# Presentation: 707782

## Advances in the treatment of chronic hepatitis C:Update to the Committee

***PEG-Intron/Rebetol***

## Treating chronic hepatitis C10 years of progress

**0**

**20**

**40**

**60**

**80**

**100**

**% Sustained vriologic response **

**1991**

**2001**

***PEG-Intron/Rebetol***

## Advancements in the treatment of chronic hepatitis C Participant Introduction

- Schering-Plough Team
- Dr. J.J. Garaud		Exec. V.P., Clinical Research
- Dr. Kenneth Koury	Director, Biostatistics
- Dr. Mark Laughlin		Director, Clinical Pharmacology

- Dr. Penelope J. Giles 	Director, Regulatory Affairs
- Dr. Janice K. Albrecht 	Vice President, Clinical Research

- Consultants
- Dr. J. McHutchison	Medical Director, Liver Transplantation, Scripps Clinic
- Dr. L.J. Wei		Professor, Biostatistics, Harvard School of Public Health

***PEG-Intron/Rebetol***

## Indication:  Chronic Hepatitis C(Treatment Naïve Adults)

- Approved Dose
- PEG-Intron 1.5g/kg Once Weekly
- plus
- Rebetol 800mg/day
- 48 Weeks

## Treatment chronic hepatitis CInformation provided to the committee

- Intron A + Rebetol
- Treatment of Relapse Patients
*NEJM* 1998, Davis et al
- Treatment of Naïve Patients
*NEJM* 1998, McHutchison et al
*Lancet* 1998, Poynard et al
- PEG-Intron Monotherapy
- Treatment of Naïve Patients
*Hepatology* 2001, Lindsay et al
- PEG-Intron + Rebetol
- Treatment of Naïve Patients
*Lancet* 2001, Manns et al

## The PEG-Intron molecule

## Intron A 3MU TIWSustained virologic response by patient weight

**9%**

**12%**

**19%**

**25%**

**Intron**** ****A 3 MU TIW 48 weeks**

## PEG-Intron monotherapystudy design

**Primary Endpoint: ****Loss of serum HCV-RNA 24 weeks post-treatment**

## PEG-Intron monotherapyvirologic response

**49%**

**41%**

**33%**

**24%**

***HCV <100 copies/ml**

## PEG-Intron monotherapyvirologic response

**25%**

**23%**

**18%**

**12%**

***HCV <100 copies/ml**

## PEG-Intron monotherapyFactors Associated withSustained Virologic Response*

- HCV Genotype - Non-1*
- HCV-RNA level - Lower*
- Cirrhosis or bridging fibrosis - Absence**
- Age - Younger ***
- Body weight - Lighter (p=0.9336)

******* ****Multivariate logistic regression, n=914**

- *   p0.0001
- **  p<0.006
- *** p<0.05

## PEG-Intron dose selection 

**PEG-Intron doses selected for use in combination with Rebetol**
**1.5 ********g/kg - had maximum antiviral activity**
**	****    ****particularly in HCV-1**
**0.5 ********g/kg - had similar antiviral activity to**
- 			    **Intron A and was better tolerated**

***PEG-Intron/Rebetol***

## PEG-Intron plus Rebetol 

**Primary Endpoint: ****Loss of serum HCV-RNA 24 weeks post-treatment**

***PEG-Intron/Rebetol***

## Demographics

***PEG-Intron/Rebetol***

## Disease Characteristics

- HCV RNA  copies/ml

- HCV genotype

- Fibrosis/Cirrhosis*

*** Knodell HAI F3/4**

- 29%

- 30%

- 29%

- Geno 2/3

- 68%

- 68%

- 68%

- Geno 1

- 68%

- 67%

- 69%

- >2 million

- 29%

- 30%

- 28%

- Present

- Geno 4/5/6

- 3%

- 2%

- 3%

- Intron A/R(n=505)

- PEG 0.5/R        (n=514)

- PEG 1.5/R (n=511)

***PEG-Intron/Rebetol***

## Sustained Virologic Response

**52%**

**46%**

**46%**

*** PEG 1.5/800 vs. I/R   p=0.03**

- *

***PEG-Intron/Rebetol***

## Sustained Virologic Response

**54%**

**47%**

**47%**

*** PEG 1.5/800 vs. I/R  p=0.01**

- *

***PEG-Intron/Rebetol***

## Variables associated with sustained response logistic regression analysis

***PEG-Intron/Rebetol***

## Effect of Rebetol dose mg/kg on virologic response(Logistic regression analysis)

**Rebetol mg/kg**

**PEG 1.5 ********g/kg**

***PEG-Intron/Rebetol***

**Notes:**
Alex,

Trepo slide, weight is important for response to standard interferon, under conditions where the dose of ribavirin was kept constant at 1000-1200 mg/day.

## All genotypesSustained virologic response Controlling for Rebetol dose (mg/kg)  

- *p=0.01

***PEG-Intron/Rebetol***

**Notes:**
To this end, a novel interferon molecule has been design to provide
Improved Compliance
Improved Antiviral activity
Maintain a similar tolerability profile

## HCV-1Sustained virologic response Controlling for Rebetol dose (mg/kg)

- *p=0.02

***PEG-Intron/Rebetol***

**Notes:**
To this end, a novel interferon molecule has been design to provide
Improved Compliance
Improved Antiviral activity
Maintain a similar tolerability profile

## HCV-2/3Sustained virologic response Controlling for Rebetol dose (mg/kg)

***PEG-Intron/Rebetol***

**Notes:**
To this end, a novel interferon molecule has been design to provide
Improved Compliance
Improved Antiviral activity
Maintain a similar tolerability profile

## Sustained virologic response Controlling for Rebetol dose (mg/kg)

**Intron A**
**Rebetol**

**PEG-Intron ****1.5 ********g/kg**
**Rebetol 800mg**

**PEG-Intron ****1.5 ********g/kg**
**Rebetol (mg/kg)**

******10.6**

**>10.6**

****** ****2 million**

**> 2 million**

**HCV-1**

**HCV-2/3**

**80%**

**77%**

**74%**

**89%**

**81%**

**94%**

**76%**

**91%**

****** ****2 million**

**> 2 million**

**45%**

**29%**

**74%**

**27%**

**71%**

**37%**

**73%**

**30%**

***PEG-Intron/Rebetol***

**Notes:**
To this end, a novel interferon molecule has been design to provide
Improved Compliance
Improved Antiviral activity
Maintain a similar tolerability profile

## RelapseControlling for Rebetol dose and genotype

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

***PEG-Intron/Rebetol***

## Efficacy summary

- PEG-Intron 1.5 g/kg/Rebetol is significantly more effective than Intron A/Rebetol and 		      PEG-Intron 0.5 g/kg /Rebetol
- Approved Regimen: 48 weeks of treatment
- PEG-Intron 1.5g/kg once weekly
- 			plus
- Rebetol 800mg/day
- Further analyses suggest that weight based dosing of ribavirin (mg/kg) results in improved sustained virologic response

***PEG-Intron/Rebetol***

## PEG-Intron/Rebetol Safety

***PEG-Intron/Rebetol***

## Adverse events

- Incidence >10% difference between groups

**Application site**
-   Injection site inflammation	18%	25%	28%	20%
-   Injection site reaction	36%	58%	61%	54%
**Body as a whole**
-   Fever	33%	46%	49%	41%
-   Rigors	41%	48%	51%	43%
-   Weight decrease	20%	29%	28%	30%
**GI side effects**
-   Nausea	33%	43%	44%	43%
**Skin**
-   Alopecia	32%	36%	31%	45%

**PEG 1.5/R**
_**<**_**10.6 mg/kg****N=323**

**PEG 1.5/R**
**>10.6 mg/kg****N=188**

**Intron/R**
**N=505**

**PEG 1.5/R**
**800 mg**
**N=511**

***PEG-Intron/Rebetol***

## Discontinuations and dose modificationsdue to adverse events

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

**Dose Modifications**

**Discontinuations**

**13%**

**15%**

**14%**

**34%**

**38%**

**49%**

**42%**

**14%**

**PEG 1.5/R**
_**<**_**10.6 mg/kg****N=323**

**PEG 1.5/R**
**>10.6 mg/kg****N=188**

**Intron/R**
**N=505**

**PEG 1.5/R**
**800 mg**
**N=511**

***PEG-Intron/Rebetol***

## Dose modification>2% difference between groups

**PEG 1.5/R**
_**<**_**10.6 mg/kg****N=323**

**PEG 1.5/R**
**>10.6 mg/kg****N=188**

**Intron/R**
**N=505**

- 8%	18%	16%	21%
- 13%	9%	7%	12%
- 1%	3%	4%	2%
- 6%	9%	9%	10%
- 4%	7%	6%	9%

- Neutropenia
- Anemia
- Platelet
- Body as a Whole
- Gastrointestinal

**PEG 1.5/R**
**800 mg**
**N=511**

- Psychiatric Events        4%	             5%	              4%	                6%

***PEG-Intron/Rebetol***

## Adverse hematologic effects Neutrophils 

- *Number of patients

***PEG-Intron/Rebetol***

## Adverse hematologic effects Hemoglobin

- Decrease below
- 10g Hemoglobin

- Discontinued
- for Anemia

**12%****	****9%****	****6%****	****14%**
**0.2%****	****0.8%****	****0%****	****  2%**
- (1)*	(4)	(0)	 (4)

**PEG 1.5/R**
_**<**_**10.6 mg/kg****N=323**

**PEG 1.5/R**
**>10.6 mg/kg****N=188**

**Intron /R**
**N=505**

**PEG 1.5/R**
**800 mg**
**N=511**

- *Number of patients

***PEG-Intron/Rebetol***

**Notes:**

Leave results blank until we have the new data

## Safety Summary

- The types of adverse events observed in the I/R and PEG 1.5/R groups are similar, but there is a somewhat higher incidence with PEG1.5/R
- Neutropenia (<750) was more frequent with PEG 1.5/R than with I/R for both the fixed-dose and weight-based dose analyses
- With weight-based Rebetol >10.6 mg/kg there was an increased occurrence of anemia and neutropenia than with  PEG 1.5/800
- Discontinuations due to adverse events were low and similar between the groups; dose modifications due to the adverse events were more frequent with PEG 1.5/R
- The higher incidence of AE’s associated with PEG 1.5/R for either fixed-dose or weight-based Rebetol were adequately managed by dose modifications

## Post-marketing studies

**Study 1**-(n~4000) PEG1.5g/kg QW
- Rebetol 800mg vs. weight-based dosing (800 to 1400mg)
- (n~1000) evaluate effect of duration (6 vs.12 months) for patients with favorable prognostic factors
**Study 2**-(n~1500)
- PEG1.5g/kg vs. PEG1.0g/kg
- Rebetol dose regimen determined from study 1
- Evaluate effect of therapy in African Americans (n~100)
- PK food effect of ribavirin (fasted vs. low fat vs. high fat)

***PEG-Intron/Rebetol***

## Dr. J. McHutchison	

- Medical Director, Liver Transplantation, Scripps Clinic, La Jolla, California

## The Decision to Treat Hepatitis C

**Complex**
**Controversial**
**Host**
**Severity disease**
**Co-morbid conditions**
**Viral**
**Genotype **
**Therapy**
**Efficacy**
**Side effects**
**Cost**

**Weighing the Risks and Benefits**

**Likelihood of response**
**side effects**
**investments**

**Sustained response**
**ALT normal**
**HCV RNA neg**
**Histologic improvement**
**Improved HQOL**
**Durable **

## Decision to Treat

**Majority hepatitis C patients**
**Unfavorable profile**
**Genotype 1**
**Significant investment and commitment**
**Time (48 weeks)**
**More “aggressive” therapy**
**Patient**
**Doctor**
**Other Staff**

## Decision to Treat Hepatitis C

**Practitioner and patients**
**“****Do our best first time around”**

## How can we achieve the greatest benefit  whilst diminishing the risk?