wkWeeks 4-7: 15 mg/wkWeeks 4-7: 15 mg/wk

Weeks 8-24: 20 mg/wkWeeks 8-24: 20 mg/wk

Primary Endpoint (ACR 20)Primary Endpoint (ACR 20) 24 weeks24 weeks

Patient PopulationPatient Population MTX naMTX naïïve or not previously failed ve or not previously failed MTX for efficacy/safetyMTX for efficacy/safety

P 59

Monotherapy:Monotherapy:WA17824 Study DesignWA17824 Study Design

ScreeningScreening

6-Months6-Months

Sub-studySub-studyPlacebo (N=101)Placebo (N=101)


RandomizationRandomization

Day 1Day 1


Double-blind Open-label

Treated (N=673)Treated (N=673) MTX 7.5-20 mg/kg (N=284) MTX 7.5-20 mg/kg (N=284)

2 Months2 Months

TCZ 8 mg/kg TCZ 8 mg/kg


P 60

Monotherapy: Monotherapy: Baseline Characteristics Baseline Characteristics ITT PopulationITT Population

MTX*MTX*N=284N=284

8 mg/kg TCZ8 mg/kg TCZN=286N=286

Female (%)Female (%) 7979 8383

Age, Mean, YrsAge, Mean, Yrs 5050 5151

Duration RA, Mean, YrsDuration RA, Mean, Yrs 6.36.3 6.46.4

Duration RA < 2 Years (%)Duration RA < 2 Years (%)**** 125 (44)125 (44) 117 (41)117 (41)

RF Positive (%)RF Positive (%) 7575 7474

DAS28, MeanDAS28, Mean 6.86.8 6.86.8

SJC/TJC, MeanSJC/TJC, Mean 19/3119/31 19/3219/32

CRP, Mean, mg/dLCRP, Mean, mg/dL 3.13.1 3.03.0

HAQ. MeanHAQ. Mean 1.51.5 1.61.6

No. Prior DMARDs, MeanNo. Prior DMARDs, Mean 1.11.1 1.21.2

Oral CS/NSAIDs (%)Oral CS/NSAIDs (%) 47/7747/77 48/8048/80

MTX/DMARD Naïve (%)MTX/DMARD Naïve (%) 67/4567/45 67/4067/40

* * Escalating dose from 7.5 mg to 20 mg/week over 8 weeks, ** Safety PopulationEscalating dose from 7.5 mg to 20 mg/week over 8 weeks, ** Safety Population

WA17824WA17824

P 61

Monotherapy: Disposition at 24 WeeksMonotherapy: Disposition at 24 WeeksAll PatientsAll Patients


MTXMTXN=284 (%)N=284 (%)

TCZ TCZ N=288 (%)N=288 (%)

Completed 24 weeks Completed 24 weeks (inc. Escape)(inc. Escape)

262 (92)262 (92) 268 (93)268 (93)

EscapeEscape 1111 77

Discontinued*Discontinued* 22 (8)22 (8) 19 (7)19 (7)

Adverse EventsAdverse Events 10 (4)10 (4) 5 (2)5 (2)

DeathDeath 1 (<1)1 (<1) 3 (1)3 (1)

Lack of EfficacyLack of Efficacy 3 (1)3 (1) 1 (<1)1 (<1)

Failure to ReturnFailure to Return 1 (<1)1 (<1) 4 (1)4 (1)

Refused TreatmentRefused Treatment 7 (3)7 (3) 6 (2)6 (2)

* Excludes discontinuations on Escape* Excludes discontinuations on Escape

P 62

Monotherapy: ACR20 Response Monotherapy: ACR20 Response at Week 8 – Placebo Controlled Substudyat Week 8 – Placebo Controlled Substudy


13

34

56

0

10

20

30

40

50

60

Placebo (n=99) MTX (N=284) TCZ 8 mg/kg (n=286)

WA17824WA17824


Weighted Difference vs. PlaceboWeighted Difference vs. Placebo 0.210.21 0.43 0.43

95% C.I. of Weighted Difference 95% C.I. of Weighted Difference 0.12, 0.30.12, 0.3 0.34, 0.520.34, 0.52

Statistical Significance DemonstratedStatistical Significance Demonstrated Lower Limit of Lower Limit of 95% CI 95% CI ≥ 0≥ 0

P 63

Monotherapy: ACR20 Response Rate at Week 24Monotherapy: ACR20 Response Rate at Week 24PP PopulationPP Population

WA17824WA17824

Weighted Difference vs. MTX: Weighted Difference vs. MTX: 0.210.21

95% C.I. of Weighted Difference:95% C.I. of Weighted Difference: 0.13, 0.290.13, 0.29

Non-inferiority Demonstrated: Non-inferiority Demonstrated: Lower Limit of Lower Limit of 95% CI 95% CI ≥ -0.12≥ -0.12

52

71

01020304050607080

MTX (n=259) TCZ 8 mg/kg (n=265)


P 64** p<0.01 *** p<0.0001, TCZ Vs. MTX** p<0.01 *** p<0.0001, TCZ Vs. MTX

53%

34%

15%

28%

44%

70%

0%

10%

20%

30%

40%

50%

60%

70%

80%% Responders% Responders

WA17824WA17824

******

****

****

MTXMTX(N=284)(N=284)

8 mg/kg8 mg/kgTCZTCZ

(N=286)(N=286)

ACR20ACR20


(N=286)(N=286)


ACR50ACR50


(N=286)(N=286)


ACR70ACR70

Monotherapy: ACR20, ACR50, ACR70 Monotherapy: ACR20, ACR50, ACR70 Response at Week 24Response at Week 24


P 65

Monotherapy: DAS28 Monotherapy: DAS28 ≤≤ 3.2 and 3.2 and DAS28 < 2.6 Response at Week 24DAS28 < 2.6 Response at Week 24

PP PopulationPP Population

8 mg/kg TCZ8 mg/kg TCZ(n=236)(n=236)

MTXMTX(n=228)(n=228)

44

18

0

5

10

15

20

25

30

35

40

45

50

DAS28 ≤ 3.2DAS28 ≤ 3.2 DAS28 < 2.6DAS28 < 2.6

% Responders

WA17824WA17824

8 mg/kg TCZ8 mg/kg TCZ(N=236)(N=236)


32

11

0

5

10

15

20

25

30

35

% Responders

P 66







• Tocilizumab Monotherapy Tocilizumab Monotherapy


P 67

ConclusionsConclusions

• Primary endpoint was met in all 5 DB, PC studiesPrimary endpoint was met in all 5 DB, PC studies

• Tocilizumab is effective as monotherapy or in combination Tocilizumab is effective as monotherapy or in combination with DMARDswith DMARDs

• Tocilizumab Tocilizumab shown to alleviate signs and symptoms of RAshown to alleviate signs and symptoms of RA across a range of RA patientsacross a range of RA patients

– Early RAEarly RA– DMARD Inadequate RespondersDMARD Inadequate Responders– Anti-TNF Inadequate Responders Anti-TNF Inadequate Responders

• Consistent and robust effects on all endpoints particularly Consistent and robust effects on all endpoints particularly – ACR50, ACR70, DAS28 < 2.6ACR50, ACR70, DAS28 < 2.6

• Rapid response within 2 weeks with continued improvement Rapid response within 2 weeks with continued improvement up to 2 yrsup to 2 yrs

• Improvement in patients’ quality of life and physical functionImprovement in patients’ quality of life and physical function

P 68

Conclusions Conclusions (cont.)(cont.)

• Tocilizumab in Combination with DMARDsTocilizumab in Combination with DMARDs

– Patients with Inadequate Response to Anti-TNF therapyPatients with Inadequate Response to Anti-TNF therapy

• 8 mg/kg (q4w) consistently more effective than 4 mg/kg8 mg/kg (q4w) consistently more effective than 4 mg/kg


• Both 4 and 8 mg/kg (q4w) effective however TCZ 8 mg/kg Both 4 and 8 mg/kg (q4w) effective however TCZ 8 mg/kg consistently more efficacious than 4 mg/kgconsistently more efficacious than 4 mg/kg

• A dose of 4 mg/kg may be considered followed by adjustment A dose of 4 mg/kg may be considered followed by adjustment to TCZ 8 mg/kg based upon clinical responseto TCZ 8 mg/kg based upon clinical response


– Effective at a dose of 8 mg/kg in reducing signsEffective at a dose of 8 mg/kg in reducing signsand symptoms across a range of RA patientsand symptoms across a range of RA patients

P 69

SafetySafety

Joel Krasnow, MDJoel Krasnow, MDClinical Science LeaderClinical Science Leader

P 70

Safety Presentation OutlineSafety Presentation Outline

• Safety PopulationsSafety Populations

• ExposureExposure

• Safety ProfileSafety Profile

• Events of Special InterestEvents of Special Interest

• Pharmacovigilance PlansPharmacovigilance Plans

P 71

Key Safety PopulationsKey Safety Populations

• 6-month controlled study population6-month controlled study population– 5 Pivotal trials until the time of Escape 5 Pivotal trials until the time of Escape

– Events occurring up to 3 months from Events occurring up to 3 months from the last dose of study drugthe last dose of study drug

• All patients exposed to TCZ All patients exposed to TCZ – Controlled 6-month RA studiesControlled 6-month RA studies

– EscapeEscape

– Transition phase (Monotherapy trial)Transition phase (Monotherapy trial)

– Long-term extensions Long-term extensions

– Data provided in rates/100 pt yrsData provided in rates/100 pt yrs

• Chugai Program*Chugai Program*

*RA indication only unless otherwise stated*RA indication only unless otherwise stated

P 72STmed_exp_dur 05FEB2008STmed_exp_dur 05FEB2008

3,0162,792

2,016

1323

491

1,323

787

23

842546

0

500

1000

1500

2000

2500

3000

3500

3 Months 6 Months 12 Months 18 Months 24 Months

PatientsPatients

TCZ TCZ 88

mg/kgmg/kg

ControlControl TCZ TCZ 44

mg/kgmg/kg

TCZ TCZ 88

mg/kgmg/kg


mg/kgmg/kg

TCZ TCZ 88

mg/kgmg/kg


mg/kgmg/kg

TCZ TCZ 88

mg/kgmg/kg


mg/kgmg/kg

TCZ TCZ 88

mg/kgmg/kg


mg/kgmg/kg

Total Patient YearsTotal Patient YearsControlControl 628628TCZ 4 mg/kgTCZ 4 mg/kg 435435TCZ 8 mg/kgTCZ 8 mg/kg 37073707

Patient ExposurePatient ExposureControlled Studies and Open-Label ExtensionControlled Studies and Open-Label Extension

P 73

TCZ 8 mg TCZ 8 mg (n=288)(n=288)

MTX MTX (n=284)(n=284)

%% %%

AEsAEs 79.979.9 77.577.5

SAEsSAEs 3.83.8 2.82.8

AE LeadingAE Leadingto Withdrawalto Withdrawal 3.83.8 5.35.3

AE Leading AE Leading to Dose Modificationto Dose Modification 19.419.4 22.222.2

Deaths (N)Deaths (N) 1.0 1.0 (3 pts)(3 pts)

0.40.4(1 pt)(1 pt)

TCZ 4 mg TCZ 4 mg + DMARD + DMARD (n=774)(n=774)

%%

70.770.7

5.95.9

4.94.9

13.313.3

––


DMARD DMARD (n=1170)(n=1170)

%% %%

71.771.7 62.662.6

6.06.0 5.35.3

4.74.7 2.42.4

12.312.3 7.27.2

0.10.1(2 pts)(2 pts)

0.30.3(4 pts)(4 pts)

Overview of Adverse EventsOverview of Adverse EventsControlled 6-Month StudiesControlled 6-Month Studies

P 74

Adverse Events Reported in > 2% of TCZ-treated Adverse Events Reported in > 2% of TCZ-treated Patients and with ≥ 1% Difference ControlPatients and with ≥ 1% Difference Control

Controlled 6-Month StudiesControlled 6-Month Studies

1 Includes increased ALT, increased transaminase, increased hepatic enzyme, abnormal liver function test, increased AST, abnormal ALT, ALT1 Includes increased ALT, increased transaminase, increased hepatic enzyme, abnormal liver function test, increased AST, abnormal ALT, ALT2 Includes upper abdominal pain2 Includes upper abdominal painstae11_1 30 Aug 2007; rhstae11_inf 04 Feb 2008stae11_1 30 Aug 2007; rhstae11_inf 04 Feb 2008

Upper Respiratory Tract InfectionUpper Respiratory Tract Infection

Increased TransaminasesIncreased Transaminases11 Preferred Term Preferred Term

5.3 5.3 7.3 7.3

13.0 13.0 11.1 11.1 % % % %

MTX MTX N=284N=284

TCZ 8 mg/kgTCZ 8 mg/kgN=288N=288

Anxiety Anxiety

Depression Depression

Hypertension Hypertension

Pharyngolaryngeal Pain Pharyngolaryngeal Pain

Cough Cough Dizziness Dizziness

Arthralgia Arthralgia

Back Pain Back Pain

Pruritus Pruritus

Rash Rash

Mouth Ulceration Mouth Ulceration

Abdominal PainAbdominal Pain22

Bronchitis Bronchitis

Nasopharyngitis Nasopharyngitis

0.7 0.7 2.4 2.4

0.7 0.7 2.1 2.1

2.1 2.1 5.6 5.6

1.1 1.1 2.4 2.4

0.4 0.4 2.8 2.8 1.4 1.4 3.1 3.1

1.4 1.4 2.4 2.4

1.1 1.1 2.4 2.4

1.1 1.1 2.8 2.8

1.4 1.4 2.4 2.4

2.1 2.1 2.1 2.1

4.2 4.2 5.6 5.6

2.1 2.1 3.1 3.1

6.0 6.0 6.9 6.9

InsomniaInsomnia 1.1 1.1 2.1 2.1

Headache Headache 2.5 2.5 7.3 7.3

6.1 6.1 7.8 7.8

2.3 2.3 8.0 8.0

0.8 0.8 0.8 0.8

1.2 1.2 1.3 1.3

2.7 2.7 4.4 4.4

1.1 1.1 1.7 1.7

1.9 1.9 2.3 2.3 1.7 1.7 3.1 3.1

2.0 2.0 1.1 1.1

2.4 2.4 3.3 3.3

0.9 0.9 1.6 1.6

1.3 1.3 3.3 3.3

0.5 0.5 2.0 2.0

2.8 2.8 3.8 3.8

3.2 3.2 3.2 3.2

4.4 4.4 5.6 5.6

1.3 1.3 1.0 1.0

3.4 3.4 5.3 5.3

6.2 6.2

7.1 7.1 % % % % % %

Placebo + Placebo + DMARD N=1170DMARD N=1170

TCZ 8 mg/kg + TCZ 8 mg/kg + DMARD N=1582DMARD N=1582

TCZ 4 mg/kg + TCZ 4 mg/kg + DMARD N=774DMARD N=774

0.6 0.6

1.0 1.0

4.1 4.1

1.9 1.9

2.1 2.1 1.9 1.9

1.4 1.4

2.1 2.1

1.4 1.4

3.9 3.9

1.3 1.3

4.4 4.4

4.3 4.3

4.3 4.3

2.1 2.1

5.8 5.8

P 75

Serious Adverse EventsSerious Adverse Eventsin in at Least at Least 3 Patients on TCZ3 Patients on TCZ


TCZ 8 mg TCZ 8 mg (n=288)(n=288)

MTX MTX (n=284)(n=284)




Preferred TermPreferred Term N (%)N (%) N (%)N (%) N (%)N (%) N (%)N (%) N (%)N (%)

PneumoniaPneumonia 2 (0.7)2 (0.7) 1 (0.3)1 (0.3) 6 (0.8)6 (0.8) 9 (0.6)9 (0.6) 4 (0.3)4 (0.3)

CellulitisCellulitis –– –– –– 9 (0.6)9 (0.6) 1 (0.08)1 (0.08)

Herpes ZosterHerpes Zoster –– –– –– 5 (0.3)5 (0.3) ––

SepsisSepsis –– 1 (0.4)1 (0.4) 2 (0.1)2 (0.1) 1 (0.06)1 (0.06) 1 (0.08)1 (0.08)

GastroenteritisGastroenteritis –– –– 3 (0.4)3 (0.4) –– ––

MI/ACSMI/ACS –– –– 1 (0.1)1 (0.1) 2 (0.1)2 (0.1) 3 (0.3)3 (0.3)

Carotid Artery StenosisCarotid Artery Stenosis –– –– 2 (0.3)2 (0.3) 1 (0.06)1 (0.06) ––

FallFall 1 (0.3)1 (0.3) –– –– 3 (0.2)3 (0.2) 1 (0.09)1 (0.09)

Femur FractureFemur Fracture –– –– 1 (0.1)1 (0.1) 2 (0.1)2 (0.1) --

Pulmonary EmbolismPulmonary Embolism –– 1 (0.4)1 (0.4) –– 3 (0.2)3 (0.2) 1 (0.09)1 (0.09)

Back PainBack Pain –– –– –– 3 (0.2)3 (0.2) 1 (0.09)1 (0.09)

NeutropeniaNeutropenia –– –– 2 (0.3)2 (0.3) 1 (0.06)1 (0.06) ––

ISS Table 15ISS Table 15

P 76

TCZ 8 mg TCZ 8 mg (n=288)(n=288)

MTX MTX (n=284)(n=284)




NN NN NN NN NN

Cardiac and VascularCardiac and Vascular 22 –– –– 11 11

InfectionInfection –– –– –– 11 11

GastrointestinalGastrointestinal 11 –– –– –– 11

MalignancyMalignancy –– 11 –– –– ––

Wegener’s Wegener’s GranulomatosisGranulomatosis –– –– –– –– 11

Total 3 1 – 2 4

Rate (100 PY)Rate (100 PY)

All TCZAll TCZ All ControlAll Control1132 PY1132 PY 628 PY628 PY

0.40.4 0.80.8

DeathsDeathsControlled 6-Month StudiesControlled 6-Month Studies

P 77

DeathsDeathsSafety UpdateSafety Update

TCZ 4 mg TCZ 4 mg + DMARD+ DMARD

435 PY435 PY

TCZ 8 mg TCZ 8 mg +/- DMARD+/- DMARD

3707 PY3707 PY

All All ControlControl683 PY683 PY

All TCZAll TCZ4142 PY4142 PY

Chugai*Chugai*2024 PY2024 PY

NN NN NN NN NN

Cardiac and VascularCardiac and Vascular –– 77 2 2 77 22

InfectionInfection –– 55 11 55 22

GastrointestinalGastrointestinal –– 22 11 22 --

MalignancyMalignancy –– 22 11 22 22

SuicideSuicide –– 22 –– 22 ––

Wegener’s GranulomatosisWegener’s Granulomatosis –– –– 11 –– ––

PolyneuropathyPolyneuropathy –– 11 –– 11 ––

Renal FailureRenal Failure –– 11 –– 11 ––

UnknownUnknown –– 11 –– 11 ––

Total No. of Deaths – 21 6 21 6

Rate (100 PY) – 0.57 0.88 0.51 0.30

* RA only * RA only

P 78

Tocilizumab Safety Presentation TopicsTocilizumab Safety Presentation Topics

• InfectionsInfections

• NeutrophilsNeutrophils

• GI PerforationGI Perforation

• DemyelinationDemyelination

• MalignanciesMalignancies

• Cardiovascular RiskCardiovascular Risk

– LipidsLipids

– HypertensionHypertension

• PlateletsPlatelets

• Liver Enzyme ElevationsLiver Enzyme Elevations

• Infusion ReactionsInfusion Reactions

P 79Rhstae11_inf, rhstae11_inf_s, rhstrate_ae_inf, rhstae11_inf_wd,Rhstae11_inf, rhstae11_inf_s, rhstrate_ae_inf, rhstae11_inf_wd,

3838Pt with at Least Pt with at Least 1 Infection AE1 Infection AE 3939

TCZ 8 mg TCZ 8 mg (n=288)(n=288)140 PY140 PY

MTXMTX(n=284)(n=284)134 PY134 PY

%% %%

Pt Withdrawal Pt Withdrawal Due to InfectionDue to Infection 11 < 1< 1

InfectionsInfections 118.6118.6(101.3, 138.1)(101.3, 138.1)

122.0122.0(104.0, 142.2)(104.0, 142.2)

Serious InfectionsSerious Infections 3.63.6(1.2, 8.3)(1.2, 8.3)

1.51.5(0.2, 5.4) (0.2, 5.4)

DeathsDeaths –– ––

Rate/100PYRate/100PY Rate/100PYRate/100PY

TCZ 8 mgTCZ 8 mg+ DMARD + DMARD (n=1582)(n=1582)754 PY754 PY

DMARD DMARD (n=1170)(n=1170)507 PY507 PY

%% %%

4040 3434

11 11

TCZ 4 mgTCZ 4 mg+ DMARD + DMARD (n=774)(n=774)345 PY345 PY

3737

%%

11

133.4133.4(121.5, 146.2)(121.5, 146.2)

126.7126.7(118.8, 135.0)(118.8, 135.0)

112.0112.0(103.0, 121.6)(103.0, 121.6)

4.44.4(2.4, 7.2) (2.4, 7.2)

5.3 5.3 (3.8, 7.2)(3.8, 7.2)

3.93.9(2.4, 6.1) (2.4, 6.1)

–– 0.130.13 0.200.20

Rate/100PYRate/100PY Rate/100PYRate/100PY Rate/100PYRate/100PY

InfectionsInfectionsControlled 6-Month StudiesControlled 6-Month Studies

P 80

Rates of Serious InfectionsRates of Serious Infectionsper 100 Patient Yearsper 100 Patient Years

Safety UpdateSafety Update

* Death due to all causes: N=957* Death due to all causes: N=957STae_ratebp_din 26 June 2008; STae_ratex_sinfpl 13 June 2008; STae_rate824tp_iser 13 June 2008STae_ratebp_din 26 June 2008; STae_ratex_sinfpl 13 June 2008; STae_rate824tp_iser 13 June 2008

TCZTCZ4 mg + 4 mg + DMARDDMARD435 PY435 PY

TCZTCZ8 mg +/- 8 mg +/- DMARDDMARD3707 PY3707 PY

All All ControlControl683 PY683 PY

All TCZ All TCZ 4142 PY4142 PY

Chugai*Chugai*2024 PY2024 PY

No. of Infection SAEsNo. of Infection SAEs 2020 165165 2525 185185 121121

Rate of Infection Rate of Infection SAEs per 100 pt Yrs SAEs per 100 pt Yrs Exp (95% CI)Exp (95% CI)

4.6 4.6 (2.8, 7.1)(2.8, 7.1)

4.5 4.5 (3.8, 5.2) (3.8, 5.2)

3.73.7(2.4, 5.4)(2.4, 5.4)

4.54.5(3.8, 5.1)(3.8, 5.1)

6.36.3(5.3, 7.5)(5.3, 7.5)

No. of Deaths No. of Deaths due to Infectiondue to Infection –– 55 11 55 22

Deaths Due to Deaths Due to Infections per Infections per 100 Pt Yrs100 Pt Yrs

–– 0.130.13 0.150.15 0.120.12 0.10*0.10*

P 81

0

2

4

6

8

10

12

0 to 6 7 to 12 13 to 18 19 to 24 >24

Rate of All Serious Infections Rate of All Serious Infections per 100 PY by 6 Monthly Periodsper 100 PY by 6 Monthly Periods


STrate_6_inf_sSTrate_6_inf_s

1633 PY1633 PY 1092 PY1092 PY 832 PY832 PY 452 PY452 PY 148 PY148 PY

Rate per 100 PY and Rate per 100 PY and 95% Confidence Intervals95% Confidence Intervals

P 82

Overview of Opportunistic InfectionsOverview of Opportunistic InfectionsSafety UpdateSafety Update


435 PY435 PY

TCZ 8 mg TCZ 8 mg ± DMARD± DMARD3707 PY3707 PY

All ControlAll Control683 PY683 PY

All TCZAll TCZ4142 PY4142 PY

ChugaiChugai2024 PY2024 PY

N N (Rate/100 PY)(Rate/100 PY)





MAC/MAIMAC/MAI –– 1 (0.03)1 (0.03) –– 1 (0.02)1 (0.02) ––

TBTB –– 2 (0.05)2 (0.05) –– 2 (0.05)2 (0.05) 3 (0.15)3 (0.15)

PCPPCP 1 (0.23)1 (0.23) –– –– 1 (0.02)1 (0.02) 1 (0.05)1 (0.05)

EBV ReactivationEBV Reactivation –– –– –– 1 (0.05)1 (0.05)

Pulmonary Pulmonary AspergillosisAspergillosis –– –– –– 1 (0.05)1 (0.05)

Candida Candida Osteomyelitis*Osteomyelitis* –– 1 1 (0.03)(0.03) –– 1 (0.02)1 (0.02) ––

Total 1 (0.23) 4 (0.1) – 5 (0.1) 6 (0.3)

*Post-Safety update*Post-Safety updateStae11c_1_inf 13 June 2008; stae11_inf 30 Aug 2007 Stae11c_1_inf 13 June 2008; stae11_inf 30 Aug 2007

P 83

Overview of Herpes InfectionsOverview of Herpes InfectionsSafety UpdateSafety Update


435 PY435 PY

TCZ 8 mg TCZ 8 mg + DMARD+ DMARD3707 PY3707 PY

ControlControl683 PY683 PY

TCZTCZ4142 PY4142 PY

ChugaiChugai1984 PY*1984 PY*

N N (Rate/(Rate/

100PY)100PY)

N N (Rate/(Rate/

100PY)100PY)

N N (Rate/(Rate/

100PY)100PY)

N N (Rate/(Rate/

100PY)100PY)

N N (Rate/(Rate/

100PY)100PY)

Oral HerpesOral Herpes 10 (2.3)10 (2.3) 79 (2.1)79 (2.1) 11 (1.6)11 (1.6) 89 (2.1)89 (2.1)

Herpes ZosterHerpes Zoster 9 (2.1)9 (2.1) 57 (1.5)57 (1.5) 9 (1.3)9 (1.3) 66 (1.6)66 (1.6) 48 (2.4)*48 (2.4)*

Herpes SimplexHerpes Simplex 3 (0.7)3 (0.7) 13 (0.4)13 (0.4) 7 (1.0)7 (1.0) 16 (0.4)16 (0.4) 55 (2.8)*55 (2.8)*

Herpes Virus Inf.Herpes Virus Inf. 1 (0.2)1 (0.2) 11 (0.3)11 (0.3) 2 (0.3)2 (0.3) -- 9 (0.5)*9 (0.5)*

Genital HerpesGenital Herpes 1 (0.2)1 (0.2) 6 (0.2)6 (0.2) -- 7 (0.2)7 (0.2)

HSV OphthalmicHSV Ophthalmic -- 2 (0.1)2 (0.1) -- 2 (<0.1)2 (<0.1)

HZ OphthalmicHZ Ophthalmic -- 2 (0.1)2 (0.1) -- 2 2 (<0.1)(<0.1)

Requiring HospitalizationRequiring Hospitalization -- 9 (0.2)9 (0.2) -- 9 (0.2)9 (0.2) 15 (0.7)**15 (0.7)**

* As of August 31, 2007* As of August 31, 2007** As of September 30, 2007** As of September 30, 2007

P 84

Summary and Risk Mitigation: InfectionsSummary and Risk Mitigation: Infections

Summary Summary

• Rates of serious infections, including opportunistic infections, are Rates of serious infections, including opportunistic infections, are elevated over control and do not increase over timeelevated over control and do not increase over time

• Rates of serious infections are consistent with those observed with Rates of serious infections are consistent with those observed with anti-TNFs (5.32 per 100 pt yrs)anti-TNFs (5.32 per 100 pt yrs)11

Risk MitigationRisk Mitigation

• TCZ treatment should not be initiated in patients with active infection TCZ treatment should not be initiated in patients with active infection

• TCZ should be interrupted if a patient develops a serious infection or TCZ should be interrupted if a patient develops a serious infection or an infection that could become serious until the infection is controlledan infection that could become serious until the infection is controlled

• TB screen prior to initiating TCZTB screen prior to initiating TCZ

– If positive, initiate TB treatment according to clinical practice guidelinesIf positive, initiate TB treatment according to clinical practice guidelines22

• Live attenuated vaccines should not be given while on TCZLive attenuated vaccines should not be given while on TCZ

1 Dixon A & R 20061 Dixon A & R 2006

2 ACR Guidelines2 ACR Guidelines

P 85








– LipidsLipids





P 86

WeeksWeeks

Mean AbsoluteMean AbsoluteNeutrophils (10**9/L) Neutrophils (10**9/L)

0

1

2

3

4

5

6

7

8

0 2 4 6 8 12 14 16 20 24

LLNLLN

ULNULN

Neutrophil CountsNeutrophil Counts Controlled 6-Month Studies (Combination Therapy)Controlled 6-Month Studies (Combination Therapy)

8 mg/kg + DMARD8 mg/kg + DMARD

4 mg/kg + MTX 4 mg/kg + MTX Placebo + DMARDPlacebo + DMARD

P 87

Overview on Grade 3 and 4 NeutropeniaOverview on Grade 3 and 4 NeutropeniaLowest Value Reported (CTC Grades)Lowest Value Reported (CTC Grades)


TCZ TCZ 8 mg 8 mg

(n=288)(n=288)MTX MTX

(n=284)(n=284)

TCZ TCZ 4 mg + 4 mg + DMARD DMARD (n=774)(n=774)

TCZ TCZ 8 mg + 8 mg + DMARD DMARD (n=1582)(n=1582)


Grade 1 Grade 1 (1500-LLN/mm(1500-LLN/mm33))

51 51 (18%)(18%)

22 22 (8%)(8%)

88 88 (11%)(11%)

298 298 (19%)(19%)

30 30 (3%)(3%)

Grade 2 Grade 2 (1000-1500/mm(1000-1500/mm33))

30 30 (10%)(10%)

6 6 (2%)(2%)

53 53 (7%)(7%)

179 179 (11%)(11%)

10 10 (< 1%)(< 1%)

Grade 3 Grade 3 (500-1000/mm(500-1000/mm33))

9 9 (3%)(3%)

1 1 (< 1%)(< 1%)

9 9 (1%)(1%)

48 48 (3%)(3%) ––

Grade 4 Grade 4 (< 500/mm(< 500/mm33))

–– ––3 3

(< 1%)(< 1%)5 5

(< 1%) (< 1%) – –

• No serious infections observed with grade 3 and 4 neutropeniaNo serious infections observed with grade 3 and 4 neutropenia• 5 Non-serious infections seen in grade 3, 4 neutropenia 5 Non-serious infections seen in grade 3, 4 neutropenia (two bronchitis events, (two bronchitis events,

one sinusitis, one pharyngitis, and one conjunctivitis) one sinusitis, one pharyngitis, and one conjunctivitis)

P 88

Risk Mitigation: NeutrophilsRisk Mitigation: Neutrophils

• TCZ should not be initiated in patients with Neutrophils TCZ should not be initiated in patients with Neutrophils < 2000 cells/mm< 2000 cells/mm33

• Neutrophils should be monitored 4-8 weeks after the Neutrophils should be monitored 4-8 weeks after the first infusion in all patientsfirst infusion in all patients

– Repeat labs as clinically indicated Repeat labs as clinically indicated

Lab ValueLab Value(cells/mm(cells/mm33)) TCZ ModificationTCZ Modification

ANC ANC ≥≥ 1000 1000 Maintain doseMaintain dose

ANC 500-1000ANC 500-1000 InterruptionInterruption

when ANC > 1000 then resume with 4 mg/kg when ANC > 1000 then resume with 4 mg/kg and return to 8 mg/kg as clinically appropriateand return to 8 mg/kg as clinically appropriate

ANC < 500ANC < 500 Discontinue TCZDiscontinue TCZ

P 89








– LipidsLipids





P 90

GI Perforations GI Perforations Controlled 6-Month StudiesControlled 6-Month Studies

TCZ 8 TCZ 8 mg/kgmg/kgn=n=288 288

MTXMTXn=n=284 284

TCZ 4 TCZ 4 mg/kg mg/kg

+ DMARD+ DMARDn=n=774774

TCZ 8 TCZ 8 mg/kg mg/kg

+ DMARD+ DMARDn=n=15821582

DMARDDMARDn=n=1170 1170

N (%)N (%) N (%)N (%) N (%)N (%) N (%)N (%) N (%)N (%)

Upper GI

DuodenumDuodenum 1 (0.3)1 (0.3) –– –– ––

Lower GI

Diverticular Diverticular PerforationPerforation –– –– –– 2 (0.13)2 (0.13) ––

Total 1 (0.3) – – 2 (0.13) –

P 91

Number (%) and Rate per 1000 PY of GI Perforations Number (%) and Rate per 1000 PY of GI Perforations Reported in the TCZ Arthritis Indication StudiesReported in the TCZ Arthritis Indication Studies

March 31, 2008March 31, 2008

SiteSite

Roche RA ProgramRoche RA ProgramRocheRocheAll TCZAll TCZ ChugaiChugai

TCZ TCZ 4 mg/kg 4 mg/kg + DMARD+ DMARD

N=774*N=774*524 PY 524 PY

TCZ TCZ 8 mg/kg 8 mg/kg ± DMARD± DMARDN=3215*N=3215*6101 PY 6101 PY

MTX/MTX/DMARDDMARDN=1555 N=1555 683 PY683 PY

TCZ TCZ ± DMARD± DMARDN= 3778*N= 3778*6627 PY6627 PY

TCZTCZAll dosesAll doses

N=945N=9452235 PY2235 PY

Upper GI

N (%)N (%) 00 3 (0.09)3 (0.09) 00 3 (0.08)3 (0.08) 3 (0.32)3 (0.32)

Rate/1000 PY 00 0.50.5 00 0.50.5 1.31.3

Lower GI

N (%)N (%) 1 (0.13)1 (0.13) 9 (0.28)9 (0.28) 00 10 (0.26)10 (0.26) 4 (0.41)4 (0.41)

Rate/1000 PYRate/1000 PY 1.91.9 1.51.5 00 1.51.5 1.81.8

*Some patients received both 4 mg/kg and 8 mg/kg and are counted twice in the 4 mg/kg and 8 mg/kg columns. *Some patients received both 4 mg/kg and 8 mg/kg and are counted twice in the 4 mg/kg and 8 mg/kg columns. They are only counted once in the ALL TCZ Column. They are only counted once in the ALL TCZ Column.

P 92

Upper Gastrointestinal PerforationUpper Gastrointestinal PerforationBackground RatesBackground Rates

CohortCohortRate of Upper GI PerforationRate of Upper GI Perforation

(1000 PY)(1000 PY)

VIGORVIGOR 1.31.3

RocheRoche 0.50.5

ChugaiChugai 1.31.3

• VIGOR Study: 8076 RA patients randomized to rofecoxib or NaproxenVIGOR Study: 8076 RA patients randomized to rofecoxib or Naproxen

(Bombardier, et al, NEJM, 2000; 343:1520-1528)(Bombardier, et al, NEJM, 2000; 343:1520-1528)

P 93

Lower Intestinal PerforationLower Intestinal PerforationBackground RatesBackground Rates

Rate/1000 PYsRate/1000 PYs 95% CI95% CI

Whole Cohort (Crude Rate)Whole Cohort (Crude Rate) 0.90.9 0.74; 1.060.74; 1.06

Exposed to MTXExposed to MTX 1.11.1 0.76 to 1.520.76 to 1.52

Exposed to Anti-TNFExposed to Anti-TNF 1.31.3 0.77 to 1.870.77 to 1.87

Exposed to CorticosteroidExposed to Corticosteroid 3.93.9 3.05 to 4.763.05 to 4.76

Current exposure, or stopped exposure within last 12 monthsCurrent exposure, or stopped exposure within last 12 months

Intestinal Perforation Rate per 1000 Person-Years, in RA Patients, Intestinal Perforation Rate per 1000 Person-Years, in RA Patients, United Health Care DatabaseUnited Health Care Database

P 94

Summary and Risk Mitigation: GI Perforations Summary and Risk Mitigation: GI Perforations

SummarySummary• Rate of GI perforations at 8 mg/kg dose elevated over control Rate of GI perforations at 8 mg/kg dose elevated over control

but similar to RA background rate in RA databasesbut similar to RA background rate in RA databases

Risk Mitigation Risk Mitigation • TCZ should be used with caution in patients with a history TCZ should be used with caution in patients with a history

of diverticulitis of diverticulitis • GI mucosal protection advised for patients receiving NSAIDs GI mucosal protection advised for patients receiving NSAIDs

and corticosteroidsand corticosteroids• Patient education should includePatient education should include

– Potential risk for GI perforation Potential risk for GI perforation – Information on the signs and symptoms of diverticulitis Information on the signs and symptoms of diverticulitis

(e.g., abdominal pain)(e.g., abdominal pain)– Reporting GI symptoms promptly to physicianReporting GI symptoms promptly to physician

• Patients presenting with abdominal symptoms should be Patients presenting with abdominal symptoms should be promptly evaluated with appropriate referral as needed promptly evaluated with appropriate referral as needed

P 95








– LipidsLipids





P 96

Demyelination EventsDemyelination Events

• Use of anti-TNF inhibitors in RA patients has been Use of anti-TNF inhibitors in RA patients has been associated with central demyelinating diseaseassociated with central demyelinating disease11

– Pattern and time course similar to that observed Pattern and time course similar to that observed in multiple sclerosisin multiple sclerosis

– Diagnosis of exclusion supported by the presence Diagnosis of exclusion supported by the presence of white matter lesions (WML) on MRIof white matter lesions (WML) on MRI

1 Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. 1 Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides.

Arthritis Rheum.Arthritis Rheum. 2001 Dec;44(12):2862-9. Mohan N et al. 2001 Dec;44(12):2862-9. Mohan N et al.

P 97

Potential Demyelination CasesPotential Demyelination Cases

*Chugai patient*Chugai patient

1 Previously reported as demyelination1 Previously reported as demyelination

22742274 74 yo F74 yo F 607607 Bilateral Optic NeuritisBilateral Optic Neuritis No DemyelinationNo Demyelination

46304630 36 yo F36 yo F 582582 Arnold (occipital)Arnold (occipital) NeuropathyNeuropathy

53265326 68 yo F68 yo F 112112 Chronic Idiopathic Chronic Idiopathic RadiculoneuropathyRadiculoneuropathy

ResolvedResolved

Hx paresthesia, peroneal Hx paresthesia, peroneal nerve palsy carpal tunnel, nerve palsy carpal tunnel, Presented with progressive Presented with progressive weakness, weight lossweakness, weight loss

PIDPIDAge/Age/

GenderGender

EventEventOnsetOnset(SD)(SD) EventEvent Clinical/Dx FindingsClinical/Dx Findings

56895689 62 yo M62 yo M 253253 WML, Chronic WML, Chronic Brain IschemiaBrain Ischemia1 1

(+) Babinski, (+) Babinski, Essential TremorsEssential Tremors

114002*114002* 72 yo F72 yo F White Matter White Matter Lesions (WML)Lesions (WML)

Subacute Subacute Progressive DementiaProgressive Dementia

14011401 56 yo F56 yo F 799799 Multifocal Multifocal Periventribular WMLPeriventribular WML SyncopeSyncope

12781278

P 98

Summary and Risk Mitigation:Summary and Risk Mitigation:Potential DemyelinationPotential Demyelination

SummarySummary

• All cases of potential demyelination reported to date All cases of potential demyelination reported to date also have other causes for the clinical findings also have other causes for the clinical findings (e.g., vascular) or have improved spontaneously (e.g., vascular) or have improved spontaneously


• If new neurological symptoms develop or progression If new neurological symptoms develop or progression of an existing neurological condition occurs, patients of an existing neurological condition occurs, patients should be evaluated and treated as appropriateshould be evaluated and treated as appropriate

• If demyelination is suspected, TCZ should be If demyelination is suspected, TCZ should be discontinued discontinued

P 99








– LipidsLipids





P 100

MalignanciesMalignanciesControlled 6-Month StudiesControlled 6-Month Studies

TCZ 8 mgTCZ 8 mgN=288N=288

MTXMTXN=284N=284


N=774N=774

TCZ 8 mg TCZ 8 mg + DMARD+ DMARDN=1582N=1582

DMARDDMARDN=1170N=1170

N(%)N(%) N(%)N(%) N(%)N(%) N(%)N(%) N(%)N(%)

Non-Melanoma Skin CancerNon-Melanoma Skin Cancer 1 (0.35)1 (0.35) –– 2 (0.26)2 (0.26) 3 (0.19)3 (0.19) 2 (0.17)2 (0.17)

LungLung –– 1 (0.35)1 (0.35) 2 (0.26) 2 (0.26) 1 (0.06)1 (0.06) ––

Female BreastFemale Breast –– –– –– –– 1 (0.09)1 (0.09)

Colon and RectumColon and Rectum –– 1 (0.35)1 (0.35) –– 1 (0.06)1 (0.06) 1 (0.09)1 (0.09)

Non-Hodgkin LymphomaNon-Hodgkin Lymphoma –– 1 (0.35)1 (0.35) –– –– ––

CervicalCervical –– –– 1 (0.13)1 (0.13) –– ––

EndometrialEndometrial –– –– –– 1 (0.06)1 (0.06) ––

StomachStomach 1 (0.35)1 (0.35) –– –– –– ––

ProstateProstate –– –– –– –– 1 (0.09)1 (0.09)

Thyroid Thyroid –– –– –– 1 (0.06)1 (0.06) ––

Metastatic Squamous Cell CAMetastatic Squamous Cell CA –– –– –– 1 (0.06)1 (0.06) ––

Total 2 (0.69) 3 (1.05) 5 (0.65) 8 (0.51) 5 (0.43)

P 101

Malignancies Reported Malignancies Reported in All Patients Exposed to TCZin All Patients Exposed to TCZ



+ DMARD+ DMARD

435 PY435 PYN (Rate/100 PY)N (Rate/100 PY)

TCZ 8 mg/kg TCZ 8 mg/kg ±± DMARD DMARD


All ControlAll Control


ALL TCZALL TCZ


ChugaiChugai


TOTAL 5 (1.15) 55 (1.48) 8 (1.27) 60 (1.45) 18 (0.90)

SolidSolid LungLung 2 (0.46)2 (0.46) 10 (0.27)10 (0.27) 1 (0.16)1 (0.16) 12 (0.29)12 (0.29) 2 (0.10)2 (0.10)

BreastBreast –– 4 (0.11)4 (0.11) 1 (0.16)1 (0.16) 4 (0.10)4 (0.10) 4 (0.20)4 (0.20)

CervicalCervical 1 (0.31)1 (0.31) 3 (0.08)3 (0.08) -- 4 (0.10)4 (0.10) 1 (0.05)1 (0.05)

ColorectalColorectal –– 3 (0.08)3 (0.08) 2 (0.32)2 (0.32) 3 (0.07)3 (0.07) 4 (0.20)4 (0.20)

GastricGastric –– 3 (0.08)3 (0.08) -- 3 (0.07)3 (0.07) 1 (0.05)1 (0.05)

ProstateProstate –– 2 (0.05)2 (0.05) 1 (0.16)1 (0.16) 2 (0.05)2 (0.05) ––

EndometrialEndometrial –– 2 (0.05)2 (0.05) –– 2 (0.05)2 (0.05) ––

ThyroidThyroid –– 2 (0.05)2 (0.05) –– 2 (0.05)2 (0.05) ––

Metastatic Metastatic (Primary Unk.)(Primary Unk.) –– 2 (0.05)2 (0.05) –– 2 (0.05)2 (0.05) ––

Gall bladderGall bladder –– –– –– –– 1 (0.05)1 (0.05)

BladderBladder –– –– –– –– 2 (0.10)2 (0.10)

Pancreatic CancerPancreatic Cancer –– –– –– –– 1 (0.05)1 (0.05)

OvarianOvarian –– 1 (0.03)1 (0.03) –– 1 (0.02)1 (0.02) ––

GlioblastomaGlioblastoma –– 1 (0.03)1 (0.03) –– 1 (0.02)1 (0.02) ––

SkinSkin Non-melanomaNon-melanoma 2 (0.46)2 (0.46) 20 (0.54)20 (0.54) 2 (0.32)2 (0.32) 22 (0.53)22 (0.53) ––

HematologicalHematological LymphomaLymphoma –– 1 (0.03)1 (0.03) 1 (0.16)1 (0.16) 1 (0.02)1 (0.02) 2 (0.10)2 (0.10)

P 102

Summary and Risk Mitigation: Malignancy Summary and Risk Mitigation: Malignancy

SummarySummary

• No signal has been detected to date but numbers No signal has been detected to date but numbers have been small, further PV (5 yr) is plannedhave been small, further PV (5 yr) is planned


• Caution should be exercised in patients with a history Caution should be exercised in patients with a history of malignancy as immunosuppression may affect host of malignancy as immunosuppression may affect host defenses against malignancies defenses against malignancies

• All patients receiving tocilizumab should be screened All patients receiving tocilizumab should be screened per guidelinesper guidelines

P 103







• Cardiovascular RiskCardiovascular Risk– LipidsLipids





P 104

Mean LDL and HDLMean LDL and HDLControlled 6-Month StudiesControlled 6-Month Studies

40

60

80

100

120

140

160

0 6 14 24Week

Source: stlb10_sum (HLS) [6-Month pooled safety]Source: stlb10_sum (HLS) [6-Month pooled safety]

Standard Deviations were approximately 25-30% of LDL and HDL values Standard Deviations were approximately 25-30% of LDL and HDL values

LDLLDL

HDLHDL

Mean Lipid Level (mg/dL)Mean Lipid Level (mg/dL)

TCZ 8 mg/kg + DMARDTCZ 8 mg/kg + DMARDTCZ 8 mg/kgTCZ 8 mg/kg

TCZ 4 mg/kgTCZ 4 mg/kgMTXMTXPlacebo + DMARDPlacebo + DMARD

TCZ 8 mg/kg + DMARDTCZ 8 mg/kg + DMARDTCZ 8 mg/kgTCZ 8 mg/kgTCZ 4 mg/kgTCZ 4 mg/kgPlacebo + DMARDPlacebo + DMARDMTXMTX

P 105

Mean (SD) LDL Mean (SD) LDL (mg/dL)(mg/dL)

TCZ TCZ 8 mg/kg8 mg/kgn=n=260 260

MTXMTXn=n=253 253

BaselineBaseline 115 115 34 34 114 114 33 33

Week 14Week 14(2 Weeks (2 Weeks

from Infusion)from Infusion)144 144 44 44 117 117 34 34

Week 24Week 24(4 Weeks (4 Weeks

from Infusion)from Infusion)140 140 43 43 118 118 35 35


n=n=714 714


n=n=14671467DMARDDMARDn=n=1068 1068

114 114 33 33 115 115 35 35 114 114 3434

133 133 38 38 137 137 43 43 115 115 3434

127 127 36 36 135 135 42 42 117 117 3535

Mean Low Density Lipoprotein (LDL) Mean Low Density Lipoprotein (LDL) Values Over TimeValues Over Time


P 106

LDL LDL (mg/dL)(mg/dL)


MTXMTXn=n=284284

< 130 to< 130 to≥ ≥ 130 130 22.6%22.6% 11.3%11.3%

< 160 to < 160 to ≥ ≥ 160160 17.4%17.4% 6.7%6.7%

Stlbshift.bl.lipidStlbshift.bl.lipid

Baseline to Last ObservationBaseline to Last ObservationLDL-C ATP III GuidelinesLDL-C ATP III Guidelines



n=n=774 774


n=n=15821582DMARDDMARDn=n=1174 1174

15.4%15.4% 21.8%21.8% 8.8%8.8%

11.0%11.0% 13.2%13.2% 3.5%3.5%

P 107

Statin Therapy Effectively Reduces LDL Statin Therapy Effectively Reduces LDL

135

169

128

80

120

160

200

240

Baseline Pre-Statin Post-Statin

Baseline, Pre- and Post-Statin LDL in All TCZ Exposed Patients Baseline, Pre- and Post-Statin LDL in All TCZ Exposed Patients Who Received a Statin at Any Time Point (N=180)Who Received a Statin at Any Time Point (N=180)

Mean, 25Mean, 25thth and 75 and 75thth Percentile Shown Percentile Shown

LDL (mg/dl)LDL (mg/dl)

P 108

Key Atherogenic IndicesKey Atherogenic Indices Controlled 6-Month Studies – Controlled 6-Month Studies – Baseline, Week 14 and Week 24Baseline, Week 14 and Week 24

Source: stlb10_sum (HLS)Source: stlb10_sum (HLS)

LDL/HDL Ratio

ApoB/ApoA1

TCZ TCZ 8 mg/kg8 mg/kgn=n=260 260

MTXMTXn=n=253 253

BaselineBaseline 2.182.18 2.252.25

Week 14Week 14 2.482.48 2.232.23

Week 24Week 24 2.442.44 2.202.20

BaselineBaseline 0.770.77 0.780.78

Week 14Week 14 0.790.79 0.740.74

Week 24Week 24 0.780.78 0.730.73

TCZ 4 mg/kg TCZ 4 mg/kg + DMARD+ DMARD

n=n=714714

TCZ 8 mg/kg TCZ 8 mg/kg + DMARD+ DMARDn=n=1467 1467


2.112.11 2.162.16 2.142.14

2.332.33 2.352.35 2.132.13

2.252.25 2.312.31 2.162.16

0.730.73 0.740.74 0.740.74

0.740.74 0.750.75 0.730.73

0.700.70 0.720.72 0.720.72

P 109

Summary and Risk Mitigation: LipidsSummary and Risk Mitigation: Lipids

SummarySummary

• LDL increases with TCZ treatmentLDL increases with TCZ treatment

• 11-23% of pts will shift ATP III categories11-23% of pts will shift ATP III categories


• A lipid panel should be obtained after 4-8 wks A lipid panel should be obtained after 4-8 wks of TCZof TCZ

• Lipid levels should be maintained within target ranges Lipid levels should be maintained within target ranges of ATP III (or local guidelines) and managed with lipid of ATP III (or local guidelines) and managed with lipid lowering agents if appropriatelowering agents if appropriate

P 110

Adverse Events of HypertensionAdverse Events of HypertensionControlled 6-Month StudiesControlled 6-Month Studies

TCZ 8 TCZ 8 mg/kgmg/kg

N=288N=288

MTXMTX

N=284N=284

N (%)N (%) N (%)N (%)

Hypertension*Hypertension* 18 (6.3)18 (6.3) 8 (2.8)8 (2.8)

Infusion related (During Infusion related (During or Within 24 Hours)or Within 24 Hours) 9 (3.1)9 (3.1) 2 (0.7)2 (0.7)

History of Hypertension**History of Hypertension** 4 (1.4)4 (1.4) 1 (0.4)1 (0.4)

No History of Hypertension** No History of Hypertension** 5 (1.7)5 (1.7) 5 (1.8)5 (1.8)

* * Hypertension, blood pressure increased, essential hypertension, systolic blood pressure increased, diastolic blood Hypertension, blood pressure increased, essential hypertension, systolic blood pressure increased, diastolic blood pressure increased, blood pressure abnormal, diastolic hypertension, procedural hypertension, hypertensive crisispressure increased, blood pressure abnormal, diastolic hypertension, procedural hypertension, hypertensive crisis

**Not infusion-related**Not infusion-related

HLS Ad hocs stae11_hypHLS Ad hocs stae11_hyp

TCZ TCZ 4 mg/kg4 mg/kg

+ DMARD+ DMARD

N=774N=774

TCZ TCZ 8 mg/kg8 mg/kg

+ DMARD+ DMARD

N=1582N=1582DMARDDMARD

N=1170N=1170

N (%)N (%) N (%)N (%) N (%)N (%)

40 (5.2)40 (5.2) 81 (5.1)81 (5.1) 36 (3.1)36 (3.1)

10 (1.3)10 (1.3) 26 (1.6)26 (1.6) 11 (0.9)11 (0.9)

18 (2.3)18 (2.3) 28 (1.8)28 (1.8) 19 (1.6)19 (1.6)

12 (1.6)12 (1.6) 27 (1.7)27 (1.7) 6 (0.5)6 (0.5)

P 111

Mean Systolic and Diastolic Blood PressureMean Systolic and Diastolic Blood PressureControlled 6-Month StudiesControlled 6-Month Studies

Source: stvs13_vs from HLS\Vital Signs Source: stvs13_vs from HLS\Vital Signs (6-Month Pooled Data) (6-Month Pooled Data)

(WA17822, WA17823, WA17824, WA18062, WA18063) (WA17822, WA17823, WA17824, WA18062, WA18063)

TCZ 8TCZ 8mg/kgmg/kg N=288N=288

MTXMTXN=284N=284

Baseline Baseline 126 ± 17.6126 ± 17.6 125 ± 18.0125 ± 18.0

Week 16 Week 16 125 ± 17.3125 ± 17.3 121 ± 16.7121 ± 16.7

Mean ChangeMean Change -1-1 -4-4

BaselineBaseline 77 ± 10.177 ± 10.1 76 ± 10.476 ± 10.4

Week 16Week 16 77 ± 9.877 ± 9.8 74 ± 9.374 ± 9.3

Mean ChangeMean Change 00 -2-2

Systolic

Diastolic


N=774N=774

TCZ TCZ 8 mg/kg 8 mg/kg

+ DMARD+ DMARDN=1582N=1582

Placebo Placebo + DMARD+ DMARDN=1170N=1170

124 ± 17.0124 ± 17.0 125 ± 17.4125 ± 17.4 125 ± 17.1125 ± 17.1

123 ± 16.9123 ± 16.9 123 ± 16.7123 ± 16.7 123 ± 16.2123 ± 16.2

-1-1 -2-2 -2-2

76 ± 10.076 ± 10.0 76 ± 10.476 ± 10.4 76 ± 10.076 ± 10.0

76 ± 10.676 ± 10.6 76 ± 10.276 ± 10.2 75 ± 10.175 ± 10.1

00 00 -1-1

P 112

Box Plot of Systolic Blood Pressure Over TimeBox Plot of Systolic Blood Pressure Over TimeAll Patients Exposed to TCZAll Patients Exposed to TCZ

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

210

220

230

BL 12 24 36 48 60 72 84 96 108 120 132 144

Time Windows (Weeks)Time Windows (Weeks)

SBP (mmHG)SBP (mmHG)

P 115

Serious Cardiac Events Serious Cardiac Events All Patients Exposed to TCZAll Patients Exposed to TCZ


4 mg/kg 4 mg/kg (435 PY)(435 PY)

8 mg/kg8 mg/kg(3707 PY)(3707 PY)

Control Control (628 PY)(628 PY)

EventEventN (Rate/N (Rate/100 PY)100 PY)

N (Rate/N (Rate/100 PY)100 PY)

N (Rate/N (Rate/100 PY)100 PY)

Total 4 (0.92) 45 (1.20) 8 (1.27)

MI/ACSMI/ACS 2 (0.46)2 (0.46) 12 (0.32)12 (0.32) 4 (0.64)4 (0.64)

Ischemic Heart DiseaseIschemic Heart Disease –– 13 (0.35)13 (0.35) 1 (0.16)1 (0.16)

ArrhythmiaArrhythmia 1 (0.23)1 (0.23) 13 (0.35)13 (0.35) 2 (0.32)2 (0.32)

Cardiac FailureCardiac Failure 1 (0.23)1 (0.23) 3 (0.08)3 (0.08) ––

Cardio-Respiratory ArrestCardio-Respiratory Arrest –– 1 (0.03)1 (0.03) 1 (0.16)1 (0.16)

Excludes 3 events diastolic dysfunction, stress cardiomyopathy, Mixed aortic valve diseaseExcludes 3 events diastolic dysfunction, stress cardiomyopathy, Mixed aortic valve diseaseSource: sta11c_1_sSource: sta11c_1_s

P 116

0.64

0.16

0.46

0.230.3

0.19

0.00

0.25

0.50

0.75

1.00

MI Stroke

DMARDDMARD TCZ 4 mgTCZ 4 mg

Rate/100 PYRate/100 PY

TCZ 8 mgTCZ 8 mg

Rates of MI and Stroke Rates of MI and Stroke All Patients Exposed to TCZAll Patients Exposed to TCZ


*1 event updated to carpal tunnel*1 event updated to carpal tunnelDocumentum\Docbases\rapidprd\Repository\RO4877533\11935\Clinical\Statistical Analysis\Documentum\Docbases\rapidprd\Repository\RO4877533\11935\Clinical\Statistical Analysis\Clinical Other Document\Safety Update Signs and Symptoms BLA\Ad-hoc Requests Clinical Other Document\Safety Update Signs and Symptoms BLA\Ad-hoc Requests STrate_6_mi + STrate_6_strSTrate_6_mi + STrate_6_str

DMARDDMARD TCZ 4 mgTCZ 4 mg TCZ 8 mgTCZ 8 mg

*

P 117STrate_6_serathALLSTrate_6_serathALL

Per 100 PY by 6-Monthly PeriodsPer 100 PY by 6-Monthly Periods

Myocardial InfarctionsMyocardial Infarctions StrokeStroke

Rate of Myocardial Infarctions and StrokesRate of Myocardial Infarctions and StrokesAll Patients Exposed to TCZAll Patients Exposed to TCZ

Rate of EventsRate of Events

148 PY148 PY

> 24> 240.0

0.5

1.0

1.5

2.0

2.5

1633 PY1633 PY

0 to 60 to 6

1092 PY1092 PY

7 to 127 to 12

832 PY832 PY

13 to 1813 to 18

452 PY452 PY

19 to 2419 to 24

No EventsNo Events

P 118

Summary and Summary and Risk AssessmentRisk Assessment: Cardiovascular: Cardiovascular

SummarySummary

• No increase in mean SBP and DBP on TCZ No increase in mean SBP and DBP on TCZ

• Rate of CV events is stable with prolonged exposure Rate of CV events is stable with prolonged exposure to TCZ and comparable to controlto TCZ and comparable to control

Risk AssessmentRisk Assessment

• Long-term follow up is required to more accurately Long-term follow up is required to more accurately estimate the effect of TCZ on CV eventsestimate the effect of TCZ on CV events

P 119

Risk Mitigation: CardiovascularRisk Mitigation: Cardiovascular

• CV risk factors should be addressed and optimally managedCV risk factors should be addressed and optimally managed

– A lipid panel should be obtained after 4-8 wks of TCZ A lipid panel should be obtained after 4-8 wks of TCZ and patients should be managed according to ATP III and patients should be managed according to ATP III (or local) guidelines(or local) guidelines

– Blood pressure should be monitored routinely and Blood pressure should be monitored routinely and optimally managed according to JNC7 (or local) guidelinesoptimally managed according to JNC7 (or local) guidelines

• Physician and patient education programs regarding Physician and patient education programs regarding CV risk factors and impact of TCZ therapy will be initiated CV risk factors and impact of TCZ therapy will be initiated

• Patients will be followed for the occurrence of CV events while Patients will be followed for the occurrence of CV events while on TCZ for a minimum of 5 years in the LTE and in registries on TCZ for a minimum of 5 years in the LTE and in registries

P 120








– LipidsLipids





P 121

PlateletsPlateletsControlled 6-Month Studies (Combination)Controlled 6-Month Studies (Combination)

WeeksWeeks

Mean AbsoluteMean AbsolutePlatelets Platelets (10**9/L)(10**9/L)

0

100

200

300

400

0 2 4 6 8 12 14 16 20 24

LLNLLN

ULNULN

8 mg/kg + DMARD8 mg/kg + DMARD

4 mg/kg + MTX 4 mg/kg + MTX

Placebo + DMARDPlacebo + DMARD

P 122

Overview on Grade 3 and 4 PlateletsOverview on Grade 3 and 4 PlateletsLowest Value Reported (CTC Grades)Lowest Value Reported (CTC Grades)


TCZ TCZ 8 mg/kg 8 mg/kg (N=288) (N=288)

MTXMTX (N=284) (N=284)

TCZ TCZ 4 mg/kg 4 mg/kg + DMARD+ DMARD (N=774) (N=774)


+ DMARD + DMARD (N=1582) (N=1582)

DMARDDMARD(N=1170)(N=1170)

Grade 1Grade 1(75,000-LLN/mm(75,000-LLN/mm33))

26 (9.0%)26 (9.0%) 2 (< 1%)2 (< 1%) 42 (5.4%)42 (5.4%) 136 (8.6%)136 (8.6%) 15 (1.3%)15 (1.3%)

Grade 2Grade 2(50,000-75,000/mm(50,000-75,000/mm33))

1 (< 1%)1 (< 1%) 1 (< 1%)1 (< 1%) 3 (< 1%)3 (< 1%) 4 (< 1%)4 (< 1%) 1 (< 1%)1 (< 1%)

Grade 3Grade 3(25,000-50,000/mm(25,000-50,000/mm33))

—— —— —— 3 (< 1%)3 (< 1%) 1 (< 1%)1 (< 1%)

Grade 4Grade 4(< 25,000/mm(< 25,000/mm33))

—— —— 3 (< 1%)3 (< 1%) 2 (< 1%)2 (< 1%) 1 (< 1%)1 (< 1%)

Events of epistaxis (2), hemoptysis (1), and hemorrhagic stomatitis (1) Events of epistaxis (2), hemoptysis (1), and hemorrhagic stomatitis (1) were reported with grade 3 and 4 plateletswere reported with grade 3 and 4 platelets

Stae11_1; slae03; sllb10_a; stlb_gradtt_lab; individual PSS reportsStae11_1; slae03; sllb10_a; stlb_gradtt_lab; individual PSS reports

P 123

Risk Mitigation: PlateletsRisk Mitigation: Platelets

• TCZ should not be initiated in patients with Platelets TCZ should not be initiated in patients with Platelets < 100,000 cells/mm< 100,000 cells/mm33

• Platelets should be monitored 4-8 weeks after the first infusion Platelets should be monitored 4-8 weeks after the first infusion in all patientsin all patients

– Repeat labs as clinically indicated Repeat labs as clinically indicated

Lab ValueLab Value(cells/mm(cells/mm33)) TCZ ModificationTCZ Modification

Platelets 50-100KPlatelets 50-100KInterrupt TCZInterrupt TCZ

Plts > 100K resume TCZ at 4 mg/kg Plts > 100K resume TCZ at 4 mg/kg and return to 8 mg/kg as clinically appropriateand return to 8 mg/kg as clinically appropriate

Platelets < 50KPlatelets < 50K Discontinue TCZDiscontinue TCZ

P 124








– LipidsLipids





P 125

Serum ALTSerum ALTControlled 6-Month StudiesControlled 6-Month Studies

Sglb52_ab_sgpt; stlb10_sum [6-Month pooled safety]Sglb52_ab_sgpt; stlb10_sum [6-Month pooled safety]

Sglb52_ab_sgpt [6-Month pooled safety]Sglb52_ab_sgpt [6-Month pooled safety]

Median ALT (U/L)Median ALT (U/L)

Placebo + DMARDPlacebo + DMARD

4 mg TCZ + DMARD4 mg TCZ + DMARD

8 mg TCZ + DMARD8 mg TCZ + DMARD

MTXMTX

8 mg/kg TCZ 8 mg/kg TCZ

ULNULN

20

25

30

35

40

45

50

55

60

BL 4 8 12 16 20 24

Week

P 126

* Percentages based on number of patients normal at baseline* Percentages based on number of patients normal at baseline

** Percentages based on total population sample size** Percentages based on total population sample size

STLB_shift_btow_bchem, SLae01_dmod, SLae01_wd STLB_shift_btow_bchem, SLae01_dmod, SLae01_wd

Change in ALT/ASTChange in ALT/ASTBaseline Normal to Highest ValueBaseline Normal to Highest Value


MTX MTX (n=284)(n=284)

N (%)N (%)

86 (32)7 (3)7 (3)3 (1)3 (1)

67 (25)3 (1)3 (1)

1 (<1)1 (<1)

28 (10)28 (10)

4 (1)4 (1)

> 1-3 x ULN> 3-5 x ULN> 3-5 x ULN> 5 x ULN> 5 x ULN

TCZ 8 mg TCZ 8 mg (n=288)(n=288)

N (%)N (%)

91 (34)3 (1)3 (1)

2 (<1)2 (<1)

> 1-3 x ULN> 3-5 x ULN> 3-5 x ULN> 5 x ULN> 5 x ULN

59 (21)1 (<1)1 (<1)2 (<1)2 (<1)

% Dose Held**% Dose Held** 23 (8)23 (8)

% Discontinued**% Discontinued** 1 (<1)1 (<1)

AST (# Normal @ BL)*AST (# Normal @ BL)* n=283n=283 n=269n=269

n=269n=269ALT (# Normal @ BL)*ALT (# Normal @ BL)* n=269n=269

206 (19)9 (<1)9 (<1)3 (<1)3 (<1)

163 (15)3 (<1)3 (<1)1 (<1)1 (<1)



N (%)N (%) N (%)N (%)

672 (46)63 (4)63 (4)20 (1)20 (1)

583 (39)23 (2)23 (2)3 (<1)3 (<1)

39 (3)39 (3) 8 (<1)8 (<1)

21 (1)21 (1) 2 (<1)2 (<1)

241 (32)7 (1)7 (1)

––


N (%)N (%)

302 (43)28 (4)28 (4)7 (1)7 (1)

19 (3)19 (3)

10 (1)10 (1)

n=743n=743 n=1502n=1502 n=1123n=1123

n=706n=706 n=1465n=1465 n=1080n=1080

P 127

Adjudicated Cases of Liver AbnormalitiesAdjudicated Cases of Liver AbnormalitiesConcurrent Aminotransferases (> 3 x ULN) Concurrent Aminotransferases (> 3 x ULN)

and TBILI (> 2 x ULN) Elevationsand TBILI (> 2 x ULN) Elevations

50982/7194 50982/7194 (WA18063)(WA18063)

• 31 year old female, 31 year old female, RA 9 years durationRA 9 years duration

• AE: Biliary colicAE: Biliary colic

• Concurrent AST (158 U/L) Concurrent AST (158 U/L) and total bilirubin (6.6 mg/dL)and total bilirubin (6.6 mg/dL)

• Diagnosis: Passed gallstoneDiagnosis: Passed gallstone

64069/4798 64069/4798 (WA17824 and WA18696)(WA17824 and WA18696)

• 57 year old female, 57 year old female, RA 9 years durationRA 9 years duration

• AE: Transaminases increasedAE: Transaminases increased– Total bilirubin (2.7 mg/dL): Total bilirubin (2.7 mg/dL):

indirect (2.2 mg/dL), indirect (2.2 mg/dL), direct (0.5 mg/dL)direct (0.5 mg/dL)

– ALT (569 U/L), AST (359 U/L)ALT (569 U/L), AST (359 U/L)

• Diagnosis: Bilirubin elevation due Diagnosis: Bilirubin elevation due to Gilbert’s Syndrometo Gilbert’s Syndrome

Two Cases Observed

P 128

* Percentages based on number of patients normal at baseline* Percentages based on number of patients normal at baseline

** Percentages based on total population sample size** Percentages based on total population sample size

STLB_shift_btow_bchem, SLae01_dmod, SLae01_wd STLB_shift_btow_bchem, SLae01_dmod, SLae01_wd

MTX MTX (n=284)(n=284)

N (%)N (%)

86 (32)86 (32)7 (3)3 (1)

67 (25)67 (25)3 (1)

1 (<1)

28 (10)

4 (1)

> 1-3 x ULN> 1-3 x ULN> 3-5 x ULN> 5 x ULN

TCZ 8 mg TCZ 8 mg (n=288)(n=288)

N (%)N (%)

91 (34)91 (34)3 (1)

2 (<1)

> 1-3 x ULN> 1-3 x ULN> 3-5 x ULN> 5 x ULN

59 (21)59 (21)1 (<1)2 (<1)

% Dose Held** 23 (8)

% Discontinued** 1 (<1)

AST (# Normal @ BL)*AST (# Normal @ BL)* n=283n=283 n=269n=269

n=269n=269ALT (# Normal @ BL)*ALT (# Normal @ BL)* n=269n=269

206 (19)206 (19)9 (<1)3 (<1)

163 (15)163 (15)3 (<1)1 (<1)



N (%)N (%) N (%)N (%)

672 (46)672 (46)63 (4)20 (1)

583 (39)583 (39)23 (2)3 (<1)

39 (3) 8 (<1)

21 (1) 2 (<1)

241 (32)241 (32)7 (1)

–


N (%)N (%)

302 (43)302 (43)28 (4)7 (1)

19 (3)

10 (1)

n=743n=743 n=1502n=1502 n=1123n=1123

n=706n=706 n=1465n=1465 n=1080n=1080

Change in ALT/ASTChange in ALT/ASTBaseline Normal to Highest ValueBaseline Normal to Highest Value


P 129

N (%)N (%)N (%)N (%)Patterns of ChangePatterns of Change

TCZ TCZ 8 mg/kg8 mg/kg(N=288) (N=288)

MTX MTX (N=284)(N=284)

A Single Time A Single Time Point OnlyPoint Only ASTAST 29 (10)29 (10) 39 (13)39 (13)

2 or More 2 or More Consecutive Consecutive Values > 1 x ULN Values > 1 x ULN ASTAST 11 (4)11 (4) 9 (3)9 (3)

Non-consecutive Non-consecutive Elevation of 2 Elevation of 2 or More Valuesor More Values ASTAST 22 (8)22 (8) 27 (10)27 (10)

Incidence of ALT/AST elevations is not increased in the LTEIncidence of ALT/AST elevations is not increased in the LTE

STlb_elevsum_ast1 or alt1STlb_elevsum_ast1 or alt1

Patterns of Change in ALT/AST (> 1x ULN)Patterns of Change in ALT/AST (> 1x ULN)Controlled 6-Month StudiesControlled 6-Month Studies

ALTALT 40 (14)40 (14) 36 (13)36 (13)

ALT ALT 14 (5)14 (5) 15 (5)15 (5)

ALTALT 36 (13)36 (13) 47 (17)47 (17)

N (%)N (%)N (%)N (%)N (%)N (%)

TCZ TCZ 4 mg/kg 4 mg/kg + DMARD+ DMARD (N=774)(N=774)

TCZ TCZ 8 mg/kg 8 mg/kg + DMARD+ DMARD(N=1582(N=1582))

DMARDDMARD(N=1170)(N=1170)

138 (18)138 (18) 260 (16)260 (16) 101 (9)101 (9)

19 (3)19 (3) 80 (5)80 (5) 22 (2)22 (2)

111 (14)111 (14) 286 (18)286 (18) 66 (6)66 (6)

116 (15)116 (15) 224 (14)224 (14) 127 (11)127 (11)

41 (5)41 (5) 117 (7)117 (7) 40 (3)40 (3)

209 (27)209 (27) 391 (25)391 (25) 105 (9)105 (9)

P 130

Summary: Liver Enzyme Elevations Summary: Liver Enzyme Elevations

• Most ALT/AST elevations were transient and returned Most ALT/AST elevations were transient and returned to normal without dose adjustment or treatment to normal without dose adjustment or treatment discontinuationdiscontinuation

• Elevated transaminases were not associated Elevated transaminases were not associated with reduced liver function in 4,142 patient years with reduced liver function in 4,142 patient years of exposureof exposure

• No serious adverse events were associated No serious adverse events were associated with transaminase elevationswith transaminase elevations

P 131

Risk Mitigation: Liver EnzymesRisk Mitigation: Liver Enzymes

• TCZ should not be initiated in patients with ALT/AST > 1.5 x ULN or TCZ should not be initiated in patients with ALT/AST > 1.5 x ULN or other evidence of liver diseaseother evidence of liver disease

• ALT/AST should be monitored 4-8 weeks after the first infusion ALT/AST should be monitored 4-8 weeks after the first infusion in all patientsin all patients

– Repeat labs as clinically indicatedRepeat labs as clinically indicated

*Follow ACR 2008 recommendations for DMARDs*Follow ACR 2008 recommendations for DMARDs

Lab ValueLab Value ActionAction

> 1-3 x ULN> 1-3 x ULN Dose modify concomitant DMARDs*Dose modify concomitant DMARDs*For persistent increases (in association with MTX, For persistent increases (in association with MTX, LFN, and sulfasalazine), dose modify TCZ to normalize LFN, and sulfasalazine), dose modify TCZ to normalize ALT/AST levelsALT/AST levels

> 3- 5 x ULN> 3- 5 x ULN Interrupt TCZ until < 3 x ULNInterrupt TCZ until < 3 x ULNDose reduce TCZ to 4 mg/kg or resume full doseDose reduce TCZ to 4 mg/kg or resume full doseFor persistent increases, discontinue TCZFor persistent increases, discontinue TCZ

> 5 x ULN > 5 x ULN Discontinue TCZDiscontinue TCZ

P 132








– LipidsLipids





P 133


MTXMTXn=n=284 284

N (%)N (%) N (%)N (%)

Anaphylactic ReactionAnaphylactic Reaction -- --

HypersensitivityHypersensitivity 1 (0.3)1 (0.3) --

Hypertension / BP IncreasedHypertension / BP Increased 7 (2.4)7 (2.4) 2 (0.7)2 (0.7)

Hypotension / BP DecreasedHypotension / BP Decreased 1 (0.3)1 (0.3) 1 (0.4)1 (0.4)

Skin Rxn*Skin Rxn* 1 (0.4)1 (0.4) 3 (1.0)3 (1.0)

HeadacheHeadache 4 (1.4)4 (1.4) 1 (0.4)1 (0.4)

*Rash, pruritis, hyperhidrosis, urticaria, erythema, allergic dermatitis, face swelling*Rash, pruritis, hyperhidrosis, urticaria, erythema, allergic dermatitis, face swellingRhstae11_ir, feb 4 08Rhstae11_ir, feb 4 08

Infusion reactions were not correlated to the development Infusion reactions were not correlated to the development of anti-TCZ HAHA antibodies. of anti-TCZ HAHA antibodies.

Infusion ReactionsInfusion ReactionsControlled 6-Month StudiesControlled 6-Month Studies

TCZ 4 mg/kg TCZ 4 mg/kg + DMARD+ DMARD

n=n=774774

TCZ 8 mg/kg TCZ 8 mg/kg + DMARD+ DMARDn=n=1582 1582


N (%)N (%) N (%)N (%) N (%)N (%)

2 (0.3)2 (0.3) 1 (<0.1)1 (<0.1) --

-- 1 (<0.1)1 (<0.1) --

7 (0.9)7 (0.9) 17 (1.1)17 (1.1) 10 (0.9)10 (0.9)

3 (0.4)3 (0.4) 3 (0.2)3 (0.2) 6 (0.5)6 (0.5)

16 (2.1)16 (2.1) 23 (1.5)23 (1.5) 6 (0.5)6 (0.5)

11 (1.4)11 (1.4) 27 (1.7)27 (1.7) 13 (1.1)13 (1.1)

P 134

Infusion Reactions Infusion Reactions All Patients Exposed to TCZAll Patients Exposed to TCZ



435 PY435 PY


+/- DMARD+/- DMARD3707 PY3707 PY

All ControlAll Control683 PY683 PY

Total TCZTotal TCZ4142 PY4142 PY

N (rate/100 PY)N (rate/100 PY) N (rate/100 PY)N (rate/100 PY) N (rate/100 PY)N (rate/100 PY) N (rate/100 PY)N (rate/100 PY)

Anaphylactic ReactionAnaphylactic Reaction 3 (0.7)3 (0.7) 3 (0.1)3 (0.1) -- 6 (0.1)6 (0.1)

HypersensitivityHypersensitivity -- 1 (<0.1)1 (<0.1) -- 1 (<0.1)1 (<0.1)

Hypertension / BP increasedHypertension / BP increased 9 (2.1)9 (2.1) 63 (1.7)63 (1.7) 12 (1.8)12 (1.8) 72 (1.7)72 (1.7)

Hypotension / BP DecreasedHypotension / BP Decreased 3 (0.7)3 (0.7) 14 (0.4)14 (0.4) 7 (1.0)7 (1.0) 17 (0.4)17 (0.4)

Skin Rxn*Skin Rxn* 19 (4.4)19 (4.4) 57 (1.5)57 (1.5) 9 (1.3)9 (1.3) 76 (1.8)76 (1.8)

HeadacheHeadache 12 (2.8)12 (2.8) 61 (1.6)61 (1.6) 14 (2.0)14 (2.0) 73 (1.8)73 (1.8)

*Rash, pruritis, hyperhidrosis, urticaria, erythema, allergic dermatitis, face swelling, pruritic rash, *Rash, pruritis, hyperhidrosis, urticaria, erythema, allergic dermatitis, face swelling, pruritic rash, erythematous rash, macular rash, generalized pruritis, angioedemaerythematous rash, macular rash, generalized pruritis, angioedema

Rhstae11_ir, feb 4 08; stae11c_ir_24in 09 July 2008; stae11c_ir_dinf 09 July 2008Rhstae11_ir, feb 4 08; stae11c_ir_24in 09 July 2008; stae11c_ir_dinf 09 July 2008

P 135

Summary and Risk Mitigation: Summary and Risk Mitigation: Infusion ReactionsInfusion Reactions

SummarySummary

• Infusion reactions and the development of anti-TCZ Infusion reactions and the development of anti-TCZ antibodies were rareantibodies were rare

• 6 cases of anaphylactic reaction were reported overall6 cases of anaphylactic reaction were reported overall

– 3 each on the 4 and 8 mg/kg dose3 each on the 4 and 8 mg/kg dose


• The infusion setting should be staffed with The infusion setting should be staffed with experienced personnel and appropriate medications experienced personnel and appropriate medications and equipment to manage anaphylactic reactions and equipment to manage anaphylactic reactions

P 136

Safety RecommendationsSafety Recommendations

• Patients and their healthcare professionals need to be vigilant for Patients and their healthcare professionals need to be vigilant for early signs of infection and diverticulitis. TCZ should be withheld early signs of infection and diverticulitis. TCZ should be withheld if infection is suspectedif infection is suspected

• Laboratory monitoring of hepatic transaminases, neutrophils and Laboratory monitoring of hepatic transaminases, neutrophils and platelets should be performed after initiation of TCZ therapy platelets should be performed after initiation of TCZ therapy and periodically thereafter. Lipids should be assessed 4-8 weeks and periodically thereafter. Lipids should be assessed 4-8 weeks after initiation of TCZ to determine if lipid lowering agents are after initiation of TCZ to determine if lipid lowering agents are requiredrequired

• Healthcare providers administering TCZ need to be alert for signs Healthcare providers administering TCZ need to be alert for signs of anaphylaxis and should be prepared to intervene promptlyof anaphylaxis and should be prepared to intervene promptly

• Accurate assessment of malignancy rates and CV events require Accurate assessment of malignancy rates and CV events require ongoing surveillanceongoing surveillance

P 137

Risk Mitigation/PharmacovigilanceRisk Mitigation/Pharmacovigilance

Philippe Van der Auwera, MD, PhDPhilippe Van der Auwera, MD, PhDGlobal Head of Drug SafetyGlobal Head of Drug Safety

P 138

Integrated Risk Management Integrated Risk Management

Risk Mitigation:Risk Mitigation:

• Label/Patient Package InsertLabel/Patient Package Insert

• Patient, nurse and physician educationPatient, nurse and physician education

PharmacovigilancePharmacovigilance

• Long-term observational cohort studies in RA Long-term observational cohort studies in RA and biologic registries and biologic registries

• Enhanced pharmacovigilance for specific eventsEnhanced pharmacovigilance for specific events

• Pregnancy registryPregnancy registry

• Claims database analysesClaims database analyses

• Long-term safety studies (> 2,500 patients for 5 years)Long-term safety studies (> 2,500 patients for 5 years)

P 139

Mitigation Strategy: ClinicalMitigation Strategy: Clinical

• Expected risks in RA for immunomodulating biologic Expected risks in RA for immunomodulating biologic agents, including TCZ:agents, including TCZ:

– Anaphylaxis, serious and opportunistic infections, Anaphylaxis, serious and opportunistic infections, malignancy, demyelinating disordersmalignancy, demyelinating disorders

– Gastrointestinal perforationsGastrointestinal perforations

• Risk Mitigation Strategies for TCZ:Risk Mitigation Strategies for TCZ:

– Labeling, patient information, education of patients, Labeling, patient information, education of patients, physicians and nursesphysicians and nurses

P 140

Mitigation Strategy: Laboratory ParametersMitigation Strategy: Laboratory Parameters

• Recognized pharmacodynamic changes Recognized pharmacodynamic changes in lab parameters in lab parameters

– ALT/AST, neutrophils, platelets and lipidsALT/AST, neutrophils, platelets and lipids

• Risk Mitigation StrategyRisk Mitigation Strategy

– Monitoring Monitoring

– Dose modification/dose interruptionDose modification/dose interruption

• TCZTCZ

• Concomitant medications (e.g., lipid lowering agents)Concomitant medications (e.g., lipid lowering agents)

P 141

Pharmacovigilance Pharmacovigilance Prospective Observational Cohort StudiesProspective Observational Cohort Studies

• A TCZ cohort will be added to existing biologics/RA registries A TCZ cohort will be added to existing biologics/RA registries

– Providing control populations with patients on other therapiesProviding control populations with patients on other therapies

– US RegistryUS Registry: final selection tbd: final selection tbd

– EU RegistriesEU Registries: BSRBR, ARTIS, RABBIT : BSRBR, ARTIS, RABBIT

– 5-year follow-up 5-year follow-up

• Registries are powered to detect RR > 1.4 for MIRegistries are powered to detect RR > 1.4 for MI

– Power will be sufficient to examine stroke and serious infectionPower will be sufficient to examine stroke and serious infection

• Interim and final summary reports are plannedInterim and final summary reports are planned

• Pregnancy registries (OTIS/ENTIS)Pregnancy registries (OTIS/ENTIS)

P 142

PharmacovigilancePharmacovigilanceClaims Database AnalysesClaims Database Analyses

Claims data analyses for the events of interestClaims data analyses for the events of interest

• Large data source Large data source

• Real world data allowing to:Real world data allowing to:

– Define an RA populationDefine an RA population

– Define comparison groupsDefine comparison groups

– Use various methods to help control for biasUse various methods to help control for bias

– Adequate sensitivity and specificity for rare eventsAdequate sensitivity and specificity for rare events

P 143

PharmacovigilancePharmacovigilanceOngoing Clinical TrialsOngoing Clinical Trials

Continuation of long-term extension Continuation of long-term extension of pivotal trials for 5 yearsof pivotal trials for 5 years

• > 2,500 patients> 2,500 patients

• Annual updatesAnnual updates

P 144

Summary: PharmacovigilanceSummary: Pharmacovigilance

• Good understanding of the data obtained so far Good understanding of the data obtained so far in a large development programin a large development program

• Clear identification of the needs for more data Clear identification of the needs for more data in areas of interest and how to acquire themin areas of interest and how to acquire them

• Comprehensive strategy to mitigate recognized Comprehensive strategy to mitigate recognized and potential risksand potential risks

P 145

Tocilizumab: SummaryTocilizumab: Summary

Kenneth Bahrt, MDKenneth Bahrt, MD Global Medical Director, AutoimmunityGlobal Medical Director, Autoimmunity

P 146

SummarySummary

• Rheumatoid arthritis: A multifactorial disease Rheumatoid arthritis: A multifactorial disease with a common clinical phenotype reached with a common clinical phenotype reached via many routes via many routes

• New therapies with novel mechanisms of action are New therapies with novel mechanisms of action are still needed still needed

• Many patients respond sub-optimally to currently Many patients respond sub-optimally to currently approved therapies or lose their effect over timeapproved therapies or lose their effect over time

• TCZ offers a new approach to the management TCZ offers a new approach to the management of this diseaseof this disease

P 147

Summary: BenefitSummary: Benefit

• In a comprehensive clinical program TCZ demonstrated:In a comprehensive clinical program TCZ demonstrated:– Reliable and consistent efficacy in monotherapy or in combination Reliable and consistent efficacy in monotherapy or in combination

with DMARDs in a range of RA patients with DMARDs in a range of RA patients

– Improvement in patient’s quality of life and physical functioningImprovement in patient’s quality of life and physical functioning

– Effective control of inflammation throughout the dosing periodEffective control of inflammation throughout the dosing period

– Clinical benefit sustained over 2 yearsClinical benefit sustained over 2 years

• In anti-TNF IR, In anti-TNF IR, TCZ 8 mg/kg consistently more efficacious than 4 mg/kgTCZ 8 mg/kg consistently more efficacious than 4 mg/kg

• In DMARD IR, although both doses are effective, 8 mg/kg TCZ every In DMARD IR, although both doses are effective, 8 mg/kg TCZ every 4 weeks more efficacious than 4 mg/kg in reducing signs and symptoms 4 weeks more efficacious than 4 mg/kg in reducing signs and symptoms in majority of patientsin majority of patients

– 4 mg/kg may be considered followed by an adjustment to 8 mg/kg 4 mg/kg may be considered followed by an adjustment to 8 mg/kg based upon clinical responsebased upon clinical response

• In patients where DMARDs are not considered appropriate, In patients where DMARDs are not considered appropriate, TCZ monotherapy at 8 mg/kg provides a clinical response TCZ monotherapy at 8 mg/kg provides a clinical response (ACR20, 50, 70) that is superior to MTX(ACR20, 50, 70) that is superior to MTX

P 148

Summary: RiskSummary: Risk

• In a comprehensive clinical program, TCZ monotherapy In a comprehensive clinical program, TCZ monotherapy and in combination with DMARDs has demonstrated:and in combination with DMARDs has demonstrated:

– Well characterized adverse event profileWell characterized adverse event profile

– Risk of serious infection comparable to other biologicsRisk of serious infection comparable to other biologics

– Risk of malignancy and CV events similar to background rate Risk of malignancy and CV events similar to background rate in RA populationin RA population

– Rate of GI perforations at 8 mg/kg dose elevated over control Rate of GI perforations at 8 mg/kg dose elevated over control but similar to RA background rate in RA databasesbut similar to RA background rate in RA databases

– Hematologic and biochemical effects (ALT/AST, neutrophils, Hematologic and biochemical effects (ALT/AST, neutrophils, platelets, lipid changes) that are identifiable and manageable platelets, lipid changes) that are identifiable and manageable in clinical practice in clinical practice

• Dose modification and/or interruption of TCZ / Dose modification and/or interruption of TCZ / concomitant medicationsconcomitant medications

• Lipid lowering agentsLipid lowering agents

P 149

Pharmacovigilance and Risk MitigationPharmacovigilance and Risk Mitigation

PharmacovigilancePharmacovigilance

• Continuation of open label extension studies Continuation of open label extension studies (> 2,500 pts for 5 yrs)(> 2,500 pts for 5 yrs)

• 4 Registry studies (1 US, 3 EU)4 Registry studies (1 US, 3 EU)

• Pregnancy registry (OTIS/ENTIS)Pregnancy registry (OTIS/ENTIS)

• Claims databaseClaims database

Risk Mitigation:Risk Mitigation:

• Appropriate labelling for physicians and patients around AEs Appropriate labelling for physicians and patients around AEs of interestof interest

– Monitoring for laboratory abnormalitiesMonitoring for laboratory abnormalities

• Educational programsEducational programs

P 150

SummarySummary

• These data support a positive benefit risk assessment These data support a positive benefit risk assessment supporting use of TCZ 8 mg/kg every 4 weeks as supporting use of TCZ 8 mg/kg every 4 weeks as monotherapy or in combination with other DMARDs monotherapy or in combination with other DMARDs

– To reduce the signs and symptoms in adult patients To reduce the signs and symptoms in adult patients with moderate to severely active rheumatoid arthritis with moderate to severely active rheumatoid arthritis who had an inadequate response to one or more who had an inadequate response to one or more DMARDs or TNF antagonists or in whom DMARDs DMARDs or TNF antagonists or in whom DMARDs are not considered appropriateare not considered appropriate

– In some DMARD IR patients a dose of 4 mg/kg may be In some DMARD IR patients a dose of 4 mg/kg may be considered followed by adjustment to 8 mg/kg based considered followed by adjustment to 8 mg/kg based upon clinical responseupon clinical response

P 151

TocilizumabTocilizumabArthritis Advisory CommitteeArthritis Advisory Committee

Hoffmann-La Roche Inc.Hoffmann-La Roche Inc.July 29, 2008 July 29, 2008

p 1 tocilizumab arthritis advisory committee hoffmann-la roche inc. july 29, 2008

Documents

clinical response slide

adult patients

inadequate response

dmardir patients

range of ra patients

membrane bound il

active rheumatoid arthritis

administration dose