Vosevi Drug Information
Generic name: SOFOSBUVIR, VELPATASVIR, AND VOXILAPREVIR
Hepatitis C Virus Nucleotide Analog NS5B Polymerase Inhibitor [EPC] Hepatitis C Virus NS5A Inhibitor [EPC] Hepatitis C Virus NS3/4A Protease Inhibitor [EPC]
Uses of Vosevi
is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have : genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor. genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Additional benefit of VOSEVI over sofosbuvir/velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor. VOSEVI is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, velpatasvir, an HCV NS5A inhibitor, and voxilaprevir, an HCV NS3/4A protease inhibitor, and is indicated for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have : genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor. genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor.
Additional benefit of VOSEVI over sofosbuvir/velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor.
Dosage & Administration of Vosevi
| 1, 2, 3, 4, 5, or 6 | An NS5A inhibitor |
|---|---|
| 1a or 3 | Sofosbuvir without an NS5A inhibitor |
Side Effects of Vosevi
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in HCV-Infected Subjects without Cirrhosis or with Compensated Cirrhosis The adverse reactions data for VOSEVI were derived from two Phase 3 clinical trials (POLARIS-1 and POLARIS-4) that evaluated a total of 445 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis (Child-Pugh A), who received VOSEVI for 12 weeks. VOSEVI was studied in placebo- and active-controlled (sofosbuvir/velpatasvir) trials.
The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received VOSEVI for 12 weeks. The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache, fatigue, diarrhea, and nausea in subjects treated with VOSEVI for 12 weeks. Table 2 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 12 weeks of treatment with VOSEVI in the Phase 3 clinical trials.
The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 2 Adverse Reactions (All Grades) Reported in ≥5% of Subjects With HCV Without Cirrhosis or With Compensated Cirrhosis Receiving VOSEVI in POLARIS-1 and POLARIS-4 POLARIS-1 POLARIS-4 VOSEVI 12 weeks (N=263) Placebo 12 weeks (N=152) VOSEVI 12 weeks (N=182) SOF/VEL 12 weeks (N=151) Headache 21% 14% 23% 23% Fatigue 17% 15% 19% 23% Diarrhea 13% 9% 14% 3% Nausea 13% 7% 10% 3% Asthenia 6% 4% 4% 6% Insomnia 6% 3% 3% 1% In POLARIS-1, of the subjects receiving VOSEVI who experienced adverse reactions, 99% were mild or moderate (Grade 1 or 2) in severity. In POLARIS-4, of the subjects receiving VOSEVI who experienced adverse reactions, all the reported adverse reactions were mild or moderate (Grade 1 or 2) in severity.
Less Common Adverse Reactions Reported in Clinical Trials The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with VOSEVI for 12 weeks and are included because of a potential causal relationship. Rash: In the POLARIS-1 and POLARIS-4 trials, rash occurred in less than 1% and 2% of subjects treated with VOSEVI, respectively. Rash was reported in 1% of subjects treated with placebo in POLARIS-1 and was not reported by any subject taking sofosbuvir/velpatasvir in POLARIS-4. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity.
Depression: In the POLARIS-1 and POLARIS-4 trials, depressed mood occurred in less than 1% and 1% of subjects treated with VOSEVI, respectively. Depressed mood was not reported by any subject taking placebo in POLARIS-1 and was reported in 1% of subjects treated with sofosbuvir/velpatasvir in POLARIS-4. No serious adverse reactions of depressed mood occurred and all events were mild or moderate in severity. Laboratory Abnormalities Lipase Elevations: Isolated, asymptomatic lipase elevations of greater than 3×ULN were observed in POLARIS-1 in 2% of subjects treated with VOSEVI and 3% of subjects treated with placebo, and in POLARIS-4 in 2% of subjects treated with VOSEVI and less than 1% of subjects treated with sofosbuvir/velpatasvir.
Creatine Kinase: Isolated, asymptomatic creatine kinase elevations greater than or equal to 10×ULN were reported in POLARIS-1 in 1% of subjects treated with VOSEVI and 1% of subjects treated with placebo, and in POLARIS-4 in less than 1% of subjects treated with VOSEVI and no subjects treated with sofosbuvir/velpatasvir. Total bilirubin: Increases in total bilirubin less than or equal to 1.5×ULN were observed in subjects treated with VOSEVI due to inhibition of OATP1B1 and OATP1B3 by voxilaprevir: 4% and 6% of subjects without cirrhosis in POLARIS-1 and POLARIS-4, respectively; and 7% and 13% of subjects with compensated cirrhosis in POLARIS-1 and POLARIS-4, respectively. No subjects experienced jaundice and total bilirubin levels decreased after completing VOSEVI treatment.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of sofosbuvir-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders Hepatic decompensation, hepatic failure with NS3/4A protease inhibitor-containing regimens.
Cardiac Disorders Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a sofosbuvir-containing regimen. Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema
Warnings & Cautions for Vosevi
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with
HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with VOSEVI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VOSEVI and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease
Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including treatment with VOSEVI. Reported cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure.
VOSEVI is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation .
Serious Symptomatic Bradycardia
When Coadministered with Amiodarone Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (HARVONI ® (ledipasvir/sofosbuvir)). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with VOSEVI is not recommended.
For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered VOSEVI: Counsel patients about the risk of symptomatic bradycardia. Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking VOSEVI who need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above.
Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting VOSEVI should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems.
Risk of Reduced Therapeutic Effect Due to
Concomitant Use of VOSEVI with Inducers of P-gp and/or Moderate to Strong Inducers of CYP Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir, leading to potentially reduced therapeutic effect of VOSEVI. The use of these agents with VOSEVI is not recommended.
Drug Interactions with Vosevi
Potential for Other Drugs to Affect
VOSEVI Sofosbuvir, velpatasvir, and voxilaprevir are substrates of drug transporters P-gp and BCRP while GS-331007 (predominant circulating metabolite of sofosbuvir) is not. Voxilaprevir is also a substrate of OATP1B1 and OATP1B3. 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 strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St.
John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir leading to reduced therapeutic effect of VOSEVI. The use of these agents with VOSEVI is not recommended. VOSEVI may be coadministered with P-gp, BCRP, and CYP inhibitors. The use of OATP inhibitors which may substantially increase exposure of voxilaprevir (e.g., cyclosporine) with VOSEVI is not recommended.
Potential for
VOSEVI to Affect Other Drugs Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3. Velpatasvir is also an inhibitor of OATP2B1. Coadministration of VOSEVI with drugs that are substrates of these transporters may alter the exposure of such drugs. Coadministration of VOSEVI with BCRP substrates (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) is not recommended.
Established and Potentially Significant Drug Interactions Clearance of
HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.
Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 3 provides a listing of established or potentially clinically significant drug interactions.
The drug interactions described are based on studies conducted with either VOSEVI, the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir), or are predicted drug interactions that may occur with VOSEVI. Table 3 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase. Clinical Effect/Recommendation Acid Reducing Agents: ↓ velpatasvir Velpatasvir solubility decreases as pH increases.
Drugs that increase gastric pH are expected to decrease concentration of velpatasvir. Antacids (e.g., aluminum and magnesium hydroxide) Separate antacid and VOSEVI administration by 4 hours. H 2 -receptor antagonists (e.g., famotidine) These interactions have been studied in healthy adults.
H 2 -receptor antagonists may be administered simultaneously with or staggered from VOSEVI at a dose that does not exceed doses comparable with famotidine 40 mg twice daily. Proton-pump inhibitors (e.g., omeprazole) Omeprazole 20 mg can be administered with VOSEVI. Use with other proton pump-inhibitors has not been studied. Antiarrhythmics: amiodarone Effect on amiodarone, sofosbuvir, velpatasvir, and voxilaprevir concentrations unknown Coadministration of amiodarone with VOSEVI may result in serious symptomatic bradycardia.
The mechanism of this effect is unknown. Coadministration of amiodarone with VOSEVI is not recommended; if coadministration is required, cardiac monitoring is recommended. digoxin ↑ digoxin Therapeutic concentration monitoring of digoxin is recommended when coadministered with VOSEVI. Refer to digoxin prescribing information for monitoring and dose modification recommendations for concentration increases with unclear magnitude. Anticoagulants: dabigatran etexilate ↑ dabigatran Clinical monitoring of dabigatran is recommended when coadministered with VOSEVI. Refer to dabigatran etexilate prescribing information for dose modification recommendations in the setting of moderate renal impairment.
Anticonvulsants: carbamazepine phenytoin phenobarbital ↓ sofosbuvir ↓ velpatasvir ↓ voxilaprevir Coadministration is not recommended. Antimycobacterials: rifampin ↓ sofosbuvir ↓ velpatasvir ↑ voxilaprevir (single dose) ↓ voxilaprevir (multiple dose) Coadministration with rifampin is contraindicated. rifabutin rifapentine ↓ sofosbuvir ↓ velpatasvir ↓ voxilaprevir Coadministration is not recommended. Antiretrovirals: atazanavir lopinavir ↑ voxilaprevir Coadministration of VOSEVI with atazanavir- or lopinavir-containing regimens is not recommended. tipranavir/ritonavir ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended.
The effect on voxilaprevir is unknown. efavirenz ↓ velpatasvir ↓ voxilaprevir Coadministration of VOSEVI with efavirenz-containing regimens is not recommended. tenofovir disoproxil fumarate (tenofovir DF) ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving VOSEVI concomitantly with a regimen containing tenofovir DF. Refer to the prescribing information of the tenofovir DF-containing product for recommendations on renal monitoring. Herbal Supplements: St. John's wort ↓ sofosbuvir ↓ velpatasvir ↓ voxilaprevir Coadministration is not recommended.
HMG-CoA Reductase Inhibitors: pravastatin ↑ pravastatin Coadministration of VOSEVI with pravastatin has been shown to increase the concentration of pravastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Pravastatin may be administered with VOSEVI at a dose that does not exceed pravastatin 40 mg. rosuvastatin ↑ rosuvastatin Coadministration of VOSEVI with rosuvastatin may significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of VOSEVI with rosuvastatin is not recommended. pitavastatin ↑ pitavastatin Coadministration with VOSEVI may increase the concentration of pitavastatin and is not recommended, due to an increased risk of myopathy, including rhabdomyolysis. atorvastatin fluvastatin lovastatin simvastatin ↑ atorvastatin ↑ fluvastatin ↑ lovastatin ↑ simvastatin Coadministration with VOSEVI may increase the concentrations of atorvastatin, fluvastatin, lovastatin, and simvastatin.
Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Use the lowest approved statin dose. If higher doses are needed, use the lowest necessary statin dose based on a risk/benefit assessment.
Immunosuppressants: cyclosporine ↑ voxilaprevir Coadministration of voxilaprevir with cyclosporine has been shown to substantially increase the plasma concentration of voxilaprevir, the safety of which has not been established. Coadministration of VOSEVI with cyclosporine is not recommended.
Drugs without Clinically Significant Interactions with
VOSEVI Based on drug interaction studies conducted with the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir) or VOSEVI, no clinically significant drug interactions have been observed with the following drugs : VOSEVI: cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole Sofosbuvir/velpatasvir: dolutegravir, ketoconazole, raltegravir Sofosbuvir: methadone, tacrolimus
Pregnancy Safety for Vosevi
Pregnancy Risk Summary No adequate human data are available to establish whether or not VOSEVI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of VOSEVI (sofosbuvir, velpatasvir, or voxilaprevir) at exposures greater than those in humans at the recommended human dose (RHD) . During organogenesis in the mouse, rat, and rabbit, systemic exposures (AUC) of velpatasvir were approximately 23 (mice), 4 (rats), and 0.5 (rabbits) times the exposure in humans at the RHD, while exposures of voxilaprevir were approximately 141 (rats) and 4 (rabbits) times the exposure in humans at the RHD. Exposures of the predominant circulating metabolite of sofosbuvir (GS-331007) were approximately 6 (rats) and 16 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) for each component of VOSEVI were approximately 7 (sofosbuvir metabolite GS-331007), 3 (velpatasvir), and 238 (voxilaprevir) times the exposure in humans at the RHD. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) from gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of the predominant circulating metabolite of sofosbuvir (GS-331007) during gestation were approximately 6 (rats) and 16 (rabbits) times the exposure in humans at the RHD. Velpatasvir: Velpatasvir was administered orally to pregnant mice (up to 1000 mg/kg/day), rats (up to 200 mg/kg/day) and rabbits (up to 300 mg/kg/day) from gestation days 6 to 15, 6 to 17, and 7 to 20, respectively, and also to rats (oral doses up to 200 mg/kg) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (mice, rats, and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of velpatasvir during gestation were approximately 23 (mice), 4 (rats), and 0.5 (rabbits) times the exposure in humans at the RHD. Voxilaprevir: Voxilaprevir was administered orally to pregnant rats (up to 100 mg/kg/day) and rabbits (up to 600 mg/kg/day) from gestation days 6 to 17, and 7 to 19, respectively, and also to rats (oral doses up to 100 mg/kg) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested.
The systemic exposures (AUC) of voxilaprevir during gestation were approximately 141 (rats) and 4 (rabbits) times the exposure in humans at the RHD.
Pediatric Use of Vosevi
Pediatric Use Safety and effectiveness of VOSEVI have not been established in pediatric patients.
Contraindications for Vosevi
is contraindicated with rifampin. Coadministration with rifampin.
Overdosage Information for Vosevi
No specific antidote is available for overdose with VOSEVI. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with VOSEVI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of velpatasvir or voxilaprevir since velpatasvir and voxilaprevir are highly bound to plasma protein.
Clinical Studies of Vosevi
Description of Clinical Trials
The efficacy of VOSEVI was evaluated in two Phase 3 trials in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis, as summarized in Table 8. Table 8 Trials Conducted With VOSEVI in DAA-Experienced Subjects With HCV Infection Trial Population Study Arms and Comparator Groups (Number of Subjects Treated) DAA: direct-acting antiviral; SOF: sofosbuvir; VEL: velpatasvir POLARIS-1 Double-blind, placebo-controlled. (NCT02607735) Genotype 1, 2, 3, 4, 5, or 6 NS5A inhibitor-experienced In clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir., without cirrhosis or with compensated cirrhosis VOSEVI 12 weeks Placebo 12 weeks POLARIS-4 Open-label. (NCT02639247) Genotype 1, 2, 3, or 4 DAA-experienced In clinical trials, prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). who have not received an NS5A inhibitor, without cirrhosis or with compensated cirrhosis VOSEVI 12 weeks SOF/VEL 12 weeks Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in both trials. Relapse is defined as HCV RNA greater than or equal to LLOQ after end-of-treatment response among subjects who completed treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.
Clinical Trials in
HCV DAA-Experienced Subjects NS5A Inhibitor-Experienced Adults Without Cirrhosis or With Compensated Cirrhosis (POLARIS-1) POLARIS-1 was a randomized, double-blind, placebo-controlled trial that evaluated 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 without cirrhosis or with compensated cirrhosis who previously failed a regimen containing an NS5A inhibitor. Subjects with genotype 1 HCV infection were randomized 1:1 to each group. Subjects with genotype 2, 3, 4, 5, or 6 HCV infection were enrolled to the VOSEVI group.
Randomization was stratified by the presence or absence of cirrhosis. Demographics and baseline characteristics were generally balanced across treatment groups. Of the 415 treated subjects, the median age was 59 years (range: 27 to 84); 77% of the subjects were male; 81% were White; 14% were Black; 6% were Hispanic or Latino; 33% had a baseline body mass index at least 30 kg/m 2 ; the majority of subjects had genotype 1 (72%) or genotype 3 (19%) HCV infection; 82% had a non-CC IL28B genotype (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; and 41% had compensated cirrhosis.
In the POLARIS-1 trial, prior DAA regimens contained the following NS5A inhibitors: ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), and elbasvir (3%). Table 9 presents the SVR12 by HCV genotype for the POLARIS-1 trial. No subjects in the placebo group achieved SVR12. Table 9 POLARIS-1 Trial: Virologic Outcomes by HCV Genotype in VOSEVI-Treated Subjects Without Cirrhosis or With Compensated Cirrhosis (12 Weeks After Treatment) VOSEVI 12 Weeks (N=263) Total (all GTs) One subject with undetermined genotype achieved SVR12. (N=263) GT-1 GT-2 (N=5) GT-3 (N=78) GT-4 (N=22) GT-5 (N=1) GT-6 (N=6) GT-1a (N=101) GT-1b (N=45) Total Four subjects had GT-1 subtypes other than GT-1a or GT-1b; all 4 subjects achieved SVR12. (N=150) GT: genotype SVR12 96% (253/263) 96% (97/101) 100% (45/45) 97% (146/150) 100% (5/5) 95% (74/78) 91% (20/22) 100% (1/1) 100% (6/6) Outcome for Subjects without SVR On-Treatment Virologic Failure <1% (1/263) 1% (1/101) 0/45 1% (1/150) 0/5 0/78 0/22 0/1 0/6 Relapse The denominator for relapse is the number of subjects with HCV RNA Subjects with genotype 1, 2, or 3 HCV infection were randomized 1:1 to each group. Randomization was stratified by HCV genotype and by the presence or absence of cirrhosis. Subjects with genotype 4 HCV infection were enrolled to the VOSEVI group. No subjects with genotype 5 or 6 were enrolled. Demographics and baseline characteristics were generally balanced across treatment groups. Of the 333 treated subjects, the median age was 58 years (range: 24 to 85); 77% of the subjects were male; 87% were White, 9% were Black; 8% were Hispanic or Latino; 35% had a baseline body mass index at least 30 kg/m 2 ; 81% had non-CC IL28B genotypes (CT or TT); 75% had baseline HCV RNA levels at least 800,000 IU/mL; and 46% had compensated cirrhosis. In the POLARIS-4 trial, prior DAA regimens contained sofosbuvir (85%) with the following: peginterferon alfa and ribavirin or ribavirin (69%), HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir; 15%), and investigational DAA (<1%). Of the 15% of subjects without prior sofosbuvir exposure, most received investigational HCV DAAs or approved HCV NS3/4A protease inhibitors, with or without peginterferon alfa and ribavirin. Treatment with VOSEVI for 12 weeks resulted in numerically higher SVR12 rates than treatment with sofosbuvir/velpatasvir for 12 weeks in subjects with HCV genotype 1a and 3 infection. Comparable SVR12 rates were observed in subjects with HCV genotype 1b and 2 infection treated with VOSEVI for 12 weeks or with sofosbuvir/velpatasvir for 12 weeks. No comparison data are available for HCV genotypes 4, 5, and 6. Given these data, the additional benefit of VOSEVI has not been shown over sofosbuvir/velpatasvir for these genotypes and VOSEVI is only indicated for the treatment of HCV genotypes 1a or 3 infection in adults who previously received sofosbuvir without an NS5A inhibitor. Table 10 presents the comparative virologic outcome data for HCV genotype 1, 2, and 3 subjects with prior exposure to a sofosbuvir-containing regimen. Table 10 POLARIS-4 Trial: Virologic Outcomes by HCV Genotype in VOSEVI-Treated Subjects* and SOF/VEL-Treated Subjects* Without Cirrhosis or With Compensated Cirrhosis (12 Weeks After Treatment) *Subjects with prior exposure to a SOF-containing regimen VOSEVI 12 Weeks (N=139) SOF/VEL 12 Weeks (N=125) Overall (Genotypes 1, 2, and 3) SVR12 97% (135/139) 88% (110/125) Not achieving SVR12 On-treatment virologic failure 0% (0/139) 1% (1/125) Relapse The denominator for relapse is the number of subjects with HCV RNA All subjects achieved SVR12.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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