| |
Pegasys Plus Ribavirin Combination Therapy for Hep C is Recommended 11-0 for
Approval by FDA Advisory Committee
Reported by Jules Levin
Bethesda, MD, Nov 14, 2002
|
| |
| |
FDA Advisory Committee met in a public hearing in Bethesda, MD, at the
wonderful Holiday Inn and voted 11-0 to recommend to the FDA approval for the
combination therapy of Pegasys plus Copegus (the Roche brand of ribavirin)
for treating chronic hepatitis C for previously untreated patients. Copegus
is the name of Roche's ribavirin which the FDA said today was equivalent to
the Schering brand of ribavirin. Both Pegasys and Copegus will be available
soon in the pharmacy and can both be purchased separately.
The discussion was lively and lasted from 8:30am to 4pm. The FDA Committee
commended Roche for their research efforts. As expected there were no
surprises at today's hearing. The data presented by Roche and the FDA on the
Pegasys studies were similar to data reported previously on the two Roche
phase 3 studies. There were no surprises. So below I'm going to review some
key information reported at the hearing.
Pegasys study NV15801 was the study published and reported by Michael Fried.
1121 patients were randomized to:
Pegasys 180 mcg alone
vs
Pegasys 180 mcg plus Copegus 1000/1200 mg/day
vs
REBETRON (interferon a-2b plus ribavirin 1000/1200mg/day
Patients received 48 weeks treatment. 65% of patients had genotype 1; 13%
cirrhosis; 66% high viral load.
RESULTS
Treatment with Pegasys/Copegus was significantly superior to interferon a-2b
plus ribavirin (p=0.001), as measued by sustained viral response. The factors
that predicted outcome in the study were genotype 1 had a worse response,
high viral load (>2 million) was a worse predictor, having cirrhosis was a
predictor for worse outcome, older age predicted worse outcome, and higher
body weight predicted worse outcome. The Patients with cirrhosis did not
achieve as high a sustained viral response (SVR) as patients without
cirrhosis (41% vs 55% for patients on Pegasys/Copegus). The same was true for
patients receiving interferon a-2b plus ribavirin. The number of Blacks in
the study were small but had a lower sustained response rate. 27 Blacks
received Pegasys/Copegus and 6 achieved an SVR (22%). Age was also a
predictive factor in response: 61% of patients <44 years on Pegasys/RBV had
SVR vs 41% >45 years.
The FDA analysis broke age down further and found the younger a patient was
the better response to Pegasys/RBV therapy:
AGE PREDICTS SVR to Pegasys plus Copegus
-- <35 years, 68% had SVR
-- 35-44 yrs, 56% had SVR
-- 45-54 yrs, 43% had SVR
-- 55-64 yrs, 35% had SVR
The FDA reported about 20% of patients achieving an SVR had improved
histology as measured by 2 point improvement in HAI. And many patients
improved inflammation. They did not report how many patients slowed or
stopped fibrosis but studies show that a high percentage of patients
achieving SVR can stop fibrosis progression. There was discussion about the
long term clinical benefit of achieving an SVR and there was general
agreement that this generally results in better clinical outcome. More long
term studies are needed to evaluate long term clinical outcomes.
SAFETY
Severe adverse events were similar in Pegasys and interferon arms: 29%
Pegasys/Copegus had a higher incidence of certain adverse events compared to
IFN/RBV:
--serious adverse events (12% vs 9%)
--serious infections (3.4% vs 1.7%)
--grade 4 neutropenia (5% vs 1%)
--grade 3 thrombocytopenia (5% vs 0.2%)
--dose modifications (32% vs 18%).
The rate of premature withdrawals were,
however, about the same (10% vs 11%). The dose modifications were due to more
neutropenia associated with Pegasys than standard interferon. And also to
more thrombocytopenia.
There was greater toxicity with lower body weight.
Pegasys study NV15942 looked at 1300 patients randomized by genotype and
viral load to 4 arms receiving Pegasys (180 mcg): two treatment arms
comparing 24 weeks therapy to 48 weeks; 2 ribavirin dose arms (800 and
1000/1200mg). The FDA concluded: Patients with genotype 2/3 had similar SVR
using 24 or 48 weeks therapy and using either 800 or 1000/1200mg RBV. SVR in
patients with genotype 1 were highest in patients receiving 1000/1200 mg
ribavirin and receiving 48 weeks therapy rather than patients treated for 24
weeks and receiving 800 mg ribavirin. 24 week therapy is associated with
lower incidence of severe or serious adverse events, withdrawal, and dose
modifications of either Pegasys or ribavirin. 48 week/1000-1200 mg RBV
therapy is associated with higher serious infections rate, and withdrawals
for neutropenia. Using 800 vs 1000/1200mg ribavirin has a lower incidence of
RBV dose modification and less serious adverse events.
|
| |
| |
|
|
|
