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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.
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.
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.
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