**FOOD AND DRUG ADMINISTRATION**

**Center for Drug Evaluation and Research**

**ANTIVIRAL DRUGS ADVISORY COMMITTEE (AVAC) MEETING**

**QUESTIONS TO THE COMMITTEE**

**November 14, 2002**

**Holiday Inn, 8120 Wisconsin Avenue, Bethesda, MD**

**BLA 125061, peginterferon alfa-2a in combination with ribavirin, NDA
21-511, Hoffmann-La**

**Roche, Inc., proposed for treatment of chronic hepatitis C**

**PEGINTERFERON AND RIBAVIRIN DOSE OPTIMIZATION**

The dose of the pegylated interferon (PEGASYS) used in the combination
therapy studies, 180 mcg fixed dose administered once weekly SC, was
selected based on the monotherapy studies. No dose ranging studies of
PEGASYS in combination with ribavirin (COPEGUS) were carried out.

The selection of the ribavirin (COPEGUS) dose was based in part on its
similarity to the 'Schering ribavirin' (Rebetol). In study 1 (#15801),
the COPEGUS dose was crudely weight adjusted (1000 mg for body weight
\<75 kg and 1200mg for body weight [\>]{.underline} 75 kg administered
in split dose once daily with food ). In study 2 (#15942), two doses of
ribavirin were compared, a "low" fixed dose (800 mg) and the "standard"
or crudely weight adjusted dose(1000-1200mg).

Exploratory analyses suggested that individuals treated with the
combination therapy who were \> 85 kg had a lower sustained viral
response (SVR) than those \< 85 kg, and experienced less toxicity,
particularly hematologic toxicity, compared to patients with a lower
body weight.

1.  Should the sponsor evaluate lower doses (e.g. 135 g) and/or
    weight-based dosing (vs. fixed dosing) of PEGASYS in combination
    with COPEGUS?

2.  Should the sponsor evaluate additional dosages of COPEGUS? If so,
    please discuss, in light of the dose comparison performed in study
    #2, what additional doses should be studied.

    Note that if licensed, such studies could be performed in the
    post-marketing period

    **DOSE AND Treatment Duration**

In study 2, in addition to the two doses of COPEGUS, two intervals of
combination therapy, 24 weeks and 48 weeks, were evaluated. Because of
the unequal randomization, with higher risk patients preferentially
placed in the higher dose of COPEGUS and longer treatment duration, it
is not possible to directly compare total SVRs across all four
treatments. Based on comparisons across randomization strata, patients
with HCV genotype 1 achieved higher SVRs with the higher COPEGUS dose
and longer duration of treatment. For patients with HCV genotype non- 1,
neither more COPEGUS nor a longer duration of treatment appear to
improve the SVR. However, the SVR data in the small subset of patients
infected with HCV genotype 4 suggest a possible benefit for higher
COPEGUS dose and longer duration of treatment.

3.  If licensed, please discuss what dose of COPEGUS and what duration
    of treatment should be recommended based on viral factors that
    predict treatment response. Are there sufficient data in genotype 2
    and 3 patients, regardless of viral load, to recommend shorter
    treatment duration and or 800 mg COPEGUS? If not, what additional
    studies should be conducted?

4\. Should a separate study of patients with genotype 4 be undertaken to
determine the optimal dosing regimen? What should be recommended at the
present time?

# OUTCOMES BY GEOGRAPHIC REGION

US patients achieved lower SVRs than non-US patients, regardless of
treatment arm. For example, in study 1, response rates were in US
patients and non-US patients were 42% and 61%, respectively. The US
patients had a greater preponderance of higher risk factors, including
genotype 1, cirrhosis, older age, and higher body weight. In the
multivariate analysis, these factors had more of an impact on ultimate
treatment response, while geographic region contributed less.

Assuming the differences across regions are real, regardless of
causative factors, studies conducted predominantly in the US will yield
lower SVRs than studies conducted predominantly outside the US.

The overall reported incidence of adverse events per patient was higher
in US patients compared to non-US patients.

5\. Please discuss the implications of these geographical differences;
in particular, the implications if cross study comparisons are
attempted. What additional factors (other than stated above) might help
explain these differences?

### PATIENTS WITH CIRRHOSIS 

Of the three efficacy studies conducted in the PEGASYS monotherapy
program, one specifically targeted patients with cirrhosis.
Approximately 80% of the patients in that study had cirrhosis or
bridging fibrosis. In contrast, approximately 20% of patients enrolled
in the other two trials had cirrhosis, a percentage more representative
of studies in chronic hepatitis C. The monotherapy label specifically
identifies the cirrhotic population as one in which efficacy had been
demonstrated.

In the PEGASYS/COPEGUS combination studies, patients with cirrhosis
comprised 13 and 25% of the patients.

6.  Please discuss the implications of cirrhosis. Should clinical
    development programs for products intended for treatment of patients
    with chronic hepatitis C infection include separate studies for
    patients with cirrhosis? Should presence of cirrhosis be a
    stratification variable?

#### RECOMMENDATIONS FOR DISCONTINUATION OF TREATMENT FOR INADEQUATE EARLY VIRAL RESPONSE

In both studies, study subjects who did not demonstrate either an early
virologic response (HCV negative or ≥2 log~10~ decrease) or an early
biochemical response (normal ALT) *could* be withdrawn from the study by
12 weeks of therapy and were to be withdrawn from study if
unresponsiveness persisted by 24 weeks. Ninety-six percent of patients
who showed no early virologic response by week 12 failed to achieve a
SVR.

7\. Please discuss what advice should be provided regarding early
discontinuation of treatment for lack of efficacy.

#### ADVERSE EVENTS

> Compared to Interferon combination therapy, Peginterferon combination
> therapy was associated with a higher incidence of serious adverse
> events (12% vs. 9%) including serious infections (4% vs 2%) and a
> higher incidence of grade 4 neutropenia (5% vs 1%) and grade 3
> thrombocytopenia (5% vs. 0.2%). There is the suggestion that some
> patients had a blunted ability to respond to infections. PEGASYS
> combination treatment resulted in a high incidence of reversible
> lymphopenia. Interferon treatment in general appears to result in
> higher triglyceride levels, but this parameter was not rigorously
> assessed in clinical studies.

8.  Please discuss how best to further evaluate, characterize, and
    minimize the toxicity of PEGASYS/COPEGUS, specifically with regard
    to the hematologic and infectious events. Note that some of these
    assessments could be incorporated into the design of ongoing studies
    conducted in other clinical settings.

###  OVERALL Safety and Efficacy

9\. Do these data demonstrate the safety and efficacy of PEGASYS/COPEGUS
for the treatment of patients with chronic hepatitis C infection?