The European Commission has granted marketing authorization for Harvoni ( Ledipasvir 90 mg / Sofosbuvir 400 mg ), the first once-daily single tablet regimen to treat the majority of chronic hepatitis C genotype 1 and 4 infection in adults.
Harvoni combines the NS5A inhibitor Ledipasvir ( LDV ) with the nucleotide analog polymerase inhibitor Sofosbuvir ( SOF ), approved by the European Commission under the tradename Sovaldi in January 2014.
Harvoni is indicated for the treatment of chronic hepatitis C virus ( HCV ) in adults and is recommended in treatment-naïve and treatment-experienced cirrhotic and non-cirrhotic genotype 1 and 4 patients with a treatment duration of 12 or 24 weeks depending on prior treatment history and cirrhosis status.
Eight weeks of treatment with Harvoni may be considered in non-cirrhotic treatment-naïve genotype 1 patients.
In genotype 1 and 4 patients with decompensated cirrhosis, and genotype 3 patients with cirrhosis and/or prior treatment failure, Harvoni should be used in combination with Ribavirin for 24 weeks. Harvoni is also indicated for patients with HCV who have HIV co-infection.
The marketing authorization is supported primarily by data from three phase 3 studies, ION-1, ION-2 and ION-3. These studies evaluated eight, 12 or 24 weeks of treatment with Harvoni, with or without Ribavirin, among nearly 2,000 genotype 1 HCV patients with compensated liver disease.
These studies included non-cirrhotic treatment-naïve patients ( ION-3 ), cirrhotic and non-cirrhotic treatment-naïve patients ( ION-1 ) and cirrhotic and non-cirrhotic patients who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor ( ION-2 ).
The primary endpoint for each study was sustained virologic response ( HCV undetectable ) 12 weeks after completing therapy ( SVR12 ).
Patients who achieve SVR12 are considered cured of HCV.
In these studies, Ribavirin was not shown to increase response rates. Trial participants in the Ribavirin-free arms ( n=1,080 ) achieved SVR12 rates of 94 to 99%.
The approval was also supported by preliminary data from the SOLAR-1 trial, which evaluated difficult to treat patients with decompensated cirrhosis and patients who have undergone liver transplantation, and from the ERADICATE trial, which evaluated genotype 1 HCV patients co-infected with HIV.
The primary endpoint in these studies was SVR12. At the time of submission, only preliminary results were available.
In the SOLAR-1 trial, participants with decompensated cirrhosis receiving a 12-week treatment regimen of Harvoni plus Ribavirin had an SVR4 rate of 90% ( n=45/50 ). In post-liver transplant patients without decompensated liver disease, SVR4 rates were greater than 95% ( n=109 ).
In an interim analysis of the ERADICATE trial, 40 of the 50 patients had reached 12 weeks post treatment and had SVR12 rates of 98% ( n=39/40 ).
The ELECTRON-2 trial, a phase 2 open-label study, provided preliminary data on genotype 3 infected HCV patients demonstrating 100% ( n=26/26 ) SVR12 when Harvoni was used in combination with Ribavirin for 12 weeks.
In these clinical studies, fatigue and headache were more common in patients treated with Harvoni compared to placebo. ( Xagena )
Source: Gilead, 2014