Two new hepatitis C drugs recommended for US approval

Two new direct acting antiviral agents for the treatment of hepatitis C have been unanimously recommended for approval by expert advisory panels in the United States. Full marketing approval from the US Food and Drug Administration is likely before the end of 2013.

Sofosbuvir, a nucleotide polymerase inhibitor, has been recommended for use in two different treatment regimens.

For people with genotype 1 or 4 hepatitis C infection, sofosbuvir has been recommended for use in combination with pegylated interferon and ribavirin for 12 weeks.

For people with genotype 2 or 3 hepatitis C infection, sofosbuvir has been recommended for use in combination with ribavirin alone. At this point it is not clear whether the final product licence will recommend treatment for 12 or 16 weeks. A longer duration of treatment was associated with a much higher cure rate in people with genotype 3 infection, and a modest increase in the cure rate in genotype 2 infection.

Sofosbuvir did not significantly increase the rate of adverse events when used in combination with pegylated interferon and ribavirin.

Sofosbuvir and ribavirin will be the first interferon-free drug combination for the treatment of hepatitis C. Further interferon-free combinations for the treatment of genotype 1 hepatitis C infection are likely to be reviewed in 2014 and 2015.

Gilead Sciences, the developer of sofosbuvir, expects to receive full marketing approval for the product by 8 December 2013. Sofosbuvir is administered as a single pill, once a day.

Simeprevir, a protease inhibitor, has been recommended for approval for treatment of genotype 1 hepatitis C infection, for use in combination with pegylated interferon and ribavirin for 12 weeks (followed by 12 or 36 weeks of therapy with pegylated interferon and ribavirin, according to virologic response to therapy at weeks 4 and 12).

Simeprevir has been approved for people who have not been treated previously, and for people who had experienced virologic relapse after a previous course of pegylated interferon and ribavirin. Phase III licensing studies found no substantive difference in cure rates (SVR 12) between previously treated or untreated patients (79% and 80% achieved a cure, respectively).

Cure rates were lower in patients with bridging fibrosis and cirrhosis, and older patients, African-Americans and those who lacked the IL28B CC genotype. Patients with high viral loads were also less likely to achieve a cure.

Review of the three phase III studies also identified that people with genotype 1a hepatitis C and a naturally occurring HCV mutation (Q80K) had a much lower rate of cure. In the studies of previously untreated patients there was no significant difference in cure rates between those who received simeprevir plus pegylated interferon and ribavirin and those who received pegylated interferon and ribavirin.

This finding led the expert advisory panel to recommend that patients with genotype 1a hepatitis C should be tested prior to treatment to exclude the presence of the Q80K polymorphism, and that alternative options should be considered for patients found to have the polymorphism.

This difference in response is likely to have a big impact on the use of simeprevir in the United States, where the polymorphism is found in around half of genotype 1a infections, compared to approximately one in five people with genotype 1a in Europe. Genotype 1a hepatitis C infection is more common in the United States than in Europe and Japan.

Simeprevir was fairly well tolerated in phase III studies; 2% of the simeprevir-treated patients experienced serious adverse events compared to 3% of the control group.

There was no significant difference in side-effects between people in the simeprevir group and the control group. Severe rash and photosensitivity were observed in the simeprevir group and the frequency of these adverse events was greater in patients of East Asian origin. The advisory panel recommended that further studies should be carried out in patients of East Asian origin to explore the frequency of these serious adverse events in a larger patient population.

The expert advisory group did not reach a firm conclusion as to whether the product labelling for simeprevir should include a recommendation that all patients should use sunscreen, in order to reduce the risk of photosensitivity when taking this drug.

The manufacturer was asked to carry out further studies to more fully explore the benefits of simeprevir treatment in African-Americans, who were significantly under-represented in licensing studies of the drug.

Janssen, a Johnson & Johnson company, hopes to receive full marketing approval for simeprevir in December, and European Union approval in the first half of 2014. Simeprevir has already been approved for treatment of genotype 1b infection in Japan.