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Summary of FDA Peg-Intron Hearing
  This is a report from the FDA hearing held on Peg-Intron held December 12 . The FDA presented their data analysis from the large Peg-Intron phase III study of Peg-Intron 1.5 ug/kg plus ribavirin 800 mg compared to standard interferon 3 MIU 3x/week plus ribavirin 1000-1200 mg breaking it down by genotype and viral load. When patients had high viral load and genotype 1 the SVR was the same whether they received IFN/RBV or Peg 1.5/RBV. The FDA reported 28% with genotype1 and hi viral load receiving standard IFN+RBV had a sustained viral response (SVR) compared to 29% for those receiving Peg-Intron+RBV 800mg with genotype 1/hi viral load. Regarding patients with genotype 2-6 and high viral load the FDA reported responses: 74% who received standard IFN/RBV had SVR compared to 72% receiving Peg-Intron 1.5/RBV 800mg. Schering reported patients with genotype 2/3 & hi-viral load (>2 million) had 77% SVR with IntronA/Rebetol and 76% SVR with Pegintron 1.5 ug/kg/Rebetol 800mg.
For patients with low viral load, patients receiving Peg 1.5/RBV 800 mg had a better SVR than patients receiving IFN/RBV 1000-1200 mg. For those patients with lo viral load & genotype 1, PegIntron/RBV showed 72% SVR vs 44% using standard IFN/RBV. For patients with genotype 2-6 & lo viral load, 72% receiving standard IFN/RBV had SVR vs 81% using PegIntron/RBV. Schering reported that for genotype 2/3 and <2 million 80% receiving IntronA/Rebetol had SVR and 91% receiving PegIntron 1.5 ug/kg/RBV had SVR.
Pegasys is still in the FDA review process for approval, which is expected in the 2nd half of 2002. Therefore, although Pegasys+RBV data has been presented publicly by Roche, it has not been presented yet by the FDA nor has the data been published yet. At AASLD at the Roche symposium in November 2001, Morris Sherman, MD reported data on response to Pegasys+RBV for various genotypes and viral load levels from their large phase III study. In persons with genotype 1 and high viral load (>2 million), 41% receiving Pegasys+RBV 1000-1200mg had an SVR vs 33% for patients receiving standard IFN+RBV 1000-1200. In patients with genotype 2/3 and high viral load 74% receiving Pegasys/RBV had an SVR vs 59% receiving standard IFN/RBV.
Differences in response in patients with low viral load were also reported between Pegasys+RBV vs standard IFN+RBV: genotype 1 + low viral load --56% had an SVR receiving Pegasys/RBV vs 44% receiving standard IFN/RBV; genotype 2/3 + low viral load 81% had an SVR receiving Pegasys/RBV vs 65% receiving IFN/RBV.
Ribavirin (RBV) Weight Based Dosing
In the large phase 3 study of Pegintron+RBV only one dose regimen consisting of 800 mg per day was studied in combination with Pegintron. Although Schering culled data in a retrospective nature from this study suggesting therapy may be more effective in terms of antiviral response, the FDA finds the data inadequate and is requiring Schering to conduct a large prospective study, which is ongoing. The FDA said the cost/risk benefit of RBV weight based dosing is not resolved. Data shows more adverse events occur at higher doses of RBV. The following data on weight based dosing was gathered from a post hoc (after the study) retrospective analysis. The FDA expressed several concerns about the data on weight based dosing from Schering's analysis. Preliminary antiviral efficacy data suggests benefit to higher dosing, but the number of patients in parts of the analysis were too small to make conclusions about the potential anitiviral benefit. For example, patients receiving <10.7 mg/kg of RBV plus PegIntron 1.5 ug/kg numbered 326 and 156 had a SVR. 126 patients received10.7 to 13.3 mg/kg RBV +Peg 1.5 and 70 had an SVR. This suggests a better SVR for those patients receiving the higher RBV dose based on weight. But in higher weight based dosing categories the number of patients were small. Only 38 patients received 13.3-14.7 RBV mg/kg along with Peg 1.5 and 25 had an SVR. This suggests a better response with higher weight based dosing. In the higher weight category where only 21 patients received 14.7 or more mg/kg of RBV, 13 had a SVR. The FDA said the numbers of patients in the higher dosing groups were too small to draw a conclusion that higher dosing concentration is beneficial to antiviral effect. The FDA said the true reason for better response at higher RBV concentration by weight could be due to patient body weight: body weight could be a surrogate for RBV dosing. The Schering analysis was not randomized and said there were additional unknown factors. They felt across arm comparisons were inappropriate. The FDA data showed patients receiving higher RBV dosing (>10.7) had more incidence of dose modification (IFN or RBV) for all causes as well as for anemia and neutropenia. The incidence of anemia was higher for patients with lower body weight and greater RBV concentration (>10.7). But the incidence of severe anemia was not greater. As well, the incidence of neutropenia as well as the incidence of severe neutropenia was greater for patients at lower body weights & higher concentration of RBV dosing (>10.7). In HIV/HCV coinfected the potential for certain adverse events such as decreased hemoglobin (anemia) and neutropenia may be particularly concerning. Therefore, as part of the FDA Peg-Intron approval Schering is conducting a phase 4 retrospective study to explore the question of weight-based dosing.
Several committee panelists expressed concern that since the PegIntron monotherapy study does not show a difference in SVR between the PegIntron 1.0 dose and the 1.5 dose and since adverse events may be less using the lower dose, the FDA approved dosing of 1.5 may not be well founded. But since it has already been approved it may be too late to make changes. The already in progress phase 4 studies are based on using the FDA approved 1.5 dose.