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FDA New Drug Approval: VoseviTM for Hepatitis C therapy in treatment-experienced adults

Tuesday, September 19, 2017  
Posted by: Caroline Santayana
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FDA New Drug Approval: VoseviTM for Hepatitis C therapy in treatment-experienced adults

Christine Starrs, PharmD Candidate 2018
Jennifer Andres, PharmD, BCPS
Temple University School of Pharmacy

Chronic hepatitis C virus (HCV) infection is a disease of the liver caused by a bloodborne virus. HCV is transmitted through various modes, such as injection drug use, unsafe injection practices, and the transfusion of unscreened blood and blood products. An estimated 71 million people are infected by chronic hepatitis C worldwide. A great number of this population will develop cirrhosis or liver cancer.1 Drug treatment and therapeutic response is based on a patient’s genotype (genotypes 1-6), genetic polymorphisms, prior treatment history, and stage of liver disease. Providers use sustained virologic response (SVR) evaluated 12 weeks after treatment completion as indication of a successful hepatitis C treatment.2 The World Health Organization recommends that HCV infected patients be treated with direct-acting antiviral agents (DAAs) regimens with few exclusions.2

DAAs provide an added benefit when used in double or triple therapy combination minimizing the occurrence of resistant mutations.3 Due to the lack of a proofreading enzyme, HCV has frequent mutations which can cause resistance. Up to 10-15% of HCV genotype 1-infected patients without prior exposure to NS5A inhibitors will have a detectable HCV NS5A resistance-associated substitution (RASs) at baseline which may cause a reduction in the activity of NS5A-containing regimens.2 Drug resistance can also pose a challenge in the retreatment of some patients who have failed prior DAA treatment. Patients with genotype 1a and 3, as well as those with HIV co-infection, and those with more advanced liver disease are more prone to resistance.4 Exact numbers on how many patients fail DAA therapy are not available. However, approximately 5-10% of HCV genotype 1 infected patients without cirrhosis that are treated with simeprevir and sofosbuvir for 12 weeks will experience treatment failure.2 Limited information is available to guide treatment in patients of most genotypes and NS5A or sofosbuvir treatment-experience. Current guidelines suggest triple or quadruple therapy based on prior combinations used, with durations ranging from 12 weeks to 24 weeks and a possible addition of weight-based ribavirin.2

The U.S. Food and Drug Administration (FDA) recently approved Gilead Science’s three-drug combination tablet known as VoseviTM.4 This medication contains two previously approved drugs, sofosbuvir (SOF) and velpatasvir (VEL), as well as a new drug, voxilaprevir (VOX).5 Sofosbuvir is a nucleotide analogue HCV NS5B polymerase inhibitor, and velpatasvir is an HCV NS5A inhibitor. This combination was pangenotypic and this continues with the addition of voxilaprevir (formerly known as GS-9857) which is a HCV NS3-NS4A protease inhibitor.6 SOF/VEL/VOX dosing is one tablet (sofosbuvir 400 mg – velpatasvir 100 mg – voxilaprevir 100 mg) taken orally once daily with food.7 SOF/VEL/VOX’s FDA approval in the U.S. market comes with the recent release of results from two phase 3 trials, POLARIS-1 and POLARIS-4. These trials included previously treated patients with DAAs, multicenter enrollment, and similar inclusion and exclusion criteria. The only eligibility criteria that differed between trials was POLARIS-1 enrolled patients whose only previous treatment included an NS5A inhibitor, whereas POLARIS-4 enrolled patients who had been previously treated with any DAA regimen that did not include an NS5A inhibitor.6 POLARIS-1 evaluated patients with HCV genotype 1 infection, and assigned these patients to placebo or SOF/VEL/VOX for 12-week treatment. If a patient was infected with another genotype, then automatic enrollment into the SOF/VEL/VOX arm occurred. Both trials used a prespecified performance goal of 85%, which was designed to test for the superiority of the rate of SVR achieved among patients receiving SOF/VEL/VOX or SOF/VEL. This was based on the efficacy of the combination of SOF/VEL/VOX in phase 2 trials.  Results in efficacy showed a significant superiority to the prespecified performance goal in the SOF/VEL/VOX group (P < 0.001).6 The POLARIS-4 trial consisted of HCV genotype 1, 2, or 3 infected patients who were randomly assigned to either SOF/VEL/VOX or SOF/VEL for 12-week treatment and genotype 4 patients who all received SOF/VEL/VOX for 12 weeks. A significantly superior performance with SOFVEL/VOX can be seen in Table 1.6 In both trials, adverse effects (shown in Table 1) were limited. Limitations of the trials included small numbers of patients with non-genotype 1 infection and patients with cirrhosis. In addition, exclusion of patients with coinfected hepatitis B, HIV, and decompensated cirrhosis cannot make these results generalizable to these populations.6 Due to the presence of VOX, a protease inhibitor, the combination can not be used in decompensated cirrhosis. This is unfortunate as HCV patients are known to have a coinfection of hepatitis B or HIV, and medication treatment for decompensated cirrhosis is limited.1,9

SOF/VEL/VOX is approved for the treatment of adult, chronic HCV infected patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) that fall into one of the following categories: (1) genotypes 1- 6 with previous treatment of an NS5A inhibitor, or (2) genotypes 1a or 3 with previous treatment of sofosbuvir without an NS5A inhibitor. In either case, the treatment duration will be for 12 weeks.7 SOF/VEL/VOX is currently not recommended for the treatment naive patient population.7 This recommendation comes from the POLARIS-2 trial, which compared 8 weeks of SOF/VEL/VOX vs 12 weeks of SOF/VEL in treatment naïve HCV infected patients. The results did not meet criteria to show noninferiority to 12 weeks of SOF/VEL. In addition, a difference in efficacy with a lower SVR rate in genotype 1a patients could be seen in the 8-week SOF/VEL/VOX arm.8 Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) or end stage renal disease should not use this combination as it has not been studied. SOF/VEL/VOX is contraindicated in coadministration with rifampin, as rifampin was shown in clinical trials to significantly decrease concentrations of SOF and VEL, while showing increased or decreased concentrations of VOX depending on the dose of rifampin.7 The wholesale acquisition cost (WAC) for SOF/VEL/VOX is $890 per pill, or $74,760 for a 12-week duration of therapy. This price is in the same range as Gilead Science’s EpclusaTM (SOF/VEL) combination tablet.10 Patient assistance is available for eligible patients through Gilead’s drug website (www.vosevi.com) or by phone with Support PathTM.11

With SOF/VEL/VOX’s recent FDA approval, this medication becomes the first treatment approved for HCV infected patients across various genotypes who have previously been treated with drugs that inhibit NS5A or sofosbuvir.5 The benefit of having three drugs with different mechanisms of action in one tablet given once daily will help with patient adherence to avoid future drug resistance that may be caused by patient’s not taking medications. However, providers should be cautious to generalize these results to patient populations such as coinfected HIV or hepatitis B patients. Patients with decompensated cirrhosis and severe renal impairment can not use SOF/VEL/VOX.6 In addition, healthcare providers should watch for known drug-drug interactions, contraindications (e.g. rifampin), and the side effects of headache, fatigue, and diarrhea. For patients with unsuccessful treatments in the past, SOF/VEL/VOX offers a 12-week option for a successful cure of HCV.

Table 1. Comparison of HCV RNA levels (to a prespecified performance goal of 85%) and adverse events of POLARIS-1 trial (SOF/VEL/VOX vs Placebo) and POLARIS-4 trial (SOF/VEL/VOX vs SOF/VEL)6

 

POLARIS-1

POLARIS -4

 

PLACEBO

(N = 152)

SOF/VEL/VOX

(N = 152)

SOF/VEL/VOX

(N = 182)

SOF/VEL

(N = 151)

HCV RNA level < 15 IU/ml

 

 

 

 

During Treatment

 

 

 

 

At 8 weeks

N/A

100%

100%

99%

At 12 weeks

N/A

100%

99%

99%

After end of treatment

 

 

 

 

At 12 weeks (SVR12)

N/A

96%

98%

90%

Adverse Events

 

 

 

 

Headache

17%

25%

27%

28%

Fatigue

20%

21%

24%

28%

Diarrhea

12%

18%

20%

5%

References:

1.      World Health Organization. Hepatitis C: fact sheet. July 2017. (http://www.who.int/mediacentre/factsheets/fs164/en/). Accessed August 18, 2017.

2.      AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 18, 2017.

3.      Kim S, Han K-H, Ahn SH. Hepatitis C Virus and Antiviral Drug Resistance. Gut and Liver. 2016;10(6):890-895. doi:10.5009/gnl15573.

4.      Colpitts CC, Baumert TF. Addressing the Challenges of Hepatitis C Virus Resistance and Treatment Failure. Viruses. 2016;8(8):226. doi:10.3390/v8080226.

5.      U.S. Food and Drug Administration. FDA approves Vosevi for Hepatitis C. (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm567467.htm). Accessed July 26, 2017.

6.      Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017;376(22):2134-2146.

7.      Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.

8.      Jacobson I, Lawitz E, Gane E, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. 2017;153:113–122

9.      Naggie S, Muir AJ. Oral combination therapies for hepatitis C virus infection: successes, challenges, and unmet needs. Annu Rev Med 2017;68:345-358.

10. Hepatitis C Online – AWS. Sofosbuvir-Velpatasvir-Voxilaprevir (Vosevi). 2017. (http://www.hepatitisc.uw.edu/page/treatment/drugs/sofosbuvir-velpatasvir-voxilaprevir/drug-summary). Accessed August 8, 2017.

11. Gilead Sciences, Inc. Vosevi. 2017. (www.vosevi.com). Accessed August 18, 2017. 


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