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Pegasys + Copegus Combination Therapy. BLA 125061/NDA 21-511 Antiviral Drugs Advisory Committee Meeting November 14, 2002. Pegasys Monotherapy Indication. Indication:

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pegasys copegus combination therapy

Pegasys + Copegus Combination Therapy

BLA 125061/NDA 21-511

Antiviral Drugs Advisory Committee Meeting

November 14, 2002

pegasys monotherapy indication
Pegasys Monotherapy Indication
  • Indication:

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

  • Dosage and Administration

180 g once weekly for 48 weeks

pegasys copegus proposed label additions
Pegasys + Copegus Proposed Label Additions
  • Pegasys, Peginterferon alfa-2a, in combination with Copegus, ribavirin, is indicated for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated cirrhosis.
  • Dosage and administration accordingto genotype:
    • Treatment duration
    • Ribavirin dose
regulatory history of application
Regulatory History of Application

July 16, 1998US IND submitted

October 6, 1998End of phase II meeting

August 9, 2000Fast-Track designation

May 7, 2002Pre-BLA/NDA meeting

June 3, 2002BLA/NDA Filed to FDA

October 16, 2002Pegasys monotherapy approved

November 14, 2002Advisory Committee

roche presentation agenda
Roche Presentation Agenda

IntroductionCandice Teuber, Pharm.D.

Overview of

Pegasys-CopegusJoseph Hoffman, M.D.

Development Program

EfficacyFrank Duff, M.D.

SafetyJonathan Solsky, M.D.

ConclusionsJoseph Hoffman, M.D.

experts available for q a
Experts Available for Q & A

Donald M. Jensen, M.D.

Director, Section of Hepatology

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

Mitchell Shiffman, M.D.

Chief, Hepatology Section,Virginia Commonwealth University Health System

Medical College of Virginia Richmond, VA

roche experts available for q a
Roche Experts Available for Q & A

Clinical ScienceMichael Brunda, Ph.D.

ToxicologyCeline Eliahou, M.S.

StatisticsAmy Lin, M.S.

Clinical PharmacologyMatthew Lamb, Pharm.D.

Clinical PharmacologyKarin Jorga, Ph.D.

pegasys copegus combination therapy8

Pegasys + Copegus Combination Therapy

Overview

Dr. Joseph Hoffman

VP & Group Leader,Virology and Transplantation

background
Background
  • Rationale for development of Pegasys
  • Overview of clinical program
  • Dose selection in combination therapy program
svr difficult to treat disease
SVR: Difficult-to-Treat Disease

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

SVR

11% -19%

7%

5%

1% - 2%

<1%

Overall

Geno 1

Cirrhosis

Geno 1,HVL

Geno 1,Cirrhosis

Zeuzem et al. N Engl J Med. 2000;343:1666-1672

Heathcote et al. N Engl J Med. 2000;343:1673-1680

Pockros et al. 41st ICAAC Meeting. 2001:285(Abstract H-457)

Roche data on file

pharmacokinetics of standard alpha interferons

Mon

Tue

Wed

Thu

Fri

Sat

Sun

14

12

10

8

Periods of time

when IFN is not detectable in circulation

6

4

2

0

0

24

48

72

96

120

144

168

192

Pharmacokinetics of Standard Alpha Interferons

Interferon (U/mL)

Time (hours)

First dose measured; others simulated

Roche data on file

peginterferon alfa 2a 40kd

O

CH3OCH2CH2(OCH2CH2)n O  C  NH

a CH2

Lysine

(CH2)3

mPEG

e CH

Interferon

O

CH3OCH2CH2(OCH2CH2)n O  C  NH

CNH

O

Peginterferon Alfa-2a (40KD)
pegasys
Pegasys
  • Soluble formulation
  • Retains immunomodulatory and antiproliferative properties
  • Sustained action
    • Decreased clearance
    • Extended absorptive phase
  • Limited volume of distribution
    • Allows unit dosing
nv15496 pegasys systemic concentrations 180 g sc once weekly

After first dose

15

10

Mean Concentration (ng/mL)

5

0

Weekly

Dose

Given

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Weekly

Dose

Given

NV15496Pegasys Systemic Concentrations – 180 g sc Once Weekly
comprehensive pegasys clinical program
Comprehensive Pegasys Clinical Program
  • Dose-finding study
  • Study in patients with cirrhosis
  • Study vs standard IFN
  • Study vs induction regimen IFN

Monotherapy

2/97

12/99

  • 1600 patients were enrolled in 4 separate Phase II and III trials in cirrhotic and noncirrhotic patients
  • 1001 patients were randomized to Pegasysand 599 patientswere randomized to Roferon-A
nv15489 phase ii dose finding study
NV15489Phase II Dose-finding Study

SVR

N = 33

N = 20

N = 20

N = 45

N = 41

Roferon-A

3 MIU

Pegasys

45 µg

Pegasys

90 µg

Pegasys

180 µg

Pegasys

270 µg

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

nv15489 dose finding study svr in genotype 1
NV15489Dose-finding Study: SVR in Genotype 1

31%

Genotype 1

SVR

14%

N = 14

N = 35

Pegasys

90 µg

Pegasys

180 µg

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

nv15495 sustained virological response in patients with cirrhosis
NV15495Sustained Virological Response in Patients with Cirrhosis

SVR

N = 88

N = 96

N = 87

*P= 0.001 vs Roferon-A; **NS vs Roferon-A

Heathcote et al. N Engl J Med. 2000;343:1673-1680

nv15496 virological response at weeks 24 and 72 pegasys 135 g vs 180 g
NV15496Virological Response at Weeks 24 and 72 Pegasys 135 g vs 180 g

Virological Response

N = 214

N = 215

N = 210

N = 214

N = 215

N = 210

HCV RNA undetectable (<100 copies/mL)

*P = 0.01 vs Roferon-A at week 72

Pockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on file

nv15496 histological response pegasys 135 g vs 180 g in patients with paired biopsies
NV15496Histological Response: Pegasys 135 g vs 180 g in Patients with Paired Biopsies

Histological Response†

N = 147

N = 171

N = 160

†Histological response defined as 2 point decrease in HAI score

*NS vs Roferon-A **P = 0.017 vs Roferon-A

Pockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on file

overview of adverse events in integrated summary of safety for pegasys monotherapy
Overview of Adverse Events in Integrated Summary of Safety for Pegasys Monotherapy

Pegasys Pegasys 135 g 180 g

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

Severe AEs 30% 32%

Serious AEs 10% 9%

Treatment-related serious AEs* 3% 5%

AEs and laboratory abnormalities leading to withdrawal 10% 10%

AEs and laboratory abnormalities

requiring dose modification 21% 27%

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

svr difficult to treat disease23
SVR: Difficult-to-Treat Disease

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

SVR

11% -19%

7%

5%

1% - 2%

<1%

Overall

Geno 1

Cirrhosis

Geno 1,HVL

Geno 1,Cirrhosis

Zeuzem et al. N Engl J Med. 2000;343:1666-1672

Heathcote et al. N Engl J Med. 2000;343:1673-1680

Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457)

Roche data on file

svr difficult to treat disease24
SVR: Difficult-to-Treat Disease

Pegasys 180 g qw x 48 wks

28% -39%

SVR

30%

22% - 28%

14%

13%

Overall

Geno 1

Cirrhosis

Geno 1,HVL

Geno 1,Cirrhosis

Zeuzem et al. N Engl J Med. 2000;343:1666-1672

Heathcote et al. N Engl J Med. 2000;343:1673-1680

Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457)

Roche data on file

comprehensive pegasys clinical program25
Comprehensive Pegasys Clinical Program

Monotherapy

2/97

12/99

Combination Therapy

10/98

1/02

  • Pilot safety study
  • Comparative trial vs Rebetron
  • Duration and dosing by genotype trial
ribavirin
Ribavirin
  • Better efficacy seen with combination than IFN alone
  • Teratogenic and mutagenic; induces hemolysis
  • Dose of 1000 or 1200 mg is safe and efficacious with standard IFN
  • Pegasys 180 g and 1000 or 1200 mg of ribavirin tolerated in pilot safety study (NV15800)
  • No PK interaction between ribavirin and IFN
predicted copegus exposure 1000 or 1200 mg body weight adjusted dose

0-24h

AUC

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

70

1000 mg

1200 mg

60

50

40

<75 kg

75 kg

30

20

10

0

40

50

60

70

80

90

100

110

120

130

140

Body Weight (kg)

pegasys combination development program
PegasysCombination Development Program
  • Pegasys (180 g) + Placebo
  • Intron A (3 MIU) + Rebetol (1000 or 1200 mg)
  • Pegasys (180 g) + Copegus (1000 or 1200 mg)

Phase II: NV15800

10/98

3/00

Phase III: NV15801

2/99

4/01

48 Weeks

svr rebetron registration trials
SVR: Rebetron Registration Trials

SVR

N = 505

N = 504

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

pegasys combination development program30
PegasysCombination Development Program

Phase II: NV15800

10/98

3/00

Phase III: NV15801

2/99

4/01

  • Comparative Trial vs Rebetron

Phase III: NV15942

11/99

1/02

  • Duration and Dosing by Genotype Trial
pegasys copegus
Pegasys + Copegus

Optimization of Therapy

  • Duration of combination therapy
  • Pegasys weekly dose
  • Copegus daily dose
copegus dose selection
Copegus Dose Selection
  • Chose Copegus 1000 or 1200 mg in control arm to bridge to comparative trial
  • No powered dose-finding trials with ribavirin were available
  • Literature and anecdotal experience suggested ribavirin dose of 800 mg might be adequate but 600 mg too low
pegasys copegus33
Pegasys + Copegus

Optimization of Therapy

  • Duration of combination therapy 24 vs 48 weeks
  • Pegasys weekly dose 180 g
  • Copegus daily dose 800 vs 1000 or 1200 mg
pegasys combination program
Pegasys Combination Program

Designed to Evaluate:

  • Efficacy and safety of Pegasys + Copegus across genotypes
    • vs Rebetron
    • vs Pegasys monotherapy
  • Impact of shorter treatment duration on response for genotype 1 and genotype non-1
  • Impact of lower Copegus dose on response for genotype 1 and genotype non-1
pegasys copegus combination therapy35

Pegasys + Copegus Combination Therapy

Efficacy Results

Dr. Frank Duff

Clinical Leader

study nv15801
Study NV15801

Comparative Trial vs Rebetron

nv15801 efficacy objectives
NV15801Efficacy Objectives

Primary

  • Compare efficacy of Pegasys + Copegusvs Rebetron

Secondary

  • Compare efficacy of Pegasys + Copegusvs Pegasys monotherapy
  • Compare efficacy across treatment armsby HCV genotype
nv15801 study design
NV15801Study Design
  • Randomized
  • Open label for Pegasys and Rebetron
  • Blinded for Copegus vs placebo (Pegasys arms)
  • Stratified by
    • Country
    • HCV genotype
nv15801 study design treatment
NV15801Study Design: Treatment

Pegasys 180 g sc qw + Copegus

1000 or 1200 mg po daily

Follow-up

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

Follow-up

Screen

Pegasys 180 g sc qw +

Placebo

Follow-up

0

48

72

Weeks

nv15801 study design40
NV15801Study Design
  • Primary endpoint
    • Combined sustained virological response (SVR) and sustained biochemical response (SBR) at end of follow-up
  • Secondary endpoints
    • SVR
    • SBR
    • End-of-follow-up histological response (20% of patients)
  • Analysis population
    • All patients randomized
nv15801 major inclusion criteria
NV15801Major Inclusion Criteria
  • Serological evidence of HCV infection
  • HCV RNA >2000 copies/mL
  • Elevated serum ALT
  • Liver biopsy consistent with CHC
  • Compensated liver disease
    • Child-Pugh grade A
  • Age 18 years
  • Naïve to interferon and ribavirin
nv15801 major exclusion criteria
NV15801Major Exclusion Criteria
  • Decompensated liver disease
    • Child-Pugh grades B and C
  • Coinfection with HIV or HBV
  • Anemia or inability to tolerate anemia
    • Hb <12 g/dL (F) or 13 g/dL (M)
  • Significant co-morbid medical conditions
nv15801 patient characteristics
NV15801Patient Characteristics

Pegasys +

Pegasys Copegus Rebetron

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

Genotype 1 (%) 64 66 64

HCV RNA titer(mean, x 106 copies/mL) 5.8 6.0 6.0

Cirrhosis/Bridging Fibrosis (%) 15 12 12

Age (mean, y) 42 43 42

Weight (mean, kg) 79 80 78

Male (%) 67 71 73

All patients randomized

nv15801 summary of reasons for premature withdrawal from treatment
NV15801Summary of Reasons for Premature Withdrawal from Treatment

Pegasys +

Pegasys Copegus Rebetron

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

Safety 7% 10% 11%

Nonsafety

Insufficient therapeutic response 22% 8% 13%

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

Protocol violation0% <1% <1%

Administrative 0% 0% <1%

Total 25% 12% 21%

Total prematurely withdrawn 32% 22% 32%

nv15801 protocol defined analyses
NV15801Protocol Defined Analyses

Pegasys Pegasys + +Copegus Rebetron Copegus Pegasys

(N = 465) (N = 457) P-value (N = 465) (N = 227) P-value

SVR 50% 42% 0.004 50% 27% 0.001

SBR 50% 43% 0.022 50% 32% 0.001

SVR +SBR 45% 39% 0.057 45% 24% 0.001

All patients randomized

nv15801 virological analyses
NV15801Virological Analyses
  • Validated HCV RNA assays now available
  • Virological response preferred as efficacy endpoint
  • SVR defined as 2 negative HCV RNA assessments (<100 copies/mL) at least 21 days apart after week 60
  • All treated population
nv15801 svr all genotypes
NV15801 SVR – All Genotypes

P = 0.001

P = 0.005

SVR

N = 224

N = 453

N = 444

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

nv15801 svr by genotype
NV15801 SVR by Genotype

P = 0.002

P = 0.044

P = 0.001

P = 0.046

SVR

N = 145

N = 298

N = 285

N = 79

N = 155

N = 159

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

nv15801 svr genotype 1 by viral load
NV15801 SVR Genotype 1 by Viral Load

SVR

N = 44

N = 115

N = 94

N = 101

N = 182

N = 189

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

nv15801 efficacy findings
NV15801Efficacy Findings
  • Pegasys and Copegus SVR superior to Rebetron and to Pegasys monotherapy
    • Overall
    • Genotype 1
      • Contributed to by HVL and LVL responses
    • Genotype non-1
study nv15942
Study NV15942

Duration and Dosing by Genotype Trial

nv15942 efficacy objectives
NV15942Efficacy Objectives

Primary

  • Compare efficacy of Pegasys + Copegus for 24 weeks vs 48 weeks

Secondary

  • Compare efficacy of Copegus 800 mg vs 1000 or 1200 mg in combination with Pegasys
nv15942 study design
NV15942Study Design
  • Randomized
  • Treatment duration blinded until week 24
  • Copegus dose blinded throughout study
  • Stratified by:
    • Genotype (1 vs non-1)
    • Viral load (LVL vs HVL)
    • Geographic region
  • Patient selection criteria as per NV15801
nv15942 study design treatment

Pegasys + Copegus

1000 or 1200 mg for 48 weeks

Follow-up

Pegasys + Copegus

800 mg for 48 weeks

Follow-up

Pegasys + Copegus

1000 or 1200 mg

for 24 weeks

Follow-up

Pegasys + Copegus

800 mg

for 24 weeks

Follow-up

NV15942Study Design: Treatment

Screen

0

24

48

72

Weeks

nv15942 study design55
NV15942Study Design
  • Primary endpoint
    • Sustained virological response (SVR)
  • Secondary endpoints
    • SBR
    • End-of-follow-up histological response(20% of patients)
  • Analysis population
    • All patients treated
nv15942 patient characteristics
NV15942 Patient Characteristics

24 Weeks 24 Weeks 48 Weeks 48 Weeks Pegasys + Pegasys + Pegasys + Pegasys + Copegus Copegus Copegus Copegus 800 mg 1000 or 1200 mg 800 mg 1000 or 1200 mg (N = 207) (N = 280) (N = 361) (N = 436)

Genotype 1 (%) 49 42 69 62

HCV RNA titer(mean, x 106 5.0 5.5 7.2 6.1copies/mL)

Cirrhosis/Bridging Fibrosis (%) 21 25 25 26

Age (mean, y) 41 42 43 43

Weight (mean, kg) 78 77 77 77

Male (%) 68 66 63 66

nv15942 summary of reasons for premature withdrawal from treatment
NV15942 Summary of Reasons for Premature Withdrawal from Treatment

24 Weeks 24 Weeks 48 Weeks 48 Weeks Pegasys + Pegasys + Pegasys + Pegasys + Copegus Copegus Copegus Copegus 800 mg 1000 or 1200 mg 800 mg 1000 or 1200 mg (N = 207) (N = 280) (N = 361) (N = 436)

Safety 5% 5% 16% 15%

Nonsafety

Insufficient therapeuticresponse 0% 0% 9% 6%

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

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

Administrative 0% <1% <1% 0%

Total 2% 3% 16% 11%

Total prematurelywithdrawn 7% 8% 32% 27%

nv15942 statistical comparisons
NV15942 Statistical Comparisons
  • Primary comparison – treatment duration
    • 48 weeks statistically superior to 24 weeks(P = 0.039)
  • Secondary comparison – Copegus dose
    • 1000 or 1200 mg statistically superior to 800 mg (P = 0.018)
nv15942 statistical comparisons by genotype
NV15942 Statistical Comparisons by Genotype
  • Genotype 1
    • 24 weeks vs 48 weeks P = 0.001
    • 800 vs 1000/1200 mg P = 0.01
  • Genotype non-1
    • 24 weeks vs 48 weeks P = 0.25
    • 800 vs 1000/1200 mg P = 0.74
nv15942 svr genotype 1
NV15942 SVR Genotype 1

SVR

N = 101

N = 118

N = 250

N = 271

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

nv15942 svr genotype 1 high viral load
NV15942 SVR Genotype 1, High Viral Load

SVR

N = 50

N = 47

N = 190

N = 186

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

nv15942 svr genotype 1 low viral load
NV15942 SVR Genotype 1, Low Viral Load

SVR

N = 51

N = 71

N = 60

N = 85

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

nv15942 svr genotype non 1
NV15942 SVR Genotype Non-1

SVR

N = 106

N = 162

N = 111

N = 165

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

nv15942 efficacy findings
NV15942Efficacy Findings
  • Overall population
    • Superiority of longer treatment duration and higher Copegus dose
  • Genotype 1
    • Consistent with overall population – highest SVR with 48 week treatment and Copegus 1000 or 1200 mg
  • Genotype non-1
    • High and maximal responses with 24 week treatment and 800 mg of Copegus
predictability analysis
Predictability Analysis
  • Objective – confirmation of predictability findings from monotherapy program
  • Exploratory analysis performed on Phase III patients receiving 48 weeks of treatment and 1000 or 1200 mg of Copegus
  • Early virological response (EVR) defined as undetectable HCV RNA or 2 log reduction by week 12
nv15942 and nv15801 predictability analysis genotype 1
NV15942 and NV15801Predictability Analysis – Genotype 1

N = 467(82%)

EVR

2-Log10 Drop orNeg HCV RNAby Week 12

Pegasys +Copegus(N = 569)

N = 98

(96%)

No SVR

N = 102

(18%)

No EVR

N = 4

(4%)

SVR

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

predictability findings
Predictability Findings
  • Week 12 predictability supported byPhase III combination data
  • Allows early decision-making for those with low likelihood of SVR
pegasys copegus program efficacy conclusions
Pegasys + Copegus Program:Efficacy Conclusions
  • SVR superior to Rebetron and to Pegasys monotherapy
  • Genotype 1 – highest SVR with Pegasys and Copegus (1000 or 1200 mg) for 48 weeks
  • Genotype non-1 – maximal SVR with Pegasys and Copegus 800 mg for 24 weeks
pegasys copegus combination therapy69

Pegasys + Copegus Combination Therapy

Safety Results

Dr. Jonathan Solsky

Director, Drug Safety and Risk Management

well characterized safety profile
Well-Characterized Safety Profile

Large Safety Database on Pegasys + Copegus

1735 HCV patients on Pegasys + Copegus

(377 with cirrhosis/bridging fibrosis)

  • Study NV15801
    • 451 HCV patients on Pegasys + Copegus
      • 56 with cirrhosis/bridging fibrosis
  • Study NV15942
    • 1284 HCV patients on Pegasys + Copegus
      • 321 with cirrhosis/bridging fibrosis
safety presentation
Safety Presentation

Pegasys + Copegus Combination

  • Safety comparison of Pegasys combination therapy versus Pegasys monotherapy and Rebetron
  • Safety comparison of Pegasys combination therapy by duration of treatment and Copegus dose
nv15801 overview of safety profile
NV15801Overview of Safety Profile

Pegasys +Intron A +

Copegus Rebetol Pegasys 1000 or 1200 mg 1000 or 1200 mgAdverse Event (N = 223) (N = 451) (N = 443)

All AEs 212 (95%) 446 (99%) 435 (98%)

Serious AEs 26 (12%) 53 (12%) 38 (9%)

Treatment-related 8 (4%) 16 (4%) 19 (4%)

Deaths 2 0 1

Dose Modification

Pegasys or Intron A 61 (27%) 145 (32%) 81 (18%)

AEs 14 (6%) 48 (11%) 47 (11%)

Neutropenia 38 (17%) 91 (20%) 24 (5%)

Thrombocytopenia 14 (6%) 18 (4%) 1 (<1%)

Ribavirin – 181 (40%) 164 (37%)

Premature Withdrawal 15 (7%) 44 (10%) 47 (11%)

nv15801 overview of safety profile73
NV15801Overview of Safety Profile
  • All AEs
  • Serious AEs
  • Deaths
  • Dose modification
  • Premature withdrawal
nv15801 common adverse events 20 of patients
NV15801Common Adverse Events(20% of Patients)

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

Fatigue 98 (44%) 242 (54%) 244 (55%)

Headache 115 (52%) 211 (47%) 230 (52%)

Pyrexia 85 (38%) 195 (43%) 247 (56%)

Myalgia 94 (42%) 189 (42%) 220 (50%)

Insomnia 52 (23%) 168 (37%) 174 (39%)

Nausea 58 (26%) 130 (29%) 145 (33%)

Alopecia 48 (22%) 128 (28%) 151 (34%)

Rigors 52 (23%) 106 (24%) 157 (35%)

Arthralgia 64 (29%) 121 (27%) 112 (25%)

Irritability 56 (25%) 109 (24%) 123 (28%)

Depression 44 (20%) 95 (21%) 131 (30%)

Pruritus 41 (18%) 101 (22%) 88 (20%)

Appetite Decreased 24 (11%) 96 (21%) 98 (22%)

Dermatitis 29 (13%) 95 (21%) 80 (18%)

Diarrhea 54 (24%) 77 (17%) 68 (15%)

nv15801 overview of safety profile75
NV15801Overview of Safety Profile
  • All AEs
  • Serious AEs
  • Deaths
  • Dose modification
  • Premature withdrawal
nv15801 serious adverse events n 1 including unrelated
NV15801Serious Adverse Events (N>1)(Including Unrelated)

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

Abdominal Pain – 3 (1%) 2 (<1%)

Anemia – 2 (<1%) –

Cellulitis 2 (<1%) 1 (<1%) –

Dehydration – – 2 (<1%)

Depression – 2 (<1%) 6 (1%)

Malignant Hepatic

Neoplasm 1 (<1%) 2 (<1%) –

Otitis Externa – 2 (<1%) –

Pericarditis 2 (<1%) – –

Pneumonia – 2 (<1%) 1 (<1%)

Pyrexia 1 (<1%) 2 (<1%) –

Suicide Attempt 1 (<1%) 2 (<1%) 4 (<1%)

Suicidal Ideation 1 (<1%) - 2 (<1%)

Appendicitis - 1 (<1%) 2 (<1%)

nv15801 patients with infections
NV15801Patients with Infections

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

All Infections(including unrelated) 89 (40%) 207 (46%) 156 (35%)

³5%

Sinusitis 12 (5%) 35 (8%) 23 (5%)

URI 13 (6%) 23 (5%) 25 (6%)

Tooth Abscess 9 (4%) 23 (5%) 12 (3%)

Herpes Simplex 15 (7%) 22 (5%) 20 (5%)

Bronchitis 9 (4%) 21 (5%) 17 (4%)

Influenza 18 (8%) 18 (4%) 22 (5%)

Serious Infections(including unrelated) 7 (3%) 16 (4%) 8 (2%)

nv15801 patients with serious infections on pegasys copegus
NV15801Patients with Serious Infections on Pegasys + Copegus
  • No predominance of any particular type of infection, involved organ system or pathogen
  • Time to onset
    • <6 months 6
    • >6 months - 1 year 7
    • >1 year (off drug) 3
  • No correlation of onset of infection and preceding marked neutropenia
  • Nadir ANC
    • 500 1
    • >500 - 1000 1
    • >1000 - 1500 2
    • >1500 12
  • 3 patients withdrawn from therapy – epiglotitis, interstitial pneumonitis and appendicitis
  • Treated with antibiotic; resolved
nv15801 incidence and severity of depression
NV15801Incidence and Severity of Depression

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

Overall Incidence of Depression* 45 (20%) 100 (22%) 134 (30%)

Severe Depression 3 (1%) 11 (2%) 14 (3%)

Serious Depression 0 2 (<1%) 7 (2%)

Treatment for Depression 25 (11%) 64 (14%) 91 (21%)

Dose Modification for Depression 1 (<1%) 4 (<1%) 6 (1%)

Suicidal Ideation 1 (<1%) 3 (<1%) 5 (1%)

Suicide Attempt 1 (<1%) 2 (<1%) 4 (<1%)

Premature Withdrawals 2 (<1%) 10 (2%) 11 (2%)

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

nv15801 overview of safety profile80
NV15801Overview of Safety Profile
  • All AEs
  • Serious AEs
  • Deaths
  • Dose modification
  • Premature withdrawal
nv15801 deaths
NV15801Deaths

Treatment Last Rx Day of

Group Event Age Sex Day Death Relationship

Pegasys MVA/drowning 40 F 337 485 Unrelated

Pegasys Hepatic Neoplasm 57 F 316 680 Unrelated

Intron A + Hypertensive 44 M 295 340 UnrelatedRebetol Heart Disease

No deaths occurred on Pegasys + Copegus treatment

nv15801 overview of safety profile82
NV15801Overview of Safety Profile
  • All AEs
  • Serious AEs
  • Deaths
  • Dose modification
  • Premature withdrawal
nv15801 dose modification of pegasys or intron a for safety reasons
NV15801Dose Modification of Pegasys or Intron A for Safety Reasons

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

AE or Lab Abnormalities 61 (27%) 145 (32%) 81 (18%)

AEs 14 (6%) 48 (11%) 47 (11%)

Lab Abnormalities 54 (24%) 111 (25%) 36 (8%)

Anemia 0 4 (<1%) 13 (3%)

Neutropenia 38 (17%) 91 (20%) 24 (5%)

Thrombocytopenia 14 (6%) 18 (4%) 1 (<1%)

nv15801 dose modification of copegus or rebetol for safety reasons
NV15801Dose Modification of Copegus or Rebetol for Safety Reasons

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

AE or Lab Abnormalities 181 (40%) 164 (37%)

AEs 95 (21%) 97 (22%)

Lab Abnormalities 108 (24%) 84 (19%)

Anemia 99 (22%) 83 (19%)

Neutropenia 6 (1%) 1 (<1%)

Thrombocytopenia 2 (<1%) 0

laboratory abnormalities
Laboratory Abnormalities
  • Neutrophil count
  • Platelet count
  • Hemoglobin
nv15801 patients with grade 4 neutropenia 0 5 x 10 9 l
NV15801 Patients with Grade 4 Neutropenia(<0.5 x 109/L)

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

Grade 4 Neutropenia 8 (4%) 21 (5%) 5 (1%)

Withdrawn from Both Treatment(s) 0 3 (<1%) 1 (<1%)

Dose Modification ofPegasys or Intron A

Permanent 6 (3%) 10 (2%) 1 (<1%)

Temporary 1 (<1%) 5 (1%) 3 (<1%)

None 1 (<1%) 3 (<1%) 0

  • No serious infections were preceded by grade 4 neutropenia
nv15801 patients with grade 3 thrombocytopenia 20 50 x 10 9 l
NV15801Patients with Grade 3 Thrombocytopenia(20 - <50 x 109/L)

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

Grade 3Thrombocytopenia 14 (6%) 22 (5%) 1 (<1%)

Withdrawn fromBoth Treatment(s) 1 (<1%) 4 (<1%) 0

Dose Modification of Pegasys or Intron A

Permanent 6 (3%) 12 (3%) 0

Temporary 5 (2%) 2 (<1%) 0

None 2 (<1%) 4 (<1%) 1 (<1%)

  • No serious bleeding events associated with grade 3 thrombocytopenia
nv15801 patients with hemoglobin 10 g dl
NV15801Patients with Hemoglobin <10 g/dL

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

Hemoglobin <10 g/dL 8 (4%) 49 (11%) 48 (11%)

Withdrawn from Both Treatment(s) 0 2 (<1%) 1 (<1%)

Dose Modification of Ribavirin

Permanent N/A 34 (8%) 35 (8%)

Temporary N/A 3 (<1%) 4 (<1%)

None N/A 1 (<1%) 7 (2%)

Discontinuation of Ribavirin N/A 9 (2%) 1 (<1%)

N/A = not applicable

nv15801 overview of safety profile89
NV15801Overview of Safety Profile
  • All AEs
  • Serious AEs
  • Deaths
  • Dose modification
  • Premature withdrawal
nv15801 premature withdrawal for safety reasons
NV15801Premature Withdrawal for Safety Reasons*

Pegasys + Copegus Intron A + Rebetol

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

All Body Systems 15 (7%) 44 (10%) 47 (11%)

Psychiatric Disorders 3 (1%) 12 (3%) 18 (4%)

Blood Disorders 2 (<1%) 7 (2%) 3 (<1%)

General Disorders 2 (<1%) 3 (<1%) 5 (1%)

Skin Disorders 2 (<1%) 3 (<1%) 5 (1%)

MusculoskeletalDisorders 1 (<1%) 3 (<1%) 1 (<1%)

*N >2 Pegasys + Copegus Patients

study nv1594291
Study NV15942

Safety Comparison of Pegasys Combination Therapy by Duration of Treatment and Copegus Dose

nv15942 overview of safety profile
NV15942Overview of Safety Profile

24 Weeks 24 Weeks 48 Weeks 48 Weeks

Pegasys + Pegasys + Pegasys + Pegasys +

Copegus Copegus Copegus Copegus

800 mg 1000 or 1200 mg 800 mg 1000 or 1200 mg

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

All AEs 200 (97%) 275 (98%) 355 (98%) 427 (98%)

Serious AEs 7 (3%) 19 (7%) 33 (9%) 44 (10%) Treatment Related 3 (1%) 8 (3%) 15 (4%) 14 (3%)

Deaths 0 1 1 2

Dose Modification

Pegasys 63 (30%) 73 (26%) 120 (33%) 159 (36%)

Copegus 39 (19%) 76 (27%) 101 (28%) 166 (38%)

PrematureWithdrawals 10 (5%) 13 (5%) 59 (16%) 67 (15%)

slide93

NV15942Incidence of Serious Adverse Events* (Including Unrelated)

24 Weeks 24 Weeks 48 Weeks 48 Weeks

Pegasys + Pegasys + Pegasys + Pegasys +

Copegus Copegus Copegus Copegus

800 mg 1000 or 1200 mg 800 mg 1000 or 1200 mg

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

All Body Systems 7 (3%) 19 (7%) 33 (9%) 44 (10%)

Infections 1 (<1%) 3 (1%) 4 (1%) 7 (2%)

Injury 0 2 (<1%) 2 (<1%) 7 (2%)

Psychiatric 1 (<1%) 5 (2%) 3 (<1%) 4 (<1%)

Neurologic 0 1 (<1%) 5 (1%) 3 (<1%)

Gastrointestinal 1 (<1%) 0 2 (<1%) 5 (1%)

General 1 (<1%) 0 4 (1%) 4 (<1%)

*1% of Pegasys + Copegus Patients

nv15942 patients with hemoglobin concentrations of 10 g dl
NV15942Patients with Hemoglobin Concentrations of <10 g/dL

24 Weeks 24 Weeks 48 Weeks 48 Weeks

Pegasys + Pegasys + Pegasys + Pegasys +

Copegus Copegus Copegus Copegus

800 mg 1000 or 1200 mg 800 mg 1000 or 1200 mg

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

Hemoglobin <10 7 (3%) 28 (10%) 23 (6%) 67 (15%)

Withdrawn from Both Treatments 0 0 1 (<1%) 2 (<1%)

Dose Modification of Copegus

Permanent 4 (2%) 15 (5%) 13 (4%) 45 (10%)

Temporary 0 0 1 (<1%) 7 (2%)

None 3 (1%) 9 (3%) 6 (2%) 12 (3%)

Discontinuation 0 4 (1%) 2 (<1%) 1 (<1%)

nv15942 deaths
NV15942Deaths

Treatment Last Rx Day of

Group Event Age Sex Day Death Relationship

24 WeekPegasys + Copegus Heroin 1000/1200 mg Overdose 32 M 32 33 Unrelated

48 WeekPegasys + Copegus Septicemia 45 M 63 65 Related 800 mg

48 Week Pegasys + Suicide 38 F 177 182 Related Copegus 1000/1200 mg Polysubstance Overdose 40 M 172 317 Unrelated

slide96

Pregnancy on Pegasys + Copegus

10 Pregnancies (N = 1735)

  • 3 patients; 7 partners of male patients

Outcome

  • Elective abortion 3
  • Spontaneous abortion 0
  • Normal baby 5
  • Premature birth/death 1
  • Loss to follow-up 1
copegus pregnancy risk management program
Copegus Pregnancy RiskManagement Program
  • Package insert
  • Patient medication guide
  • Patient and partner educational brochure on pregnancy prevention
  • Physician educational guide
  • Central pregnancy registry
safety findings
Safety Findings
  • Safety profile is comparable to Rebetron
  • Higher incidence of lab AEs vs Rebetron
    • Clinically manageable by dose modification
  • Incidence of discontinuation for safety reasons was the same as Rebetron
safety findings99
Safety Findings

Pegasys + Copegus combination

Shorter duration and lower dose Copegus

  • Fewer serious adverse events
  • Fewer cases of anemia
  • Fewer dose modifications
  • Fewer premature withdrawals
pegasys copegus combination therapy100

Pegasys + Copegus Combination Therapy

Conclusions

Dr. Joseph Hoffman

VP & Group Leader,Virology and Transplantation

comprehensive pegasys clinical program101
Comprehensive Pegasys Clinical Program

Monotherapy

2/97

12/99

Combination Therapy

10/98

1/02

Special Populations

4/00

  • HCV/HIV Coinfection Trial
  • Normal ALT Trial
ongoing studies
Ongoing Studies
  • Ongoing studies in special populations
    • Coinfected (HCV/HIV)
    • Normal ALT
    • African-American
    • Cirrhotics
    • Pediatric patients
    • Transplant patients
    • Methadone users
    • Nonresponders
  • New combinations
  • Other indications – HBV, oncology
major findings pegasys copegus vs pegasys
Major FindingsPegasys + Copegus vs Pegasys
  • Superior efficacy
    • Overall population
    • Genotype 1
    • Genotype non-1
  • Comparable safety profile with major exception of increased anemia
major findings pegasys copegus vs rebetron
Major Findings Pegasys + Copegus vs Rebetron
  • Superior efficacy
    • Overall population
    • Genotype 1 (contributed to by both LVL and HVL)
    • Genotype non-1
  • Similar overall safety profile
    • Higher incidence of neutropenia, thrombocytopenia,infections [managed]
    • Lower incidence of depression and flu-like symptoms
duration and dosing by genotype
Duration and Dosing by Genotype
  • Genotype 1
    • Highest efficacy with Copegus 1000 or 1200 mg for 48 weeks
  • Genotype 2 or 3
    • Similar efficacy with Copegus 1000 or 1200 mg for 48 weeks and Copegus 800 mg for 24 weeks
  • Safety advantages with Copegus 800 mg for 24 weeks
  • Identification of nonresponders using week 12 virological response
conclusions
CONCLUSIONS

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

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

  • Genotype 1:
    • 48 weeks, 1000 or 1200 mg daily Copegus
    • Week 12 predictability
  • Genotype 2 or 3:
    • 24 weeks, 800 mg daily Copegus