General Information

Harvoni is a a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor.

Harvoni is specifically indicated for the treatment of chronic hepatitis C genotype 1 infection in adults.

Harvoni is a two-drug fixed-dose combination product that contains 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet. The recommended dosage of Harvoni is one tablet taken orally once daily with or without food.

Clinical Results

FDA Approval

The FDA approval of Harvoni was based on three phase III trials in 1,518 subjects with genotype 1 chronic hepatitis C with compensated liver disease. These three trials are ION-3: noncirrhotic treatment-naïve subjects, ION-1: cirrhotic and noncirrhotic treatment-naïve subjects and ION-2: cirrhotic and noncirrhotic subjects who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Each trial evaluated efficacy of Harvoni (one fixed-dose tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir administered once daily) with or without ribavirin. Treatment duration was fixed in each trial. The primary endpoint was sustained virologic response (SVR), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment.

ION-3

ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 CHC. Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): Harvoni for 8 weeks, Harvoni for 12 weeks, or Harvoni + ribavirin for 8 weeks. The SVR rate was 94% and 96% for the Harvoni 8 and 12-week duration arms, respectively. Ribavirin was not shown to increase the response rates observed with Harvoni. By genotype the SVR rates were: Genotype 1a 93% (8 wks) and 96% (12 wks) and Genotype 1b 98% for both 8 and 12 weeks.

ION-1

ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with Harvoni with or without ribavirin in 865 treatment-naïve subjects with genotype 1 CHC including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive Harvoni for 12 weeks, Harvoni + ribavirin for 12 weeks, Harvoni for 24 weeks, or Harvoni + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b). The interim primary endpoint analysis for SVR included all subjects enrolled in the 12-week treatment groups. The overall SVR rate in treatment-naïve subjects with Genotype 1 CHC with and without Cicrhosis was 99%. Ribavirin was not shown to increase the response rates observed with Harvoni. When stratified by genotype: Genotype 1a 98% and Genotype 1b 100% and cirrhosis: yes - 94% and no - 99%.

ION-2

ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with Harvoni with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive Harvoni for 12 weeks, Harvoni + ribavirin for 12 weeks, Harvoni for 24 weeks, or Harvoni + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs non-response). The overall SVR rates were 94% for the 12-week arm and 99% in the 24-week arm. Ribavirin was not shown to increase the response rates observed with Harvoni.

Mechanism of Action

Harvoni is a a fixed-dose combination of ledipasvir and sofosbuvir. Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication.