Vosevi Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ...................................................................................... 2

TABLE OF CONTENTS ........................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ............................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics (<18 years of age) ............................................................................. 4

1.2 Geriatrics (≥ 65 years of age) ............................................................................. 4

2 CONTRAINDICATIONS ................................................................................................ 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ...................................................... 5

4 DOSAGE AND ADMINISTRATION .............................................................................. 5

4.1 Dosing Considerations ....................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment ................................................... 5

4.5 Missed Dose ...................................................................................................... 6

5 OVERDOSAGE ............................................................................................................. 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ....................... 7

7 WARNINGS AND PRECAUTIONS ............................................................................... 7

7.1 Special Populations ......................................................................................... 10

7.1.1 Pregnant Women ............................................................................................. 10

7.1.2 Breast-feeding ................................................................................................. 10

7.1.3 Pediatrics (< 18 years of age) .......................................................................... 10

7.1.4 Geriatrics (≥ 65 years of age) ........................................................................... 10

7.1.5 Others .............................................................................................................. 10

8 ADVERSE REACTIONS ............................................................................................. 11

8.1 Adverse Reaction Overview ............................................................................. 11

8.2 Clinical Trial Adverse Reactions ....................................................................... 11

8.3 Less Common Clinical Trial Adverse Reactions ............................................... 12

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ......................................................................................................... 13

8.5 Post-Market Adverse Reactions ....................................................................... 14

9 DRUG INTERACTIONS .............................................................................................. 14

9.2 Drug Interactions Overview .............................................................................. 14

9.3 Drug-Behavioural Interactions .......................................................................... 14

9.4 Drug-Drug Interactions ..................................................................................... 14

9.5 Drug-Food Interactions .................................................................................... 28

9.6 Drug-Herb Interactions ..................................................................................... 28

9.7 Drug-Laboratory Test Interactions .................................................................... 29

10 CLINICAL PHARMACOLOGY .................................................................................... 29

10.1 Mechanism of Action ........................................................................................ 29

10.2 Pharmacodynamics ......................................................................................... 29

10.3 Pharmacokinetics ............................................................................................. 30

11 STORAGE, STABILITY AND DISPOSAL ................................................................... 34

12 SPECIAL HANDLING INSTRUCTIONS ...................................................................... 34

PART II: SCIENTIFIC INFORMATION ................................................................................... 35

13 PHARMACEUTICAL INFORMATION ......................................................................... 35

14 CLINICAL TRIALS ...................................................................................................... 37

14.1 Trial Design and Study Demographics ............................................................. 37

14.2 Study Results ................................................................................................... 41

15 MICROBIOLOGY ........................................................................................................ 44

16 NON-CLINICAL TOXICOLOGY .................................................................................. 49

17 SUPPORTING PRODUCT MONOGRAPHS ............................................................... 51

PATIENT MEDICATION INFORMATION ............................................................................... 52

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

VOSEVI (sofosbuvir/velpatasvir/voxilaprevir) is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adult patients, without cirrhosis or with compensated cirrhosis, 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 1, 2, 3, or 4 infection and have been previously treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor.

1.1 Pediatrics (<18 years of age)

Safety and effectiveness in pediatric patients have not been established. Therefore, Health Canada has not authorized an indication for pediatric use in patients less than 18 years of age.

1.2 Geriatrics (≥ 65 years of age)

The response rates observed for patients 65 years of age and over were similar to those of younger patients across treatment groups. VOSEVI can be administered in geriatric patients (see 10 CLINICAL PHARMACOLOGY and 14 CLINICAL TRIALS).

2 CONTRAINDICATIONS

VOSEVI is contraindicated in patients with known hypersensitivity to any of the components of the product. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Table 1 lists drugs which are contraindicated with VOSEVI (see 9 DRUG INTERACTIONS).

Table 1. Drugs that are Contraindicated with VOSEVI

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• VOSEVI should be taken with food
• Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with VOSEVI

4.2 Recommended Dose and Dosage Adjustment

VOSEVI is a single tablet regimen. No dosage adjustments are possible for VOSEVI.

The recommended dose of VOSEVI is one tablet of 400 mg/100 mg/100 mg sofosbuvir/velpatasvir/voxilaprevir, taken orally, once daily with food (see 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Effects of Food).

The recommended treatment duration for VOSEVI is provided in Table 2.

Table 2. Recommended Treatment Regimen

a. In clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir.

b. 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).

Special Populations

Pediatrics (< 18 Years of age)

VOSEVI is not indicated for use in pediatric patients less than 18 years of age.

Geriatrics (≥ 65 years of age)

No dose adjustment is warranted for elderly patients (see 10 CLINICAL PHARMACOLOGY).

Hepatic Impairment

VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). No dose adjustment of VOSEVI is required for patients with mild hepatic impairment (Child-Pugh A) (see 10 CLINICAL PHARMACOLOGY).

Renal Impairment

No dose adjustment of VOSEVI is required for patients with any stage of renal impairment, including end-stage renal disease (ESRD) requiring dialysis based on extrapolation of relevant clinical data (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).

4.5 Missed Dose

If a patient misses a dose of VOSEVI within 18 hours of the time it is usually taken, the patient should take VOSEVI as soon as possible, and then take the next dose of VOSEVI at the regularly scheduled time.

If a patient misses a dose of VOSEVI and it is after 18 hours of the time it is usually taken, the patient should not take the missed dose, but resume the usual dosing schedule. A double dose of VOSEVI must not be taken.

If a patient vomits less than 4 hours after taking a dose of VOSEVI, the patient should take another dose of VOSEVI. If a patient vomits more than 4 hours after taking a dose of VOSEVI, the patient should take the next dose at the regularly scheduled time.

5 OVERDOSAGE

Administration of activated charcoal may be used to aid in the removal of unabsorbed active substance. General supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient are recommended.

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.

The highest documented doses of sofosbuvir, velpatasvir, and voxilaprevir were single doses of 1200 mg, 500 mg, and 900 mg, respectively. In healthy volunteer studies with sofosbuvir and velpatasvir, there were no untoward effects observed at these dose levels, and adverse events were similar in frequency and severity to those reported in the placebo groups. The most common adverse events in subjects receiving voxilaprevir 900 mg were diarrhea (34%), vomiting (19%), and nausea (17%). The effects of higher doses/exposures are not known.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 3. Dosage Forms, Strengths, Composition and Packaging

VOSEVI is a single tablet regimen containing sofosbuvir, velpatasvir, and voxilaprevir for oral administration.

VOSEVI is available as a beige-colored, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “ 3 ” on the other side of the tablet. Each bottle contains 28 tablets, a polyester coil and silica gel desiccant and is closed with a child-resistant closure.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Treatment with VOSEVI should be initiated and monitored by a physician experienced in the management of chronic HCV infection.

Data to support the treatment of patients infected with HCV genotype 5 or genotype 6 who have failed prior therapy of an HCV regimen containing an NS5A inhibitor are limited. The indication for treatment of these patients is based on extrapolation of relevant clinical and in vitro data (see 14 CLINICAL TRIALS and 15 MICROBIOLOGY).

No clinical data are available to support the treatment of HCV patients with genotype 5 or genotype 6 infection who have failed prior therapy of an HCV regimen containing sofosbuvir without an NS5A inhibitor (see 14 CLINICAL TRIALS).

VOSEVI should not be administered concurrently with other medicinal products containing sofosbuvir.

Use with P-gp Inducers and/or Moderate to Strong Inducers of CYP

Medicinal products that are inducers of P-glycoprotein (P-gp) and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 [eg, St. John’s wort (Hypericum perforatum) and carbamazepine] may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, or voxilaprevir leading to reduced therapeutic effect of VOSEVI and potential loss of virologic response. These agents should not be used with VOSEVI (see 9 DRUG INTERACTIONS).

Cardiovascular

Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with daclatasvir or simeprevir. 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 (see 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions, and 9 DRUG INTERACTIONS).

Gastrointestinal

VOSEVI contains lactose. This medicine is not recommended for patients with rare hereditary problems of galactose intolerance (severe lactase deficiency or glucose-galactose malabsorption).

Hepatic/Biliary/Pancreatic

VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to significant increases in the exposures of voxilaprevir in these patients (AUC ↑ 299% and 500% in HCV-negative patients with moderate and severe hepatic impairment, respectively); the safety and efficacy of VOSEVI have not been established in HCV-infected patients with moderate or severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Hepatic Decompensation and Hepatic Failure

VOSEVI is not recommended in patients with moderate or severe hepatic impairment. There have been post-marketing case reports of hepatic decompensation and hepatic failure, including fatal outcomes, mostly in cirrhotic patients treated with HCV NS3/4A protease inhibitor-containing regimens, including VOSEVI. 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.

Monitoring and Laboratory Tests

If VOSEVI is administered with amiodarone, close monitoring for bradycardia is recommended (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular). Refer to the amiodarone Product Monograph.

Clearance of HCV may lead to increased replication of HBV in patients who are co-infected with HCV and HBV. Co-infected patients should be monitored for clinical and laboratory signs (eg, HBsAg, anti-HBc, HBV DNA, serum aminotransferase levels, bilirubin) for hepatitis flare or HBV reactivation during and at post-treatment follow-up as clinically appropriate (see 7 WARNINGS AND PRECAUTIONS, Potential for HBV Reactivation).

As liver function may improve during treatment with VOSEVI, monitoring of certain laboratory parameters and/or concomitant medications may be required. For guidance see 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Other Forms of Interactions.

Potential for HBV Reactivation

Cases of HBV reactivation, including those resulting in fulminant hepatitis, hepatic failure, and death have been reported in HCV/HBV co-infected patients who were undergoing, or completed treatment with DAAs. To decrease the risk of HBV reactivation in patients co-infected with HBV, HBV screening should be performed in all patients prior to initiation of HCV treatment. Patients with positive HBV serology (HBsAg positive) and patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) should be monitored and treated according to current clinical practice guidelines to manage potential HBV reactivation (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Renal

Support for safety and efficacy of VOSEVI in patients with severe renal impairment and ESRD requiring dialysis is derived from an open-label trial of 59 patients who received sofosbuvir/velpatasvir 400/100 mg once daily for 12 weeks. Voxilaprevir has not been studied in this patient population. VOSEVI should be used in this patient population only if no suitable alternative is justified. Close monitoring for adverse events is recommended.

Reproductive Health: Female and Male Potential

• Fertility

There are no data on the effect of sofosbuvir, velpatasvir, or voxilaprevir on human fertility. No effects on fertility were observed in animal studies for sofosbuvir, velpatasvir or voxilaprevir (see 16 NON-CLINICAL TOXICOLOGY).

7.1 Special Populations

7.1.1 Pregnant Women

Pregnancy should be avoided while taking VOSEVI as there are no data on the use of VOSEVI in pregnant women. VOSEVI should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Patients should be advised to notify their healthcare provider immediately in the event of a pregnancy.

No effects on pre- or post-natal development were observed in animal reproduction studies at the highest doses of sofosbuvir tested. In the rat and rabbit embryo fetal studies, and the rat pre/post-natal study, exposure to the predominant circulating metabolite GS-331007 at the highest dose was approximately 6-fold, 16-fold, and 7-fold the exposure in humans at the recommended clinical dose, respectively.

No effects on pre- or post-natal development have been observed in animal reproduction studies at the highest doses of velpatasvir tested. In the mouse, rat, and rabbit embryo fetal studies, and rat pre/post-natal study velpatasvir exposure was approximately 23-fold, 4-fold, 0.5-fold, and 3-fold the exposure in humans at the recommended clinical dose, respectively.

No effects on pre- or post-natal development have been observed in animal reproduction studies at the highest doses of voxilaprevir tested. In the rat and rabbit embryo fetal studies, and rat pre/post-natal study voxilaprevir exposure was approximately 141-fold, 4-fold, and 238-fold the exposure in humans at the recommended clinical dose, respectively.

7.1.2 Breast-feeding

It is not known whether sofosbuvir, metabolites of sofosbuvir, velpatasvir, or voxilaprevir are excreted in human breast milk. The sofosbuvir predominant circulating metabolite GS-331007 and velpatasvir are present in the milk of lactating rats; they had no clear effect on nursing pups. When administered to lactating rats, voxilaprevir was detected in the plasma of nursing pups. Because a risk to the newborn/infant cannot be excluded, mothers should be instructed not to breast-feed if they are taking VOSEVI.

7.1.3 Pediatrics (< 18 years of age)

The safety and efficacy of VOSEVI in pediatric patients have not been established. Therefore, Health Canada has not authorized an indication for pediatric use in patients less than 18 years of age.

7.1.4 Geriatrics (≥ 65 years of age)

The response rates observed for patients 65 years of age and over were similar to those of patients < 65 years of age across treatment groups.

7.1.5 Others

Pre- and Post-Liver Transplant Patients

The safety and efficacy of VOSEVI have not been established in patients awaiting liver transplantation or in patients with recurrent HCV infection post-liver transplant.

HCV/HIV Co-infection

The safety and efficacy of VOSEVI have not been established in HCV patients co-infected with Human Immunodeficiency Virus (HIV).

VOSEVI has been shown to increase tenofovir exposure when used together with an HIV regimen containing tenofovir disoproxil fumarate (tenofovir DF). Patients receiving VOSEVI concomitantly with tenofovir DF, particularly those at increased risk for renal dysfunction, should be monitored for tenofovir-associated adverse reactions. Refer to Product Monographs for tenofovir DF-containing products for recommendations on renal monitoring.

Efavirenz has been shown to significantly decrease the concentration of velpatasvir and is expected to decrease the concentration of voxilaprevir; therefore coadministration of VOSEVI with an efavirenz-containing regimen is not recommended (see 9 DRUG INTERACTIONS).

HCV/HBV Co-infection

The safety and efficacy of VOSEVI have not been established in HCV patients co-infected with HBV. HBV reactivation has been reported during treatment and post-treatment with DAAs in patients co-infected with HBV who were not undergoing treatment for HBV infection (see 7 WARNINGS AND PRECAUTIONS, Potential for HBV Reactivation).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The overall safety profile of VOSEVI was established in patients infected with HCV, without cirrhosis or with compensated cirrhosis.

Adverse reactions data for VOSEVI were derived from two Phase 3 clinical trials (POLARIS-1 and POLARIS-4) that evaluated a total of 445 patients with chronic HCV infection, without cirrhosis or with compensated cirrhosis, who received VOSEVI for 12 weeks (see 14 CLINICAL TRIALS).

The proportion of patients who permanently discontinued treatment due to adverse events was 0.2% for patients receiving VOSEVI for 12 weeks. Of the 445 patients, 2% had at least one serious adverse event (SAE), with no patients experiencing a treatment-related SAE.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adverse reactions (adverse events assessed as causally related by the investigator), all grades, observed in ≥ 10% of patients receiving 12 weeks of treatment with VOSEVI in clinical trials include headache (22%), fatigue (18%), diarrhea (13%), and nausea (12%). Of patients receiving VOSEVI who experienced these adverse reactions, 76% of patients had an adverse reaction of mild (Grade 1) severity.

The adverse reactions (Grades 2 to 4) observed in ≥ 1% of patients receiving 12 weeks of treatment with VOSEVI in clinical trials are listed in Table 4.

Table 4. Adverse Reactions (Grades 2-4) Reported in ≥ 1% of Patients Receiving 12 Weeks of VOSEVI^a from the Phase 3 Studies (POLARIS-1, POLARIS-4)

• a. Frequencies of adverse reactions are based on treatment-emergent adverse events, considered related to study drug by site investigators.

8.3 Less Common Clinical Trial Adverse Reactions

Adverse reactions (Grades 2 to 4) occurring in less than 1% of patients receiving 12 weeks of treatment with VOSEVI in clinical trials are listed below in Table 5 by body system.

Table 5. Adverse Reactions (Grades 2-4) Reported in < 1% of Patients Receiving 12 Weeks of VOSEVI^a from the Pooled Phase 3 Studies (POLARIS-1, POLARIS-4)

• a. Frequencies of adverse reactions are based on treatment-emergent adverse events, considered related to study drug by site investigators.

For information on the safety profile of sofosbuvir in combination with velpatasvir, consult the EPCLUSA^® Product Monograph.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

The frequency of treatment-emergent laboratory abnormalities (Grades 2 to 4) occurring in at least 1% of patients receiving 12 weeks of treatment with VOSEVI are described in Table 6.

Table 6. Laboratory Abnormalities (Grades 2-4) Reported in ≥ 1% of Patients Receiving 12 Weeks of VOSEVI from the Phase 3 Studies (POLARIS-1, POLARIS-4)

ULN = Upper Limit of Normal

Total bilirubin

In the Phase 3 trials, increases in total bilirubin less than or equal to 1.5 × ULN were observed in 4% of patients without cirrhosis and 10% of patients with compensated cirrhosis, due to inhibition of OATP1B1 and OATP1B3 by voxilaprevir. Total bilirubin levels decreased after completing VOSEVI treatment. No patients experienced jaundice.

8.5 Post-Market Adverse Reactions

In addition to adverse reactions from clinical studies, the following adverse reactions have been identified during post-approval use of sofosbuvir-containing regimens. Because post-marketing 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.

Cardiac Disorders

Serious symptomatic bradycardia when amiodarone is coadministered with sofosbuvir in combination with another HCV DAA (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 9 DRUG INTERACTIONS).

Hepatobiliary Disorders

Hepatic decompensation, hepatic failure

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson Syndrome, skin rashes (sometimes with blisters or angioedema-like swelling) and angioedema.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

As VOSEVI contains sofosbuvir, velpatasvir, and voxilaprevir, any interactions that have been identified with these agents individually may occur with VOSEVI.

After oral administration of VOSEVI, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the primary circulating metabolite GS-331007 (dephosphorylated nucleotide metabolite) were monitored for purposes of pharmacokinetic analyses.

9.3 Drug-Behavioural Interactions

Interactions of VOSEVI with individual behavioural risks have not been established.

9.4 Drug-Drug Interactions

Potential for VOSEVI to Affect Other Drugs

Sofosbuvir and GS-331007 are not relevant inhibitors of efflux drug transporters P-gp, breast cancer resistance protein (BCRP), renal efflux transporter MRP2, hepatic efflux transporter BSEP, hepatic uptake transporters OATP1B1, OATP1B3, OCT1, and GS-331007 is not an inhibitor of renal uptake transporters OAT1, OCT2 and renal efflux transporter MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.

Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.

Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. Coadministration of VOSEVI with drugs that are substrates of these transporters may alter the exposure of such drugs. At clinically relevant concentrations, voxilaprevir is not an inhibitor of hepatic transporter OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.

Potential for Other Drugs to Affect VOSEVI

Sofosbuvir, velpatasvir, and voxilaprevir are substrates of efflux drug transporters P-gp and BCRP while GS-331007 is not. GS-331007 is not a substrate for renal transporters including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2. Voxilaprevir, and to a lesser extent velpatasvir, are also substrates of OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir primarily by CYP2B6, CYP2C8, and CYP3A4 and of voxilaprevir primarily by CYP3A4 was observed.

Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (eg, St. John’s wort or carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir leading to reduced therapeutic effect of VOSEVI. Coadministration of VOSEVI with phenobarbital, phenytoin, rifampin and St. John’s wort are contraindicated and coadministration with carbamazepine is not recommended (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS).

Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations without increasing GS-331007 plasma concentration. Coadministration with drugs that inhibit OATP may increase voxilaprevir plasma concentrations. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir and/or voxilaprevir. VOSEVI may be coadministered with P-gp, BCRP, and CYP inhibitors. The use of strong inhibitors of OATP with VOSEVI is not recommended.

Table 7 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 voxilaprevir) as individual agents, or are predicted drug interactions that may occur with VOSEVI. The table is not all-inclusive (see 10 CLINICAL PHARMACOLOGY).

Table 7. Established and Other Potentially Significant^a Drug Interactions

a. This table is not all inclusive.

b. ↑ = increase, ↓ = decrease, ↔ = no effect.

c. These interactions have been studied in healthy adults.

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 either observed or are expected when VOSEVI is combined with the following drugs: cobicistat, darunavir, dolutegravir, elvitegravir, emtricitabine, gemfibrozil, ketoconazole, methadone, raltegravir, rilpivirine, ritonavir, tacrolimus (see 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Other Forms of Interactions), tenofovir alafenamide, or voriconazole (see 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Assessment of Drug Interactions).

Other Forms of Interactions

As liver function may improve due to treatment of HCV with DAAs, it is recommended to closely monitor:

• the International Normalized Ratio (INR) in patients taking vitamin K antagonists,
• blood glucose levels in diabetic patients,
• immunosuppressive drug levels (eg, calcineurin inhibitor tacrolimus) in patients receiving immunosuppressive therapy,
• other relevant laboratory parameters in susceptible patients and/or other concomitant medications significantly affected by changes in hepatic function.

The dose of vitamin K antagonists, anti-diabetic agents, immunosuppressive agents, or other concomitant medications significantly affected by changes in hepatic function should be modified when necessary.

Assessment of Drug Interactions

The effects of coadministered drugs on the exposure of sofosbuvir, GS-331007, velpatasvir, and voxilaprevir are shown in Table 8. The effects of sofosbuvir, velpatasvir, voxilaprevir, sofosbuvir/velpatasvir, or VOSEVI on the exposure of coadministered drugs are shown in Table 9.

Table 8. Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir and the Predominant Circulating Metabolite GS-331007, Velpatasvir, and Voxilaprevir in the Presence of the Coadministered Drug^a

NA = not available/not applicable

a. All interaction studies conducted in healthy volunteers.

b. Administered as ATRIPLA^® (efavirenz/emtricitabine/tenofovir DF fixed-dose combination).

c. Administered as GENVOYA^® (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose single tablet regimen).

d. Administered as ODEFSEY™ (emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose single tablet regimen).

Table 9. Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvir, Velpatasvir, Voxilaprevir, or VOSEVI^a

NA = not available/not applicable

a. All interaction studies conducted in healthy volunteers.

b. Comparison based on exposures when administered as darunavir + ritonavir + emtricitabine/tenofovir DF.

c. Administered as ATRIPLA (efavirenz/emtricitabine/tenofovir DF fixed-dose combination).

d. Administered as GENVOYA (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose single tablet regimen).

e. Administered as ODEFSEY (emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose single tablet regimen).

9.5 Drug-Food Interactions

VOSEVI should be taken with food. Food increases the bioavailability of VOSEVI (see 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dose and Dosage Adjustment and 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics).

9.6 Drug-Herb Interactions

Coadministration of VOSEVI with St. John’s wort is contraindicated.

Coadministration of St. John’s wort, a P-gp and a strong CYP inducer, may decrease sofosbuvir, velpatasvir, and voxilaprevir plasma concentrations, which may result in loss of therapeutic effect. See 7 WARNINGS AND PRECAUTIONS, General, Use with P-gp

Inducers and/or Moderate to Strong Inducers of CYP and 2 CONTRAINDICATIONS.

9.7 Drug-Laboratory Test Interactions

Interactions of VOSEVI with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

VOSEVI

VOSEVI is a pan-genotypic single tablet regimen of sofosbuvir, velpatasvir, and voxilaprevir.

Sofosbuvir is a nucleotide analog pan-genotypic NS5B polymerase inhibitor. Velpatasvir is a pan-genotypic HCV NS5A inhibitor. Voxilaprevir is a pan-genotypic inhibitor of the NS3/4A protease.

Sofosbuvir, velpatasvir and voxilaprevir exhibit high potency and specificity as individual agents against HCV as compounds that target the HCV NS5B, NS5A, and NS3/4A proteins, respectively. Sofosbuvir, velpatasvir, and voxilaprevir individually displayed potent and broad inhibitory activity against HCV genotypes 1-6. In vitro combination of sofosbuvir and velpatasvir, sofosbuvir and voxilaprevir, or velpatasvir and voxilaprevir exhibited an additive antiviral interaction. No antiviral antagonism or exacerbated cellular toxicity was observed in either of the 2-drug combinations.

Sofosbuvir

Sofosbuvir is a pan-genotypic polymerase inhibitor of the HCV NS5B RNA-dependent RNA polymerase. Sofosbuvir is a monophosphorylated pyrimidine nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203).

Velpatasvir

Velpatasvir is a pan-genotypic HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. In vitro resistance selection and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.

Voxilaprevir

Voxilaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease. Voxilaprevir acts as a noncovalent, reversible inhibitor of the NS3/4A protease.

10.2 Pharmacodynamics

Effect on Electrocardiogram

Administration of supratherapeutic doses of sofosbuvir (1200 mg), velpatasvir (500 mg), or voxilaprevir (900 mg) (as individual drugs) demonstrated a lack of effect on QTc interval.

10.3 Pharmacokinetics

Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a less than proportional manner from 50 to 450 mg, indicating velpatasvir absorption is solubility limited. Voxilaprevir (studied under fed conditions) AUC increases in a greater than proportional manner over the dose range of 100 to 900 mg.

The pharmacokinetic properties of the components of VOSEVI are provided in Table 10. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite, GS-331007, velpatasvir, and voxilaprevir are provided in Table 11.

Table 10. Pharmacokinetic Properties of the Components of VOSEVI

CES1 = carboxylesterase 1; HINT1 = histidine triad nucleotide-binding protein 1.

a. Values refer to % increase in geometric mean exposures.

b. Single dose concomitant administration of sofosbuvir/velpatasvir 400 mg/100 mg fixed-dose combination tablet + voxilaprevir 100 mg tablet.

c. Single dose administration of VOSEVI.

d. GS-331007 is the primary circulating nucleotide metabolite of SOF.

e. t_1/2 values refer to median terminal plasma half-life.

f. Single dose administration of [¹⁴C] SOF, [¹⁴C] VEL, [¹⁴C] VOX in mass balance studies.

g. Predominantly as GS-331007.

Table 11. Multiple Dose Pharmacokinetic Parameters of Sofosbuvir and its Metabolite, GS-331007, Velpatasvir, and Voxilaprevir Following Oral Administration in HCV-Infected Adults

CV = Coefficient of Variation; NA = Not Applicable.

a. From Population PK analysis, N = 1038.

b. From Population PK analysis, N = 1593.

c. From Population PK analysis, N = 1595.

d. From Population PK analysis, N = 1591.

Sofosbuvir and GS-331007 AUC_0-24 and C_max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects, velpatasvir AUC_0-24 and C_max were 41% lower and 39% lower, respectively, in HCV-infected patients. Relative to healthy subjects, voxilaprevir AUC_0-24 and C_max were both 260% higher in HCV-infected patients. Age, sex, race, BMI, or the presence or absence of cirrhosis had no clinically relevant effects on the exposure of sofosbuvir, GS-331007, velpatasvir, or voxilaprevir.

Absorption:

Following oral administration of VOSEVI, sofosbuvir median peak plasma concentration was observed 2 hours post-dose. Median peak plasma concentration of GS-331007, velpatasvir, and voxilaprevir were observed 4 hours post-dose.

Effects of Food

The bioavailability of sofosbuvir, velpatasvir and voxilaprevir increased following single dose administration of VOSEVI with a high fat, high calorie meal or concomitant administration of a sofosbuvir/velpatasvir fixed dose combination tablet + voxilaprevir tablet with a low fat, low calorie or a moderate fat, moderate calorie meal (Table 10).

Distribution:

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [¹⁴C]-sofosbuvir in healthy subjects, the blood to plasma ratio of [¹⁴C]-radioactivity was approximately 0.7.

Velpatasvir is > 99% bound to human plasma proteins and binding is independent of drug concentration over the range of 0.09 μg/mL to 1.8 μg/mL. After a single 100 mg dose of [¹⁴C]-velpatasvir in healthy subjects, the blood to plasma ratio of [¹⁴C]-radioactivity ranged between 0.5 and 0.7.

Voxilaprevir is approximately > 99% bound to human plasma proteins. After a single 100 mg dose of [¹⁴C]-voxilaprevir in healthy male subjects, the blood to plasma ratio of [¹⁴C]-radioactivity ranged between 0.5 and 0.8.

Metabolism:

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate, GS-461203. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [¹⁴C]-sofosbuvir, GS-331007 accounted for greater than 90% of total systemic exposure.

Velpatasvir is primarily a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. Following a single dose of 100 mg [¹⁴C]-velpatasvir to healthy human male subjects, the majority (> 98%) of radioactivity in plasma was the parent drug. Unchanged velpatasvir is the major species present in feces.

Voxilaprevir is primarily a substrate of CYP3A4 with slow turnover. Following a single dose of 100 mg [¹⁴C]-voxilaprevir, the majority (approximately 91%) of radioactivity in plasma was parent drug. Unchanged voxilaprevir is the major species present in feces.

Elimination:

Sofosbuvir is primarily eliminated in the urine as GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of VOSEVI were 0.5 and 29 hours, respectively.

Biliary excretion of parent drug was the major route of elimination for velpatasvir. The median terminal half-life of velpatasvir following administration of VOSEVI was approximately 17 hours.

Biliary excretion of parent drug was the major route of elimination for voxilaprevir. The median terminal half-life of voxilaprevir following administration of VOSEVI was approximately 33 hours.

Special Populations and Conditions

• Pediatrics (< 18 years of age)

  The pharmacokinetics of VOSEVI in pediatric patients have not been established.

• Geriatrics (≥ 65 years of age)

  Based on population pharmacokinetic analyses, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, velpatasvir, or voxilaprevir. Clinical trials of VOSEVI included 74 patients aged 65 and over (17% of the total number of patients in the POLARIS-1 and POLARIS-4 Phase 3 clinical trials). The response rates observed for patients ≥ 65 years of age were similar to those of patients < 65 years of age, across treatment groups.

• Sex

  No clinically relevant pharmacokinetic differences due to gender have been identified for sofosbuvir, GS-331007, velpatasvir, or voxilaprevir.

• Ethnic Origin

  No clinically relevant pharmacokinetic differences due to race have been identified for sofosbuvir, GS-331007, velpatasvir, or voxilaprevir.

• Hepatic Insufficiency

  Hepatic impairment studies were conducted with the individual drugs, sofosbuvir, velpatasvir, and voxilaprevir. The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected patients with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC_0-24 was 126% and 143% higher in moderate and severe hepatic impairment, respectively, while the GS-331007 AUC_0-24 was 18% and 9% higher, respectively. Mild hepatic impairment is not expected to meaningfully alter the pharmacokinetics of sofosbuvir and GS-331007. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Velpatasvir plasma exposure (AUC_inf) was similar in subjects with moderate hepatic impairment, severe hepatic impairment, and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of velpatasvir.

  The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the voxilaprevir AUC_inf was 299% and 500% higher in subjects with moderate and severe hepatic impairment, respectively. Population pharmacokinetic analysis in HCV-infected patients indicated that patients with cirrhosis (Child-Pugh A) had 73% higher exposure of voxilaprevir than those without cirrhosis.

• Renal Insufficiency

  Renal impairment studies have been conducted with the individual drugs, sofosbuvir, velpatasvir, and voxilaprevir.

  The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥ 50 and < 80 mL/min/1.73m²), moderate (eGFR ≥ 30 and < 50 mL/min/1.73m²), severe renal impairment (eGFR < 30 mL/min/1.73m²) and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR > 80 mL/min/1.73m²), the sofosbuvir AUC_inf was 61%,

  107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC_inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, sofosbuvir AUC_inf was 28% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% higher when dosed 1 hour after hemodialysis. The AUC_inf of GS-331007 in subjects with ESRD administered sofosbuvir 1 hour before or 1 hour after hemodialysis was at least 10-fold and 20-fold higher, respectively, compared to normal subjects. Hemodialysis can efficiently remove (53% extraction ratio) the predominant circulating metabolite GS-331007. Following a single 400 mg dose of sofosbuvir, a 4-hour hemodialysis session removed approximately 18% of administered dose. Exposure of velpatasvir is not significantly impacted in the setting of severe renal impairment. The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV negative subjects with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). Velpatasvir AUC and C_max were approximately 50% and 11% higher, respectively, in subjects with severe renal impairment compared to control subjects with normal renal function; these differences are not considered clinically relevant.

  Additionally, the pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV negative subjects with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). Voxilaprevir AUC and C_max were approximately 71% and 45% higher, respectively, in subjects with severe renal impairment compared to control subjects with normal renal function; these differences are not considered clinically significant. The pharmacokinetics of voxilaprevir have not been studied in patients with ESRD. Voxilaprevir is not renally eliminated. Therefore, voxilaprevir exposure following administration of VOSEVI is not expected to be meaningfully altered in HCV-infected patients with ESRD requiring dialysis compared to patients with normal renal function. No dose adjustment of VOSEVI is required for patients with any stage of renal impairment, including ESRD requiring dialysis.

  The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected subjects with ESRD requiring dialysis treated with once daily sofosbuvir/velpatasvir 400/100 mg for 12 weeks. Steady-state AUC_tau of sofosbuvir, GS-331007, and velpatasvir were increased by 81%, 1719%, and 41%, respectively, compared to patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 trials.

11 STORAGE, STABILITY AND DISPOSAL

Store below 30°C (86°F).

• Dispense only in original container.
• Do not use if seal over bottle opening is broken or missing.

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

The efficacy of VOSEVI was evaluated in two Phase 3 trials with data available for a total of 445 DAA-experienced patients with genotype 1 to 6 HCV infection without cirrhosis or with compensated cirrhosis.

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 to determine the HCV cure rate. Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a LLOQ of 15 IU per mL.

NS5A Inhibitor-Experienced Adults (POLARIS-1)

Trial Design

The trial design of POLARIS-1 is described in Table 12. Patients with genotype 1 HCV infection were randomized 1:1 to each group. Randomization was stratified by the presence or absence of cirrhosis. Patients with all other HCV genotypes were enrolled into the VOSEVI 12-week group.

Table 12. Summary of Trial Design in NS5A Inhibitor-Experienced Patients with Genotypes 1, 2, 3, 4, 5, 6 HCV Infection Without Cirrhosis or with Compensated Cirrhosis (POLARIS-1)

PO = orally; QD = once a day

Demographics and Other Baseline Characteristics

The demographics and baseline characteristics for the patients in study POLARIS-1 were generally balanced across the treatment groups and are summarized in Table 13. 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 13. Demographic and Other Baseline Characteristics of NS5A Inhibitor-Experienced Patients with Genotypes 1, 2, 3, 4, 5, 6 HCV Infection Without Cirrhosis or with Compensated Cirrhosis (POLARIS-1)

DAA = direct acting antiviral; SD = standard deviation *Total percentage may not add to 100% due to rounding.

DAA-Experienced Adults Who Had Not Received an NS5A Inhibitor (POLARIS-4)

Trial Design

The trial design of POLARIS-4 is described in Table 14. Patients 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. Patients with genotype 4 HCV infection were enrolled to the VOSEVI 12-week group. Patients whose only DAA exposure was a NS3/4A protease inhibitor were excluded.

Table 14. Summary of Trial Design in DAA-Experienced Patients with Genotype 1, 2, 3, or 4 HCV Infection Without Cirrhosis or With Compensated Cirrhosis who had Not Received an NS5A Inhibitor (POLARIS-4)

PO = orally; QD = once a day; SOF = sofosbuvir; VEL = velpatasvir

Demographic and Baseline Characteristics

The demographics and baseline characteristics for the patients in study POLARIS-4 were balanced across the treatment groups and are summarized in Table 15. 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.

Table 15. Demographic and Other Baseline Characteristics of DAA-Experienced Patients with Genotype 1, 2, 3, or 4 HCV Infection Without Cirrhosis or With Compensated Cirrhosis who had Not Received an NS5A Inhibitor (POLARIS-4)

SD = standard deviation; SOF = sofosbuvir; VEL = velpatasvir *Total percentage may not add to 100% due to rounding.

14.2 Study Results

NS5A Inhibitor-Experienced Adults (POLARIS-1)

The response rates for the VOSEVI treatment group by HCV genotype in the POLARIS-1 trial are presented in Table 16. Overall, the SVR12 in NS5A inhibitor-experienced patients with genotypes 1, 2, 3, 4, 5, 6 HCV infection with compensated cirrhosis or without cirrhosis was 96%. Treatment with VOSEVI for 12 weeks in POLARIS-1 was statistically superior relative to the pre-specified performance goal of 85% (p < 0.001). No patient in the placebo group achieved SVR.

Table 16. SVR12 and Virologic Outcome in NS5A Inhibitor-Experienced Patients with Genotypes 1, 2, 3, 4, 5, 6 HCV Infection Without Cirrhosis or with Compensated Cirrhosis (POLARIS-1)

GT = genotype; SVR12 = Sustained virologic response, defined as HCV RNA less than LLOQ (Lower Limit of Quantitation, 15 IU/mL) at 12 weeks after the cessation of treatment.

a. One patient with undetermined genotype achieved SVR12.

b. Four patients had GT-1 subtypes other than GT-1a or GT-1b; all 4 patients achieved SVR12.

c. Pharmacokinetic data for the 1 patient with on-treatment virologic failure was consistent with non-adherence.

d. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment.

e. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression.

Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for selected subgroups. High SVR12 rates were achieved in all subgroups, regardless of the presence of cirrhosis (Table 17) or prior DAA class combinations or specific DAA combinations.

Table 17. SVR12 for NS5A Inhibitor-Experienced Patients with Genotypes 1, 2, 3, 4, 5, 6 HCV Infection Without Cirrhosis or With Compensated Cirrhosis (POLARIS-1)

GT = genotype

a. One patient with undetermined genotype without cirrhosis achieved SVR12.

DAA-Experienced Adults Who Had Not Received an NS5A Inhibitor (POLARIS-4)

Overall, the SVR12 rate in DAA-experienced patients with genotype 1, 2, 3, 4 HCV infection without cirrhosis or with compensated cirrhosis who had not received an NS5A inhibitor was 98%. Table 18 presents the SVR12 by HCV genotype and virologic outcome for the POLARIS-4 trial. Treatment with VOSEVI for 12 weeks in POLARIS-4 was statistically superior to the SVR12 performance goal of 85% at the pre-specified 0.025 significance level (p < 0.001). Treatment with SOF/VEL for 12 weeks was not statistically superior to a performance goal of 85% at the pre-specified 0.025 significance level (p = 0.092).

Table 18. SVR12 and Virologic Outcome in DAA-Experienced Patients with Genotype 1, 2, 3, or 4 HCV Infection Without Cirrhosis or With Compensated Cirrhosis who had Not Received an NS5A Inhibitor (POLARIS-4)

SOF = sofosbuvir; VEL = velpatasvir; SVR12 = Sustained virologic response, defined as HCV RNA less than LLOQ (Lower Limit of Quantitation, 15 IU/mL) at 12 weeks after the cessation of treatment.

a. The denominator for relapse is the number of patients with HCV RNA <LLOQ at their last on-treatment assessment.

b. Other includes patients with missing data and those who discontinued treatment prior to virologic suppression.

Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for selected subgroups. High SVR12 rates were achieved in all subgroups in the VOSEVI 12-week group, regardless of the presence of cirrhosis (Table 19) or prior DAA class combinations or specific DAA combinations.

Table 19. SVR12 for DAA-Experienced Patients with Genotype 1, 2, 3, or 4 HCV Infection Without Cirrhosis or With Compensated Cirrhosis who had Not Received an NS5A Inhibitor (POLARIS-4)

Overall in the POLARIS-1 and POLARIS-4 studies, the presence of baseline NS3, NS5A, and NS5B NI RAVs did not alter the SVR12 rates for DAA-experienced patients who received 12 weeks of VOSEVI (see 15 MICROBIOLOGY).

15 MICROBIOLOGY

Antiviral Activity in Cell Culture

The EC₅₀ values of sofosbuvir, velpatasvir, and voxilaprevir against full-length or chimeric replicons encoding NS5B, NS5A, and NS3 protease sequences from the laboratory strains are presented in Table 20. The EC₅₀ values of sofosbuvir, velpatasvir, and voxilaprevir against clinical isolates are presented in Table 21.

Table 20. Activity of Sofosbuvir, Velpatasvir, and Voxilaprevir Against Full- Length or Chimeric Laboratory Replicons

NA = not available

a. Mean value from multiple experiments of same laboratory replicon.

b. Stable chimeric 1b replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing.

c. Data from various strains of full length NS5A replicons or chimeric NS5A replicons carrying full-length NS5A genes that contain L31 or M31 polymorphisms.

d. Data from a chimeric NS5A replicon carrying NS5A amino acids 9-184.

e. Stable cell lines expressing Renilla luciferase-encoding replicons.

f. Data obtained from transiently transfected replicons.

Table 21. Activity of Sofosbuvir, Velpatasvir, and Voxilaprevir Against Transient Replicons Containing NS5A, NS5B, or NS3 Protease from Clinical Isolates

NA = not available

The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir, but reduced the anti-HCV activity of velpatasvir and voxilaprevir by 13- and 6.8-fold, respectively, against genotype 1a HCV replicons.

Evaluation of sofosbuvir in combination with velpatasvir or voxilaprevir, as well as the combination of velpatasvir and voxilaprevir, showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance

In Cell Culture

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, the ability of the active triphosphate of sofosbuvir (GS-461203) to inhibit recombinant NS5B polymerase from genotypes 1b, 2a, 3a, and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types.

In vitro selection of HCV replicons with reduced susceptibility to velpatasvir was performed in cell culture for multiple genotypes including 1a, 1b, 2a, 3a, 4a, 5a, and 6a. Variants were selected at NS5A resistance associated positions 24, 28, 30, 31, 32, 58, 92, and 93. The resistance associated variants (RAVs) selected in 2 or more genotypes were F28S, L31I/V, and Y93H. From site-directed mutagenesis studies, NS5A RAVs that showed a > 2.5-fold reduction in velpatasvir susceptibility are listed in Table 22 below. No individual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction in velpatasvir susceptibility.

Combinations of variants often showed greater reductions in susceptibility to velpatasvir than single RAVs alone.

Table 22. Phenotypic Change of Genotype 1-6 NS5A Substitutions to Velpatasvir

*Fold change was calculated as the ratio of mutant EC₅₀ to wild-type EC₅₀.

HCV genotype 1a, 1b, 2a, 3a, 4a, 5a, and 6a replicon variants with reduced susceptibility to voxilaprevir were selected in cell culture. Variants were selected at NS3 resistance associated positions 41, 156, and 168. The RAVs selected in 2 or more genotypes were Q41H, A156V/T/L, and D168E/H/Y. From site-directed mutagenesis studies, NS3 RAVs that showed a > 2.5-fold reduction in voxilaprevir susceptibility are listed in Table 23 below. No individual substitutions tested in genotypes 5a, or 6a conferred a > 100-fold reduction in voxilaprevir susceptibility. Combinations of variants often showed greater reductions in susceptibility to voxilaprevir than single RAVs alone.

Table 23. Phenotypic Change of Genotype 1-6 NS3 Substitutions to Voxilaprevir

*Fold change was calculated as the ratio of mutant EC₅₀ to wild-type EC₅₀.

In Clinical Trials

Of the 263 NS5A inhibitor-experienced patients treated with VOSEVI for 12 weeks in POLARIS-1, 7 of 263 (3%) patients (2 with genotype 1, 4 with genotype 3, and 1 with genotype 4) did not achieve SVR12 and qualified for resistance analysis; 6 relapsed and 1 experienced virologic breakthrough with pharmacokinetic data consistent with nonadherence. The patient with genotype 1a and virologic breakthrough developed the NS5A RAVs L31M and Y93H. One patient with genotype 4d who relapsed developed the NS5A RAV Y93H. No NS3, NS5A, or NS5B nucleoside inhibitor (NI) RAVs emerged in the other 5 patients who relapsed.

Of the 182 DAA-experienced patients treated with VOSEVI for 12 weeks in POLARIS-4, 1 of 182 (1%) patients relapsed and qualified for resistance analysis. No NS3, NS5A, or NS5B NI RAVs emerged in this patient infected with genotype 1a HCV.

Effect of Baseline HCV Resistance Associated Variants on Treatment Outcome

Analyses were conducted to explore the association between pre-existing baseline NS3 and NS5A RAVs and treatment outcome for patients that had previously been treated with DAA regimens in POLARIS-1 and POLARIS-4. Patients were included in the analysis if they had a known virologic outcome. Of the patients treated with VOSEVI for 12 weeks, 260 of 263 in POLARIS-1 and 179 of 182 in POLARIS-4 were included in the analysis of NS3 and NS5A RAVs. Overall, 205 of 260 (79%) patients from POLARIS-1 and 83 of 179 (46%) patients from POLARIS-4 had HCV with NS3 and/or NS5A RAVs at baseline.

SVR12 rates in patients with or without baseline NS3 and/or NS5A RAVs in the POLARIS-1 and POLARIS-4 trials are shown in Table 24.

Table 24. SVR12 in DAA-Experienced Patients with or without Baseline NS3 or NS5A RAVs by Study

• a. Patients with NS3 and/or NS5A gene sequencing failure.

SVR12 was achieved in 18 of 19 (95%) patients who had baseline NS5B NI RAVs in POLARIS-1, including 2 patients that had virus with the S282T NS5B NI RAV in addition to NS5A RAVs at baseline. In POLARIS-4, a total of 14 patients had virus with NS5B NI RAVs at baseline and all achieved SVR12.

Cross Resistance

Voxilaprevir is active in vitro against most of the NS3 RAVs that confer resistance to first generation NS3/4A protease inhibitors. Additionally, velpatasvir is active in vitro against most of the NS5A RAVs that confer resistance to ledipasvir and daclatasvir. Sofosbuvir, velpatasvir, and voxilaprevir were fully active against substitutions associated with resistance to other classes of DAAs with different mechanisms of actions; eg, voxilaprevir was fully active against NS5A and NS5B NI RAVs.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Repeat-Dose Toxicity

Sofosbuvir

Sofosbuvir or GS-9851, a 1:1 diastereomeric mixture of sofosbuvir and its stereoisomer, was evaluated in repeat-dose oral toxicity studies up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in dogs. The primary sofosbuvir target organs identified were the gastrointestinal (GI) and hematopoietic (erythroid) systems. In a 7-day toxicity dog study with GS-9851, a dose of 1500 mg/kg/day resulted in (but were not limited to) increased mucus secretions in the stomach, glycogen depletion, and increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin, with associated histopathologic liver findings and increased QT/QTc intervals in dogs. At the adverse dose, GS-331007 exposure levels in the dog study were at least 69-fold higher than HCV-infected patients treated once daily with VOSEVI. In chronic toxicity studies in rats (26 weeks) and dogs (39 weeks), sofosbuvir effects included (but were not limited to) GI-related clinical signs (eg, soft feces and emesis) and a decrease (eg, approximately 10%) in mean red cell indices that were observed mainly in the high-dose group of dogs. One male dog was euthanized moribund with intestinal hemorrhage. The relationship to sofosbuvir was undetermined. In general, exposure levels in the chronic toxicity studies at the no observed adverse effect level were at least 5-fold (based on AUC of GS-331007) higher than HCV-infected patients treated once daily with VOSEVI.

Velpatasvir

Velpatasvir was well tolerated in studies for up to 4 weeks in the mouse, 26 weeks in the rat, and 39 weeks in the dog. No target organs were identified at the highest dose evaluated in each respective repeat dose toxicity study, corresponding to exposure margins of 54-, 3-, and 7-fold greater in mice, rats, and dogs, respectively, than those in HCV-infected patients treated once daily with VOSEVI.

Voxilaprevir

Voxilaprevir was evaluated in repeat-dose oral toxicity studies up to 26 weeks in rats and up to 39 weeks in dogs. The potential target organ/tissues identified for voxilaprevir were the GI tract (rat, dog), hepatobiliary system (rat, dog), hematological system (rat), and renal system (rat, dog). Minimal hematological changes indicative of mild blood loss and an appropriate regenerative response were also observed in the rat. Observed changes were minimal in nature and considered nonadverse. Voxilaprevir exposures at the no observed adverse effect levels from the chronic repeat-dose toxicity studies in rats and dogs were approximately 244-, and 96-fold higher, respectively, than HCV-infected patients treated once daily with VOSEVI.

Carcinogenicity:

Sofosbuvir

Sofosbuvir was not carcinogenic in the 2-year mouse and rat carcinogenicity studies at doses resulting in GS-331007 exposures up to 17-fold in mice and 10-fold in rats, higher than human exposure at 400 mg dose.

Velpatasvir

Velpatasvir was not carcinogenic in the 26-week mouse study at exposures up to 42- and 67-fold higher than human exposure in male and female mice, respectively, or in the 2-year rat carcinogenicity study at exposures up to 5-times higher than human exposure.

Voxilaprevir

Carcinogenicity studies for voxilaprevir have not been conducted.

Genotoxicity:

Sofosbuvir

Sofosbuvir, when administered as the diastereomeric mixture GS-9851, was not genotoxic in a bacterial mutagenicity assay, in an in vitro chromosome aberration test using human peripheral blood lymphocytes and in an in vivo mouse micronucleus assay.

Velpatasvir

Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.

Voxilaprevir

Voxilaprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.

Reproductive and Developmental Toxicology:

Sofosbuvir

Sofosbuvir had no effects on fertility when evaluated in rats at exposures (AUC) to the predominant circulating metabolite GS-331007 of at least 4-fold the exposure in humans at the recommended clinical dose.

Velpatasvir

Velpatasvir had no adverse effects on fertility in rats at AUC exposure 4-fold higher than the human exposure at the recommended clinical dose.

Voxilaprevir

Voxilaprevir had no adverse effects on fertility in rats at AUC exposures 149-fold higher than the human exposure at the recommended clinical dose.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. Sovaldi (tablet, 400 mg sofosbuvir), submission control number 202358, Product Monograph, Gilead Sciences Canada, Inc. April 28, 2017
2. 2. Epclusa (tablet, 400 mg sofosbuvir/100 mg velpatasvir), submission control number 202377, Product Monograph, Gilead Sciences Canada, Inc. May 8, 2017