# Presentation: 685641

## Pegasys + Copegus Combination Therapy

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

## 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, 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

**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

## 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.

## Experts Available for Q & A

**Donald M. Jensen, M.D.**
*Director, Section of Hepatology *
*Rush-Presbyterian-St. Luke’s Medical Center**Chicago, 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

**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.

## Pegasys + Copegus Combination Therapy

- Overview
- Dr. Joseph Hoffman
*VP & Group Leader,**Virology and Transplantation*

## Background

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

## SVR: Difficult-to-Treat Disease

- Overall

- Geno 1

- Cirrhosis

- Geno 1,HVL

- Geno 1,Cirrhosis

- 11% -19%

- 7%

- 5%

- 1% - 2%

- <1%

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

- 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 Disease**

**SVR**

## Pharmacokinetics of Standard Alpha Interferons

**Pharmacokinetics of ****Standard Alpha Interferons**

- First dose measured; others simulated
- Roche data on file

**Interferon (U/mL)**

## Peginterferon Alfa-2a (40KD)

## 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 

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

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

## Comprehensive Pegasys Clinical Program

- Monotherapy

- 2/97

- 12/99

- Dose-finding study
- Study in patients with cirrhosis
- Study vs standard IFN
- Study vs induction regimen IFN

**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

## NV15489Phase II Dose-finding Study

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

**SVR**

**N = 33**

**N = 20**

**N = 20**

**N = 45**

**N = 41**

- NV15489**Phase II Dose-finding Study**

- Roferon-A
- 3 MIU

- Pegasys
- 45 μg

- Pegasys
- 90 μg

- Pegasys
- 180 μg

- Pegasys
- 270 μg

## NV15489Dose-finding Study: SVR in Genotype 1

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

**SVR**

**N = 14**

**N = 35**

- NV15489**Dose-finding Study: SVR in Genotype 1**

- Pegasys
- 90 μg

- Pegasys
- 180 μg

**Genotype 1**

**31%**

**14%**

## NV15495Sustained Virological Response in Patients with Cirrhosis

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

**N = 88**

**N = 96**

**N = 87**

- NV15495**Sustained Virological Response ****in Patients with Cirrhosis**

**SVR**

## NV15496Virological Response at Weeks 24 and 72 Pegasys 135 g vs 180 g

**Virological Response**

- NV15496**Virological Response at Weeks 24 and 72 ****Pegasys 135 ********g vs 180 ********g**

- 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

**N = 214**

**N = 215**

**N = 210**

**N = 214**

**N = 215**

**N = 210**

## NV15496Histological Response: Pegasys 135 g vs 180 g in Patients with Paired Biopsies

- †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

**Histological Response****†**

**N = 147**

**N = 171**

**N = 160**

- NV15496**Histological Response: Pegasys 135 ********g ****vs 180 ********g in Patients with Paired Biopsies**

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

- 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%

**	**** ****Pegasys ****	**** Pegasys ****	****135 ********g****	**** 180 ********g**
**Adverse Event ****	****(N = 215)****	**** (N = 604)**

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

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

## SVR: Difficult-to-Treat Disease

- Overall

- Geno 1

- Cirrhosis

- Geno 1,HVL

- Geno 1,Cirrhosis

- 11% -19%

- 7%

- 5%

- 1% - 2%

- <1%

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

- 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 Disease**

**SVR**

## SVR: Difficult-to-Treat Disease

- Overall

- Geno 1

- Cirrhosis

- Geno 1,HVL

- Geno 1,Cirrhosis

- 28% -39%

- 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 Disease**

**SVR**

- Pegasys 180 g qw x 48 wks

- 22% - 28%

- 30%

- 14%

- 13%

## Comprehensive Pegasys Clinical Program

- Combination Therapy

- 10/98

- 1/02

- Monotherapy

- 2/97

- 12/99

- Pilot safety study
- Comparative trial vs Rebetron
- Duration and dosing by genotype trial

## 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

- 50

- 60

- 70

- 80

- 90

- 100

- 110

- 120

- 130

- 140

**Body Weight (kg)**

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 40

**Predicted Copegus Exposure****1000 or 1200 mg Body-Weight-Adjusted Dose**

- 1000 mg

- 1200 mg

- <75 kg

- 75 kg

## PegasysCombination Development Program

- Phase III: NV15801

- 2/99

- 4/01

- Phase II: NV15800

- 10/98

- 3/00

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

- 48 Weeks

## SVR: Rebetron Registration Trials

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

**SVR**

**SVR: Rebetron Registration Trials**

- N = 505

- N = 504

## PegasysCombination Development Program

- Phase III: NV15801

- 2/99

- 4/01

- Phase III: NV15942

- 11/99

- 1/02

- Phase II: NV15800

- 10/98

- 3/00

- Comparative Trial vs Rebetron

- Duration and Dosing by Genotype Trial

## Pegasys + Copegus

**Optimization of Therapy**
- Duration of combination therapy
- Pegasys weekly dose
- Copegus daily dose

## 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 + 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

**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 Therapy

- Efficacy Results
- Dr. Frank Duff
*Clinical Leader*

## Study NV15801

- Comparative Trial vs Rebetron

## NV15801Efficacy 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

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

## NV15801Study Design: Treatment

- 1000 or 1200 mg po daily

- Follow-up

- Weeks

**72**

**48**

- Screen

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

- Follow-up

**0**

- NV15801**Study Design: Treatment**

- Pegasys 180 g sc qw +
- Placebo

- Follow-up

## NV15801Study 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

- 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

- 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

- 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

- NV15801**Patient Characteristics**

- All patients randomized

**	**** ****	**** ****Pegasys +**
**	****Pegasys****	****Copegus****	****Rebetron**
**	****(N = 227)****	****(N = 465)****	****(N = 457)**

## NV15801Summary of Reasons for Premature Withdrawal from Treatment 

**	****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%	<1%	<1%
- Administrative		0%	0%	<1%
- Total		25%	12%	21%
**Total prematurely withdrawn****	****32%****	****22%****	****32%**

- NV15801**Summary of Reasons ****for Premature Withdrawal from Treatment **

## NV15801Protocol Defined Analyses 

**(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

- NV15801**Protocol Defined Analyses **

- All patients randomized

## NV15801Virological 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**

**SVR**

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

- P = 0.005

- P = 0.001

**N = 224**

**N = 453**

**N = 444**

## NV15801 SVR by Genotype

- NV15801** SVR by Genotype**

**SVR**

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

**N = 145**

**N = 298**

**N = 285**

**N = 79**

**N = 155**

**N = 159**

- P = 0.046

- P = 0.044

- P = 0.001

- P = 0.002

## NV15801 SVR Genotype 1 by Viral Load

- NV15801** SVR Genotype 1 by Viral Load**

**N = 44**

**N = 115**

**N = 94**

**N = 101**

**N = 182**

**N = 189**

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

**SVR**

## NV15801Efficacy 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

- Duration and Dosing by Genotype Trial

## NV15942Efficacy 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

- 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

- Screen

- NV15942**Study Design: Treatment**

- Weeks

**72**

**48**

**0**

**24**

## NV15942Study Design

- NV15942**Study 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

- 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

**	****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)**

## NV15942 Summary of Reasons for Premature Withdrawal from Treatment 

**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 prematurely** **withdrawn**	7%	 8%	32%	27%

**	****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)**

## 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

- 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

**SVR**

- NV15942** SVR Genotype 1**

**N = 101**

**N = 118**

**N = 250**

**N = 271**

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

## NV15942 SVR Genotype 1, High Viral Load

**SVR**

- NV15942** SVR Genotype 1, High Viral Load**

**N = 50**

**N = 47**

**N = 190**

**N = 186**

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

## NV15942 SVR Genotype 1, Low Viral Load

**SVR**

- NV15942** SVR Genotype 1, Low Viral Load**

**N = 51**

**N = 71**

**N = 60**

**N = 85**

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

## NV15942 SVR Genotype Non-1

**SVR**

- NV15942** SVR Genotype Non-1**

**N = 106**

**N = 162**

**N = 111**

**N = 165**

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

## NV15942Efficacy 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

- 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

**N = 98**
**(96%)**

**N = 4**
**(4%)**

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

**EVR**

**No EVR**

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

**Pegasys +****Copegus****(N = 569)**

**2-Log****10**** Drop or****Neg HCV RNA****by Week 12**

**No SVR**

**SVR**

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

## 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 

- 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 Therapy

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

## 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

**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 

**	****	**** ****Pegasys +**** ****	****Intron A +**
**	****	****Copegus****	**** Rebetol****	****Pegasys****	****1000 or 1200 mg****	****1000 or 1200 mg****Adverse 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 Profile 

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

## NV15801Common Adverse Events(20% of Patients)

- 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**Common Adverse Events****(********20% of Patients)**

## NV15801Overview of Safety Profile 

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

## NV15801Serious Adverse Events (N>1)(Including Unrelated)

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

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

## NV15801Patients with Infections 

- All Infections(including unrelated)	89	(40%)	207	(46%)	156	(35%)
- 			5%
- 	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%)

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

## NV15801Patients 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 

- 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%)

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

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

## NV15801Overview of Safety Profile 

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

## NV15801Deaths

**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

- NV15801**Deaths**

- No deaths occurred on Pegasys + Copegus treatment

## NV15801Overview of Safety Profile 

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

## NV15801Dose Modification of Pegasys or Intron A for Safety Reasons

- 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 Pegasys ****or Intron A for Safety Reasons**

## NV15801Dose Modification of Copegus or Rebetol for Safety Reasons

- 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

- NV15801**Dose Modification of Copegus ****or Rebetol for Safety Reasons**

## Laboratory Abnormalities

- Neutrophil count
- Platelet count
- Hemoglobin

## NV15801  Patients with Grade 4 Neutropenia(<0.5 x 109/L)

- No serious infections were preceded by grade 4 neutropenia

**	****	****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 of****Pegasys or Intron A**
- Permanent 	6	(3%)	10	(2%)	1	(<1%)
- Temporary	1	(<1%)	5	(1%)	3	(<1%)
- None	1	(<1%)	3	(<1%)	0

## NV15801 Patients with Grade 3 Thrombocytopenia(20 - <50 x 109/L)

- No serious bleeding events associated with grade 3 thrombocytopenia

**	****	****	**** ****	****	****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%)

## NV15801 Patients with Hemoglobin <10 g/dL

- Hemoglobin <10 g/dL	8	(4%)	49	(11%)	48	(11%)
- Withdrawn from Both Treatment(s) 	0		2	(<1%)	1	(<1%)

- NV15801** ****Patients with Hemoglobin <10 g/dL**

**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 Profile 

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

## NV15801 Premature Withdrawal for Safety Reasons*

**	****Pegasys****	****1000 or 1200 mg****	****1000 or 1200 mg****Body 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%)

- NV15801** ****Premature Withdrawal for Safety Reasons***

- *N >2 Pegasys + Copegus Patients

## Study NV15942

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

## NV15942Overview of Safety Profile

- 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%)

**	****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)**

## NV15942Incidence of Serious Adverse Events* (Including Unrelated)

- *1% of Pegasys + Copegus Patients

- 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%)

**	****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)**

## NV15942Patients with Hemoglobin Concentrations of <10 g/dL

- 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%)

**	****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)**

## NV15942Deaths

**Group****	****Event****	****Age****	****Sex****	****Day****	****Death****	****Relationship**

**24 Week**Pegasys + Copegus	Heroin	1000/1200 mg	Overdose 	32	M	32	33	Unrelated
**48 Week**Pegasys + 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

- NV15942**Deaths**

## 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 Risk****Management Program**

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

## 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 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 Therapy

- Conclusions
- Dr. Joseph Hoffman
*VP & Group Leader,**Virology and Transplantation*

## Comprehensive Pegasys Clinical Program

- Combination Therapy

- 10/98

- 1/02

- Monotherapy

- 2/97

- 12/99

- HCV/HIV Coinfection Trial
- Normal ALT Trial

- Special Populations

- 4/00

## 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

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

## 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

- 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

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

**CONCLUSIONS**

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