P1

1
Pegasys Copegus Combination Therapy

• BLA 125061/NDA 21-511
• Antiviral Drugs Advisory Committee Meeting
• November 14, 2002

2
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

3
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

4
Regulatory History of Application

• July 16, 1998 US IND submitted
• October 6, 1998 End of phase II meeting
• August 9, 2000 Fast-Track designation
• May 7, 2002 Pre-BLA/NDA meeting
• June 3, 2002 BLA/NDA Filed to FDA
• October 16, 2002 Pegasys monotherapy approved
• November 14, 2002 Advisory Committee

5
Roche Presentation Agenda

• Introduction Candice Teuber, Pharm.D.
• Overview of
• Pegasys-Copegus Joseph Hoffman, M.D.
• Development Program
• Efficacy Frank Duff, M.D.
• Safety Jonathan Solsky, M.D.
• Conclusions Joseph Hoffman, M.D.

6
Experts Available for Q A

• Donald M. Jensen, M.D.
• Director, Section of Hepatology
• Rush-Presbyterian-St. Lukes Medical
  CenterChicago, IL
• Mitchell Shiffman, M.D.
• Chief, Hepatology Section,Virginia Commonwealth
  University Health System
• Medical College of Virginia Richmond, VA

7
Roche Experts Available for Q A

• Clinical Science Michael Brunda, Ph.D.
• Toxicology Celine Eliahou, M.S.
• Statistics Amy Lin, M.S.
• Clinical Pharmacology Matthew Lamb, Pharm.D.
• Clinical Pharmacology Karin Jorga, Ph.D.

8
Pegasys Copegus Combination Therapy

• Overview
• Dr. Joseph Hoffman
• VP Group Leader,Virology and Transplantation

9
Background

• Rationale for development of Pegasys
• Overview of clinical program
• Dose selection in combination therapy program

10
SVR Difficult-to-Treat Disease
IFN alfa 3 or 6/3 MIU tiw x 48 wks
SVR
11 -19
?7
?5
1 - 2
lt1
Overall
Geno 1
Cirrhosis
Geno 1,HVL
Geno 1,Cirrhosis
Zeuzem et al. N Engl J Med. 20003431666-1672 Hea
thcote et al. N Engl J Med. 20003431673-1680 Poc
kros et al. 41st ICAAC Meeting. 2001285(Abstract
H-457) Roche data on file
11
Pharmacokinetics of Standard Alpha Interferons
Interferon (U/mL)
Time (hours)
First dose measured others simulated Roche data
on file
12
Peginterferon Alfa-2a (40KD)
13
Pegasys

• Soluble formulation
• Retains immunomodulatory and antiproliferative
  properties
• Sustained action
• Decreased clearance
• Extended absorptive phase
• Limited volume of distribution
• Allows unit dosing

14
NV15496Pegasys Systemic Concentrations 180 ?g
sc Once Weekly
15
Change in Pegasys Total Apparent Body Clearance
vs Total Body Weight
16
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 Pegasys and 599
  patients were randomized to Roferon-A

17
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. 200133433-438
18
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. 200133433-438
19
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.
20003431673-1680
20
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 (lt100 copies/mL) P 0.01
vs Roferon-A at week 72 Pockros et al. 41st ICAAC
Meeting. 2001285 (Abstract H-457) and Roche data
on file
21
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. 2001285 (Abstract H-457) and Roche data
on file
22
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 requi
ring dose modification 21 27
Events judged by investigator to be possibly or
probably related to treatment
23
SVR Difficult-to-Treat Disease
IFN alfa 3 or 6/3 MIU tiw x 48 wks
SVR
11 -19
?7
?5
1 - 2
lt1
Overall
Geno 1
Cirrhosis
Geno 1,HVL
Geno 1,Cirrhosis
Zeuzem et al. N Engl J Med. 20003431666-1672 Hea
thcote et al. N Engl J Med. 20003431673-1680 Poc
kros et al. 41st ICAAC Meeting. 2001285
(Abstract H-457) Roche data on file
24
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. 20003431666-1672 Hea
thcote et al. N Engl J Med. 20003431673-1680 Poc
kros et al. 41st ICAAC Meeting. 2001285
(Abstract H-457) Roche data on file
25
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

26
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

27
Predicted Copegus Exposure1000 or 1200 mg
Body-Weight-Adjusted Dose
70
1000 mg
1200 mg
60
50
40
lt75 kg
?75 kg
30
20
10
0
50
60
70
80
90
100
110
120
130
140
40
Body Weight (kg)
28
PegasysCombination Development Program
Phase II NV15800
10/98
3/00
Phase III NV15801
2/99
4/01

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

48 Weeks
29
SVR Rebetron Registration Trials
SVR
N 505
N 504
McHutchison et al. Seminars in Liver Disease.
199919(suppl 1)57-65
30
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

31
Pegasys Copegus

• Optimization of Therapy
• Duration of combination therapy
• Pegasys weekly dose
• Copegus daily dose

32
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

33
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

34
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

35
Pegasys Copegus Combination Therapy

• Efficacy Results
• Dr. Frank Duff
• Clinical Leader

36
Study NV15801

• Comparative Trial vs Rebetron

37
NV15801Efficacy Objectives

• Primary
• Compare efficacy of Pegasys Copegusvs Rebetron
• Secondary
• Compare efficacy of Pegasys Copegusvs Pegasys
  monotherapy
• Compare efficacy across treatment armsby HCV
  genotype

38
NV15801Study Design

• Randomized
• Open label for Pegasys and Rebetron
• Blinded for Copegus vs placebo (Pegasys arms)
• Stratified by
• Country
• HCV genotype

39
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
72
48
0
Weeks
40
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

41
NV15801Major Inclusion Criteria

• Serological evidence of HCV infection
• HCV RNA gt2000 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

42
NV15801Major Exclusion Criteria

• Decompensated liver disease
• Child-Pugh grades B and C
• Coinfection with HIV or HBV
• Anemia or inability to tolerate anemia
• Hb lt12 g/dL (F) or 13 g/dL (M)
• Significant co-morbid medical conditions

43
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
44
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
violation 0 lt1 lt1 Administrative 0 0 lt1 To
tal 25 12 21 Total prematurely
withdrawn 32 22 32
45
NV15801Protocol Defined Analyses
Pegasys Pegasys Copegus Rebetron Cope
gus 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
46
NV15801Virological Analyses

• Validated HCV RNA assays now available
• Virological response preferred as efficacy
  endpoint
• SVR defined as 2 negative HCV RNA assessments
  (lt100 copies/mL) at least 21 days apart after
  week 60
• All treated population

47
NV15801 SVR All Genotypes
P 0.005
P 0.001
SVR
N 224
N 453
N 444
All treated, SVR 2 HCV RNA lt100 copies/mL
48
NV15801 SVR by Genotype
P 0.044
P 0.002
P 0.046
P 0.001
SVR
N 145
N 298
N 285
N 79
N 155
N 159
All treated, SVR 2 HCV RNA lt100 copies/mL
49
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 lt100 copies/mL
50
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

51
Study NV15942

• Duration and Dosing by Genotype Trial

52
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

53
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

54
NV15942Study Design Treatment
Screen
72
48
0
24
Weeks
55
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

56
NV15942 Patient Characteristics
24 Weeks 24 Weeks 48 Weeks 48 Weeks Pegasys
Pegasys Pegasys Pegasys Copegus Copegus C
opegus 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/Bridgin
g Fibrosis () 21 25 25 26 Age (mean,
y) 41 42 43 43 Weight (mean, kg) 78 77 77 77 Male
() 68 66 63 66
57
NV15942 Summary of Reasons for Premature
Withdrawal from Treatment
24 Weeks 24 Weeks 48 Weeks 48 Weeks Pegasys
Pegasys Pegasys Pegasys Copegus Copegus C
opegus 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 Ref
used treatment/Failure to return 1 3 7 6 Prot
ocol violation lt1 lt1 lt1 lt1 Administrative
0 lt1 lt1 0 Total 2 3 16 11 Total
prematurely withdrawn 7 8 32 27
58
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)

59
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

60
NV15942 SVR Genotype 1
SVR
N 101
N 118
N 250
N 271
All treated, SVR 2 HCV RNA lt100 copies/mL
61
NV15942 SVR Genotype 1, High Viral Load
SVR
N 50
N 47
N 190
N 186
All treated, SVR 2 HCV RNA lt100 copies/mL
62
NV15942 SVR Genotype 1, Low Viral Load
SVR
N 51
N 71
N 60
N 85
All treated, SVR 2 HCV RNA lt100 copies/mL
63
NV15942 SVR Genotype Non-1
SVR
N 106
N 162
N 111
N 165
All treated, SVR 2 HCV RNA lt100 copies/mL
64
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

65
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

66
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 lt100 copies/mL
67
Predictability Findings

• Week 12 predictability supported byPhase III
  combination data
• Allows early decision-making for those with low
  likelihood of SVR

68
Pegasys Copegus ProgramEfficacy 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

69
Pegasys Copegus Combination Therapy

• Safety Results
• Dr. Jonathan Solsky
• Director, Drug Safety and Risk Management

70
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

71
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

72
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 (lt1) Riba
virin 181 (40) 164 (37) Premature
Withdrawal 15 (7) 44 (10) 47 (11)
73
NV15801Overview of Safety Profile

• All AEs
• Serious AEs
• Deaths
• Dose modification
• Premature withdrawal

74
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
)
75
NV15801Overview of Safety Profile

• All AEs
• Serious AEs
• Deaths
• Dose modification
• Premature withdrawal

76
NV15801Serious Adverse Events (Ngt1)(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 (lt1) Anemia
2 (lt1) Cellulitis 2 (lt1) 1 (lt1) Dehydratio
n 2 (lt1) Depression
2 (lt1) 6 (1) Malignant Hepatic Neoplasm 1 (lt1)
2 (lt1) Otitis Externa 2 (lt1)
Pericarditis 2 (lt1) Pneumonia
2 (lt1) 1 (lt1) Pyrexia 1 (lt1)
2 (lt1) Suicide Attempt 1 (lt1)
2 (lt1) 4 (lt1) Suicidal Ideation 1 (lt1) - 2
(lt1) Appendicitis - 1 (lt1) 2 (lt1)
77
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)
78
NV15801Patients with Serious Infections on
Pegasys Copegus

• No predominance of any particular type of
  infection, involved organ system or pathogen
• Time to onset
• lt6 months 6
• gt6 months - 1 year 7
• gt1 year (off drug) 3
• No correlation of onset of infection and
  preceding marked neutropenia
• Nadir ANC
• ?500 1
• gt500 - ?1000 1
• gt1000 - ?1500 2
• gt1500 12
• 3 patients withdrawn from therapy epiglotitis,
  interstitial pneumonitis and appendicitis
• Treated with antibiotic resolved

79
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) 1
4 (3) Serious Depression 0 2 (lt1) 7 (2)
Treatment for Depression 25 (11) 64 (14) 91
(21) Dose Modification for
Depression 1 (lt1) 4 (lt1) 6 (1) Suicidal
Ideation 1 (lt1) 3 (lt1) 5 (1) Suicide
Attempt 1 (lt1) 2 (lt1) 4 (lt1) Premature
Withdrawals 2 (lt1) 10 (2) 11 (2)
Includes depression nos, depression aggravated,
depression reactive, depression endogenous
80
NV15801Overview of Safety Profile

• All AEs
• Serious AEs
• Deaths
• Dose modification
• Premature withdrawal

81
NV15801Deaths
Treatment Last Rx Day of Group Event Age Sex
Day Death Relationship
Pegasys MVA/drowning 40 F 337 485 Unrelated Pegasy
s Hepatic Neoplasm 57 F 316 680 Unrelated Intron
A Hypertensive 44 M 295 340 UnrelatedRebetol He
art Disease
No deaths occurred on Pegasys Copegus treatment
82
NV15801Overview of Safety Profile

• All AEs
• Serious AEs
• Deaths
• Dose modification
• Premature withdrawal

83
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 (lt1) 13 (3) Neutropenia 38 (17) 91 (20) 2
4 (5) Thrombocytopenia 14 (6) 18 (4) 1 (lt1)
84
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 9
5 (21) 97 (22) Lab Abnormalities 108 (24) 84 (1
9) Anemia 99 (22) 83 (19) Neutropenia 6 (1)
1 (lt1) Thrombocytopenia 2 (lt1) 0
85
Laboratory Abnormalities

• Neutrophil count
• Platelet count
• Hemoglobin

86
NV15801 Patients with Grade 4 Neutropenia(lt0.5
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
(lt1) 1 (lt1) Dose Modification ofPegasys or
Intron A Permanent 6 (3) 10 (2) 1 (lt1) Tempora
ry 1 (lt1) 5 (1) 3 (lt1) None 1 (lt1) 3 (lt1) 0

• No serious infections were preceded by grade 4
  neutropenia

87
NV15801 Patients with Grade 3 Thrombocytopenia(2
0 - lt50 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 (lt1)
Withdrawn fromBoth Treatment(s) 1 (lt1) 4
(lt1) 0 Dose Modification of Pegasys or Intron
A Permanent 6 (3) 12 (3) 0 Temporary 5 (2) 2 (
lt1) 0 None 2 (lt1) 4 (lt1) 1 (lt1)

• No serious bleeding events associated with grade
  3 thrombocytopenia

88
NV15801 Patients with Hemoglobin lt10 g/dL
Pegasys Copegus Intron A Rebetol
Pegasys 1000 or 1200 mg 1000 or 1200 mg (N
223) (N 451) (N 443)
Hemoglobin lt10 g/dL 8 (4) 49 (11) 48 (11) Withd
rawn from Both Treatment(s) 0 2 (lt1) 1 (lt1)
Dose Modification of Ribavirin
Permanent N/A 34 (8) 35 (8) Temporary N/A 3 (
lt1) 4 (lt1) None N/A 1 (lt1) 7 (2)
Discontinuation of Ribavirin N/A 9 (2) 1 (lt1)
N/A not applicable
89
NV15801Overview of Safety Profile

• All AEs
• Serious AEs
• Deaths
• Dose modification
• Premature withdrawal

90
NV15801 Premature 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) Psychia
tric Disorders 3 (1) 12 (3) 18 (4) Blood
Disorders 2 (lt1) 7 (2) 3 (lt1) General
Disorders 2 (lt1) 3 (lt1) 5 (1) Skin
Disorders 2 (lt1) 3 (lt1) 5 (1) MusculoskeletalD
isorders 1 (lt1) 3 (lt1) 1 (lt1)
N gt2 Pegasys Copegus Patients
91
Study NV15942

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

92
NV15942Overview of Safety Profile
24 Weeks 24 Weeks 48 Weeks 48 Weeks Pegasys
Pegasys Pegasys Pegasys Copegus Copegus C
opegus 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) Se
rious 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) Prem
atureWithdrawals 10 (5) 13 (5) 59 (16) 67 (15
)
93
NV15942Incidence of Serious Adverse Events
(Including Unrelated)
24 Weeks 24 Weeks 48 Weeks 48 Weeks Pegasys
Pegasys Pegasys Pegasys Copegus Copegus C
opegus 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) I
nfections 1 (lt1) 3 (1) 4 (1) 7 (2) Injury 0
2 (lt1) 2 (lt1) 7 (2) Psychiatric 1
(lt1) 5 (2) 3 (lt1) 4 (lt1) Neurologic 0 1
(lt1) 5 (1) 3 (lt1) Gastrointestinal 1
(lt1) 0 2 (lt1) 5 (1) General 1
(lt1) 0 4 (1) 4 (lt1)
?1 of Pegasys Copegus Patients
94
NV15942Patients with Hemoglobin Concentrations
of lt10 g/dL
24 Weeks 24 Weeks 48 Weeks 48 Weeks Pegasys
Pegasys Pegasys Pegasys Copegus Copegus C
opegus Copegus 800 mg 1000 or 1200 mg 800
mg 1000 or 1200 mg (N 207) (N 280) (N
361) (N 436)
Hemoglobin lt10 7 (3) 28 (10) 23 (6) 67
(15) Withdrawn from Both Treatments 0 0 1
(lt1) 2 (lt1) Dose Modification of
Copegus Permanent 4 (2) 15 (5) 13 (4) 45 (10)
Temporary 0 0 1 (lt1) 7 (2) None 3 (1) 9
(3) 6 (2) 12 (3) Discontinuation 0 4
(1) 2 (lt1) 1 (lt1)
95
NV15942Deaths
Treatment Last Rx Day of Group Event Age Sex D
ay 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 Relate
d Copegus 1000/1200 mg Polysubstance Overdose
40 M 172 317 Unrelated
96
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

97
Copegus Pregnancy RiskManagement Program

• Package insert
• Patient medication guide
• Patient and partner educational brochure on
  pregnancy prevention
• Physician educational guide
• Central pregnancy registry

98
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

99
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

100
Pegasys Copegus Combination Therapy

• Conclusions
• Dr. Joseph Hoffman
• VP Group Leader,Virology and Transplantation

101
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

102
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

103
Major FindingsPegasys Copegus vs Pegasys

• Superior efficacy
• Overall population
• Genotype 1
• Genotype non-1
• Comparable safety profile with major exception
  of increased anemia

104
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

105
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

106
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