P-1 Pegasys + Copegus Combination Therapy BLA 125061/NDA 21-511 Antiviral Drugs Advisory Committee Meeting November 14, 2002

P-1

Pegasys + Copegus Pegasys + Copegus Combination TherapyCombination Therapy

BLA 125061/NDA 21-511BLA 125061/NDA 21-511

Antiviral Drugs Advisory Committee MeetingAntiviral Drugs Advisory Committee Meeting

November 14, 2002November 14, 2002

P-2

Pegasys Monotherapy IndicationPegasys Monotherapy Indication

Indication:Indication:

Pegasys, Peginterferon alfa-2a, is indicated Pegasys, Peginterferon alfa-2a, is indicated for the treatment of adults with chronic hepatitis C who for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not been have compensated liver disease and have not been previously treated with interferon alpha. Patients in previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients whom efficacy was demonstrated included patients with compensated cirrhosis.with compensated cirrhosis.

Dosage and AdministrationDosage and Administration

180 180 g once weekly for 48 weeksg once weekly for 48 weeks

P-3

Pegasys + Copegus Pegasys + Copegus Proposed Label AdditionsProposed Label Additions

Pegasys, Peginterferon alfa-2a, Pegasys, Peginterferon alfa-2a, in combination with in combination with Copegus, ribavirinCopegus, ribavirin, is indicated for the treatment of , is indicated for the treatment of adults with chronic hepatitis C who have adults with chronic hepatitis C who have compensated liver disease and have not been compensated liver disease and have not been previously treated with interferon alpha. Patients in previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients whom efficacy was demonstrated included patients with compensated cirrhosis.with compensated cirrhosis.

Dosage and administration accordingDosage and administration accordingto genotype:to genotype:

Treatment durationTreatment duration Ribavirin dose Ribavirin dose

P-4

Regulatory History of ApplicationRegulatory History of Application

July 16, 1998July 16, 1998 US IND submittedUS IND submitted

October 6, 1998October 6, 1998 End of phase II meetingEnd of phase II meeting

August 9, 2000August 9, 2000 Fast-Track designationFast-Track designation

May 7, 2002May 7, 2002 Pre-BLA/NDA meetingPre-BLA/NDA meeting

June 3, 2002June 3, 2002 BLA/NDA Filed to FDABLA/NDA Filed to FDA

October 16, 2002October 16, 2002 Pegasys monotherapy Pegasys monotherapy approvedapproved

November 14, 2002November 14, 2002 Advisory CommitteeAdvisory Committee

P-5

Roche Presentation AgendaRoche Presentation Agenda

IntroductionIntroduction Candice Teuber, Pharm.D.Candice Teuber, Pharm.D.

Overview ofOverview ofPegasys-CopegusPegasys-Copegus Joseph Hoffman, M.D.Joseph Hoffman, M.D. Development ProgramDevelopment Program

EfficacyEfficacy Frank Duff, M.D.Frank Duff, M.D.

SafetySafety Jonathan Solsky, M.D.Jonathan Solsky, M.D.

ConclusionsConclusions Joseph Hoffman, M.D.Joseph Hoffman, M.D.

P-6

Experts Available for Q & AExperts Available for Q & A

Donald M. Jensen, M.D.Donald M. Jensen, M.D. Director, Section of Hepatology Director, Section of Hepatology

Rush-Presbyterian-St. Luke’s Medical CenterRush-Presbyterian-St. Luke’s Medical CenterChicago, ILChicago, IL

Mitchell Shiffman, M.D.Mitchell Shiffman, M.D.Chief, Hepatology Section,Chief, Hepatology Section,

Virginia Commonwealth University Health System Virginia Commonwealth University Health System Medical College of Virginia Medical College of Virginia

Richmond, VARichmond, VA

P-7

Roche Experts Available for Q & ARoche Experts Available for Q & A

Clinical ScienceClinical Science Michael Brunda, Ph.D.Michael Brunda, Ph.D.

ToxicologyToxicology Celine Eliahou, M.S.Celine Eliahou, M.S.

StatisticsStatistics Amy Lin, M.S.Amy Lin, M.S.

Clinical PharmacologyClinical Pharmacology Matthew Lamb, Pharm.D.Matthew Lamb, Pharm.D.

Clinical PharmacologyClinical Pharmacology Karin Jorga, Ph.D.Karin Jorga, Ph.D.

P-8


OverviewOverview

Dr. Joseph HoffmanDr. Joseph HoffmanVP & Group Leader,VP & Group Leader,

Virology and TransplantationVirology and Transplantation

P-9

BackgroundBackground

Rationale for development of PegasysRationale for development of Pegasys

Overview of clinical programOverview of clinical program

Dose selection in combination therapy programDose selection in combination therapy program

P-10

0%

10%

20%

30%

40%

50%

60%

70%

Overall Geno 1 Cirrhosis Geno 1,HVL

Geno 1,Cirrhosis

11% -19%11% -19%

7%7% 5%5%1% - 2%1% - 2% <1%<1%

IFN alfa 3 or 6/3 MIU tiw x 48 wksIFN alfa 3 or 6/3 MIU tiw x 48 wks

Zeuzem et al. N Engl J Med. 2000;343:1666-1672Zeuzem et al. N Engl J Med. 2000;343:1666-1672Heathcote et al. N Engl J Med. 2000;343:1673-1680Heathcote et al. N Engl J Med. 2000;343:1673-1680Pockros et al. 41st ICAAC Meeting. 2001:285(Abstract H-457)Pockros et al. 41st ICAAC Meeting. 2001:285(Abstract H-457)Roche data on fileRoche data on file

SVR: Difficult-to-Treat DiseaseSVR: Difficult-to-Treat Disease

SV

RS

VR

P-11

Time (hours)

Pharmacokinetics of Pharmacokinetics of Standard Alpha InterferonsStandard Alpha Interferons

First dose measured; others simulatedFirst dose measured; others simulatedRoche data on fileRoche data on file

00 2424 4848 7272 9696 120120 144144 168168 192192

00

22

44

66

88

1010

1212

1414TueTue WedWed ThuThu FriFri SatSat SunSunMonMon

Periods of timePeriods of timewhen IFN is not when IFN is not detectable in detectable in circulationcirculation

Inte

rfer

on

(U

/mL

)In

terf

ero

n (

U/m

L)

P-12

Peginterferon Alfa-2a (40KD)Peginterferon Alfa-2a (40KD)

CHCH33OCHOCH22CHCH22(OCH(OCH22CHCH22))nn O O C C NH NH

OO

CHCH33OCHOCH22CHCH22(OCH(OCH22CHCH22))nn O O C C NH NH

OO

CHCH22

CHCH

mPEGmPEG

CC NHNH

OO

InterferonInterferon

LysineLysine(CH(CH22))33

P-13

PegasysPegasys

Soluble formulationSoluble formulation

Retains immunomodulatory and Retains immunomodulatory and antiproliferative propertiesantiproliferative properties

Sustained actionSustained action Decreased clearanceDecreased clearance Extended absorptive phaseExtended absorptive phase

Limited volume of distributionLimited volume of distribution Allows unit dosingAllows unit dosing

P-14

NV15496NV15496

Pegasys Systemic Concentrations – Pegasys Systemic Concentrations – 180 180 g sc Once Weekly g sc Once Weekly

00

55

1010

1515

WeeklyWeeklyDoseDoseGivenGiven

Day 1Day 1 Day 2Day 2 Day 3Day 3 Day 4Day 4 Day 5Day 5 Day 6Day 6 Weekly Weekly Dose Dose GivenGiven

Mea

n C

on

cen

trat

ion

M

ean

Co

nce

ntr

atio

n

(ng

/mL

)(n

g/m

L)

After first dose

P-15

Pooled Data (Basic Model)

-200

-150

-100

-50

0

50

100

40 50 60 70 80 90 100 110Weight (kg)

Ch

an

ge in

CL

(C

L-T

VC

L)

(mL/h

)

Change in Pegasys Total Apparent Body Change in Pegasys Total Apparent Body Clearance vs Total Body WeightClearance vs Total Body Weight

P-16

Comprehensive Comprehensive Pegasys Clinical ProgramPegasys Clinical Program

MonotherapyMonotherapy2/97 12/99

• Dose-finding studyDose-finding study

• Study in patients with cirrhosisStudy in patients with cirrhosis

• Study vs standard IFNStudy vs standard IFN

• Study vs induction regimen IFNStudy vs induction regimen IFN

1600 patients1600 patients were enrolled in 4 separate Phase II and III trials were enrolled in 4 separate Phase II and III trials in cirrhotic and noncirrhotic patientsin cirrhotic and noncirrhotic patients

1001 patients1001 patients were randomized to Pegasys and were randomized to Pegasys and 599 patients599 patients were randomized to Roferon-Awere randomized to Roferon-A

P-17

3%

10%

30%

36%

29%

0%

10%

20%

30%

40%

Reddy et al. Hepatology. 2001;33:433-438Reddy et al. Hepatology. 2001;33:433-438

SV

RS

VR

N = 33 N = 20N = 20 N = 45 N = 41

NV15489NV15489

Phase II Dose-finding StudyPhase II Dose-finding Study

Roferon-A3 MIU

Pegasys45 µg

Pegasys90 µg

Pegasys180 µg

Pegasys270 µg

P-18

0%

10%

20%

30%

40%

Reddy et al. Hepatology. 2001;33:433-438Reddy et al. Hepatology. 2001;33:433-438

SV

RS

VR

N = 14 N = 35

NV15489NV15489

Dose-finding Study: SVR in Genotype 1Dose-finding Study: SVR in Genotype 1

Pegasys90 µg

Pegasys180 µg

Genotype 1Genotype 1

31%

14%

P-19

8%

30%*

15%**

0%

10%

20%

30%

40%

Roferon-A 3 MIU Pegasys 90 µg Pegasys 180 µg

*P= 0.001 vs Roferon-A; **NS vs Roferon-A*P= 0.001 vs Roferon-A; **NS vs Roferon-AHeathcote et al. N Engl J Med. 2000;343:1673-1680Heathcote et al. N Engl J Med. 2000;343:1673-1680

N = 88 N = 96 N = 87

NV15495NV15495

Sustained Virological Response Sustained Virological Response in Patients with Cirrhosisin Patients with Cirrhosis

SV

RS

VR

P-20

21%

11%

47%54%

28%* 28%*

0%

10%

20%

30%

40%

50%

60%

70%

80%

Week 24 Week 72

Roferon-A 3 MIU Pegasys 135 µg Pegasys 180 µg

Vir

olo

gic

al R

esp

on

seV

iro

log

ical

Res

po

nse

NV15496NV15496

Virological Response at Weeks 24 and 72 Virological Response at Weeks 24 and 72

Pegasys 135 Pegasys 135 g vs 180 g vs 180 gg

HCV RNA undetectable (<100 copies/mL) HCV RNA undetectable (<100 copies/mL) *P = 0.01 vs Roferon-A at week 72*P = 0.01 vs Roferon-A at week 72Pockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on filePockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on file

N = 214 N = 215 N = 210 N = 214 N = 215 N = 210

P-21

45%

58%**

48%*

0%

10%

20%

30%

40%

50%

60%

70%

80%

Roferon-A 3 MIU Pegasys 135 µg Pegasys 180 µg††Histological response defined as Histological response defined as 2 point decrease in HAI score2 point decrease in HAI score*NS vs Roferon-A **P = 0.017 vs Roferon-A*NS vs Roferon-A **P = 0.017 vs Roferon-APockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on filePockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on file

His

tolo

gic

al R

esp

on

seH

isto

log

ical

Res

po

nse

††

N = 147 N = 171 N = 160

NV15496NV15496

Histological Response: Pegasys 135 Histological Response: Pegasys 135 g g vs 180 vs 180 g in Patients with Paired Biopsiesg in Patients with Paired Biopsies

P-22

Severe AEs Severe AEs 30%30% 32%32%

Serious AEsSerious AEs 10%10% 9%9% Treatment-related serious AEs*Treatment-related serious AEs* 3%3% 5%5%

AEs and laboratory abnormalitiesAEs and laboratory abnormalities leading to withdrawal leading to withdrawal 10% 10% 10%10%

AEs and laboratory abnormalitiesAEs and laboratory abnormalitiesrequiring dose modification requiring dose modification 21%21% 27%27%

Pegasys Pegasys Pegasys Pegasys 135 135 gg 180 180 gg

Adverse Event Adverse Event (N = 215)(N = 215) (N = 604) (N = 604)

*Events judged by investigator to be possibly or probably related to treatment*Events judged by investigator to be possibly or probably related to treatment

Overview of Adverse Events in Integrated Overview of Adverse Events in Integrated Summary of Safety for Pegasys MonotherapySummary of Safety for Pegasys Monotherapy

P-23

0%

10%

20%

30%

40%

50%

60%

70%


Geno 1,Cirrhosis

11% -19%11% -19%

7%7% 5%5%1% - 2%1% - 2% <1%<1%

IFN alfa 3 or 6/3 MIU tiw x 48 wksIFN alfa 3 or 6/3 MIU tiw x 48 wks

Zeuzem et al. N Engl J Med. 2000;343:1666-1672Zeuzem et al. N Engl J Med. 2000;343:1666-1672Heathcote et al. N Engl J Med. 2000;343:1673-1680Heathcote et al. N Engl J Med. 2000;343:1673-1680Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457)Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457)Roche data on fileRoche data on file


SV

RS

VR

P-24

0%

10%

20%

30%

40%

50%

60%

70%


Geno 1,Cirrhosis

28% -39%28% -39%

Zeuzem et al. N Engl J Med. 2000;343:1666-1672Zeuzem et al. N Engl J Med. 2000;343:1666-1672Heathcote et al. N Engl J Med. 2000;343:1673-1680Heathcote et al. N Engl J Med. 2000;343:1673-1680Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457)Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457)Roche data on fileRoche data on file


SV

RS

VR

Pegasys 180 Pegasys 180 g qw x 48 wksg qw x 48 wks

22% - 28%22% - 28% 30%30%

14%14% 13%13%

P-25


Combination TherapyCombination Therapy10/98 1/02


• Pilot safety studyPilot safety study

• Comparative trial vs RebetronComparative trial vs Rebetron

• Duration and dosing by genotype trialDuration and dosing by genotype trial

P-26

RibavirinRibavirin

Better efficacy seen with combination than Better efficacy seen with combination than IFN aloneIFN alone

Teratogenic and mutagenic; induces hemolysisTeratogenic and mutagenic; induces hemolysis

Dose of 1000 or 1200 mg is safe and efficacious Dose of 1000 or 1200 mg is safe and efficacious with standard IFNwith standard IFN

Pegasys 180 Pegasys 180 g and 1000 or 1200 mg of ribavirin g and 1000 or 1200 mg of ribavirin tolerated in pilot safety study (NV15800)tolerated in pilot safety study (NV15800)

No PK interaction between ribavirin and IFNNo PK interaction between ribavirin and IFN

P-27

5050 6060 7070 8080 9090 100100 110110 120120 130130 140140

Body Weight (kg)Body Weight (kg)

00

1010

2020

3030

4040

5050

6060

7070

4040

AU

CA

UC

0-24

h0-

24h

Predicted Copegus ExposurePredicted Copegus Exposure1000 or 1200 mg Body-Weight-Adjusted Dose1000 or 1200 mg Body-Weight-Adjusted Dose

1000 mg1000 mg 1200 mg1200 mg

<75 kg<75 kg 75 kg75 kg

P-28

PegasysPegasysCombination Development ProgramCombination Development Program

Phase III: NV15801Phase III: NV158012/99 4/01

Phase II: NV15800Phase II: NV1580010/98 3/00

Pegasys (180 Pegasys (180 g) + Placebog) + Placebo Intron A (3 MIU) + Rebetol (1000 or 1200 mg)Intron A (3 MIU) + Rebetol (1000 or 1200 mg) Pegasys (180 Pegasys (180 g) + Copegus (1000 or 1200 mg)g) + Copegus (1000 or 1200 mg)

48 Weeks48 Weeks

P-29

66% 65%

32% 33%

10%

27%

0%

10%

20%

30%

40%

50%

60%

70%

80%

24 Weeks 48 Weeks

Genotype 2,3 Genotype 1, LVL Genotype 1, HVL

McHutchison et al. Seminars in Liver Disease. 1999;19(suppl 1):57-65McHutchison et al. Seminars in Liver Disease. 1999;19(suppl 1):57-65

SV

RS

VR

SVR: Rebetron Registration TrialsSVR: Rebetron Registration Trials

N = 505 N = 504

P-30

PegasysPegasysCombination Development ProgramCombination Development Program



Phase II: NV15800Phase II: NV1580010/98 3/00

Comparative Trial vs RebetronComparative Trial vs Rebetron

Duration and Dosing by Genotype TrialDuration and Dosing by Genotype Trial

P-31

Pegasys + CopegusPegasys + Copegus

Optimization of TherapyOptimization of Therapy

Duration of combination therapyDuration of combination therapy

Pegasys weekly dosePegasys weekly dose

Copegus daily doseCopegus daily dose

P-32

Copegus Dose SelectionCopegus Dose Selection

Chose Copegus 1000 or 1200 mg in Chose Copegus 1000 or 1200 mg in control arm to bridge to comparative trialcontrol arm to bridge to comparative trial

No powered dose-finding trials with ribavirin No powered dose-finding trials with ribavirin were availablewere available

Literature and anecdotal experience suggested Literature and anecdotal experience suggested ribavirin dose of 800 mg might be adequate but ribavirin dose of 800 mg might be adequate but 600 mg too low600 mg too low

P-33

Pegasys + CopegusPegasys + Copegus

Optimization of TherapyOptimization of Therapy

Duration of combination therapy 24 vs 48 weeksDuration of combination therapy 24 vs 48 weeks

Pegasys weekly dose 180 Pegasys weekly dose 180 gg

Copegus daily dose 800 vs 1000 or 1200 mgCopegus daily dose 800 vs 1000 or 1200 mg

P-34

Pegasys Combination ProgramPegasys Combination Program

Designed to Evaluate:Designed to Evaluate:

Efficacy and safety of Pegasys + Copegus Efficacy and safety of Pegasys + Copegus across genotypesacross genotypes

vs Rebetronvs Rebetron vs Pegasys monotherapyvs Pegasys monotherapy

Impact of shorter treatment duration on response Impact of shorter treatment duration on response for genotype 1 and genotype non-1for genotype 1 and genotype non-1

Impact of lower Copegus dose on response Impact of lower Copegus dose on response for genotype 1 and genotype non-1for genotype 1 and genotype non-1

P-35


Efficacy ResultsEfficacy Results

Dr. Frank DuffDr. Frank DuffClinical LeaderClinical Leader

P-36

Study NV15801Study NV15801

Comparative Trial vs RebetronComparative Trial vs Rebetron

P-37

NV15801NV15801

Efficacy ObjectivesEfficacy Objectives

PrimaryPrimary

Compare efficacy of Pegasys + CopegusCompare efficacy of Pegasys + Copegusvs Rebetronvs Rebetron

Secondary Secondary

Compare efficacy of Pegasys + CopegusCompare efficacy of Pegasys + Copegusvs Pegasys monotherapyvs Pegasys monotherapy

Compare efficacy across treatment armsCompare efficacy across treatment armsby HCV genotypeby HCV genotype

P-38

NV15801NV15801

Study DesignStudy Design

Randomized Randomized

Open label for Pegasys and RebetronOpen label for Pegasys and Rebetron

Blinded for Copegus vs placebo (Pegasys arms)Blinded for Copegus vs placebo (Pegasys arms)

Stratified byStratified by CountryCountry

HCV genotypeHCV genotype

P-39

Pegasys 180 Pegasys 180 g sc qw + Copegusg sc qw + Copegus1000 or 1200 mg po daily1000 or 1200 mg po daily Follow-upFollow-up

WeeksWeeks

72724848

Scr

ee

n

Rebetron (Intron A 3 MIU sc tiw +Rebetron (Intron A 3 MIU sc tiw +Rebetol 1000 or 1200 mg po daily)Rebetol 1000 or 1200 mg po daily) Follow-upFollow-up

00

NV15801NV15801

Study Design: TreatmentStudy Design: Treatment

Pegasys 180 Pegasys 180 g sc qw +g sc qw +Placebo Placebo Follow-upFollow-up

P-40

NV15801NV15801


Primary endpointPrimary endpoint Combined sustained virological response (SVR) Combined sustained virological response (SVR)

and sustained biochemical response (SBR) at and sustained biochemical response (SBR) at end of follow-upend of follow-up

Secondary endpointsSecondary endpoints SVR SVR SBRSBR End-of-follow-up histological response (20% of patients)End-of-follow-up histological response (20% of patients)

Analysis populationAnalysis population All patients randomizedAll patients randomized

P-41

NV15801NV15801

Major Inclusion CriteriaMajor Inclusion Criteria

Serological evidence of HCV infectionSerological evidence of HCV infection

HCV RNA >2000 copies/mL HCV RNA >2000 copies/mL

Elevated serum ALTElevated serum ALT

Liver biopsy consistent with CHCLiver biopsy consistent with CHC

Compensated liver diseaseCompensated liver disease Child-Pugh grade AChild-Pugh grade A

Age Age 18 years18 years

Naïve to interferon and ribavirin Naïve to interferon and ribavirin

P-42

NV15801NV15801

Major Exclusion CriteriaMajor Exclusion Criteria

Decompensated liver diseaseDecompensated liver disease Child-Pugh grades B and C Child-Pugh grades B and C

Coinfection with HIV or HBVCoinfection with HIV or HBV

Anemia or inability to tolerate anemiaAnemia or inability to tolerate anemia Hb <12 g/dL (F) or 13 g/dL (M)Hb <12 g/dL (F) or 13 g/dL (M)

Significant co-morbid medical conditionsSignificant co-morbid medical conditions

P-43

Genotype 1 (%)Genotype 1 (%) 6464 6666 6464

HCV RNA titerHCV RNA titer(mean, x 10(mean, x 106 6 copies/mL)copies/mL) 5.85.8 6.06.0 6.06.0

Cirrhosis/Cirrhosis/Bridging Fibrosis (%)Bridging Fibrosis (%) 1515 1212 1212

Age (mean, y)Age (mean, y) 4242 4343 42 42

Weight (mean, kg)Weight (mean, kg) 7979 8080 7878

Male (%)Male (%) 6767 7171 7373

NV15801NV15801

Patient CharacteristicsPatient Characteristics

All patients randomizedAll patients randomized

Pegasys +Pegasys +

PegasysPegasys CopegusCopegus RebetronRebetron

(N = 227)(N = 227) (N = 465)(N = 465) (N = 457)(N = 457)

P-44

Pegasys +Pegasys +

PegasysPegasys CopegusCopegus RebetronRebetron

(N = 224)(N = 224) (N = 453)(N = 453) (N = 444)(N = 444)

Safety Safety 7%7% 10%10% 11%11%

NonsafetyNonsafety

Insufficient therapeutic response Insufficient therapeutic response 22%22% 8%8% 13%13%

Refused treatment/failed to return Refused treatment/failed to return 4%4% 4%4% 7%7%

Protocol violationProtocol violation 0%0% <1%<1% <1%<1%

AdministrativeAdministrative 0%0% 0%0% <1%<1%

TotalTotal 25%25% 12%12% 21%21%

Total prematurely withdrawnTotal prematurely withdrawn 32%32% 22%22% 32%32%

NV15801NV15801

Summary of Reasons Summary of Reasons for Premature Withdrawal from Treatment for Premature Withdrawal from Treatment

P-45

PegasysPegasys Pegasys Pegasys + + ++CopegusCopegus RebetronRebetron CopegusCopegus PegasysPegasys(N = 465)(N = 465) (N = 457)(N = 457) P-value P-value (N = 465)(N = 465) (N = 227)(N = 227) P-valueP-value

SVR SVR 50%50% 4242%% 0.0040.004 5050%% 2727%% 0.001 0.001

SBR SBR 5050%% 4343%% 0.0220.022 5050%% 3232%% 0.001 0.001

SVR +SVR +SBR SBR 4545%% 3939%% 0.0570.057 45 45%% 2424%% 0.001 0.001

NV15801NV15801

Protocol Defined Analyses Protocol Defined Analyses

All patients randomizedAll patients randomized

P-46

NV15801NV15801

Virological AnalysesVirological Analyses

Validated HCV RNA assays now availableValidated HCV RNA assays now available

Virological response preferred as Virological response preferred as efficacy endpointefficacy endpoint

SVR defined as 2 negative HCV RNA SVR defined as 2 negative HCV RNA assessments (<100 copies/mL) at least 21 days assessments (<100 copies/mL) at least 21 days apart after week 60apart after week 60

All treated populationAll treated population

P-47

28%

52%

43%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%Pegasys Pegasys + Copegus Rebetron

NV15801NV15801

SVR – All Genotypes SVR – All Genotypes

SV

RS

VR

All treated, SVR = 2 HCV RNA <100 copies/mLAll treated, SVR = 2 HCV RNA <100 copies/mL

P = 0.005P = 0.005P = 0.001P = 0.001

N = 224 N = 453 N = 444

P-48

19%

44%43%

68%

35%

57%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Genotype 1 Genotype Non-1

Pegasys Pegasys + Copegus Rebetron

NV15801NV15801

SVR by Genotype SVR by Genotype

SV

RS

VR


N = 145 N = 298 N = 285 N = 79 N = 155 N = 159

P = 0.046P = 0.046

P = 0.044P = 0.044

P = 0.001P = 0.001

P = 0.002P = 0.002

P-49

34%

12%

50%

39%41%

32%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Genotype 1 LVL Genotype 1 HVL

Pegasys Pegasys + Copegus Rebetron

NV15801NV15801

SVR Genotype 1 by Viral Load SVR Genotype 1 by Viral Load

N = 44 N = 115 N = 94 N = 101 N = 182 N = 189


SV

RS

VR

P-50

NV15801NV15801

Efficacy FindingsEfficacy Findings

Pegasys and Copegus SVR superior Pegasys and Copegus SVR superior to Rebetron and to Pegasys monotherapyto Rebetron and to Pegasys monotherapyOverallOverall

Genotype 1 Genotype 1 • Contributed to by HVL and LVL responsesContributed to by HVL and LVL responses

Genotype non-1Genotype non-1

P-51


Duration and Dosing Duration and Dosing by Genotype Trialby Genotype Trial

P-52

NV15942NV15942

Efficacy ObjectivesEfficacy Objectives

PrimaryPrimaryCompare efficacy of Pegasys + Copegus Compare efficacy of Pegasys + Copegus

for 24 weeks vs 48 weeksfor 24 weeks vs 48 weeks

SecondarySecondaryCompare efficacy of Copegus 800 mg Compare efficacy of Copegus 800 mg

vs 1000 or 1200 mg in combination vs 1000 or 1200 mg in combination with Pegasyswith Pegasys

P-53

NV15942NV15942


RandomizedRandomized

Treatment duration blinded until week 24Treatment duration blinded until week 24

Copegus dose blinded throughout studyCopegus dose blinded throughout study

Stratified by:Stratified by: Genotype (1 vs non-1)Genotype (1 vs non-1) Viral load (LVL vs HVL) Viral load (LVL vs HVL) Geographic regionGeographic region

Patient selection criteria as per NV15801Patient selection criteria as per NV15801

P-54

Pegasys + CopegusPegasys + Copegus1000 or 1200 mg 1000 or 1200 mg

for 24 weeksfor 24 weeksFollow-upFollow-up

Scr

ee

nNV15942NV15942

Study Design: TreatmentStudy Design: Treatment

WeeksWeeks7272484800 2424

Pegasys + CopegusPegasys + Copegus1000 or 1200 mg for 48 weeks1000 or 1200 mg for 48 weeks

Follow-upFollow-up

Pegasys + CopegusPegasys + Copegus800 mg for 48 weeks800 mg for 48 weeks

Follow-upFollow-up

Pegasys + CopegusPegasys + Copegus800 mg 800 mg

for 24 weeksfor 24 weeksFollow-upFollow-up

P-55

NV15942NV15942


Primary endpointPrimary endpointSustained virological response (SVR)Sustained virological response (SVR)

Secondary endpointsSecondary endpointsSBRSBREnd-of-follow-up histological responseEnd-of-follow-up histological response

(20% of patients)(20% of patients)

Analysis populationAnalysis populationAll patients treatedAll patients treated

P-56

NV15942 NV15942

Patient CharacteristicsPatient Characteristics

Genotype 1 (%)Genotype 1 (%) 4949 4242 6969 6262

HCV RNA titerHCV RNA titer(mean, x 10(mean, x 1066 5.05.0 5.55.5 7.27.2 6.16.1copies/mL)copies/mL)

Cirrhosis/Cirrhosis/Bridging Fibrosis (%)Bridging Fibrosis (%) 2121 2525 2525 2626

Age (mean, y)Age (mean, y) 4141 4242 4343 4343

Weight (mean, kg)Weight (mean, kg) 7878 7777 7777 7777

Male (%)Male (%) 6868 6666 6363 6666

24 Weeks24 Weeks 24 Weeks24 Weeks 48 Weeks48 Weeks 48 Weeks48 WeeksPegasys +Pegasys + Pegasys +Pegasys + Pegasys +Pegasys + Pegasys +Pegasys +CopegusCopegus CopegusCopegus CopegusCopegus CopegusCopegus800 mg800 mg 1000 or 1200 mg1000 or 1200 mg 800 mg800 mg 1000 or 1200 mg1000 or 1200 mg

(N = 207)(N = 207) (N = 280)(N = 280) (N = 361)(N = 361) (N = 436)(N = 436)

P-57

NV15942 NV15942

Summary of Reasons for Premature Summary of Reasons for Premature Withdrawal from Treatment Withdrawal from Treatment

SafetySafety 5% 5% 5%5% 16%16% 15%15%

NonsafetyNonsafety

Insufficient therapeuticInsufficient therapeuticresponseresponse 0%0% 0%0% 9%9% 6%6%

Refused treatment/Refused treatment/Failure to returnFailure to return 1%1% 3%3% 7%7% 6%6%

Protocol violationProtocol violation <1%<1% <1%<1% <1%<1% <1%<1%

Administrative Administrative 0%0% <1%<1% <1%<1% 0%0%

TotalTotal 2%2% 3%3% 16%16% 11%11%

Total prematurelyTotal prematurely withdrawnwithdrawn 7%7% 8% 8% 32%32% 27%27%


(N = 207)(N = 207) (N = 280)(N = 280) (N = 361)(N = 361) (N = 436)(N = 436)

P-58

NV15942NV15942

Statistical Comparisons Statistical Comparisons

Primary comparison – treatment durationPrimary comparison – treatment duration48 weeks statistically superior to 24 weeks48 weeks statistically superior to 24 weeks

(P = 0.039) (P = 0.039)

Secondary comparison – Copegus doseSecondary comparison – Copegus dose1000 or 1200 mg statistically superior 1000 or 1200 mg statistically superior

to 800 mg (P = 0.018)to 800 mg (P = 0.018)

P-59

NV15942NV15942

Statistical Comparisons by Genotype Statistical Comparisons by Genotype

Genotype 1Genotype 124 weeks vs 48 weeks24 weeks vs 48 weeks P = 0.001P = 0.001

800 vs 1000/1200 mg800 vs 1000/1200 mg P = 0.01P = 0.01

Genotype non-1Genotype non-124 weeks vs 48 weeks24 weeks vs 48 weeks P = 0.25P = 0.25

800 vs 1000/1200 mg800 vs 1000/1200 mg P = 0.74P = 0.74

P-60

29%

39%41%

50%

0%

10%

20%

30%

40%

50%

60%

24 Weeks 48 Weeks

Pegasys + Copegus 800 mg Pegasys + Copegus 1000 or 1200 mg

SV

RS

VR

NV15942NV15942

SVR Genotype 1 SVR Genotype 1

N = 101 N = 118 N = 250 N = 271


P-61

16%

35%

26%

46%

0%

10%

20%

30%

40%

50%

60%

24 Weeks 48 Weeks


SV

RS

VR

NV15942NV15942

SVR Genotype 1, High Viral Load SVR Genotype 1, High Viral Load

N = 50 N = 47 N = 190 N = 186


P-62

41%

52%51%

60%

0%

10%

20%

30%

40%

50%

60%

70%

24 Weeks 48 Weeks


SV

RS

VR

NV15942NV15942

SVR Genotype 1, Low Viral Load SVR Genotype 1, Low Viral Load

N = 51 N = 71 N = 60 N = 85


P-63

78% 75%80%

75%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

24 Weeks 48 Weeks


SV

RS

VR

NV15942NV15942

SVR Genotype Non-1 SVR Genotype Non-1

N = 106 N = 162 N = 111 N = 165


P-64

NV15942NV15942

Efficacy FindingsEfficacy Findings

Overall populationOverall population Superiority of longer treatment duration and higher Superiority of longer treatment duration and higher

Copegus doseCopegus dose

Genotype 1Genotype 1 Consistent with overall population – highest SVR with Consistent with overall population – highest SVR with

48 week treatment and Copegus 1000 or 1200 mg48 week treatment and Copegus 1000 or 1200 mg

Genotype non-1Genotype non-1 High and maximal responses with 24 week treatment High and maximal responses with 24 week treatment

and 800 mg of Copegusand 800 mg of Copegus

P-65

Predictability AnalysisPredictability Analysis

Objective – confirmation of predictability Objective – confirmation of predictability findings from monotherapy programfindings from monotherapy program

Exploratory analysis performed on Phase III Exploratory analysis performed on Phase III patients receiving 48 weeks of treatment and patients receiving 48 weeks of treatment and 1000 or 1200 mg of Copegus 1000 or 1200 mg of Copegus

Early virological response (EVR) defined as Early virological response (EVR) defined as undetectable HCV RNA or undetectable HCV RNA or 2 log reduction 2 log reduction by week 12by week 12

P-66

NV15942NV15942 and NV15801 and NV15801

Predictability Analysis – Genotype 1Predictability Analysis – Genotype 1

N = 98(96%)

N = 4(4%)

N = 102N = 102(18%)(18%)

EVREVR

No EVRNo EVR

N = 467N = 467(82%)(82%)

Pegasys +Pegasys +CopegusCopegus(N = 569)(N = 569)

2-Log2-Log1010 Drop or Drop or

Neg HCV RNANeg HCV RNAby Week 12by Week 12

No SVR

SVR


P-67

Predictability FindingsPredictability Findings

Week 12 predictability supported byWeek 12 predictability supported byPhase III combination dataPhase III combination data

Allows early decision-making for those Allows early decision-making for those with low likelihood of SVRwith low likelihood of SVR

P-68

Pegasys + Copegus Program:Pegasys + Copegus Program:Efficacy Conclusions Efficacy Conclusions

SVR superior to Rebetron and to Pegasys SVR superior to Rebetron and to Pegasys monotherapy monotherapy

Genotype 1 – highest SVR with Pegasys and Genotype 1 – highest SVR with Pegasys and Copegus (1000 or 1200 mg) for 48 weeksCopegus (1000 or 1200 mg) for 48 weeks

Genotype non-1 – maximal SVR with Pegasys Genotype non-1 – maximal SVR with Pegasys and Copegus 800 mg for 24 weeksand Copegus 800 mg for 24 weeks

P-69


Safety ResultsSafety Results

Dr. Jonathan SolskyDr. Jonathan SolskyDirector, Drug Safety and Risk ManagementDirector, Drug Safety and Risk Management

P-70

Well-Characterized Safety ProfileWell-Characterized Safety Profile

Large Safety Database on Pegasys + CopegusLarge Safety Database on Pegasys + Copegus

1735 HCV patients on Pegasys + Copegus1735 HCV patients on Pegasys + Copegus (377 with cirrhosis/bridging fibrosis)(377 with cirrhosis/bridging fibrosis)

Study NV15801Study NV15801 451 HCV patients on Pegasys + Copegus451 HCV patients on Pegasys + Copegus

• 56 with cirrhosis/bridging fibrosis56 with cirrhosis/bridging fibrosis

Study NV15942Study NV15942 1284 HCV patients on Pegasys + Copegus1284 HCV patients on Pegasys + Copegus

• 321 with cirrhosis/bridging fibrosis321 with cirrhosis/bridging fibrosis

P-71

Safety PresentationSafety Presentation

Pegasys + Copegus CombinationPegasys + Copegus Combination

Safety comparison of Pegasys combination Safety comparison of Pegasys combination therapy versus Pegasys monotherapy therapy versus Pegasys monotherapy and Rebetronand Rebetron

Safety comparison of Pegasys combination Safety comparison of Pegasys combination therapy by duration of treatment and therapy by duration of treatment and Copegus doseCopegus dose

P-72

NV15801NV15801

Overview of Safety Profile Overview of Safety Profile Pegasys +Pegasys + Intron A +Intron A +

CopegusCopegus Rebetol RebetolPegasysPegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg

Adverse EventAdverse Event (N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

All AEsAll AEs 212212 (95%)(95%) 446446 (99%)(99%) 435435 (98%)(98%)

Serious AEsSerious AEs 2626 (12%)(12%) 5353 (12%)(12%) 3838 (9%)(9%)Treatment-relatedTreatment-related 88 (4%)(4%) 1616 (4%)(4%) 1919 (4%)(4%)

DeathsDeaths 22 00 11

Dose ModificationDose ModificationPegasys or Intron APegasys or Intron A 6161 (27%)(27%) 145145 (32%)(32%) 8181 (18%)(18%)

AEsAEs 1414 (6%)(6%) 4848 (11%)(11%) 4747 (11%)(11%)NeutropeniaNeutropenia 3838 (17%)(17%) 9191 (20%)(20%) 2424 (5%)(5%)ThrombocytopeniaThrombocytopenia 1414 (6%)(6%) 1818 (4%)(4%) 11 (<1%)(<1%)

RibavirinRibavirin –– 181181 (40%)(40%) 164164 (37%) (37%)

Premature WithdrawalPremature Withdrawal 1515 (7%)(7%) 4444 (10%)(10%) 4747 (11%)(11%)

P-73

NV15801NV15801

Overview of Safety Profile Overview of Safety Profile

All AEsAll AEs

Serious AEsSerious AEs

DeathsDeaths

Dose modificationDose modification

Premature withdrawalPremature withdrawal

P-74

Pegasys + CopegusPegasys + Copegus Intron A + Rebetol Intron A + Rebetol Pegasys Pegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg

Adverse EventAdverse Event (N = 223) (N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

FatigueFatigue 9898 (44%) (44%) 242242 (54%)(54%) 244244 (55%)(55%)HeadacheHeadache 115115 (52%) (52%) 211211 (47%)(47%) 230230 (52%)(52%)PyrexiaPyrexia 8585 (38%) (38%) 195195 (43%)(43%) 247247 (56%)(56%)MyalgiaMyalgia 9494 (42%) (42%) 189189 (42%)(42%) 220220 (50%)(50%)InsomniaInsomnia 5252 (23%) (23%) 168168 (37%)(37%) 174174 (39%)(39%)NauseaNausea 5858 (26%) (26%) 130130 (29%)(29%) 145145 (33%)(33%)AlopeciaAlopecia 4848 (22%) (22%) 128128 (28%)(28%) 151151 (34%)(34%)RigorsRigors 5252 (23%) (23%) 106106 (24%)(24%) 157157 (35%)(35%)ArthralgiaArthralgia 6464 (29%) (29%) 121121 (27%)(27%) 112112 (25%)(25%)IrritabilityIrritability 5656 (25%) (25%) 109109 (24%)(24%) 123123 (28%)(28%)Depression Depression 4444 (20%) (20%) 9595 (21%)(21%) 131131 (30%) (30%)PruritusPruritus 4141 (18%) (18%) 101101 (22%) (22%) 8888 (20%) (20%)Appetite DecreasedAppetite Decreased 2424 (11%) (11%) 9696 (21%) (21%) 9898 (22%) (22%)DermatitisDermatitis 2929 (13%) (13%) 9595 (21%) (21%) 8080 (18%) (18%)DiarrheaDiarrhea 5454 (24%)(24%) 7777 (17%)(17%) 6868 (15%)(15%)

NV15801NV15801

Common Adverse EventsCommon Adverse Events((20% of Patients)20% of Patients)

P-75

NV15801NV15801


All AEsAll AEs


DeathsDeaths



P-76

Abdominal PainAbdominal Pain –– 3 3 (1%)(1%) 22 (<1%)(<1%)AnemiaAnemia –– 2 2 (<1%)(<1%) ––CellulitisCellulitis 22 (<1%)(<1%) 1 1 (<1%)(<1%) ––DehydrationDehydration – – – – 22 (<1%)(<1%)DepressionDepression – – 2 2 (<1%)(<1%) 66 (1%)(1%)Malignant HepaticMalignant Hepatic

NeoplasmNeoplasm 11 (<1%)(<1%) 2 2 (<1%)(<1%) ––Otitis ExternaOtitis Externa – – 2 2 (<1%)(<1%) – –PericarditisPericarditis 22 (<1%)(<1%) – – – –PneumoniaPneumonia – – 2 2 (<1%)(<1%) 11 (<1%)(<1%)PyrexiaPyrexia 11 (<1%)(<1%) 2 2 (<1%)(<1%) ––Suicide AttemptSuicide Attempt 11 (<1%)(<1%) 2 2 (<1%)(<1%) 44 (<1%)(<1%)Suicidal IdeationSuicidal Ideation 11 (<1%) (<1%) -- 22 (<1%) (<1%)AppendicitisAppendicitis -- 1 1 (<1%) (<1%) 2 2 (<1%) (<1%)

NV15801NV15801

Serious Adverse Events (N>1)Serious Adverse Events (N>1)(Including Unrelated)(Including Unrelated)

PegasysPegasys Pegasys + Copegus Pegasys + Copegus Intron A + Rebetol Intron A + Rebetol 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg

Adverse EventsAdverse Events (N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

P-77

NV15801NV15801

Patients with Infections Patients with Infections

All InfectionsAll Infections(including unrelated)(including unrelated) 8989 (40%)(40%) 207207 (46%)(46%) 156156 (35%)(35%)

5%5%

SinusitisSinusitis 1212 (5%)(5%) 3535 (8%)(8%) 2323 (5%)(5%)

URIURI 1313 (6%)(6%) 2323 (5%)(5%) 2525 (6%)(6%)

Tooth AbscessTooth Abscess 99 (4%)(4%) 2323 (5%)(5%) 1212 (3%)(3%)

Herpes SimplexHerpes Simplex 1515 (7%)(7%) 2222 (5%)(5%) 2020 (5%)(5%)

BronchitisBronchitis 99 (4%)(4%) 2121 (5%)(5%) 1717 (4%)(4%)

InfluenzaInfluenza 1818 (8%)(8%) 1818 (4%)(4%) 2222 (5%)(5%)

Serious InfectionsSerious Infections(including unrelated) (including unrelated) 77 (3%)(3%) 1616 (4%)(4%) 88 (2%)(2%)

PegasysPegasys Pegasys + Copegus Pegasys + Copegus Intron A + Rebetol Intron A + Rebetol Body System/ Body System/ 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mgAdverse EventsAdverse Events (N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

P-78

NV15801NV15801

Patients with Serious Infections Patients with Serious Infections on Pegasys + Copeguson Pegasys + Copegus

No predominance of any particular type of infection, involved organ system or No predominance of any particular type of infection, involved organ system or pathogenpathogen

Time to onsetTime to onset <6 months<6 months 66 >6 months - 1 year>6 months - 1 year 77 >1 year (off drug)>1 year (off drug) 33

No correlation of onset of infection and preceding marked neutropeniaNo correlation of onset of infection and preceding marked neutropenia

Nadir ANCNadir ANC 500500 11 >500 - >500 - 10001000 11 >1000 - >1000 - 15001500 22 >1500>1500 1212

3 patients withdrawn from therapy – epiglotitis, interstitial pneumonitis 3 patients withdrawn from therapy – epiglotitis, interstitial pneumonitis and appendicitisand appendicitis

Treated with antibiotic; resolvedTreated with antibiotic; resolved

P-79

NV15801NV15801

Incidence and Severity of Depression Incidence and Severity of Depression

Overall Incidence Overall Incidence of Depression*of Depression* 4545 (20%)(20%) 100100 (22%)(22%) 134134 (30%)(30%)

Severe DepressionSevere Depression 33 (1%)(1%) 1111 (2%)(2%) 1414 (3%)(3%)

Serious DepressionSerious Depression 00 22 (<1%)(<1%) 77 (2%)(2%)

Treatment for Treatment for Depression Depression 2525 (11%)(11%) 6464 (14%)(14%) 9191 (21%)(21%)

Dose Modification Dose Modification for Depression for Depression 11 (<1%)(<1%) 44 (<1%)(<1%) 66 (1%)(1%)

Suicidal Ideation Suicidal Ideation 1 1 (<1%)(<1%) 33 (<1%)(<1%) 55 (1%)(1%)

Suicide AttemptSuicide Attempt 11 (<1%)(<1%) 22 (<1%)(<1%) 44 (<1%)(<1%)

Premature WithdrawalsPremature Withdrawals 22 (<1%)(<1%) 1010 (2%)(2%) 1111 (2%)(2%)

Pegasys + CopegusPegasys + Copegus Intron A + Rebetol Intron A + Rebetol Pegasys Pegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg(N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

*Includes depression nos, depression aggravated, depression reactive, depression endogenous*Includes depression nos, depression aggravated, depression reactive, depression endogenous

P-80

NV15801NV15801


All AEsAll AEs


DeathsDeaths



P-81

Treatment Treatment Last RxLast Rx Day ofDay ofGroupGroup EventEvent AgeAge SexSex DayDay DeathDeath RelationshipRelationship

PegasysPegasys MVA/drowningMVA/drowning 4040 FF 337337 485485 UnrelatedUnrelated

Pegasys Pegasys Hepatic NeoplasmHepatic Neoplasm 5757 FF 316316 680680 UnrelatedUnrelated

Intron A +Intron A + HypertensiveHypertensive 4444 MM 295295 340340 UnrelatedUnrelatedRebetolRebetol Heart DiseaseHeart Disease

NV15801NV15801

DeathsDeaths

No deaths occurred on Pegasys + Copegus treatmentNo deaths occurred on Pegasys + Copegus treatment

P-82

NV15801NV15801


All AEsAll AEs


DeathsDeaths



P-83

Pegasys + CopegusPegasys + Copegus Intron A + Rebetol Intron A + RebetolPegasysPegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg

Dose Modification Dose Modification (N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

AE or LabAE or LabAbnormalitiesAbnormalities 6161 (27%)(27%) 145145 (32%)(32%) 8181 (18%)(18%)

AEsAEs 1414 (6%)(6%) 4848 (11%)(11%) 4747 (11%)(11%)

Lab AbnormalitiesLab Abnormalities 5454 (24%)(24%) 111111 (25%)(25%) 3636 (8%)(8%)

AnemiaAnemia 00 44 (<1%)(<1%) 1313 (3%)(3%)

NeutropeniaNeutropenia 3838 (17%)(17%) 9191 (20%)(20%) 2424 (5%)(5%)

ThrombocytopeniaThrombocytopenia 1414 (6%)(6%) 1818 (4%)(4%) 11 (<1%)(<1%)

NV15801NV15801

Dose Modification of Pegasys Dose Modification of Pegasys or Intron A for Safety Reasonsor Intron A for Safety Reasons

P-84

Pegasys + CopegusPegasys + Copegus Intron A + Rebetol Intron A + Rebetol1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg

Dose Modification Dose Modification (N = 451)(N = 451) (N = 443)(N = 443)

AE or LabAE or LabAbnormalitiesAbnormalities 181181 (40%)(40%) 164164 (37%)(37%)

AEsAEs 9595 (21%)(21%) 9797 (22%)(22%)

Lab AbnormalitiesLab Abnormalities 108108 (24%)(24%) 8484 (19%)(19%)

AnemiaAnemia 9999 (22%)(22%) 8383 (19%)(19%)

NeutropeniaNeutropenia 66 (1%)(1%) 11 (<1%)(<1%)

ThrombocytopeniaThrombocytopenia 22 (<1%)(<1%) 00

NV15801NV15801

Dose Modification of Copegus Dose Modification of Copegus or Rebetol for Safety Reasonsor Rebetol for Safety Reasons

P-85

Laboratory AbnormalitiesLaboratory Abnormalities

Neutrophil countNeutrophil count

Platelet countPlatelet count

HemoglobinHemoglobin

P-86

NV15801NV15801 Patients with Grade 4 Neutropenia Patients with Grade 4 Neutropenia

(<0.5 x 10(<0.5 x 1099/L)/L)

No serious infections were preceded by grade 4 neutropeniaNo serious infections were preceded by grade 4 neutropenia

Pegasys + CopegusPegasys + Copegus Intron A + Rebetol Intron A + Rebetol Pegasys Pegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg 1000 or 1200 mg

Neutrophil CountNeutrophil Count (N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

Grade 4 NeutropeniaGrade 4 Neutropenia 88 (4%)(4%) 2121 (5%)(5%) 55 (1%)(1%)

Withdrawn from Withdrawn from Both Treatment(s)Both Treatment(s) 00 33 (<1%) (<1%) 11 (<1%) (<1%)

Dose Modification ofDose Modification ofPegasys or Intron APegasys or Intron A

Permanent Permanent 66 (3%)(3%) 1010 (2%)(2%) 11 (<1%)(<1%)

TemporaryTemporary 11 (<1%)(<1%) 55 (1%)(1%) 33 (<1%)(<1%)

NoneNone 11 (<1%)(<1%) 33 (<1%)(<1%) 00

P-87

NV15801NV15801 Patients with Grade 3 ThrombocytopeniaPatients with Grade 3 Thrombocytopenia

(20 - <50 x 10(20 - <50 x 1099/L)/L)

No serious bleeding events associated with grade 3 thrombocytopeniaNo serious bleeding events associated with grade 3 thrombocytopenia

Pegasys + CopegusPegasys + Copegus Intron A + Rebetol Intron A + Rebetol

Pegasys Pegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg 1000 or 1200 mg (N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

Grade 3Grade 3Thrombocytopenia Thrombocytopenia 1414 (6%)(6%) 2222 (5%)(5%) 11 (<1%)(<1%)

Withdrawn fromWithdrawn fromBoth Treatment(s)Both Treatment(s) 11 (<1%)(<1%) 44 (<1%) (<1%) 00

Dose Modification of Dose Modification of Pegasys or Intron APegasys or Intron A

Permanent Permanent 66 (3%)(3%) 1212 (3%)(3%) 00

TemporaryTemporary 55 (2%)(2%) 22 (<1%)(<1%) 00

NoneNone 22 (<1%)(<1%) 44 (<1%)(<1%) 11 (<1%)(<1%)

P-88

Pegasys + Copegus Pegasys + Copegus Intron A + Rebetol Intron A + Rebetol Pegasys Pegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg(N = 223)(N = 223) (N = 451)(N = 451) (N = 443) (N = 443)

Hemoglobin <10 g/dLHemoglobin <10 g/dL 88 (4%)(4%) 4949 (11%)(11%) 4848 (11%)(11%)

Withdrawn from Withdrawn from Both Treatment(s) Both Treatment(s) 00 22 (<1%)(<1%) 11 (<1%)(<1%)

NV15801NV15801 Patients with Hemoglobin <10 g/dLPatients with Hemoglobin <10 g/dL

Dose Modification Dose Modification of Ribavirinof Ribavirin

Permanent Permanent N/AN/A 3434 (8%)(8%) 3535 (8%)(8%)

TemporaryTemporary N/AN/A 33 (<1%)(<1%) 44 (<1%)(<1%)

NoneNone N/AN/A 11 (<1%)(<1%) 77 (2%)(2%)

Discontinuation Discontinuation of Ribavirinof Ribavirin N/AN/A 99 (2%)(2%) 11 (<1%)(<1%)

N/A = not applicableN/A = not applicable

P-89

NV15801NV15801


All AEsAll AEs


DeathsDeaths



P-90

Pegasys + CopegusPegasys + Copegus Intron A + Rebetol Intron A + RebetolPegasysPegasys 1000 or 1200 mg1000 or 1200 mg 1000 or 1200 mg1000 or 1200 mg

Body System Body System (N = 223)(N = 223) (N = 451)(N = 451) (N = 443)(N = 443)

All Body SystemsAll Body Systems 1515 (7%)(7%) 4444 (10%)(10%) 4747 (11%)(11%)

Psychiatric DisordersPsychiatric Disorders 33 (1%)(1%) 1212 (3%)(3%) 1818 (4%)(4%)

Blood DisordersBlood Disorders 22 (<1%)(<1%) 77 (2%)(2%) 33 (<1%)(<1%)

General DisordersGeneral Disorders 22 (<1%)(<1%) 33 (<1%)(<1%) 55 (1%)(1%)

Skin DisordersSkin Disorders 22 (<1%)(<1%) 33 (<1%)(<1%) 55 (1%)(1%)

MusculoskeletalMusculoskeletalDisordersDisorders 11 (<1%)(<1%) 33 (<1%)(<1%) 11 (<1%)(<1%)

NV15801NV15801

Premature Withdrawal for Safety Reasons*Premature Withdrawal for Safety Reasons*

*N >2 Pegasys + Copegus Patients*N >2 Pegasys + Copegus Patients

P-91


Safety Comparison of Safety Comparison of Pegasys Combination Therapy Pegasys Combination Therapy

by Duration of Treatment by Duration of Treatment and Copegus Doseand Copegus Dose

P-92

NV15942NV15942

Overview of Safety ProfileOverview of Safety Profile

All AEsAll AEs 200200 (97%)(97%) 275275 (98%)(98%) 355355 (98%)(98%) 427427 (98%)(98%)

Serious AEsSerious AEs 77 (3%)(3%) 1919 (7%)(7%) 3333 (9%)(9%) 4444 (10%)(10%) Treatment Related Treatment Related 33 (1%)(1%) 88 (3%)(3%) 1515 (4%)(4%) 1414 (3%) (3%)

DeathsDeaths 00 11 11 22

Dose ModificationDose Modification

PegasysPegasys 6363 (30%)(30%) 7373 (26%)(26%) 120120 (33%)(33%) 159159 (36%)(36%)

CopegusCopegus 3939 (19%)(19%) 7676 (27%)(27%) 101101 (28%)(28%) 166166 (38%)(38%)

PrematurePrematureWithdrawalsWithdrawals 1010 (5%)(5%) 1313 (5%)(5%) 5959 (16%)(16%) 6767 (15%)(15%)


Body SystemBody System (N = 207)(N = 207) (N = 280)(N = 280) (N = 361)(N = 361) (N = 436)(N = 436)

P-93

NV15942NV15942

Incidence of Serious Adverse Events* Incidence of Serious Adverse Events* (Including Unrelated)(Including Unrelated)

**1% of Pegasys + Copegus Patients1% of Pegasys + Copegus Patients

All Body SystemsAll Body Systems 77 (3%)(3%) 1919 (7%)(7%) 3333 (9%)(9%) 4444 (10%)(10%)

InfectionsInfections 11 (<1%)(<1%) 33 (1%)(1%) 44 (1%) (1%) 77 (2%)(2%)

InjuryInjury 00 22 (<1%) (<1%) 22 (<1%) (<1%) 77 (2%)(2%)

Psychiatric Psychiatric 11 (<1%) (<1%) 55 (2%)(2%) 33 (<1%) (<1%) 44 (<1%) (<1%)

NeurologicNeurologic 00 11 (<1%) (<1%) 55 (1%)(1%) 33 (<1%) (<1%)

GastrointestinalGastrointestinal 11 (<1%) (<1%) 00 22 (<1%) (<1%) 55 (1%)(1%)

GeneralGeneral 11 (<1%) (<1%) 00 44 (1%)(1%) 44 (<1%) (<1%)


Body SystemBody System (N = 207)(N = 207) (N = 280)(N = 280) (N = 361)(N = 361) (N = 436)(N = 436)

P-94

NV15942NV15942

Patients with Hemoglobin Patients with Hemoglobin Concentrations of <10 g/dLConcentrations of <10 g/dL

Hemoglobin <10Hemoglobin <10 77 (3%)(3%) 2828 (10%) (10%) 2323 (6%) (6%) 6767 (15%) (15%)

Withdrawn from Withdrawn from Both TreatmentsBoth Treatments 00 00 11 (<1%) (<1%) 22 (<1%) (<1%)

Dose Modification of CopegusDose Modification of Copegus

PermanentPermanent 44 (2%)(2%) 1515 (5%)(5%) 1313 (4%)(4%) 4545 (10%) (10%)

TemporaryTemporary 00 00 11 (<1%)(<1%) 77 (2%)(2%)

NoneNone 33 (1%)(1%) 99 (3%) (3%) 66 (2%) (2%) 1212 (3%) (3%)

DiscontinuationDiscontinuation 00 4 4 (1%) (1%) 22 (<1%) (<1%) 11 (<1%)(<1%)


(N = 207)(N = 207) (N = 280)(N = 280) (N = 361)(N = 361) (N = 436)(N = 436)

P-95

Treatment Treatment Last RxLast Rx Day ofDay ofGroupGroup EventEvent AgeAge SexSex DayDay DeathDeath RelationshipRelationship

24 Week24 WeekPegasys + Pegasys + CopegusCopegus HeroinHeroin1000/1200 mg1000/1200 mg Overdose Overdose 3232 MM 3232 3333 UnrelatedUnrelated

48 Week48 WeekPegasys + Pegasys + CopegusCopegus SepticemiaSepticemia 4545 MM 6363 6565 Related Related 800 mg 800 mg

48 Week48 WeekPegasys + Pegasys + SuicideSuicide 3838 FF 177177 182182 Related Related CopegusCopegus1000/1200 mg 1000/1200 mg PolysubstancePolysubstance

OverdoseOverdose 40 40 MM 172172 317317 UnrelatedUnrelated

NV15942NV15942

DeathsDeaths

P-96

Pregnancy on Pegasys + CopegusPregnancy on Pegasys + Copegus

10 Pregnancies (N = 1735)10 Pregnancies (N = 1735)3 patients; 7 partners of male patients3 patients; 7 partners of male patients

OutcomeOutcomeElective abortionElective abortion 33Spontaneous abortionSpontaneous abortion 00Normal babyNormal baby 55Premature birth/deathPremature birth/death 11Loss to follow-upLoss to follow-up 11

P-97

Copegus Pregnancy RiskCopegus Pregnancy RiskManagement ProgramManagement Program

Package insertPackage insert

Patient medication guidePatient medication guide

Patient and partner educational brochure Patient and partner educational brochure on pregnancy preventionon pregnancy prevention

Physician educational guidePhysician educational guide

Central pregnancy registryCentral pregnancy registry

P-98

Safety FindingsSafety Findings

Safety profile is comparable to RebetronSafety profile is comparable to Rebetron

Higher incidence of lab AEs vs RebetronHigher incidence of lab AEs vs Rebetron Clinically manageable by dose modificationClinically manageable by dose modification

Incidence of discontinuation for safety reasons Incidence of discontinuation for safety reasons was the same as Rebetronwas the same as Rebetron

P-99

Safety FindingsSafety Findings

Pegasys + Copegus combinationPegasys + Copegus combination

Shorter duration and lower dose CopegusShorter duration and lower dose Copegus

Fewer serious adverse eventsFewer serious adverse events

Fewer cases of anemiaFewer cases of anemia

Fewer dose modifications Fewer dose modifications

Fewer premature withdrawalsFewer premature withdrawals

P-100


ConclusionsConclusions

Dr. Joseph HoffmanDr. Joseph HoffmanVP & Group Leader,VP & Group Leader,

Virology and TransplantationVirology and Transplantation

P-101


Combination TherapyCombination Therapy10/98 1/02


• HCV/HIV Coinfection TrialHCV/HIV Coinfection Trial

• Normal ALT TrialNormal ALT Trial

Special PopulationsSpecial Populations4/00

P-102

Ongoing StudiesOngoing Studies

Ongoing studies in special populationsOngoing studies in special populations Coinfected (HCV/HIV)Coinfected (HCV/HIV) Normal ALTNormal ALT African-AmericanAfrican-American CirrhoticsCirrhotics Pediatric patientsPediatric patients Transplant patientsTransplant patients Methadone usersMethadone users NonrespondersNonresponders

New combinationsNew combinations

Other indications – HBV, oncologyOther indications – HBV, oncology

P-103

Major FindingsMajor FindingsPegasys + Copegus vs PegasysPegasys + Copegus vs Pegasys

Superior efficacySuperior efficacy Overall populationOverall population Genotype 1Genotype 1 Genotype non-1Genotype non-1

Comparable safety profile with Comparable safety profile with major exception of increased anemiamajor exception of increased anemia

P-104

Major Findings Major Findings Pegasys + Copegus vs RebetronPegasys + Copegus vs Rebetron

Superior efficacySuperior efficacy Overall populationOverall population Genotype 1 (contributed to by both LVL and HVL)Genotype 1 (contributed to by both LVL and HVL) Genotype non-1Genotype non-1

Similar overall safety profileSimilar overall safety profile Higher incidence of neutropenia, thrombocytopenia,Higher incidence of neutropenia, thrombocytopenia,

infections infections [managed][managed] Lower incidence of depression and flu-like symptomsLower incidence of depression and flu-like symptoms

P-105

Duration and Dosing by GenotypeDuration and Dosing by Genotype

Genotype 1Genotype 1 Highest efficacy with Copegus 1000 or 1200 mg Highest efficacy with Copegus 1000 or 1200 mg

for 48 weeksfor 48 weeks

Genotype 2 or 3Genotype 2 or 3 Similar efficacy with Copegus 1000 or 1200 mg Similar efficacy with Copegus 1000 or 1200 mg

for 48 weeks and Copegus 800 mg for 24 weeksfor 48 weeks and Copegus 800 mg for 24 weeks

Safety advantages with Copegus 800 mg Safety advantages with Copegus 800 mg for 24 weeksfor 24 weeks

Identification of nonresponders using week 12 Identification of nonresponders using week 12 virological responsevirological response

P-106

Pegasys + Copegus combination therapy represents an Pegasys + Copegus combination therapy represents an improvement in the treatment of CHC over both Pegasys improvement in the treatment of CHC over both Pegasys monotherapy and Rebetronmonotherapy and Rebetron

Treatment can be tailored according to genotype Treatment can be tailored according to genotype to optimize benefit-risk relationshipsto optimize benefit-risk relationships

CONCLUSIONSCONCLUSIONS

Genotype 1:Genotype 1: 48 weeks, 1000 or 1200 mg daily Copegus48 weeks, 1000 or 1200 mg daily Copegus Week 12 predictabilityWeek 12 predictability

Genotype 2 or 3:Genotype 2 or 3: 24 weeks, 800 mg daily Copegus24 weeks, 800 mg daily Copegus

Documents

P-1 Pegasys + Copegus Combination Therapy BLA 125061/NDA 21-511 Antiviral Drugs Advisory Committee Meeting November 14, 2002