In July 2017, the FDA approved Gilead Sciences' Vosevi, a fixed-dose combination product containing sofosbuvir, an HCV NS5B polymerase inhibitor, velpatasvir, an HCV NS5A inhibitor, and voxilaprevir, an HCV NS3/4A protease inhibitor for re-treatment of adults with chronic hepatitis C genotypes 1, 2, 3, 4, 5, or 6. With its approval, Vosevi became the first antiviral regimen that is indicated for patients who have been previously treated with sofosbuvir or other drugs that inhibit NS5A.
This article highlights several key therapeutics areas with Vosevi that every pharmacist should know.
Vosevi is indicated for the treatment of adult patients with HCV genotype 1, 2, 3, 4, 5, or 6 that have previously been treated with an HCV regimen containing an NS5A inhibitor or in patients with genotype 1a or 3 and have previously been treated with a regimen containing sofosbuvir without an NS5A inhibitor.
It can be used in those without cirrhosis or with compensated cirrhosis (Child-Pugh A).
Mechanism of Action
Vosevi is a combination of 3 direct-acting antiviral agents with distinct mechanisms of action. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication and virion assembly. Voxilaprevir is an inhibitor of the NS3/4A protease, which is necessary for proteolytic cleave for the HCV polyprotein and viral replication.
Formulation and Storage
Each Vosevi tablet contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir. The tablets are beige and film-coated. Each bottle contains 28 tablets and is closed with a child-resistant closure. Vosevi should be stored below 30°C (86ºF) and dispensed in the original container.
Vosevi is administered as one tablet taken orally once daily with food. The recommended treatment duration is 12 weeks in all individuals.
No dosage recommendation are made for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73 m2) or with end stage renal disease (ESRD), due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite. Additionally, the medication is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to higher exposures of voxilaprevir.
The efficacy of Vosevi for the treatment of chronic HCV was established in 2 randomized clinical trials in 748 DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV. Sustained virologic response (SVR12), defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment, was the primary endpoint in all the trials.
POLARIS-1 evaluated the impact of 12 weeks of treatment with Vosevi compared with 12 weeks of placebo in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection who previously failed a regimen containing an NS5A inhibitor. SVR12 rates were high across all treated individuals ranging from 91% to 100% (total SVR12 = 96%). No subjects in the placebo group achieved SVR12.
POLARIS-4 evaluated 12 weeks of treatment with Vosevi and 12 weeks of treatment with sofosbuvir/velpatasvir (Epclusa) in subjects with genotype 1, 2, 3, or 4 HCV infection who had previously failed a HCV DAA-containing regimen that did not include an NS5A inhibitor. Study results showed that treatment with Vosevi resulted in numerically higher SVR12 rates than treatment with sofosbuvir/velpatasvir for 12 weeks in subjects with HCV genotype 1a and 3 infection (97% vs 82% genotype 1; 96% vs 85% genotype 3).
Comparable SVR12 rates were observed in subjects with HCV genotype 1b and 2 infection treated with Vosevi or sofosbuvir/velpatasvir for 12 weeks. No comparison data are available for HCV genotypes 4, 5, and 6. Based on the data, Vosevi was only approved for the treatment of HCV genotypes 1a or 3 infection in adults who previously received sofosbuvir without an NS5A inhibitor
The most common adverse reactions of Vosevi reported in clinical trials include headache, fatigue, diarrhea, and nausea. Coadministration with rifampin is contraindicated. The safety and effectiveness of Vosevi have not been established in pediatric patients.
Sofosbuvir, velpatasvir, and voxilaprevir are substrates of drug transporters P-gp and BCRP. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed.
Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine) may decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir leading to reduced therapeutic effect of Vosevi. Therefore, the use of these agents with Vosevi is not recommended.
Co-administration of amiodarone with Vosevi may result in serious symptomatic bradycardia and is not recommended. Acid reducing agents may decrease velpatasvir concentrations and therefore administration of Vosevi should be separated by 4 hours with antacids. Omeprazole 20 mg can be administered with Vosevi.
|FDA Indication||Dosing||# Tablets/ Day||
|Vosevi (sofosbuvir/velpatasvir/ voxilaprevir)||GT 1, 2, 3, 4, 5, 6||QD x 12 weeks||1||$29,904|
|GT 1, 2, 3, 4, 5, 6||QD x 12 weeks||1||$29,904|
|GT 1, 4, 5, 6||QD x 12-24 weeks||1||$37,800|
|GT 1, 4||QD x 12-16 weeks||1||$21,840|
(ombitasvir/paritaprevir/ ritonavir and dasabuvir)
|GT 1||BID x 12-24 weeks||4||$33,328|
Viekira Pak XR
(ombitasvir/paritaprevir/ ritonavir and dasabuvir)
|GT 1||QD x 12-24 weeks||3||$33,328|
|Daklinza (daclatasvir) + Sovaldi (sofosbuvir)||GT 1, 3||QD x 12-24 weeks||2||$58,800|
|Olysio (simeprevir) + Sovaldi (sofosbuvir)||GT 1||QD x 12-24 weeks||2||$60,144|
|GT 4||QD x 12 weeks||2||$32,851|
Cost based on AWP, per Lexi-Drugs. Cost to the patient will vary based on individual insurance coverage.
In clinical studies, Vosevi was shown to be highly effective in treating HCV genotypes 1, 2, 3, 4, 5, and 6 who have previously been treated with an HCV regimen containing an NS5A inhibitor and in those with HCV genotype 1a or 3 who have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Additionally, the medication was well-tolerated across both studies. Current HCV AASLD guidelines have not yet been updated to provide a recommendation for Vosevi’s place in therapy; however it will likely provide valuable in previous treated adults with HCV where no medication had previously been indicated. Finally, unlike some other HCV medications, Vosevi is only given as one tablet once a day, and does not require a 24 week treatment duration in more complicated patients.
- Viral Hepatitis - Hepatitis C. Centers for Disease Control and Prevention. http://www.cdc.gov/hepatitis/hcv/. Accessed September 1, 2017.
- Vosevi [Prescribing Information]. Gilead Sciences, Inc. Foster City, California. July 2017.
- Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 5, 2017.
- AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed September 5, 2017.
Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD, is a Clinical Pharmacist working at a regional health insurance plan on the east coast. Additionally he works per diem at a nationwide retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. He completed his M.S. in Health Services Administration, with a focus on Health Economics and Outcomes, in 2018. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.