Gilead Sciences' Sovaldi

The FDA has approved Sovaldi (sofosbuvir) with ribavirin or ribavirin plus interferon alfa for treatment of chronic hepatitis C infection in patents with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4.


In an FDA press release dated December 6, 2013, the agency announced approval of Sovaldi (sofosbuvir) tablets or the treatment of chronic hepatitis C infection with hepatitis C virus (HCV) genotype 1, 2, 3, or 4 as part of an antiviral regimen. Sovaldi is approved for use in patients with hepatocellular carcinoma awaiting a liver transplant and in patients coinfected with HIV-1.1,2 Contraindications include use in pregnant women, use in men with pregnant female partners, and all contraindications that apply to interferon or ribavirin (eg, use in patients with autoimmune hepatitis, use in patients with decompensated cirrhosis, use in infants or neonates, use in patients with hypersensitivity to interferon, use in patients with hemoglobinopathies, or use in patients taking didanosine).1-4
 
Pharmacology and Pharmacokinetics

Sovaldi inhibits a key enzyme in HCV known as NS5B RNA-dependent RNA polymerase. This enzyme is important in viral replication. Biochemical studies prove enzyme inhibition with Sovaldi in genotypes 1b, 2a, 3a, and 4a HCV. The RNA polymerase–inhibitory effect of Sovaldi does not extend to human DNA, RNA, or mitochondrial RNA polymerases.2
 
Studies with carbon-14 labeled sofosbuvir show liver metabolism to the pharmacologically active nucleoside analog triphosphate GS-461203 through a series of enzymes and the pyrimidine biosynthetic pathway. An inactive form of sofosbuvir, GS-331007, is eliminated primarily through the kidneys. This inactive metabolite has a 27-hour terminal elimination half-life.2
 
No dose adjustment of Sovaldi is required in patients with mild to moderate renal impairment, or in patients with mild to severe hepatic impairment, although safety and efficacy have not been evaluated in patients with decompensated cirrhosis, severe renal impairment, or end-stage renal disease requiring hemodialysis.2
 
Dosage and Administration
 
Each 400-mg tablet of Sovaldi may be taken with or without food. Genotype-1 or genotype-4 HCV infection requires use of triple therapy with Sovaldi, peginterferon alfa, and ribavirin for 12 weeks. An all-oral regimen of Sovaldi and ribavirin in patients may be used for 12 weeks in patients with genotype-2 HCV infection, for 24 weeks in patients with genotype-3 HCV, and for 24 weeks in patients with genotype-1 HCV infection who cannot use interferon. Patients with hepatocellular carcinoma awaiting a liver transplant may use Sovaldi for 48 weeks unless the patient receives a liver transplant before 48 weeks of treatment are complete, in which case the patient should stop using Sovaldi before receiving the liver transplant.2
 
Clinical Trials
 
A total of 1724 patients received Sovaldi in 5 phase-3 trials known by the names NEUTRINO, FISSION, POSITRON, VALENCE, and PHOTON-1.2
 
NEUTRINO evaluated 12 weeks of treatment with Sovaldi, peginterferon alfa-2a, and ribavirin in treatment-naive adults with genotype 1, 4, 5, or 6 HCV infection in 327 patients with a median age of 54 years. Sustained viral response (SVR) rates were 90% overall, 82% in genotype-1b infection, 92% in genotype-1a infection, and 96% in genotype-4 infection.2
 
FISSION evaluated 12 weeks to 24 weeks of treatment with Sovaldi and ribavirin in treatment-naive adults with genotype-2 or -3 HCV infection in 499 patients with a median age of 50 years. Overall sustained SVR rates were 67% with 12 weeks of therapy and unchanged (67%) with 24 weeks of therapy.2
 
In patients who were intolerant to, ineligible for, or unwilling to use interferon, POSITRON evaluated 12 weeks of treatment with Sovaldi and ribavirin in 207 patients compared with 71 patients receiving placebo. In all subjects, the median age was 54 years, and all patients had genotype-2 or genotype-3 HCV infection. Most patients (81%) had never received treatment for HCV before. With 12 weeks of therapy, the overall SVR rate was 78%, 93% for patients with genotype-2 HCV, and 61% for patients with genotype-3 HCV. Unsurprisingly, none of the 71 patients receiving placebo achieved SVR.2
 
VALENCE evaluated Sovaldi with weight-based ribavirin dosing in 323 treatment-naive patients with genotype-2 or -3 HCV infection. Overall, 93% of patients with genotype-2 infection and 84% of patients with genotype-3 infection achieved SVR.2
 
PHOTON-1 evaluated 12 to 24 weeks of Sovaldi with weight-based ribavirin dosing in with HIV-1 infection and genotype-1, -2, or -3 HCV infection. All genotype-1 patients were treatment naive, whereas some patients with genotype-2 and -3 HCV infection had received treatment for HCV infection before. SVR rates were 76% with 24 weeks of treatment in genotype-1 patients, 92% with 24 weeks of treatment in genotype-3 patients, and 88% with 12 weeks of treatment in genotype-2 patients.2
 
Contraindications, Warnings, and Precautions
 
In clinical trials, fatigue and headache were the most common adverse events with Sovaldi, each occurring in ≥20% of patients. In patients using Sovaldi with peginterferon alfa and ribavirin, common adverse events included fatigue, headache, nausea, insomnia, and anemia.2
 
Inducers of intestinal p-glycoprotein, such as rifampin or St John’s Wort, may alter levels of Sovaldi. Use with carbamazepine, phenytoin, phenobarbital or oxcarbazepine, rifabutin, rifapentine, or the combination tablet tipranavir/ritonavir may also reduce levels of Sovaldi, which may reduce efficacy. For a complete discussion of potential drug interactions and adverse events, please consult the package insert.2
 
 
References
1. FDA. FDA approves Sovaldi for chronic hepatitis C. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm377888.htm. Accessed December 2013.
2. Sovaldi (sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc; 2013.
3. Pegasys (peginterferon alfa-2a) injection for subcutaneous use [package insert]. South San Francisco, CA: Genentech USA, Inc; 2013.
4. Copegus (ribavirin) tablets [package insert]. South San Francisco, CA: Genentech USA, Inc; 2013.

 


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