Epclusa 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

4.2 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)..................................................................... 11

7.1.4 Geriatrics (≥ 65 years of age) ..................................................................... 11

7.1.5 Others ....................................................................................................... 11

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

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

8.2 Clinical Trial Adverse Reactions ................................................................. 12

8.2.1 Clinical Trial Adverse Reactions – Pediatrics .............................................. 14

8.3 Less Common Clinical Trial Adverse Reactions .......................................... 14

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ...................................................................................................... 16

8.5 Post-Market Adverse Reactions ................................................................. 18

9 DRUG INTERACTIONS ............................................................................................ 18

9.2 Drug Interactions Overview ........................................................................ 18

9.3 Drug-Behavioural Interactions .................................................................... 18

9.4 Drug-Drug Interactions ............................................................................... 18

9.5 Drug-Food Interactions .............................................................................. 31

9.6 Drug-Herb Interactions ............................................................................... 31

9.7 Drug-Laboratory Test Interactions .............................................................. 32

10 CLINICAL PHARMACOLOGY .................................................................................. 32

10.1 Mechanism of Action.................................................................................. 32

10.2 Pharmacodynamics ................................................................................... 32

10.3 Pharmacokinetics ...................................................................................... 33

11 STORAGE, STABILITY AND DISPOSAL ................................................................. 37

12 SPECIAL HANDLING INSTRUCTIONS .................................................................... 37

PART II: SCIENTIFIC INFORMATION ................................................................................. 38

13 PHARMACEUTICAL INFORMATION ....................................................................... 38

14 CLINICAL TRIALS ................................................................................................... 39

14.1 Clinical Trials by Indication ......................................................................... 39

Treatment of Chronic Hepatitis C Virus (HCV) Infection.............................................. 39

15 MICROBIOLOGY...................................................................................................... 58

16 NON-CLINICAL TOXICOLOGY ................................................................................ 63

PATIENT MEDICATION INFORMATION ............................................................................. 65

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

EPCLUSA (sofosbuvir/velpatasvir) is indicated for the treatment of chronic hepatitis C virus (HCV) infection:

• in adults and pediatric patients ≥ 12 years of age and weighing ≥ 30 kg without cirrhosis or with compensated cirrhosis
• in combination with ribavirin in adults with decompensated cirrhosis.

Patients Co-infected with Human Immunodeficiency Virus (HIV-1)

Safety and efficacy have been established in HCV-infected adult patients, with or without cirrhosis, who are co-infected with HIV-1 (see 4 DOSAGE AND ADMINISTRATION and 14 CLINICAL TRIALS).

Safety and efficacy have not been studied in pediatric patients co-infected with HIV-1. The treatment of pediatric patients ≥ 12 years of age and weighing ≥ 30 kg and co-infected with HIV-1 is based on extrapolation of relevant clinical data (see 10 CLINICAL PHARMACOLOGY and 14 CLINICAL TRIALS).

1.1 Pediatrics (<18 years of age)

The safety and efficacy of EPCLUSA in pediatric patients ≥ 12 years of age receiving EPCLUSA once daily have been established (see 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS). Exposures to EPCLUSA in pediatric patients ≥ 12 to <18 years of age and weighing ≥ 30 kg were similar to those observed in adults.

The safety and efficacy of EPCLUSA in pediatric patients < 12 years of age or weighing < 30 kg have not been established.

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. EPCLUSA can be administered in geriatric patients (see 10 CLINICAL PHARMACOLOGY and 14 CLINICAL TRIALS).

2 CONTRAINDICATIONS

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

When EPCLUSA is used in combination with ribavirin, the contraindications to ribavirin are also applicable to the combination regimen. Refer to the Product Monograph containing information on ribavirin for a list of contraindications for ribavirin.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose and Dosage Adjustment

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

The recommended dose of EPCLUSA is one tablet of 400 mg/100 mg sofosbuvir/velpatasvir, taken orally, once daily with or without food (see Effects of Food).

The recommended dose and treatment duration for EPCLUSA is provided in Table 1.

Table 1. Recommended Dose and Treatment Regimen for HCV Mono-infected and HCV/HIV-1 Co-infected Adult Patients^a (All HCV Genotypes)

a. Refer to Tables 9-11 for dosing recommendations for concomitant HIV-1 antiviral agents and for observed drug exposure levels when coadministered with HIV antiviral agents (see 9 DRUG INTERACTIONS).

b. Limited data for genotypes 2, 4, 5 and 6 (see 7 WARNINGS AND PRECAUTIONS, and 14 CLINICAL TRIALS).

c. When administered with EPCLUSA, the recommended dose of ribavirin is based on weight: 1000 mg per day for patients less than 75 kg and 1200 mg for those weighing at least 75 kg, divided and administered twice daily with food. For ribavirin dose modifications, refer to the Product Monograph containing ribavirin information.

Special Populations

Pediatrics (< 18 years of age)

In pediatric patients ≥ 12 years of age and weighing ≥ 30 kg, the recommended dose of EPCLUSA is one 400/100 mg tablet taken orally, once daily with or without food for 12 weeks. No dose adjustments are possible for EPCLUSA.

EPCLUSA is not indicated for use in pediatric patients < 12 years of age or weighing < 30 kg.

Geriatrics (≥ 65 years of age)

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

Hepatic Impairment

No dose adjustment of EPCLUSA is required for adult patients with mild or moderate hepatic impairment (Child-Pugh A or B). Based on pharmacokinetic data, no dose adjustment of EPCLUSA is required for adult patients with Child-Pugh C hepatic impairment (see 10 CLINICAL PHARMACOLOGY). However, safety and efficacy of EPCLUSA have not been established in adult patients with Child-Pugh C decompensated cirrhosis.

No dose adjustment of EPCLUSA is required for pediatric patients with mild hepatic impairment (Child-Pugh A). Safety and efficacy of EPCLUSA have not been established in pediatric patients with moderate or severe hepatic impairment (Child-Pugh B or C).

Renal Impairment

No dose adjustment of EPCLUSA is required for patients with any stage of renal impairment, including end stage renal disease (ESRD) requiring dialysis (see 8 ADVERSE REACTIONS, 10 CLINICAL PHARMACOLOGY and 14 CLINICAL TRIALS).

No safety data are available in patients with both decompensated cirrhosis (Child-Pugh B or C hepatic impairment) and severe renal impairment, including ESRD requiring dialysis. In addition, no safety data are available in pediatric patients with renal impairment.

When EPCLUSA is used in combination with ribavirin, refer also to the Product Monograph for ribavirin for patients with creatinine clearance < 50 mL/min.

4.5 Missed Dose

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

If a patient misses a dose of EPCLUSA 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 EPCLUSA must not be taken.

If a patient vomits less than 3 hours after taking a dose of EPCLUSA, the patient should take another dose of EPCLUSA. If a patient vomits more than 3 hours after taking a dose of EPCLUSA, 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 EPCLUSA. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with EPCLUSA 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 since velpatasvir is highly bound to plasma protein.

The highest documented doses of sofosbuvir and velpatasvir were a single dose of 1200 mg and a single dose of 500 mg, respectively. In these healthy volunteer studies, 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 effects of higher doses/exposures are not known.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2. Dosage Forms, Strengths, Composition and Packaging

EPCLUSA is a single tablet regimen containing sofosbuvir and velpatasvir for oral administration.

EPCLUSA is available as a pink-colored, diamond-shaped, film-coated tablet debossed with “GSI” on one side and “7916” on the other side of the tablet. Each bottle contains 28 tablets, a polyester coil and is closed with a child-resistant closure.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

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

EPCLUSA 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 P-glycoprotein (P-gp) inducers and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 [eg, rifampin, St. John’s wort (Hypericum perforatum) and carbamazepine] may significantly decrease plasma concentrations of sofosbuvir and/or velpatasvir leading to reduced therapeutic effect of EPCLUSA and potential loss of virologic response. These agents should not be used with EPCLUSA (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 EPCLUSA is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered EPCLUSA:

• 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 EPCLUSA 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 EPCLUSA 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 8.5 Post-Market Adverse Reactions and 9 DRUG INTERACTIONS).

Hepatic/Biliary/Pancreatic

The safety and efficacy of EPCLUSA have not been established in adult patients with severe hepatic impairment (Child-Pugh C) (see 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY).

EPCLUSA has not been studied in pediatric patients with moderate or severe hepatic impairment.

Monitoring of liver function including direct bilirubin is recommended in patients with decompensated cirrhosis.

Monitoring and Laboratory Tests

If EPCLUSA is administered with amiodarone, close monitoring for bradycardia is recommended. Refer to the amiodarone Product Monograph (see 7 WARNINGS AND PRECAUTIONS, 9 DRUG INTERACTIONS).

Monitoring of liver function including direct bilirubin is recommended in patients with decompensated cirrhosis (see 8 ADVERSE REACTIONS).

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 Potential for HBV Reactivation).

As liver function may improve during treatment with EPCLUSA, monitoring of certain laboratory parameters and/or concomitant medications may be required. For guidance see Other Forms of Interactions.

Patients with Other HCV Genotypes Data to support the treatment of patients with decompensated cirrhosis who are infected with HCV genotype 2 or genotype 4 are limited, and there are no data for genotype 5 and genotype 6 HCV-infected patients with decompensated cirrhosis. 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).

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 including EPCLUSA. 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 EPCLUSA for 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 Monitoring and Laboratory Tests).

Reproductive Health: Female and Male Potential

• Fertility

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

Sensitivity/Resistance

The efficacy of EPCLUSA has not been established in patients who have previously failed treatment with other regimens that include a NS5A inhibitor (see Cross Resistance).

7.1 Special Populations

7.1.1 Pregnant Women

Use without Ribavirin

Pregnancy should be avoided while taking EPCLUSA as there are no data on the use of EPCLUSA in pregnant women. EPCLUSA 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 5-fold, 14-fold, and 6-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 31-fold, 6-fold, 0.7-fold, and 5-fold the exposure in humans at the recommended clinical dose, respectively.

Use with Ribavirin

If EPCLUSA is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for 6 months after the treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the ribavirin Product Monograph for a full list of warnings and precautions for ribavirin.

7.1.2 Breast-feeding

It is not known whether sofosbuvir, velpatasvir, or their metabolites 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. Because a risk to the newborn/infant cannot be excluded, mothers should be instructed not to breast-feed if they are taking EPCLUSA.

7.1.3 Pediatrics (< 18 years of age)

The safety, pharmacokinetics, and efficacy of EPCLUSA in pediatric patients ≥ 12 years of age have been established in an open-label trial (Study GS-US-342-1143, Cohort 1) and are comparable to that observed in adults (see 8 ADVERSE REACTIONS, Special Populations and Conditions, and 14 CLINICAL TRIALS). Population pharmacokinetics-based simulations indicated exposures of sofosbuvir, GS-331007, and velpatasvir in pediatric patients ≥ 30 kg receiving oral once daily dose of sofosbuvir/velpatasvir 400/100 mg were similar to those observed in adults.

Pediatric patients with renal impairment have not been studied.

The safety and efficacy of EPCLUSA in pediatric patients < 12 years of age or weighing < 30 kg have not been established.

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

Liver Transplant Patients

The safety and efficacy of EPCLUSA have not been established in patients with recurrent HCV infection after liver transplant.

HCV/HIV-1 Co-infection

The safety and efficacy of EPCLUSA in HCV/HIV-1 co-infected adult patients have been established (see Clinical Trial in Patients with HCV/HIV-1 Co-infection (ASTRAL-5)). Efavirenz has been shown to significantly decrease the concentration of velpatasvir. Therefore coadministration of EPCLUSA with an efavirenz-containing HIV regimen in adults is not recommended (see 9 DRUG INTERACTIONS).

EPCLUSA use in pediatric patients co-infected with HIV-1 has not been studied.

HCV/HBV Co-infection

The safety and efficacy of EPCLUSA 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 Potential for HBV Reactivation).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The overall safety profile of EPCLUSA was established in the following patient populations: non-cirrhotic and cirrhotic (compensated and decompensated) adult patients infected with HCV; adult patients co-infected with HIV-1 (without cirrhosis or with compensated cirrhosis); and pediatric patients ≥ 12 years of age without decompensated cirrhosis.

The safety assessment of EPCLUSA was based on pooled Phase 3 clinical trial data (ASTRAL-1, ASTRAL-2, and ASTRAL-3) from adult patients with HCV without cirrhosis or with compensated cirrhosis including 1035 patients who received EPCLUSA for 12 weeks. The proportion of patients who permanently discontinued treatment due to adverse events was 0.2% for patients receiving EPCLUSA for 12 weeks. Of the 1035 patients, 2% had at least one serious adverse event (SAE), with no patients experiencing a treatment-related SAE.

The safety of EPCLUSA was also assessed in adult patients with decompensated cirrhosis (Child-Pugh B) in one Phase 3 trial (ASTRAL-4). In ASTRAL-4, the proportion of patients who permanently discontinued treatment due to adverse events was 5% (4/87) for those patients treated with EPCLUSA + ribavirin (RBV) for 12 weeks, 1% (1/90) for those patients treated with EPCLUSA for 12 weeks, and 4% (4/90) for those patients treated with EPCLUSA for 24 weeks. Serious adverse events occurred in 19% (17/90), 16% (14/87) and 18% (16/90) of patients treated with EPCLUSA for 12 weeks, EPCLUSA + RBV for 12 weeks and EPCLUSA for 24 weeks, respectively. One patient (0.4%) experienced SAEs considered related to EPCLUSA.

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.

Adult Patients without Cirrhosis and Patients with Compensated Cirrhosis

The adverse reactions (Grades 2 to 4) observed in ≥ 2% of patients receiving 12 weeks of treatment with EPCLUSA in clinical trials are listed in Table 3.

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

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

Adult Patients with Decompensated Cirrhosis

The adverse reactions (Grades 2 to 4) observed in ≥ 2% of patients receiving 12 or 24 weeks of treatment with EPCLUSA or 12 weeks of treatment with EPCLUSA plus ribavirin in the ASTRAL-4 study are listed in Table 4.

Table 4. Adverse Reactions (Grades 2-4) Reported in ≥ 2% of Patients Receiving 12 or 24 Weeks of EPCLUSA^a without Ribavirin or 12 Weeks of EPCLUSA with Ribavirin in ASTRAL-4

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

Adult Patients with HCV/HIV-1 Co-infection

The safety of EPCLUSA was assessed in an open-label trial of 106 patients with HCV/HIV-1 co-infection who were on stable antiretroviral therapy (see 14 CLINICAL TRIALS). The safety profile in HCV/HIV-1 co-infected patients was similar to that observed in HCV mono-infected patients treated with EPCLUSA. The most common adverse reactions occurring in at least 10% of patients were fatigue (22%) and headache (10%). No adverse drug reactions specific to EPCLUSA were identified. Adult Patients with Renal Impairment

The safety of EPCLUSA was assessed in an open-label trial (Study GS-US-342-4062) of 59 patients with HCV and ESRD requiring dialysis who received EPCLUSA for 12 weeks (see 14 CLINICAL TRIALS). The adverse events observed were consistent with expected clinical sequelae of ESRD. No adverse reactions specific to EPCLUSA were identified.

People Who Inject Drugs (PWID) Including Those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

The safety of EPCLUSA was assessed in an open-label trial (SIMPLIFY) of 103 adult PWID with chronic HCV genotype 1, 2, 3, or 4 infection. Patients who self-reported injection drug use within 6 months prior to starting treatment were eligible and received EPCLUSA for 12 weeks (see 14 CLINICAL TRIALS). The trial included a subset of 58 patients who were taking MAT for opioid use disorder. The adverse events observed were consistent with the known safety profile of EPCLUSA. The most common adverse reactions occurring in at least 10% of patients were fatigue (18%), nausea (13%), and headache (11%). No adverse reactions lead to permanent discontinuation of EPCLUSA in any patient.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Pediatrics Patients (≥ 12 Years of Age)

The safety of EPCLUSA in pediatric patients ≥ 12 years of age was assessed in an open-label trial (Study GS-US-342-1143, Cohort 1) of 102 patients who were treated with EPCLUSA for 12 weeks. The adverse reactions observed were consistent with those observed in clinical trials of EPCLUSA in adults (see 14 CLINICAL TRIALS).

The safety of EPCLUSA in pediatric patients with renal impairment or co-infected with HIV-1 has not been studied.

8.3 Less Common Clinical Trial Adverse Reactions

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

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

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

Less Common Clinical Trial Adverse Drug Reactions (< 2%)

Adverse reactions (Grades 2 to 4) occurring in less than 2% of patients receiving 12 or 24 weeks of EPCLUSA or 12 weeks of EPCLUSA with ribavirin in ASTRAL-4 are listed below by body system:

Table 6. Adverse Reactions (Grades 2-4) Reported in < 2% of Patients Receiving 12 or 24 Weeks of EPCLUSA^a or 12 Weeks of EPCLUSA with Ribavirin from ASTRAL-4

N/A = Not applicable

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

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

Clinical Trial Findings

The frequency of treatment-emergent laboratory abnormalities (Grades 2-4) occurring in at least 2% of patients receiving 12 weeks of treatment with EPCLUSA are described in Table 7.

Table 7. Laboratory Abnormalities (Grades 2-4) Reported in ≥ 2% of Patients Receiving 12 Weeks of EPCLUSA from the Pooled Phase 3 Studies (ASTRAL-1, ASTRAL-2, ASTRAL-3)

ULN = Upper Limit of Normal

Abnormal Hematologic and Clinical Chemistry Findings

The frequency of treatment-emergent laboratory abnormalities (Grades 2-4) occurring in at least 2% of patients receiving 12 or 24 weeks of treatment with EPCLUSA or 12 weeks of treatment with EPCLUSA + RBV are described in Table 8 below.

Table 8. Laboratory Abnormalities (Grades 2-4) Reported in ≥ 2% of Patients Receiving 12 or 24 Weeks of EPCLUSA or 12 Weeks of EPCLUSA with Ribavirin from ASTRAL-4

ULN = Upper Limit of Normal

Among patients with decompensated cirrhosis in the ASTRAL-4 trial, direct bilirubin was found to remain stable (< 17.1 µmol/L change from baseline throughout treatment) in the majority of patients. One patient randomized to receive 24 weeks of treatment with EPCLUSA had a

> 17.1 µmol/L increase from baseline in direct bilirubin from Week 6 through Week 10 for which no clinical explanation could be identified; this patient completed 24 weeks of treatment.

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 or EPCLUSA. 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 Cardiovascular and 9 DRUG INTERACTIONS).

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

After oral administration of EPCLUSA, 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 EPCLUSA with individual behavioural risks have not been established.

9.4 Drug-Drug Interactions

Potential for EPCLUSA to Affect Other Drugs

Velpatasvir is an inhibitor of drug transporter P-gp, breast cancer resistance protein (BCRP), OATP1B1 and OATP1B3. Coadministration of EPCLUSA with drugs that are substrates of these transporters may increase the exposure of such drugs. The drug-drug interaction potential of velpatasvir is limited to the presystemic processes (intestinal efflux and hepatic uptake); clinically relevant interactions in systemic circulation are not expected.

At clinically relevant concentration, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.

Sofosbuvir and GS-331007 are not relevant inhibitors of efflux drug transporters P-gp, 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.

Potential for Other Drugs to Affect EPCLUSA

Sofosbuvir and velpatasvir 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. Velpatasvir is poorly transported by OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed.

Drugs that are P-gp inducers and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (eg, rifampin, St. John’s wort or carbamazepine) may significantly decrease plasma concentrations of sofosbuvir and/or velpatasvir leading to reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended (see 7 WARNINGS AND PRECAUTIONS).

Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir and/or velpatasvir plasma concentrations without increasing GS-331007 plasma concentration. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. EPCLUSA may be coadministered with P-gp, BCRP, and CYP inhibitors.

Table 9 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either EPCLUSA, the components of EPCLUSA (sofosbuvir and velpatasvir) as individual agents, or are predicted drug interactions that may occur with EPCLUSA. The table is not all-inclusive (see 10 CLINICAL PHARMACOLOGY).

Table 9. Established and Other Potentially Significant^a Drug Interactions

a. This table is not all-inclusive.

b. ↑ = increase, ↓ = decrease. c. These interactions have been studied in healthy adults.

Drugs without Clinically Significant Interactions with EPCLUSA

Based on drug interaction studies conducted with the components of EPCLUSA (sofosbuvir or velpatasvir) or EPCLUSA, no clinically significant drug interactions have either been observed or are expected when EPCLUSA is used with the following drugs: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, ketoconazole, lopinavir/ritonavir, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine or tacrolimus (see, Other Forms of Interactions, Assessment of Drug Interactions and 7 WARNINGS AND PRECAUTIONS).

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 inhibitors cyclosporine and 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 and velpatasvir are shown in Table 10. The effects of sofosbuvir, velpatasvir or EPCLUSA on the exposure of coadministered drugs are shown in Table 11.

Table 10. Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir and the Predominant Circulating Metabolite GS-331007, and Velpatasvir in the Presence of the Coadministered Drug^a

NA = not available/not applicable; ND = not dosed

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 STRIBILD^® (elvitegravir/cobicistat/emtricitabine/tenofovir DF fixed-dose single tablet regimen).

e. Administered as COMPLERA^® (emtricitabine/rilpivirine/tenofovir DF fixed-dose combination).

f. These studies have not been performed w ith EPCLUSA; they w ere conducted w ith either sofosbuvir or velpatasvir administered as single agents.

Table 11. Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvir, Velpatasvir, or EPCLUSA^a

NA = not available/not applicable; ND = not dosed

a. All interaction studies conducted in healthy volunteers.

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

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

d. Administered as ATRIPLA (efavirenz, emtricitabine and tenofovir DF fixed-dose combination).

e. Administered as GENVOYA (elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide fixed-dose single tablet regimen).

f. Administered as STRIBILD (elvitegravir, cobicistat, emtricitabine and tenofovir DF fixed-dose single tablet regimen).

g. Administered as COMPLERA (emtricitabine, rilpivirine and tenofovir DF fixed-dose combination).

h. These studies have not been performed w ith EPCLUSA; they w ere conducted w ith either sofosbuvir or velpatasvir administered as single agents.

9.5 Drug-Food Interactions

No interactions between EPCLUSA and food have been identified.

9.6 Drug-Herb Interactions

St. John’s wort should not be used with EPCLUSA.

Coadministration of St. John’s wort, a P-gp and a strong CYP inducer, may decrease sofosbuvir and velpatasvir plasma concentrations, which may result in loss of therapeutic effect. See General, Use with P-gp Inducers and/or Moderate to Strong CYP Inducers.

9.7 Drug-Laboratory Test Interactions

Interactions of EPCLUSA with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

EPCLUSA

EPCLUSA is a fixed-dose single tablet regimen of sofosbuvir and velpatasvir.

Sofosbuvir is a nucleotide analogue pan-genotypic NS5B polymerase inhibitor. Velpatasvir is a pan-genotypic HCV NS5A inhibitor.

Both sofosbuvir and velpatasvir exhibit high potency and specificity as individual agents against HCV as compounds that target the HCV NS5B and NS5A proteins, respectively. Both compounds display low cytotoxicity in a number of distinct cell lines and display no significant antiviral activity against other viruses tested. In vitro combination studies using both sofosbuvir and velpatasvir showed an additive effect as measured by in vitro cell based HCV replicon assays, with no antagonism detected. As individual components, both sofosbuvir and velpatasvir showed additive to synergistic activity with all other anti-HCV agents.

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.

10.2 Pharmacodynamics

Effect on Electrocardiogram

The effects of administration of supratherapeutic doses of sofosbuvir (1200 mg) and velpatasvir (500 mg) (as individual drugs) demonstrated a lack of effect of sofosbuvir or velpatasvir 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.

The pharmacokinetics of EPCLUSA are shown in Table 12.

Table 12. Summary of Pharmacokinetics for Once-Daily Administration of EPCLUSA in Healthy Adult Subjects and HCV-Infected Patients

ND = not determined; SOF = sofosbuvir; VEL = velpatasvir

a. Population PK analysis from Phase 1 studies.

b. Population PK analysis from Phase 2 and 3 studies.

c. N = 982; 446 patients did not have estimable PK parameters for SOF.

d. N = 1425; 3 patients did not have estimable PK parameters for VEL.

Based on population PK analyses, sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (N=331), velpatasvir AUC0-24 and Cmax were 37% lower and 41% lower, respectively, in HCV-infected patients. Age, race, BMI, HCV genotype or the presence or absence of cirrhosis had no clinically relevant effects on the exposure of sofosbuvir, GS-331007, or velpatasvir.

Absorption

Following oral administration of EPCLUSA, sofosbuvir median peak plasma concentration was observed 0.5-1.0 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.0 hours post-dose. Velpatasvir median peak concentrations were observed 3.0 hours post-dose.

Effects of Food

Relative to fasting conditions, the administration (to healthy subjects) of a single dose of EPCLUSA with a moderate fat (~600 kcal, 30% fat) or high fat (~800 kcal, 50% fat) meal delayed the absorption of both sofosbuvir (median tmax delayed from 0.5 hours to 2.0 hours) and velpatasvir (median tmax delayed from 3.0 hours to 4.0 hours).

The extent of sofosbuvir absorption was significantly higher when administered with food (AUC increased 60% and 78% with a moderate fat or a high fat meal, respectively) and the Cmax was unchanged. Food did not alter GS-331007 AUC but resulted in a 25% and 37% decrease in Cmax, when EPCLUSA was administered with a moderate fat or a high fat meal, respectively.

The extent of velpatasvir absorption was increased more with a moderate fat meal (AUC increased 35% and Cmax increased 31%) than with a high fat meal (AUC increased by 22% and no significant change in Cmax).

The response rates in Phase 3 trials were similar in HCV-infected patients who received EPCLUSA with food or without food. EPCLUSA can be administered without regard to food.

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 > 99.5% 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 0.52 and 0.67.

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.

In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. 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.

Elimination

Sofosbuvir is primarily eliminated in the urine as GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of EPCLUSA were 0.5 and 25 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 EPCLUSA was approximately 15 hours.

Special Populations and Conditions

• Pediatrics (< 18 years of age)

  Exposures of sofosbuvir, GS-331007 and velpatasvir in 102 pediatric patients ≥ 12 years of age who received EPCLUSA in Study GS-US-342-1143 were similar to those observed in adult patients following administration of EPCLUSA. Population pharmacokinetics-based simulations indicated exposures of sofosbuvir, GS-331007, and velpatasvir in pediatric patients weighing ≥ 30 kg receiving oral once daily doses of sofosbuvir/velpatasvir 400/100 mg were similar to those observed in adults.

  The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir in pediatric patients < 12 years of age or weighing < 30 kg 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 or velpatasvir. Clinical studies of EPCLUSA included 156 patients aged 65 and over. The response rates observed for patients ≥ 65 years of age were similar to that 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, or velpatasvir.

• Ethnic Origin

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

• Hepatic Insufficiency

  Hepatic impairment studies were conducted with the individual drugs, sofosbuvir and velpatasvir. 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 AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 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 (including decompensated cirrhosis) 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 (AUCinf ) 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 (including decompensated cirrhosis) had no clinically relevant effect on the exposure of velpatasvir.

• Renal Insufficiency

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

  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 (N=6/group). Relative to subjects with normal renal function (eGFR > 80 mL/min/1.73m²), the sofosbuvir AUCinf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUCinf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, sofosbuvir AUCinf was 28% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% higher when dosed 1 hour after hemodialysis. The AUCinf 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. Velpatasvir is primarily excreted in feces. 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 Cmax 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.

  The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected patients with ESRD requiring dialysis treated with EPCLUSA for 12 weeks. Steady-state AUCtau 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.

  No dose adjustment of EPCLUSA is required for patients with any stage of renal impairment, including ESRD requiring dialysis.

  No data are available regarding the safety of EPCLUSA in pediatric patients with renal impairment.

• HCV/HIV-1 Co-infection

  The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were similar in HCV/HIV-1 co-infected and HCV mono-infected adult patients.

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 Clinical Trials by Indication

Treatment of Chronic Hepatitis C Virus (HCV) Infection

The efficacy of EPCLUSA was evaluated in three Phase 3 trials in 1035 adult patients with genotype 1 to 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (ASTRAL-1, ASTRAL-2, and ASTRAL-3). The efficacy of EPCLUSA was also evaluated in one Phase 3 trial in 267 adult patients with HCV infection with decompensated cirrhosis (ASTRAL-4). The demographics and baseline characteristics for the patients in studies ASTRAL-1, ASTRAL-2, ASTRAL-3, and ASTRAL-4 were balanced across the treatment groups for each study and are summarized in Table 14, Table 17, Table 18, and Table 23, respectively.

The efficacy of EPCLUSA in 106 HCV/HIV-1 co-infected adult patients, without cirrhosis or with compensated cirrhosis, was evaluated in an open-label Phase 3 trial (ASTRAL-5). All patients in the trial were treated with EPCLUSA for 12 weeks. The demographics and baseline characteristics for the patients in ASTRAL-5 are summarized in Table 26.

The efficacy of EPCLUSA in 59 patients with genotype 1, 2, 3, 4 and 6 chronic HCV infection without cirrhosis or with compensated cirrhosis, and with ESRD requiring dialysis was evaluated in one Phase 2 trial (Study GS-US-342-4062).

The efficacy of EPCLUSA in 103 adult PWID (defined as self-reported injection drug use within previous 6 months), including a subset of patients on MAT for opioid use disorder, with genotype 1, 2, 3, and 4 chronic HCV infection without cirrhosis or with compensated cirrhosis, was evaluated in one Phase 2 trial (SIMPLIFY).

The RBV dose was weight-based (1000 mg daily administered in two divided doses for adult patients < 75 kg and 1200 mg for those ≥ 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 trials or in combination with EPCLUSA in the ASTRAL-4 trial. RBV dose adjustments were performed according to the Product Monograph for RBV. 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 per mL.

Sustained virologic response (SVR), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint to determine the HCV cure rate.

The efficacy of EPCLUSA in HCV-infected pediatric patients ≥ 12 years of age was evaluated in 102 patients in an open-label Phase 2 trial (Study GS-US-342-1143, Cohort 1).

Clinical Trials in Adult Patients Without Cirrhosis and Patients With Compensated Cirrhosis

Genotypes 1, 2, 4, 5, 6 HCV Infected Adults (ASTRAL-1)

Trial Design

Table 13. Summary of Trial Design in Genotypes 1, 2, 4, 5, 6 HCV Patients with or without Cirrhosis (ASTRAL-1)

PO = orally; QD = once a day

Patients with genotype 1, 2, 4, or 6 HCV were randomized in a 5:1 ratio to treatment with EPCLUSA for 12 weeks or placebo for 12 weeks. Patients with genotype 5 HCV were enrolled to the EPCLUSA group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of cirrhosis.

Demographics and Other Baseline Characteristics

Table 14. Demographic and Other Baseline Characteristics of Genotypes 1, 2, 4, 5, 6 HCV Patients with or without Cirrhosis (ASTRAL-1)

DAA = direct acting antiviral; Peg-IFN = pegylated interferon; RBV= ribavirin; SD = standard deviation *Total percentage may not add to 100% due to rounding.

Study Results

The response rates for the EPCLUSA treatment group by HCV genotypes and for selected subgroups in the ASTRAL-1 trial are presented in Table 15. The EPCLUSA 12-week group met the primary endpoint of an SVR12 rate that was statistically superior relative to the prespecified performance goal of 85% (p < 0.001). No patient in the EPCLUSA 12-week group had on-treatment virologic failure (ie, breakthrough, rebound or nonresponse). No patient in the placebo group achieved SVR12.

Table 15. SVR12^a and Treatment Outcomes in Genotypes 1, 2, 4, 5, 6 HCV Infected Patients with or without Cirrhosis and for Selected Subgroups (ASTRAL-1)

GT = genotype

a. 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.

b. The exact 95% CI for the proportion of within treatment group was based on the Clopper-Pearson method.

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

d. Other includes patients who did not achieve SVR and did not meet virologic failure criteria.

High SVR12 rates were achieved in all subgroups across all HCV genotypes. Among patients in the EPCLUSA 12-week group, the SVR12 rates in selected subgroups were as follows: with IL28B C/C allele (99.5%), non-CC (C/T or T/T) allele (98.8%); baseline HCV RNA < 800,000 IU/mL (98.8%), baseline HCV RNA ≥ 800,000 IU/mL (99.1%); baseline BMI < 30 kg/m² (99.0%), baseline BMI ≥ 30 kg/m² (99.3%); sex (males [98.7%], females [99.6%]); and race (White [99.0%], Black [98.1%], Other [100.0%]). All patients previously treated with a DAA + Peg-IFN+RBV achieved SVR12 (56 of 56, 100%), which included 48, 6, and 2 patients with genotype 1, 4, and 5 HCV infection, respectively.

Genotype 2 HCV Infected Adults (ASTRAL-2)

Trial Design

Table 16. Summary of Trial Design in Genotype 2 HCV Patients with or without Cirrhosis (ASTRAL-2)

BID = twice a day; PO = orally; QD = once a day; RBV = ribavirin; SOF = sofosbuvir

Patients were randomized in a 1:1 ratio to treatment with EPCLUSA for 12 weeks or SOF+RBV for 12 weeks. Randomization was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve vs treatment experienced).

Demographic and Baseline Characteristics

Table 17. Demographic and Other Baseline Characteristics of Genotype 2 HCV Patients with or without Cirrhosis (ASTRAL-2)

Peg-IFN = pegylated interferon; RBV = ribavirin; SD = standard deviation; SOF = sofosbuvir *Total percentage may not add to 100% due to rounding.

Study Results

The response rates for the treatment groups and for selected subgroups in the ASTRAL-2 trial are presented in Table 18. Treatment with EPCLUSA for 12 weeks demonstrated statistical superiority (p = 0.018) compared to treatment with SOF+RBV for 12 weeks (treatment difference +5.2%; 95% confidence interval: +0.2% to +10.3%).

Table 18. SVR12^a and Treatment Outcomes in Genotype 2 HCV Infected Patients with or without Cirrhosis and for Selected Subgroups (ASTRAL-2)

RBV = ribavirin; SOF = sofosbuvir

• a. 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.
• b. The exact 95% CI for the proportion of within treatment group was based on the Clopper-Pearson method.
• c. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.
• d. Other includes patients who did not achieve SVR and did not meet virologic failure criteria.

Among patients who received EPCLUSA for 12 weeks, the SVR12 rates in selected subgroups were as follows: with IL28B C/C allele (100.0%), non-CC (C/T or T/T) allele (98.7%); baseline HCV RNA < 800,000 IU/mL (100.0%), baseline HCV RNA ≥ 800,000 IU/mL (99.1%); baseline

BMI of < 30 kg/m² (98.9%), baseline BMI ≥ 30 kg/m² (100.0%); sex (males [98.8%], females [100.0%]); and race (White [100.0%], Black [83.3%], Other [100.0%]).

Genotype 3 HCV Infected Adults (ASTRAL-3)

Trial Design

Table 19. Summary of Trial Design in Genotype 3 HCV Patients with or without Cirrhosis (ASTRAL-3)

BID = twice a day; PO = orally; QD = once a day; RBV = ribavirin; SOF = sofosbuvir

Patients were randomized in a 1:1 ratio to treatment with EPCLUSA for 12 weeks or SOF+RBV for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve vs treatment experienced). Demographics and Other Baseline Characteristics

Table 20. Demographic and Other Baseline Characteristics of Genotype 3 HCV Patients with or without Cirrhosis (ASTRAL-3)

DAA = direct acting antiviral; Peg-IFN = pegylated interferon; RBV = ribavirin; SD = standard deviation; SOF = sofosbuvir *Total percentage may not add to 100% due to rounding.

Study Results

The response rates for the treatment groups and for selected subgroups in study ASTRAL-3 are presented in Table 21. Treatment with EPCLUSA for 12 weeks demonstrated statistical superiority (p < 0.001) compared to treatment with SOF+RBV for 24 weeks (treatment difference +14.8%; 95% confidence interval: +9.6% to +20.0%).

Table 21. SVR12^a and Treatment Outcomes in Genotype 3 HCV Infected Patients with or without Cirrhosis and for Selected Subgroups (ASTRAL-3)

DAA = direct acting antiviral; Peg-IFN = pegylated interferon; RBV = ribavirin; SOF = sofosbuvir

• a. 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.
• b. The exact 95% CI for the proportion of within treatment group was based on the Clopper-Pearson method.
• c. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.
• d. Other includes patients who did not achieve SVR and did not meet virologic failure criteria.

Among patients who received EPCLUSA for 12 weeks, the SVR12 rates in selected subgroups were as follows: with IL28B C/C allele (94.3%), non-CC (C/T or T/T) allele (95.9%); baseline HCV RNA < 800,000 IU/mL (98.8%), baseline HCV RNA ≥ 800,000 IU/mL (93.7%); baseline BMI < 30 kg/m² (94.7%), baseline BMI ≥ 30 kg/m² (98.0%); sex (males [93.5%], females [98.1%]); and race (White [95.2%], Black [100.0%], Other [95.8%]). SVR12 rates for cirrhotic patients (91.3%) and treatment-experienced patients (90.1%) were higher in the EPCLUSA 12-week group compared with the SOF + RBV 24-week group.

The overall SVR12 (virologic cure) across the three trials (ASTRAL-1, ASTRAL-2, ASTRAL-3) was 98% (1015/1035).

Clinical Trial in Adult Patients with Decompensated Cirrhosis (ASTRAL-4)

Trial Design

Table 22. Summary of Trial Design in HCV Patients with Decompensated Cirrhosis (ASTRAL-4)

BID = twice a day; PO = orally; QD = once a day; RBV = ribavirin; SOF = sofosbuvir

Patients were randomized in a 1:1:1 ratio to treatment with EPCLUSA for 12 weeks, EPCLUSA + RBV for 12 weeks or EPCLUSA for 24 weeks. Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate). No patients with genotype 5 HCV infection were enrolled.

Demographics and Other Baseline Characteristics

Table 23. Demographic and Other Baseline Characteristics of HCV Patients with Decompensated Cirrhosis (ASTRAL-4)

CPT = Child-Pugh Turcotte; DAA = direct acting antiviral; MELD = model for end stage liver disease; Peg-IFN = pegylated interferon; RBV = ribavirin; SD = standard deviation *Total percentage may not add to 100% due to rounding.

Study Results

Table 24 presents the SVR12 for the ASTRAL-4 trial by HCV genotype, the SVR12 for genotype 1 or 3 HCV infected patients stratified by prior HCV treatment, and virologic outcomes. All 3 treatment groups met their primary efficacy endpoints with SVR12 rates that were statistically superior compared with the assumed spontaneous rate of 1%. The p-value was < 0.001 for the comparison with the SVR12 for each treatment group.

Table 24. SVR12 and Treatment Outcomes in Study ASTRAL-4 by HCV Genotype and Selected Subgroups

RBV = ribavirin

• a. The exact 95% CI for the proportion of within treatment group was based on the Clopper-Pearson method.
• b. N=4 for genotype 2 and N=4 for genotype 4.
• c. N=4 for genotype 2 and N=2 for genotype 4.
• d. N=4 for genotype 2, N=2 for genotype 4 and N=1 for genotype 6.
• e. Data for genotypes 2, 4, and 6 are not included.
• f. Genotype 1 and 3 HCV patients who did not achieve SVR and did not have virologic failure are not included in this Table.
• g. No patients with genotype 1 HCV had on-treatment virologic failure.
• h. One patient had on-treatment virologic failure; PK data for this patient was consistent with non-adherence.
• i. One patient had on-treatment virologic failure.

Note: There were no patients enrolled with genotype 5 infection.

The overall SVR12 (virologic cure) in ASTRAL-4 for the recommended treatment regimen was 94% (82/87). No patients with genotype 2, 4 or 6 HCV experienced virologic failure. Among patients who received EPCLUSA + RBV for 12 weeks, the SVR12 rates in selected subgroups were as follows: with IL28B C/C allele (100.0%), non-CC (C/T or T/T) allele (92.3%); baseline HCV RNA < 800,000 IU/mL (95.2%), baseline HCV RNA ≥ 800,000 IU/mL (93.3%); baseline BMI < 30 kg/m² (92.6%), baseline BMI ≥ 30 kg/m² (97.0%); sex (males [92.4%], females [100.0%]); and race (White [93.7%], Black [100.0%], Other [100.0%]).

Changes in MELD and CPT score from baseline to post-treatment Week 12 (secondary endpoint) were analyzed for patients who achieved SVR12 and for whom data were available (N = 234) to assess the effect of SVR12 on hepatic function post-treatment. Of the 82 patients treated with EPCLUSA + RBV for 12 weeks who achieved SVR12, 81 had MELD and CPT assessments at baseline and post-treatment Week 12.

Change in MELD score: Among those who achieved SVR12 with 12 Weeks treatment with EPCLUSA + RBV, 51% (41/81) and 15% (12/81) had an improvement or no change in MELD score from baseline to post-treatment Week 12, respectively; of the 10 patients whose MELD score was ≥ 15 at baseline, 40% (4/10) had a MELD score < 15 at post-treatment Week 12. Improvement in MELD score was due to improvement (decreases) in bilirubin.

Change in CPT: Among those who achieved SVR12 with 12 Weeks treatment with EPCLUSA + RBV, 41% (33/81) and 49% (40/81) had an improvement or no change of CPT scores from baseline to post-treatment Week 12, respectively. Of the 72 patients who had CPT B cirrhosis at baseline, 11% (8/72) had CPT A cirrhosis at post-treatment Week 12. Improvement in CPT score was due to improvements in albumin (increases) and bilirubin (decreases).

Similar proportions of patients treated with EPCLUSA for 12 or 24 weeks had improvements in MELD and CPT scores compared with patients treated with EPCLUSA + RBV for 12 weeks.

Clinical Trial in Adult Patients with HCV/HIV-1 Co-infection (ASTRAL-5)

Trial Design

Table 25. Summary of Trial Design in Patients with HCV/HIV-1^a Co-infection with or without Cirrhosis (ASTRAL-5)

PO = orally; QD = once a day

• a. Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, raltegravir or elvitegravir/cobicistat.

Demographics and Other Baseline Characteristics

Table 26. Demographic and Other Baseline Characteristics of HCV/HIV-1 Co-infected Patients with or without Cirrhosis (ASTRAL-5)

DAA = direct acting antiviral; Peg-IFN = pegylated interferon; RBV= ribavirin; SD = standard deviation *Total percentage may not add to 100% due to rounding.

Study Results

Table 27 presents the SVR12 for the ASTRAL-5 trial by HCV genotype and for selected subgroups.

Table 27. SVR12^a and Treatment Outcomes in HCV/HIV-1^b Co-infected Patients with or without Cirrhosis and for Selected Subgroups (ASTRAL-5)

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

b. Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir or abacavir/lamivudine administered with a ritonavir boosted protease-inhibitor (atazanavir, darunavir, or lopinavir), rilpivirine, raltegravir or elvitegravir/cobicistat/emtricitabine/tenofovir DF. c. The exact 95% CI for the proportion of within treatment group was based on the Clopper-Pearson method. d. The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. e. One GT-1a patient discontinued the study due to adverse event. f. Other includes patients who did not achieve SVR and did not meet virologic failure criteria.

Among patients who received EPCLUSA for 12 weeks, the SVR12 rates in selected subgroups were as follows: with IL28B C/C allele (95.8%), non-CC (C/T or T/T) allele (95.1%); baseline HCV RNA < 800,000 IU/mL (96.4%), baseline HCV RNA ≥ 800,000 IU/mL (94.9%); baseline BMI < 30 kg/m² (96.4%), baseline BMI ≥ 30 kg/m² (91.3%); sex (males [96.7%], females [86.7%]); and race (White [96.3%], Black [93.8%], Other [100.0%]).

No patient had HIV-1 rebound during the study, and CD4+ counts were stable during treatment.

Clinical Trial in Patients with Renal Impairment

Study GS-US-342-4062 was an open-label clinical trial that evaluated 12 weeks of treatment with EPCLUSA in 59 HCV-infected patients with ESRD requiring dialysis. The proportions of patients with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%, 12%, 27%, 7%, 3%, and 9%, respectively. At baseline, 29% of patients had cirrhosis, 22% were treatment experienced, 32% had received a kidney transplant, 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7.3 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59); of the 3 patients that did not achieve SVR12, 1 had completed EPCLUSA treatment and relapsed and 2 did not meet virologic failure criteria.

Clinical Trial in People Who Inject Drugs (PWID) Including Those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

SIMPLIFY was an open-label clinical trial that evaluated 12 weeks of treatment with EPCLUSA in 103 HCV-infected adult PWID (defined as self-reported injection drug use within previous 6 months), including 58 patients on MAT for opioid use disorder. The proportions of patients with genotype 1, 2, 3, and 4 HCV infection were 35%, 5%, 58%, and 2%, respectively. The median age was 48 years (range: 24 to 67); 71% were male; 89% were White; and 2% were Black. At baseline, 74% and 26% of patients reported injection drug use or daily injection drug use, respectively, in the past month; 54% and 60% of patients reported non-injection drug use and alcohol use, respectively, in the past month; 56% had baseline HCV RNA levels at least 800,000 IU/mL; 10% had compensated cirrhosis; and all patients were naïve to prior exposure with SOF or an HCV NS5A inhibitor. Patients on MAT for opioid use disorder reported concomitant use of methadone (76%) and buprenorphine/naloxone (17%) with EPCLUSA. Overall, 99/103 subjects (96%) completed 12 weeks of EPCLUSA. The overall SVR rate was 94% (97/103; 95% confidence interval: 87.8% to 97.8%). One patient completed EPCLUSA treatment and was re-infected; the other 5 patients who did not achieve SVR12 did not meet virologic failure criteria.

Clinical Trial in Pediatric Patients

Trial Design and Study Demographics

The efficacy of EPCLUSA once daily for 12 weeks in HCV-infected pediatric patients ≥ 12 years of age was evaluated in a Phase 2, open-label clinical trial (Study GS-US-342-1143, Cohort 1) in 102 pediatric patients with HCV infection. Pediatric patients with HIV-1 co-infection were excluded from the study. The demographic and baseline characteristics of this patient population are summarized in Table 28.

Table 28. Demographic and Other Baseline Characteristics in Pediatric Patients (GS-US-342-1143, Cohort 1)

a. Total percentage may not add to 100% due to rounding.

b. The one patient with a missing HCV genotype at baseline was subsequently confirmed to have genotype 1b HCV infection.

Study Results

Table 29 presents the response rates for pediatric patients by HCV genotype. The overall SVR rate was 95% (97/102; 95% confidence interval: 88.9% to 98.4%). One patient who discontinued treatment subsequently relapsed at Week 4; the other four patients who did not achieve SVR12 did not meet virologic failure criteria (eg, lost to follow-up).

Table 29. Sustained Virologic Response (SVR12)^a in Pediatric Patients (GS-US-342-1143, Cohort 1)

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

15 MICROBIOLOGY

Antiviral Activity in Cell Culture

The EC50 values of sofosbuvir and velpatasvir against full-length or chimeric replicons encoding NS5B and NS5A sequences from the laboratory strains are presented in Table 30. The EC50 values of sofosbuvir and velpatasvir against clinical isolates are presented in Table 31.

Table 30. Activity of Sofosbuvir and Velpatasvir 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 replicon or chimeric NS5A replicons carrying full-length NS5A gene that contains L31 or M31 polymorphisms.
• d. Data from a chimeric NS5A replicon carrying NS5A amino acids 9-184.

Table 31. Activity of Sofosbuvir and Velpatasvir Against Transient Replicons Containing NS5A or NS5B from Clinical Isolates

NA = not available

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 8 genotypes 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, 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 32 below. No individual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction in velpatasvir susceptibility (see Resistance, In Clinical Trials, Effect of Baseline HCV Resistance Associated Variants on Treatment Outcome). Combinations of these variants often showed greater reductions in susceptibility to velpatasvir than single RAVs alone.

Table 32. Phenotypic Change of Genotype 1-6 NS5A Substitutions to Velpatasvir

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

In Clinical Trials

Studies in Adult Patients with Compensated Cirrhosis

In a pooled analysis of patients without cirrhosis or with compensated cirrhosis who received EPCLUSA for 12 weeks in Phase 3 trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3), 12 patients (2 with genotype 1 and 10 with genotype 3) qualified for resistance analysis due to virologic failure. One additional virologic failure patient with genotype 3 HCV infection at baseline was reinfected with genotype 1a HCV at virologic failure and was excluded from the virological analysis. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic failure.

Of the two genotype 1 virologic failure patients, one patient had virus with emergent NS5A RAV Y93N and the other patient had virus with emergent NS5A RAVs L31I/V and Y93H at virologic failure. Both patients had virus at baseline harboring NS5A RAVs. No NS5B nucleoside inhibitor (NI) RAVs were observed at failure in the two patients.

Of the ten genotype 3 virologic failure patients, Y93H was observed in all 10 patients at failure (6 had Y93H emerge post-treatment and 4 patients had Y93H at baseline and post-treatment). No NS5B NI RAVs were observed at failure in the ten patients.

Studies in Adult Patients with Decompensated Cirrhosis

In the ASTRAL-4 trial in patients with decompensated cirrhosis who received EPCLUSA + RBV for 12 weeks, 3 patients (one with genotype 1 and two with genotype 3) qualified for resistance analysis due to virologic failure. No patients with genotype 2 or 4 HCV infection in the EPCLUSA + RBV 12-week group experienced virologic failure.

The one virologic failure patient with genotype 1 HCV had no NS5A or NS5B RAVs at failure.

Of the two genotype 3 virologic failure patients, one had NS5A RAV Y93H emerge at failure. Another patient had virus with Y93H at baseline and virologic failure and also developed low levels (< 5%) of NS5B NI RAVs N142T and E237G at failure. Pharmacokinetic data of this patient was consistent with non-adherence.

In the ASTRAL-4 trial, two patients treated with EPCLUSA for 12 or 24 weeks without ribavirin had emergent NS5B S282T at low levels (< 5%) along with L159F.

Effect of Baseline HCV Resistance Associated Variants on Treatment Outcome

Adults

Studies in Patients with Compensated Cirrhosis

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients without cirrhosis or with compensated cirrhosis (ASTRAL-1, ASTRAL-2, and ASTRAL-3). Of the 1035 patients treated with EPCLUSA in the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies, 1023 patients were included in the analysis of NS5A RAVs; 7 patients were excluded as they neither achieved SVR12 nor had virologic failure and 5 additional patients were excluded as NS5A gene sequencing failed. In the pooled analysis of the Phase 3 trials, 380/1023 (37%) patients’ virus had baseline NS5A RAVs. Genotype 2, 4, and 6 HCV infected patients had a higher prevalence of NS5A RAVs (70%, 63% and 52%, respectively) compared to genotype 1 (23%), genotype 3 (16%), and genotype 5 (18%) HCV infected patients.

SVR12 in patients with or without baseline NS5A RAVs in ASTRAL-1, ASTRAL-2, and ASTRAL-3 trials is shown in Table 33.

Table 33. SVR12 in Patients with or without Baseline NS5A RAVs by HCV Genotype (ASTRAL-1, ASTRAL-2, ASTRAL-3)

RAVs = resistance associated variants; RBV = ribavirin; SVR = sustained virologic response

Among the 75 genotype 1 patients who had baseline NS5A RAVs, SVR12 was 97% (67/69) and 100% (6/6) in patients with baseline NS5A RAVs that confer ≤ 100-fold and > 100-fold reduced susceptibility to velpatasvir, respectively. Among the 43 genotype 3 patients who had baseline NS5A RAVs, SVR12 was 94% (15/16) and 85% (23/27) in patients with NS5A RAVs that confer ≤ 100-fold and > 100-fold reduced susceptibility to velpatasvir, respectively. The four genotype 3 patients who had baseline NS5A RAVs conferring > 100-fold reduced susceptibility to velpatasvir and failed to achieve SVR12 all had NS5A substitution Y93H at baseline. Twenty-one of 25 genotype 3 patients with baseline NS5A substitution Y93H achieved SVR12.

The NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient in Phase 3 trials. SVR12 was achieved in all 77 patients who had baseline NS5B NI RAVs including N142T, L159F, E/N237G, C/M289L/I, L320F/I/V, V321A/I, and S282G+V321I.

Studies in Patients with Decompensated Cirrhosis

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients with decompensated cirrhosis (ASTRAL-4). Of the 87 patients treated with EPCLUSA + RBV in the ASTRAL-4 study, 85 patients were included in the analysis of NS5A RAVs; 2 patients were excluded as they neither achieved SVR12 nor had virologic failure. Among the patients who received treatment with EPCLUSA + RBV for 12 weeks, 29% (25/85) of patients had baseline virus with NS5A RAVs [29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) for patients with genotype 1, 2, 3 and 4 HCV, respectively].

SVR12 in patients with or without baseline NS5A RAVs in the EPCLUSA + RBV 12-week group of ASTRAL-4 trial is shown in Table 34.

Table 34. SVR12 in Patients with or without Baseline NS5A RAVs by HCV Genotype (ASTRAL-4)

RAVs = resistance associated variants; RBV = ribavirin

The single genotype 3 patient who had baseline NS5A RAVs and failed to achieve SVR12 had NS5A substitution Y93H at baseline and the pharmacokinetic data of this patient was consistent with non-adherence. Three patients in the EPCLUSA + RBV 12-week group had baseline NS5B NI RAVs (N142T and L159F) and all three patients achieved SVR12.

Pediatrics

In Study GS-US-342-1143, the presence of NS5A and NS5B RAVs did not impact treatment outcome; all pediatric patients 12 years to <18 years of age with baseline NS5A or NS5B NI RAVs (16.3% [16/98] and 5.2% [5/97], respectively) achieved SVR following 12 weeks treatment with EPCLUSA.

Cross Resistance

Sofosbuvir retained activity against the NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. In vitro data suggests that the majority of NS5A RAVs that confer resistance to ledipasvir and daclatasvir remained susceptible to velpatasvir. Velpatasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all velpatasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and velpatasvir were fully active against substitutions associated with resistance to other classes of DAAs with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of EPCLUSA has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.

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 63-fold higher than HCV-infected patients treated once daily with EPCLUSA. 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 EPCLUSA.

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 74-, 5-, and

10-fold greater in mice, rats, and dogs, respectively, than those in HCV-infected patients treated once daily with EPCLUSA.

Carcinogenicity:

Sofosbuvir

Sofosbuvir was not carcinogenic in the 2-year mouse and rat carcinogenicity studies at doses resulting in GS-331007 exposures up to 15-times in mice and 9-times in rats, higher than human exposure at 400 mg dose.

Velpatasvir

Velpatasvir was not carcinogenic in the 26-week transgenic mouse and 2-year rat carcinogenicity studies at exposures up to 91- and 7-times, respectively, higher than human exposure.

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.

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.

Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through lactation day 20 at daily GS-331007 exposures of approximately 6-fold higher than human exposures at the recommended clinical dose.

Velpatasvir

Velpatasvir had no adverse effects on fertility in rats at AUC exposure 6-fold higher than the human exposure at the recommended clinical dose.