Maviret Product Monograph

Recent Major Label Changes

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Table of Contents

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 5

1. 1.

   Indications ....................................................................................................................... 5

   1.1. Pediatrics .................................................................................................................. 5

   1.2. Geriatrics .................................................................................................................. 5

2. 2. Contraindications ............................................................................................................ 5
3. 3. Serious Warnings and Precautions Box ............................................................................ 7
4. 4.

   Dosage and Administration ............................................................................................. 7

   4.1. Dosing Considerations .............................................................................................. 7

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 7

   4.3. Reconstitution ........................................................................................................ 10

   4.4. Administration ........................................................................................................ 10

   4.5. Missed Dose ........................................................................................................... 10

5. 5. Overdose ....................................................................................................................... 10
6. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................. 11
7. 7.

   Warnings and Precautions ............................................................................................. 12

   General ............................................................................................................................... 12

   Endocrine and Metabolism ................................................................................................. 12

   HCV/HBV Co-infection ........................................................................................................ 12

   Hepatic/Biliary/Pancreatic .................................................................................................. 12

   Monitoring and Laboratory Tests ....................................................................................... 13

   Reproductive Health ........................................................................................................... 13

   7.1. Special Populations ................................................................................................ 13

   7.1.1. Pregnancy ...................................................................................................... 13

   7.1.2. Breastfeeding ................................................................................................ 14

   7.1.3. Pediatrics ....................................................................................................... 14

   7.1.4. Geriatrics ....................................................................................................... 14

8. 8.

   Adverse Reactions ......................................................................................................... 15

   8.1. Adverse Reaction Overview .................................................................................... 15

   8.2. Clinical Trial Adverse Reactions .............................................................................. 15

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics .................................................. 18

   8.3. Less Common Clinical Trial Adverse Reactions ....................................................... 19

   8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics ........................... 19

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................... 19

   8.5. Post-Market Adverse Reactions ............................................................................. 19

9. 9.

   Drug Interactions ........................................................................................................... 20

   9.2. Drug Interactions Overview .................................................................................... 20

   9.4. Drug-Drug Interactions ........................................................................................... 20

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

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

   9.7. Drug-Laboratory Test Interactions ......................................................................... 28

10. 10.

    Clinical Pharmacology ................................................................................................... 28

    10.1. Mechanism of Action .............................................................................................. 28

    10.2. Pharmacodynamics ................................................................................................ 28

    10.3. Pharmacokinetics ................................................................................................... 28

11. 11. Storage, Stability, and Disposal ...................................................................................... 33

Part 2: Scientific Information ................................................................................................ 34

1. 13. Pharmaceutical Information .......................................................................................... 34
2. 14.

   Clinical Trials .................................................................................................................. 36

   14.1. Clinical Trials by Indication ..................................................................................... 36

   Chronic HCV Infection ................................................................................................... 36

   Acute HCV Infection ...................................................................................................... 63

3. 15. Microbiology ................................................................................................................. 65
4. 16. Non-Clinical Toxicology .................................................................................................. 70

Patient Medication Information ........................................................................................... 71

Patient Medication Information ........................................................................................... 77

Part 1: Healthcare Professional Information

1. Indications

MAVIRET (glecaprevir/pibrentasvir) is indicated for the treatment of acute and chronic hepatitis C virus (HCV) infection in adults and pediatric patients 3 years of age and older and weighing ≥ 12 kg (see 4. Dosage and Administration and 14. Clinical Trials).

1.1. Pediatrics

Pediatrics (3 to less than 18 years old): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of MAVIRET in pediatric patients 3 to less than 18 years old has been established. Therefore, Health Canada has authorized an indication for pediatric use (see 4. Dosage and Administration and 14. Clinical Trials).

MAVIRET has not been authorized for use in pediatric patients less than 3 years of age.

1.2. Geriatrics

In clinical studies of MAVIRET in patients with chronic HCV infection, 328 patients were age 65 and over and 47 were age 75 and over. In a clinical study of MAVIRET in patients with acute HCV infection, 16 patients were age 65 and over and 1 was age 75 and over. No overall difference in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the geriatric and younger patients.

2. Contraindications

MAVIRET is contraindicated:

• in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see the 6. Dosage Forms, Strengths, Composition and Packaging section.
• in patients with severe hepatic impairment (Child-Pugh C), as the safety and efficacy have not been established (see 10.3. Pharmacokinetics, Special populations and conditions, Hepatic Insufficiency).

Table 1. Drugs that Are Contraindicated with MAVIRET

3. Serious Warnings and Precautions Box

Potential for Hepatitis B virus (HBV) reactivation: Screen all patients for evidence of current or prior HBV infection before initiating MAVIRET therapy. Cases of HBV reactivation, including those resulting in fulminant hepatitis, hepatic failure, and death, have been reported during HCV treatment and/or post-treatment with regimens containing direct-acting HCV antivirals (DAAs) in patients co-infected with HBV (see 7. Warnings and Precautions, Hepatic/Biliary/Pancreatic, Risk of Hepatitis B Virus Reactivation).

4. Dosage and Administration

4.1. Dosing Considerations

• MAVIRET treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection.
• Treatment durations depend on HCV genotype, cirrhosis status, and treatment history.
• Screen all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating treatment for HCV with MAVIRET (see 7. Warnings and Precautions, Hepatic/Biliary/Pancreatic, Risk of Hepatitis B Virus Reactivation).

4.2. Recommended Dose and Dosage Adjustment

Table 2 and Table 3 provide the recommended MAVIRET treatment duration based on the patient population in HCV mono-infected and HCV/HIV-1 co-infected patients with compensated liver disease (with or without cirrhosis) and with or without renal impairment including patients receiving dialysis.

Table 2. Recommended MAVIRET Treatment Duration for Treatment-Naïve Patients^a Infected by Genotypes 1 to 6

Table 3. Recommended MAVIRET Treatment Duration for Treatment-Experienced Patients^a Infected by Genotypes 1 to 6

Recommended Dosage of MAVIRET Tablets in Adults, Adolescents 12 Years and Older, or Pediatric Patients Weighing at Least 45 kg

MAVIRET tablets are a fixed-dosed combination product containing glecaprevir 100 mg and pibrentasvir 40 mg in each tablet.

MAVIRET tablets should be taken with food; they should be swallowed whole and not chewed, crushed or broken.

The recommended daily dose of MAVIRET is three glecaprevir/pibrentasvir 100/40 mg tablets (total dose: glecaprevir 300 mg and pibrentasvir 120 mg) taken orally at the same time with food without regard to fat or calorie content (see 10. Clinical Pharmacology).

The treatment duration for adults and adolescents are noted in Table 2 and Table 3 above.

Recommended Dosage of MAVIRET Granules in Sachets in Pediatric Patients 3 Years and Older (Weighing at least 12 kg to less than 45 kg)

MAVIRET granules in sachets are a fixed-dose combination product containing glecaprevir 50 mg and pibrentasvir 20 mg in each sachet.

MAVIRET granules should be taken with food. The number of sachets and dosage based on body weight for pediatric patients 3 years and older and weighing 12 kg to less than 45 kg are in Table 4.

The treatment duration for pediatric patients 3 years and older and weighing 12 kg to less than 45 kg are the same as those for adults and adolescents as noted in Table 2 and Table 3 above.

Because the formulations have different pharmacokinetic profiles, the tablets and the granules are not interchangeable.

Table 4. Recommended Dosage of MAVIRET Granules in Sachets for Pediatric Patients 3 Years to Less than 12 Years Old and Weighing 12 kg to less than 45 kg

The adult and adolescent dose of MAVIRET tablets should be used in children weighing 45 kg or greater (See Recommended Dosage of MAVIRET Tablets in Adults, Adolescents 12 Years and Older, or Pediatric Patients Weighing at Least 45 kg). See the Instructions for Use for details on the preparation and administration of MAVIRET granules in sachets.

• The sachets should be taken together, with food, once daily. In addition, the total daily dose of the granules should be sprinkled on a small amount of soft food with a low water content that will stick to a spoon and can be swallowed without chewing (e.g., peanut butter, chocolate hazelnut spread, cream cheese, thick jam, or Greek yogurt). Liquids or foods that would drip or slide off the spoon should not be used as the drug may dissolve quickly and become less effective.
• The mixture of food and granules should be swallowed immediately (within 15 minutes of preparation); the granules should not be crushed or chewed.

Note: Opened sachets with granules should be used immediately and not stored.

Pediatrics (< 18 years of age)

Pediatric patients from 3 to less than 12 years of age should receive doses based on body weight. See Recommended Dosage of MAVIRET Granules in Sachets in Pediatric Patients 3 Years and Older (Weighing at least 12 kg to less than 45 kg).

No dose adjustment for MAVIRET is required in adolescents 12 years and older (see 10.3. Pharmacokinetics, Special populations and conditions, Pediatrics).

The safety and efficacy of MAVIRET in patients less than 3 years of age or weighing less than 12 kg have not been established.

MAVIRET has not been authorized for use in pediatric patients less than 3 years of age.

Geriatrics (> 65 years of age)

No dose adjustment of MAVIRET is required in geriatric patients.

Gender

No dose adjustment of MAVIRET is necessary based on gender.

Race/Ethnicity

No dose adjustment of MAVIRET is necessary based on race or ethnicity.

Hepatic Impairment

No dose adjustment of MAVIRET is required in patients with mild hepatic impairment (Child-Pugh A). MAVIRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see 2. Contraindications and 10.3. Pharmacokinetics, Special populations and conditions, Hepatic Insufficiency).

Renal Impairment

No dose adjustment of MAVIRET is required in patients with any degree of renal impairment including patients on dialysis (see 10.3. Pharmacokinetics, Special populations and conditions, Renal Insufficiency).

Liver or Kidney Transplant Patients

MAVIRET is recommended for 12 weeks in liver or kidney transplant recipients who are HCV genotype 1 to 6 treatment-naïve (TN) or genotype 1, 2, 4, 5, 6 PRS-treatment experienced. A 16-week treatment duration should be considered in transplant patients who are genotype 1 NS5A inhibitor-experienced (NS3/4A inhibitor-naïve) or genotype 3 PRS-treatment experienced (see Table 2, Table 3 and 14.1. Clinical Trials by Indication, Clinical Study in Liver or Kidney Transplant Recipients).

4.3. Reconstitution

Not applicable.

4.4. Administration

MAVIRET should be administer with food without regard to fat or calorie content (see 10.3. Pharmacokinetics, Absorption, Effects of Food on Oral Absorption).

4.5. Missed Dose

Patients should be informed that in case a dose is missed, the prescribed dose can be taken within 18 hours of the scheduled time for the dose that was missed.

If more than 18 hours has passed since the dose is usually taken, the missed dose should NOT be taken and the patient should take the next dose as per the usual dosing schedule.

If vomiting occurs within 3 hours of dosing, an additional dose of MAVIRET should be taken. If vomiting occurs more than 3 hours after dosing, an additional dose of MAVIRET is not needed.

5. Overdose

The highest documented doses administered to healthy volunteers is 1200 mg once daily for 7 days for glecaprevir and 600 mg once daily for 10 days for pibrentasvir. In case of overdose, the patient should be monitored for any signs and symptoms of toxicities. Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir were not significantly removed by hemodialysis.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 5. Dosage Forms, Strengths and Composition

Tablets

MAVIRET 100/40 mg tablets are pink-colored, film-coated, oblong biconvex shaped and debossed with “NXT” on one side.

MAVIRET tablets are dispensed in a monthly carton. Each monthly carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.

Each daily dose pack contains three 100/40 mg glecaprevir/pibrentasvir tablets.

MAVIRET tablets are gluten free.

Granules in sachet

MAVIRET granules are for oral administration, supplied as small pink and yellow granules in unit-dose sachets.

MAVIRET unit-dose sachets are dispensed in a carton. Each carton contains 28 sachets.

Each unit-dose sachet of MAVIRET oral granules contains 50 mg glecaprevir and 20 mg pibrentasvir.

MAVIRET granules are gluten free.

7. Warnings and Precautions

General

MAVIRET should not be coadministered with other medicinal products containing NS3/4A protease and NS5A inhibitors.

The number of patients infected with genotype 5 and genotype 6 were limited.

Use with Potent P-gp and CYP3A4 Inducers

Medicinal products that are potent P-glycoprotein (P-gp) and CYP3A4 inducers (e.g. carbamazepine, efavirenz, St. John’s Wort, phenobarbital, and phenytoin) significantly decrease the plasma concentration of glecaprevir and pibrentasvir, which may lead to reduced therapeutic effect of MAVIRET or loss of virologic response. These drugs are not recommended with MAVIRET (see 9.4. Drug-Drug Interactions, Table 8).

Endocrine and Metabolism

Lactose Intolerance

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

HCV/HBV Co-infection

The safety and efficacy of MAVIRET have not been established in HCV patients co-infected with HBV.

Hepatic/Biliary/Pancreatic

Hepatic Decompensation and Hepatic Failure

MAVIRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B). MAVIRET is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see 2. Contraindications). 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 MAVIRET. 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. Hepatic laboratory testing should be performed as clinically indicated in patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension. In patients with cirrhosis, more frequent hepatic laboratory testing may be warranted; and patients should be monitored for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue MAVIRET in patients who develop evidence of hepatic decompensation/ failure.

Risk of Hepatitis B Virus Reactivation

Cases of hepatitis B virus (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 DAA. 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 (i.e., HBsAg negative and anti-HBc positive) should be monitored and treated according to current clinical practice guidelines to manage potential for HBV reactivation (see 7. Warnings and Precautions, Monitoring and Laboratory Tests, Patients Co-infected with HBV).

Monitoring and Laboratory Tests

Patients Co-infected with HBV

Clearance of HCV may lead to increased replication of HBV in patients who are HCV/HBV co-infected. Co-infected patients with HBV should be monitored for clinical and laboratory signs (e.g. HBsAg, anti-HBc, HBV DNA, serum aminotransferase levels, bilirubin) for hepatitis flare or HBV reactivation during HCV treatment and at post-treatment follow-up as clinically appropriate (see 7. Warnings and Precautions, Hepatic/Biliary/Pancreatic, Risk of Hepatitis B Virus Reactivation).

Patients Treated with Vitamin K Antagonist

As liver function may change during treatment with MAVIRET, a close monitoring of International Normalised Ratio (INR) is recommended.

Potential Effects of HCV Clearance by Direct-Acting Antivirals (DAA) (Class Therapeutic Effect)

Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, patients may experience improved glucose metabolism by the liver. In diabetic patients, this could lead to improved glucose control. Rare cases of symptomatic hypoglycemia have been reported with the use of HCV DAAs. Close monitoring of relevant laboratory parameters such as blood glucose levels in diabetic patients or International Normalized Ratio [INR] in patients taking vitamin K antagonists is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary (see 9. Drug Interactions).

Reproductive Health

• Fertility

  No human data on the effect of glecaprevir and/or pibrentasvir on fertility are available. Animal studies do not indicate harmful effects of glecaprevir or pibrentasvir on fertility at exposures higher than the exposures in humans at the recommended dose (see 16. Non-Clinical Toxicology, Reproductive and developmental toxicology).

7.1. Special Populations

7.1.1. Pregnancy

Pregnancy should be avoided while taking MAVIRET as there are no data on the use of MAVIRET in pregnant women. As a precautionary measure, MAVIRET use is not recommended in pregnancy unless the potential benefit justifies the potential risk to the fetus. Patients should be advised to notify their health care provider immediately in the event of a pregnancy.

In animal reproduction studies, no adverse developmental effects were observed when the components of MAVIRET were administered separately during organogenesis at exposures up to 53 and 0.07 times (rats and rabbits, respectively; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose of MAVIRET. Maternal toxicity in the rabbit precluded evaluation of glecaprevir at clinical exposures. There were no effects with either compound in rodent peri/postnatal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at the recommended dose.

7.1.2. Breastfeeding

It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from MAVIRET therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

7.1.3. Pediatrics

Because the tablet and pediatric granule formulations have different pharmacokinetic profiles, the tablets and the granules are not interchangeable.

No dose adjustment for MAVIRET is required in adolescents 12 years and older (see 10.3. Pharmacokinetics, Special populations and conditions, Pediatrics). Pediatric patients aged 3 to less than 12 years of age and weighing 12 kg to less than 45 kg should receive doses based on body weight (see 4. Dosage and Administration).

MAVIRET exposures in patients 12 to less than 18 years with chronic HCV were comparable to those in adults with chronic HCV infection. The safety and efficacy of MAVIRET in patients 3 to less than 18 years infected with HCV genotype 5 or 6 and/or with compensated cirrhosis and/or previously treated with a regimen containing NS5B inhibitor have not been studied.

Use of MAVIRET in pediatric patients with acute HCV infection is supported by extrapolation of the totality of evidence including safety and efficacy from adult patients with acute HCV infection and adult and pediatric patients with chronic HCV infection. It is expected that adult and pediatric patients with acute HCV infection have similar disease response to treatment. No clinically meaningful differences in glecaprevir and pibrentasvir exposures are expected among pediatric patients with acute HCV infection and pediatric patients with chronic HCV infection (see 10.3 Pharmacokinetics, Special populations and conditions, Pediatrics).

The safety and efficacy of MAVIRET in patients less than 3 years of age or weighing less than 12 kg have not been established.

7.1.4. Geriatrics

In clinical studies of MAVIRET in patients with chronic HCV infection, 328 patients were age 65 and over and 47 were age 75 and over. In a clinical study of MAVIRET in patients with acute HCV infection, 16 patients were age 65 and over and 1 was age 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the geriatric and younger patients.

8. Adverse Reactions

8.1. Adverse Reaction Overview

Chronic HCV Infection

The safety assessment for MAVIRET in patients with compensated liver disease (with or without cirrhosis) were derived from pooled Phase 2 and 3 registrational studies which evaluated approximately 2,300 adult patients infected with genotype 1, 2, 3, 4, 5, or 6 HCV who received MAVIRET for 8, 12, or 16 weeks.

MAVIRET was generally well-tolerated and the overall proportion of patients who permanently discontinued treatment due to adverse reactions was 0.1% for patients who received MAVIRET.

Across the Phase 2 and 3 clinical studies, the most common (occurring in at least 10% of patients) adverse reactions (adverse events assessed as possibly related by the investigator) were headache and fatigue in patients treated with MAVIRET for 8, 12, or 16 weeks.

There were no differences in the overall safety for patients receiving MAVIRET for 8, 12, or 16 weeks. The type and severity of adverse reactions in patients with cirrhosis were comparable to those seen in patients without cirrhosis.

Acute HCV Infection

The overall safety profile observed in patients with acute HCV infection treated with MAVIRET was consistent with the safety profile observed in patients with chronic HCV infection. No new safety findings were identified.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Chronic HCV Infection

Adverse reactions observed in greater than or equal to 3% of adult patients receiving 8, 12, or 16 weeks of treatment with MAVIRET are presented in Table 6. The most common adverse reactions were headache and fatigue in patients treated with MAVIRET overall. In patients receiving MAVIRET who experienced adverse reactions, 80% had an adverse reaction of mild severity (Grade 1), 19% had an adverse reaction of moderate severity (Grade 2), < 1% had an adverse reaction of severe severity (Grade 3), and no subject had a Grade 4 or 5 adverse reaction. In the placebo-controlled study (ENDURANCE-2), these adverse reactions occurred at a similar frequency in patients treated with placebo compared to patients treated with MAVIRET. In the active-controlled study (ENDURANCE-3), adverse reactions occurred at a similar frequency in patients treated with sofosbuvir and daclatasvir for 12 weeks compared to patients treated with MAVIRET for 12 weeks. The rate of discontinuation due to adverse drug reactions (ADRs) was similar for MAVIRET (0.4%) and for sofosbuvir and daclatasvir (0.9%).

Table 6. Adverse Reactions (All Grades) Observed in ≥ 3.0% of the Adult Patients with Chronic HCV Infection in Phase Registrational 2, 3 Clinical Studies

Adverse Reactions in Adult Patients with Severe Renal Impairment Including Patients on Dialysis

The safety of MAVIRET in patients with chronic kidney disease (Stage 4 or Stage 5 including patients on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in 104 patients (EXPEDITION-4). The most common adverse reactions were pruritus and fatigue in patients treated with MAVIRET for 12 weeks. Adverse reactions observed in greater than or equal to 3% of patients receiving 12 weeks of treatment with MAVIRET are presented in Table 7. In patients treated with MAVIRET who reported an adverse reaction, 55% had adverse reactions of mild severity, 35% had a severity of Grade 2, and 10% had a severity of Grade 3. No patients experienced a serious adverse reaction. The proportion of patients who permanently discontinued treatment due to adverse reactions was 1.9%.

Table 7. Adverse Reactions (All Grades) Observed in ≥ 3% of the Adult Patients with Chronic HCV Infection with Severe Renal Impairment Including Patients on Dialysis (EXPEDITION-4)

Adverse Reactions in HCV/HIV-1 Co-infected Adult Patients

The overall safety profile in HCV/HIV-1 co-infected patients (ENDURANCE-1 and EXPEDITION-2) was comparable to that observed in HCV mono-infected patients.

Adverse Reactions in Adult Patients with Liver or Kidney Transplant

The safety of MAVIRET was assessed in 100 post-liver or -kidney transplant recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was comparable to that observed in patients in the Phase 2 and 3 studies. Adverse reactions observed in greater than or equal to 5% of patients receiving MAVIRET for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%). In patients treated with MAVIRET who reported an adverse reaction, 81% had adverse reactions of mild severity. Two percent of patients experienced a serious adverse reaction, and no patients permanently discontinued treatment due to adverse reactions.

Adverse Reactions in People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

PWID

The safety of MAVIRET in PWID with HCV genotype 1, 2, 3, 4, 5 or 6 infection is based on data from Phase 2 and 3 trials of adults and adolescents in which 62 patients identified as current/recent PWID (defined as self-reported injection drug use within the last 12 months prior to starting MAVIRET), and 3,282 patients reported no injection drug use (non-PWID).

Among current/recent PWID, adverse reactions observed in greater than or equal to 5% of patients were fatigue (16%), headache (13%), diarrhea (6%), and nausea (6%). Among non-PWID patients, adverse reactions observed in greater than or equal to 5% of patients were headache (7%) and fatigue (6%). Serious adverse reactions and/or adverse reactions leading to treatment discontinuation occurred in one current/recent PWID patient (2%) as compared to less than 1% in non-PWID patients.

MAT

Among 225 patients reporting concomitant use of MAT for opioid use disorder, adverse reactions observed in greater than or equal to 5% of patients were headache (15%), fatigue (12%), nausea (11%), and diarrhea (6%). Among 4,098 patients who were not on MAT, adverse reactions observed in greater than or equal to 5% of patients were headache (9%), fatigue (8%), and nausea (5%). Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among patients on MAT and were experienced by less than 1% of patients not on MAT.

Acute HCV Infection

The safety assessment of MAVIRET is based on a Phase 3b clinical study (M20-350) involving 286 adult patients infected with HCV genotypes 1, 2, 3, or 4, who received MAVIRET for 8 weeks.

This population included individuals with HCV/HIV-1 co-infections (n=142), current/recent PWID (n=41), and those receiving MAT for opioid use disorder (n=21). At baseline, 49% of subjects had ALT elevations greater than 3 x upper limit of normal (ULN), 13% had ALT elevations greater than 10 x ULN, and 12% had total bilirubin elevations greater than ULN. The overall safety profile in these subjects was consistent with that observed in subjects with chronic HCV infection. Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among subjects with acute HCV infection.

The three most frequently reported adverse events (AEs) in the study were diarrhea (6.3%), fatigue (6.3%), and nasopharyngitis (4.9%). AEs related to study treatment that occurred in ≥ 1% of subjects were fatigue (3.5%), asthenia (2.4%), headache (2.4%), diarrhea (1.7%), and nausea (1.4%).

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

The safety of MAVIRET in adolescent patients with chronic HCV genotype 1 to 6 infection is based on data from a Phase 2 and 3 open-label trial in 47 patients aged 12 years to less than 18 years treated with MAVIRET for 8 to 16 weeks (M16-123, DORA-Part 1). The adverse reactions observed in patients 12 to less than 18 years of age were consistent with those observed in clinical trials of MAVIRET in adults. The only adverse reactions observed in greater than or equal to 3% of patients receiving MAVIRET in DORA-Part 1 were fatigue (occurring at 6%), abdominal pain, and decreased appetite (each occurring at 4%). No patients discontinued or interrupted treatment with MAVIRET due to an adverse reaction.

The safety of MAVIRET in children aged 3 to less than 12 years of age with chronic HCV genotype 1 to 6 is based on data from a Phase 2 and 3 open-label trial in 80 patients aged 3 to less than 12 years of age treated with weight-based MAVIRET granules in sachets for 8 to 16 weeks (DORA-Part 2).

The adverse reactions observed in patients 3 years to less than 12 years of age were consistent with those observed in clinical trials of MAVIRET in adults with the exception of vomiting (occurring at approximately 8%), rash, and abdominal pain upper (each occurring at approximately 4%) which were observed more frequently in pediatric patients less than 12 years of age compared to adults. Other adverse reactions observed in greater than or equal to 3% of patients receiving MAVIRET in DORA-Part 2 include fatigue and headache, each occurring at approximately 8%, and diarrhoea and nausea, each occurring at approximately 4%.

One patient discontinued treatment due to a Grade 3 adverse reaction of erythematous rash. All other adverse reactions were Grade 1 or 2 and no patients interrupted treatment due to an adverse reaction.

8.3. Less Common Clinical Trial Adverse Reactions

Not applicable

8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics

Not applicable

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

Clinical Trial Findings

Chronic HCV Infection

Serum Bilirubin Elevations

Elevations in total bilirubin of at least 2 x upper limit of normal (ULN) were observed in 1% of patients related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubin elevations were predominantly indirect, mostly in patients with pre-existing elevated bilirubin (consistent with Gilbert’s Syndrome), and not associated with ALT elevations.

Acute HCV Infection

Liver Tests

Elevations of total bilirubin greater than 1.5 x ULN occurred in 5.3% of adult patients treated with MAVIRET. Adult patients with bilirubin elevations did not have concurrent increases in ALT or AST, or signs of liver decompensation or failure, and these laboratory events did not lead to treatment discontinuation. All patients with baseline ALT greater than 3 x ULN improved from baseline by the final treatment visit.

8.5. Post-Market Adverse Reactions

The following adverse drug reactions have been identified during post approval use of MAVIRET. Given that these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary Disorders:

Hepatic decompensation, hepatic failure

Immune System Disorders:

Angioedema

9. Drug Interactions

9.2. Drug Interactions Overview

Potential for MAVIRET to Affect Other Drugs

Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Coadministration with MAVIRET may increase plasma concentration of drugs that are substrates of P-gp, BCRP, OATP1B1 or OATP1B3. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A, CYP1A2, and uridine glucuronosyltransferase (UGT) 1A1. Significant interactions are not expected when MAVIRET is coadministered with substrates of CYP3A, CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A1, or UGT1A4.

Potential for Other Drugs to Affect MAVIRET

Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP. Glecaprevir is a substrate of OATP1B1/3. Coadministration of MAVIRET with medicinal products that inhibit P-gp and BCRP expressed in the intestine is unlikely to affect glecaprevir or pibrentasvir concentrations, but inhibition of P-gp and BCRP in the liver may slow elimination of glecaprevir and pibrentasvir. Medicinal products that inhibit OATP1B1/3 may increase systemic concentrations of glecaprevir, but total liver exposure of glecaprevir is unaffected.

Coadministration of MAVIRET with drugs that are strong inducers of P-gp/CYP3A may significantly decrease glecaprevir and pibrentasvir plasma concentrations (see 7. Warnings and Precautions, General, Use with Potent P-gp and CYP3A4 Inducers).

9.4. Drug-Drug Interactions

All drug-drug interaction studies were performed in adults with the glecaprevir and pibrentasvir combination in non-HCV infected subjects.

Table 8 provides the effect of coadministration of MAVIRET on concentrations of concomitant drugs and the effect of concomitant drugs on glecaprevir and pibrentasvir. Coadministration of MAVIRET with atorvastatin, atazanavir, dabigatran etexilate, products containing more than 20 mcg of ethinyl estradiol, rifampin and simvastatin is contraindicated (see also 2. Contraindications).

Table 8. Established and Other Potentially Significant 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,

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

Assessment of Drug Interactions

Drugs with No Observed Clinically Significant Interactions with MAVIRET

No dose adjustment is required when MAVIRET is coadministered with the following medications: abacavir, amlodipine, buprenorphine, caffeine, dextromethorphan, dolutegravir, elvitegravir/cobicistat, emtricitabine, felodipine, lamivudine, lamotrigine, losartan, methadone, midazolam, naloxone, norethindrone or other progestin-only contraceptives, omeprazole, products containing 20 mcg or less of ethinyl estradiol, raltegravir, sofosbuvir, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan.

Pharmacokinetic Parameters for Clinically Relevant Drug Interactions

Drug Interaction Studies

Drug interaction studies were performed with glecaprevir/pibrentasvir and other drugs that are likely to be coadministered and with drugs commonly used as probes for pharmacokinetic interactions. Table 9 and Table 10 summarize the pharmacokinetic effects when glecaprevir/pibrentasvir was coadministered with other drugs which showed potentially clinically relevant changes.

Table 9. Drug Interactions: Changes in Pharmacokinetic Parameters of Glecaprevir (GLE) or Pibrentasvir (PIB) in the Presence of Coadministered Drug

Table 10. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Combination of Glecaprevir/Pibrentasvir (GLE/PIB)

9.5. Drug-Food Interactions

Food increases the bioavailability of MAVIRET (see 4.2. Recommended Dose and Dosage Adjustment and 10.3. Pharmacokinetics, Absorption, Effects of Food on Oral Absorption).

9.6. Drug-Herb Interactions

Coadministration of St. John’s Wort ( Hypericum perforatum) may lead to reduced therapeutic effect of MAVIRET and is not recommended (see Table 8).

9.7. Drug-Laboratory Test Interactions

Interactions of MAVIRET with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

MAVIRET is a fixed-dose combination of two pangenotypic, direct-acting antiviral agents, glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), targeting multiple steps in the HCV viral lifecycle (see 15. Microbiology).

10.2. Pharmacodynamics

Effects on Electrocardiogram

The effect of glecaprevir (up to 600 mg) in combination with pibrentasvir (up to 240 mg) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT study. At 20-fold of glecaprevir and 5-fold of pibrentasvir therapeutic concentrations, the glecaprevir and pibrentasvir combination does not prolong the QTc interval.

10.3. Pharmacokinetics

Based on the population pharmacokinetic analysis, the median steady-state pharmacokinetic parameters of glecaprevir and pibrentasvir tablets in patients with chronic HCV infection and healthy subjects are provided in Table 11.

Table 11. Pharmacokinetics of Multiple Doses of Glecaprevir 300 mg Once Daily and Pibrentasvir 120 mg Once Daily in Patients with Chronic HCV Infection and Healthy Subjects

No clinically meaningful differences in glecaprevir and pibrentasvir exposures are expected among adult patients with acute HCV infection and adult patients with chronic HCV infection.

Absorption

Tablets

Following single-dose administration of glecaprevir and pibrentasvir tablets in healthy subjects, peak plasma concentrations were observed at 5.0 hours (glecaprevir) and 5.0 hours (pibrentasvir) post-dose.

Granules

Following single-dose administration of glecaprevir and pibrentasvir granules in healthy subjects, peak plasma concentrations were observed at 3.0 hours (glecaprevir) and 5.0 hours (pibrentasvir) post-dose.

Effects of Food on Oral Absorption

Tablets

There were increases in glecaprevir AUC_T and C_max when a single 300 mg/120 mg dose of MAVIRET tablets were administered under moderate fat, moderate calorie fed conditions (approximately 142% and 210%, respectively) and high fat, high calorie fed conditions (approximately 67% and 88%, respectively) when compared to administration under fasting conditions.

Similarly, there were increases in pibrentasvir AUC_T and C_max when a single 300 mg/120 mg dose of MAVIRET was administered under moderate fat, moderate calorie fed conditions (approximately 27% and 71%, respectively) and high fat, high calorie fed conditions (approximately 42% and 87%, respectively) when compared to administration under fasting conditions.

In Phase 2 and 3 registrational studies, glecaprevir and pibrentasvir were administered with food without regard to fat and calorie content.

Granules

There were increases in glecaprevir AUC_T and C_max when a single dose of GLE 300 mg + PIB 120 mg granules (pediatric formulation) were administered under low fat fed conditions (approximately 168% and 189% respectively) and high fat fed conditions (approximately 131% and 112%, respectively) when compared to administration under fasting conditions.

Similarly, there were increases in pibrentasvir AUC_T and C_max when a single dose of GLE 300 mg + PIB 120 mg granules (pediatric formulation) were administered under low fat fed conditions (approximately 57% and 83% respectively) and high fat fed conditions (approximately 115% and 130%, respectively) when compared to administration under fasting conditions.

Distribution

Glecaprevir and pibrentasvir are highly bound to plasma proteins (97.5% and > 99.9%, respectively). Ex vivo blood to plasma ratios were 0.57 (glecaprevir) and 0.62 (pibrentasvir).

Metabolism

Only unchanged glecaprevir and pibrentasvir were detected in plasma. Several oxidative metabolites (26% of dose) of glecaprevir were identified in feces. Metabolism by CYP3A plays a secondary role in the disposition of glecaprevir. Pibrentasvir was not metabolized and was recovered in feces only as unchanged parent drug.

Elimination

Glecaprevir and pibrentasvir are primarily eliminated through the biliary-fecal route. Mean half-lives of 6 hours (glecaprevir) and 13 hours (pibrentasvir) were observed when coadministered in healthy subjects. Following a single dose of [¹⁴C] glecaprevir, 92.1% of the radioactive dose was recovered in feces and 0.7% was recovered in urine. Following a single dose of [¹⁴C] pibrentasvir, 96.6% of the radioactive dose was recovered in feces and none was recovered in urine.

Special populations and conditions

• Pediatrics

No dose adjustment of MAVIRET is required in adolescents 12 years and older or pediatric patients weighing at least 45 kg. Pediatric patients aged 3 to less than 12 years of age and weighing 12 kg to less than 45 kg should receive doses of MAVIRET granules in sachets based on body weight (See 4.2. Recommended Dose and Dosage Adjustment). At the recommended doses, exposures of glecaprevir and pibrentasvir in patients with chronic HCV infection aged 3 to less than 18 years were comparable to those in adults from Phase 2 and 3 studies.

The pharmacokinetics of glecaprevir and pibrentasvir have not been established for children less than 3 years of age or weighing less than 12 kg.

The pharmacokinetics of glecaprevir and pibrentasvir were determined in pediatric patients with chronic HCV infection who were 3 years of age and older receiving a daily dose of MAVIRET as described below in Table 12. All pediatric glecaprevir and pibrentasvir PK parameter values fell within the safe and efficacious range observed in adult patients. These differences were not considered clinically significant.

Table 12. Pharmacokinetic Parameters of Glecaprevir (GLE) and Pibrentasvir (PIB) in Pediatric Patients with Chronic HCV Infection

• Geriatrics

Within the age range (12 to 88 years) analyzed, age did not have a clinically relevant effect on exposure of glecaprevir or pibrentasvir.

• Sex

Sex did not have a clinically relevant effect on exposure of glecaprevir or pibrentasvir.

• Pregnancy and breastfeeding

There are no data on the use of MAVIRET in pregnant women, and it is unknown whether glecaprevir or pibrentasvir are excreted in human milk (see 7.1.1. Pregnancy and 7.1.2. Breastfeeding).

• Genetic polymorphism

Genetic polymorphism such as SLCO1B1 phenotype for OATP1B1 showed no clinically significant impact on glecaprevir exposure.

• Ethnic origin

Race or ethnicity did not have a clinically relevant effect on exposure of glecaprevir or pibrentasvir.

• Hepatic Insufficiency

Hepatic impairment studies were conducted with a single dose of the glecaprevir 300 mg and pibrentasvir 120 mg combination in HCV-negative subjects under non-fasting conditions. Compared to subjects with normal hepatic function, glecaprevir exposures were higher in subjects with Child-Pugh A (↑ 33% AUC), Child-Pugh B (↑ 38% C_max, ↑ 2-fold AUC), and Child-Pugh C (↑ 5-fold C_max, ↑ 11-fold AUC) hepatic impairment. Pibrentasvir exposures were similar in subjects with Child-Pugh A (≤ 20% difference in C_max or AUC), but higher in subjects with Child-Pugh B (↑ 26% C_max and AUC) and Child-Pugh C (↓ 41% C_max, ↑ 2-fold AUC) hepatic impairment.

Population pharmacokinetic analysis demonstrated that following administration of MAVIRET in patients with chronic HCV infection with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic patients with chronic HCV infection (see also 2. Contraindications, 4.2. Recommended Dose and Dosage Adjustment, Hepatic Impairment and 7. Warnings and Precaution, Hepatic/Biliary/Pancreatic, Hepatic Decompensation and Hepatic Failure).

• Renal Insufficiency

Renal impairment studies were conducted with a single dose of the glecaprevir 300 mg and pibrentasvir 120 mg combination in HCV-negative subjects with mild (eGFR 60 to 89 mL/min/1.73 m²), moderate (eGFR 30 to 59 mL/min/1.73 m²), severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²), or ESRD not on dialysis (eGFR < 15 mL/min/1.73 m²). Compared to subjects with normal renal function, glecaprevir AUC values were similar in subjects with mild renal impairment (13% difference), but higher in subjects with moderate renal impairment (↑ 30%), severe renal impairment (↑ 45%), or ESRD not on dialysis (↑ 56%). Compared to subjects with normal renal function, pibrentasvir AUC values were similar in subjects with mild (11% difference) or moderate (25% difference) renal impairment, but higher in subjects with severe renal impairment (↑ 37%), or ESRD not on dialysis (↑ 46%). C_max values were similar across all groups for glecaprevir (≤ 9% difference) and pibrentasvir (≤ 25% difference).

The glecaprevir 300 mg and pibrentasvir 120 mg combination was also administered to subjects requiring dialysis 3 hours before the start of hemodialysis and on a non-dialysis day. Exposures were similar for glecaprevir (≤ 7% difference in C_max or AUC) and pibrentasvir (≤ 18% difference in C_max or AUC) when dosed before dialysis compared to the non-dialysis day.

Overall, the changes in exposures of MAVIRET in patients with chronic HCV infection with renal impairment with or without dialysis were not considered clinically significant (see 4.2. Recommended Dose and Dosage Adjustment, Renal Impairment).

• Obesity

Body weight did not have a clinically relevant effect on exposure of glecaprevir or pibrentasvir.

1. 11. Storage, Stability, and Disposal

Temperature:

Store between 2 and 30°C.

Others:

Keep out of reach and sight of children.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: glecaprevir

Chemical name: (3aR,7S,10S,12R,21E,24aR)-7-tert-butyl-N-{(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl}-20,20-difluoro-5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1H,10H-9,12-methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononade cino[11,12-b]quinoxaline-10-carboxamide hydrate

Molecular formula and molecular mass: C₃₈H₄₆F₄N₆O₉S (anhydrate) and 838.87 g/mol (anhydrate)

Structural formula:

Physicochemical properties: Glecaprevir is a white to off-white powder with a solubility of less than 0.1 to 0.3 mg/mL across a pH range of 2 to 7 at 37⁰C and is practically insoluble in water, but is sparingly soluble in ethanol.

Pharmaceutical standard: Professed

Drug Substance

Non-proprietary name of the drug substance: pibrentasvir

Chemical name: Methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

Molecular formula and molecular mass: C₅₇H₆₅F₅N₁₀O₈ and 1113.18 g/mol

Structural formula:

Physicochemical properties: Pibrentasvir is a white to off-white to light yellow powder with a solubility of less than 0.1 mg/mL across a pH range of 1 to 7 at 37°C and is practically insoluble in water, but is freely soluble in ethanol.

Pharmaceutical standard: Professed

14. Clinical Trials

14.1. Clinical Trials by Indication

Chronic HCV Infection

The efficacy and safety of MAVIRET (glecaprevir/pibrentasvir) was evaluated in twelve Phase 2-3 clinical trials, in over 2,300 adult patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and with compensated liver disease (with or without cirrhosis), as summarized in Table 13.

Table 13. Clinical Studies Conducted with MAVIRET in Patients with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection

Serum HCV RNA values were measured during the clinical studies using the Roche COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL (except for SURVEYOR-1 and SURVEYOR-2 which used the Roche COBAS TaqMan real-time reverse transcriptase-PCR (RT-PCR) assay v. 2.0 with an LLOQ of 25 IU/mL). Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the studies to determine the HCV cure rate.

Among adult patients in the registrational Phase 2 and 3 clinical trials who received the recommended regimen (N = 1190), 97% achieved SVR (97% with cirrhosis and 97% without cirrhosis), while 0.6% experienced on treatment virologic failure and 0.9% experienced post-treatment relapse. Among the treatment naïve patients without cirrhosis (all genotypes) who received MAVIRET for 8 weeks, the SVR12 rate was 97% (639/657) with < 1% (6/657) virologic failure rate.

Clinical Studies in Treatment-Naïve or PRS-Treatment-Experienced Adult Patients with or without Cirrhosis Infected with Genotypes 1, 2, 4, 5, or 6

Demographic and baseline characteristics for treatment-naïve or PRS-treatment-experienced patients with or without cirrhosis with genotype 1, 2, 4, 5, or 6 infection in ENDURANCE-1, -2, -4, SURVEYOR-1, -2, and EXPEDITION-1 are provided in Table 14.

Table 14. Demographic and Other Baseline Disease Characteristics of the Population for the Treatment of Chronic HCV Genotypes 1, 2, 4, 5 or 6 Infection (Phase 2, 3 Studies^a)

The response rates for MAVIRET in genotype 1, 2, 4, 5 or 6 infected patients who were treatment-naïve or those who previously failed regimens containing (peg) interferon, ribavirin, and/or sofosbuvir (PRS) treated for 8 weeks (without cirrhosis) and 12 weeks (with cirrhosis) are shown in Table 15.

Table 15. Sustained Virologic Response (SVR12) in Treatment-Naïve Patients and Patients Experienced^a to (Peg)interferon, Ribavirin, and/or Sofosbuvir with Chronic HCV Infection with or without Cirrhosis after 8 or 12 Weeks of Treatment with MAVIRET (pooled data from ENDURANCE-1, -2, -4, SURVEYOR-1, -2, and EXPEDITION-1, and -4)

Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for selected subgroups of patients treated with MAVIRET for the recommended duration as summarized in Table 16.

Table 16. Sustained Virologic Response (SVR12) in Selected Subgroups of Treatment-Naïve Patients and Patients Experienced to (Peg)interferon, Ribavirin, and/or Sofosbuvir, Infected with Chronic HCV Genotypes 1, 2, 4, 5 or 6 Infection without Cirrhosis Treated for 8 weeks and with Cirrhosis Treated for 12 weeks (Phase 2, 3 Studies^a)

High SVR12 rates were achieved across all HCV genotypes in all subgroups including by age, gender, race, ethnicity, BMI, HCV RNA level, cirrhosis status, HIV co-infection, prior treatment history and IL28B genotype. The SVR12 rate of MAVIRET across all treatment-naïve patients without cirrhosis with genotype 1, 2, 4, 5, 6 chronic HCV infection treated for 8 weeks was 98.1% (462/471) with no virologic failures.

Clinical Studies in Patients with Genotypes 5 or 6 Infection

ENDURANCE-5,6 was an open-label study in 84 HCV genotype 5- (N = 23) or genotype 6-infected (N = 61) treatment-naïve or PRS-treatment-experienced patients. Patients without cirrhosis received MAVIRET for 8 weeks, and patients with compensated cirrhosis received MAVIRET for 12 weeks.

Of the 84 patients treated, the median age was 59 years (range 24 to 79); 27% had HCV genotype 5, 73% had HCV genotype 6; 54% were female, 30% were White, 68% were Asian; 90% were HCV treatment-naïve; 11% had compensated cirrhosis.

The overall SVR12 rate in study ENDURANCE-5,6 was 97.6% (82/84). The SVR12 rate was 95.7% (22/23) for genotype 5-infected patients and 98.4% (60/61) for genotype 6-infected patients. One treatment-naïve genotype 5-infected patient without cirrhosis experienced relapse, and one treatment-naïve genotype 6-infected patient with compensated cirrhosis experienced on-treatment virologic failure.

Clinical Study in Treatment-Naïve Patients with Cirrhosis Infected with Genotypes 1, 2, 4, 5, or 6 who received 8 Weeks of MAVIRET

The safety and efficacy of MAVIRET given for 8 weeks in genotype 1, 2, 4, 5 or 6 treatment-naïve patients with compensated cirrhosis was evaluated in a single-arm, open-label study (EXPEDITION-8).

Of the 280 patients treated, the median age was 60 years (range: 34 to 99); 81.8% had HCV genotype 1, 10% had HCV genotype 2, 4.6% had HCV genotype 4, 0.4% had HCV genotype 5; 3.2% had HCV genotype 6; 60% were male; 9.6% were Black.

The response rates in patients with compensated cirrhosis and genotype 1, 2, 4, 5, or 6 given MAVIRET for 8 weeks are presented in Table 17.

The overall SVR12 rate was 97.9% (274/280). There were no virologic failures.

Table 17. Sustained Virologic Response (SVR12) in Treatment-Naïve Patients Infected with Chronic HCV Genotypes 1, 2, 4, 5, or 6 Infection with Compensated Cirrhosis (EXPEDITION-8)

Clinical Studies in Genotype 3 Infected Adult Patients

The efficacy of MAVIRET in patients who were treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir with genotype 3 chronic hepatitis C infection was demonstrated in the ENDURANCE-3 (treatment-naïve without cirrhosis), EXPEDITION-8 and SURVEYOR-2 Parts 1-3 (patients with and without cirrhosis and treatment-naïve and/or treatment-experienced) clinical studies.

Patients with genotype 3 HCV infection were also included in other studies, such as the two Asian regional studies, VOYAGE-1 and VOYAGE-2.

ENDURANCE-3 was a partially-randomized, open-label, active-controlled study in treatment-naïve patients. Patients were randomized (2:1) to either MAVIRET for 12 weeks or the combination of sofosbuvir and daclatasvir for 12 weeks; subsequently the study included a third arm (which was non-randomized) with MAVIRET for 8 weeks. SURVEYOR-2 Part 3 was an open-label study randomizing non-cirrhotic treatment-experienced patients to 12- or 16-weeks of treatment; in addition, the study evaluated the efficacy of MAVIRET in patients with compensated cirrhosis and genotype 3 infection in two dedicated treatment arms using 12-week (treatment-naïve only) and 16-week (treatment-experienced only) durations. Among treatment-experienced patients, 46% (42/91) failed a previous regimen containing sofosbuvir.

The demographic and disease characteristics of the population with HCV genotype 3 infection in ENDURANCE-3 and SURVEYOR-2 are summarized in Table 18.

Table 18. Demographic and Other Baseline Characteristics of the Patient Population Infected with Chronic HCV Genotype 3 (ENDURANCE-3, SURVEYOR-2)

The response rates of the treatment-naïve genotype 3-infected patients without cirrhosis treated with MAVIRET for 8 and 12 weeks and patients treated with sofosbuvir and daclatasvir for 12 weeks are presented in Table 19.

Table 19. Sustained Virologic Response (SVR12) in Treatment-Naïve Patients Infected with Chronic HCV Genotype 3 without Cirrhosis (ENDURANCE-3)

The response rates in genotype 3-infected treatment-naïve patients with cirrhosis treated with MAVIRET for 12 weeks and PRS treatment-experienced patients with or without cirrhosis treated with MAVIRET for 16 weeks in SURVEYOR-2 Part 3 are presented in Table 20.

Table 20. Sustained Virologic Response (SVR12) in Treatment-Naïve Patients and Patients Experienced to (Peg)interferon, Ribavirin, and/or Sofosbuvir, Infected with Chronic HCV Genotype 3 with or without Cirrhosis (SURVEYOR-2 Part 3)

The SVR12 rate of MAVIRET across all treatment-naïve patients without cirrhosis with genotype 3 chronic HCV infection treated in Phase 2 and 3 studies (ENDURANCE-3 or SURVEYOR-2 Parts 1 and 2) was 95.2% (177/186) with 2.8% relapse (5/178) for patients treated for 8 weeks, and 95.4% (248/260) with 1.2% relapse (3/248) for patients treated for 12 weeks.

Of the genotype 3-infected patients with end stage renal disease enrolled in EXPEDITION-4, 100% (11/11) achieved SVR12.

Among treatment-experienced patients treated for 16 weeks, SVR12 rates were 95% (n = 22) in patients without cirrhosis and 96% (n = 47) in patients with cirrhosis.

High SVR12 rates were achieved across all subgroups including by age, gender, race, ethnicity, BMI, HCV RNA level, cirrhosis status, prior treatment history and IL28B genotype.

SVR12 rate in all genotype 3 patients irrespective of cirrhosis status or prior treatment history treated with MAVIRET for the recommended durations was 95.7% (n = 324) with 3.0% virologic failures.

Patients with Genotype 3b Infection

Genotype 3b is a subtype that is uncommon in Canada but has been reported in China and other South and Southeast Asian countries. Studies VOYAGE-1 and VOYAGE-2 were conducted in China, Singapore, and South Korea in HCV genotype 1 to 6 patients without cirrhosis (VOYAGE-1) or with compensated cirrhosis (VOYAGE-2) who were treatment-naïve or treatment-experienced with PRS. Patients without cirrhosis or with compensated cirrhosis received 8 or 12 weeks of MAVIRET, respectively, except genotype 3 PRS-treatment-experienced patients who received 16 weeks of MAVIRET.

The overall SVR12 rates were 97.2% (352/362) and 99.4% (159/160) in VOYAGE-1 and VOYAGE-2, respectively.

Across both trials, subjects with HCV genotype 3b infection had a numerically lower SVR12 rate of 70% (14/20) [58% (7/12) for non-cirrhotic subjects and 88% (7/8) for subjects with compensated cirrhosis] compared to subjects infected with genotype 3a or other HCV genotypes. All six genotype 3b subjects without SVR12 experienced virologic failure (2 on-treatment virologic failure, 4 relapse). SVR12 results in subjects with genotype 3a or other HCV genotypes were comparable with other trials.

Clinical Study in Treatment-Naïve Patients with Cirrhosis Infected with Genotype 3 who received 8 Weeks of MAVIRET

The safety and efficacy of MAVIRET given for 8 weeks in genotype 3 treatment-naïve patients with compensated cirrhosis was evaluated in a single-arm, open-label study (EXPEDITION-8).

Of the 63 genotype 3 treatment-naïve patients with compensated cirrhosis treated, the median age was 52 years (range: 32 to 83); 77.8% were male; 1.6% were Black.

The response rate in patients with compensated cirrhosis and genotype 3 given MAVIRET for 8 weeks is presented in Table 21. There was 1 virologic relapse.

Table 21. Sustained Virologic Response (SVR12) in Treatment-Naïve Patients Infected with Chronic HCV Genotype 3 Infection with Compensated Cirrhosis (EXPEDITION-8)

Clinical Study in Chronic Kidney Disease (CKD) Adult Patients

The demographic and disease characteristics of the population with stages 4 and 5 chronic kidney disease are summarized in Table 22.

Table 22. Demographic and Other Baseline Characteristics of the Patient Population with and without Cirrhosis with Chronic Kidney Disease (Stages 4, 5) Infected with Chronic HCV Genotypes 1 to 6 (EXPEDITION-4)

The response rates in patients with CKD (stages 4 and 5) infected with HCV genotypes 1 to 6 are presented in Table 23.

Table 23. Sustained Virologic Response (SVR12) in Chronic Kidney Disease (Stages 4 and 5), Chronic HCV Genotypes 1 to 6 Infected Patients with or without Cirrhosis (EXPEDITION 4)

Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for selected subgroups as summarized in Table 24.

Table 24. Sustained Virologic Response (SVR12) in Selected Subgroups of Chronic Kidney Disease (Stages 4 and 5 Patients Infected with Chronic HCV Genotypes 1 to 6 (EXPEDITION-4))

Among patients with advanced renal disease, high SVR12 rates were achieved across all subgroups including by age, gender, race, ethnicity, BMI, HCV RNA level, cirrhosis status, prior treatment history, CKD stage and IL28B genotype.

Clinical Study in Treatment-Naïve or Treatment-Experienced-PRS Adult Patients with HCV/HIV-1 Co-infection with or without Cirrhosis

EXPEDITION-2 was an open-label study in HCV/HIV-1 co-infected patients, in which patients without cirrhosis received MAVIRET for 8 weeks, and patients with cirrhosis received MAVIRET for 12 weeks.

The demographic and disease characteristics of the patient population in EXPEDITION-2 are summarized in Table 25.

Table 25. Demographic and Other Baseline Characteristics of the Chronic HCV/HIV-1 Co-Infected Patient Population with or without cirrhosis (EXPEDITION-2)

The response rates in HCV/HIV-1 co-infected patients are presented in Table 26.

Table 26. Sustained Virologic Response (SVR12) in Chronic HCV/HIV-1 Co-Infected Patients (EXPEDITION-2)

Among patients without cirrhosis that received 8 weeks of MAVIRET, the overall SVR12 rate was 99.3% (136/137) (99.1% [110/111] for treatment-naïve patients and 100% [26/26] for PRS-treatment-experienced patients).

Overall SVR12 Rate from the Clinical Studies in Treatment-Naïve or Treatment-Experienced-PRS Adult Patients with or without Cirrhosis

Among all patients, regardless of renal function, cirrhosis status, or presence of HIV-1 co-infection, who were treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin, and/or sofosbuvir and infected with any HCV genotype who received the recommended treatment duration, 97.5% (1,401/1,437) achieved SVR12, 0.3% (4/1,284) experienced on-treatment virologic failure, and 0.8% (11/1,413) experienced post-treatment relapse.

In treatment-naïve patients without cirrhosis who received the recommended duration of 8 weeks, 97.5% (749/768) achieved SVR12, while 0.1% (1/768) experienced on-treatment virologic failure and 0.7% (5/755) experienced post-treatment relapse.

In PRS-treatment-experienced patients without cirrhosis who received the recommended duration, 98.2% (215/219) achieved SVR12, while 0.5% (1/219) experienced on-treatment virologic failure and 1.4% (3/218) experienced post-treatment relapse.

In treatment-naïve or PRS-treatment-experienced patients with compensated cirrhosis who received the recommended duration, 97.1% (437/450) achieved SVR12 (among which 97.7% [341/349] of treatment-naïve patients achieved SVR12), while 0.4% (2/450) experienced on-treatment virologic failure and 0.7% (3/440) experienced post-treatment relapse.

The presence of HIV-1 co-infection did not impact efficacy. Among HCV/HIV-1 co-infected patients from ENDURANCE-1 and EXPEDITION-2 combined who were treatment-naïve or PRS-treatment-experienced treated with the recommended duration, the SVR12 rate was 98.2% (165/168). One (1/168; 0.6%) patient experienced on-treatment virologic failure and no patients relapsed.

Clinical Studies in NS5A Inhibitor and/or Protease Inhibitor (NS3/4A) Treatment Experienced Adult Patients with or without Cirrhosis

Demographic and baseline characteristics for NS5A inhibitor and/or NS3/4A protease inhibitor (PI) treatment-experienced patients with or without cirrhosis with genotype 1 HCV infection in MAGELLAN-1 Part 2 are provided in Table 27.

Table 27. Demographic and Other Baseline Characteristics of NS5A Inhibitor and/or NS3/4A Protease Inhibitor Treatment-Experienced Patients Infected with Chronic HCV Genotypes 1 (MAGELLAN-1 Part 2)

The response rates in patients with NS5A inhibitor and/or NS3/4A PI treatment experience with or without cirrhosis in MAGELLAN-1 Part 2 are presented in Table 28. The SVR12 rate in patients in MAGELLAN-1 Part 1 and Part 2 with prior PI or NS5A inhibitor treatment experience treated with MAVIRET for the recommended duration was 92.9% (n = 42) with 2.4% virologic failure.

Table 28. Sustained Virologic Response (SVR12) in NS5A Inhibitor and/or NS3/4A Protease Inhibitor Treatment-Experienced Patients Infected with Chronic HCV Genotypes 1 with or without Cirrhosis (MAGELLAN-1 Part 2)

Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for selected subgroups as summarized in Table 29.

Table 29. Sustained Virologic Response (SVR12) in Selected Subgroups of NS5A Inhibitor and/or NS3/4A Protease Inhibitor Treatment-Experienced Patients Infected with Chronic HCV Genotypes 1 (MAGELLAN-1 Part 2)

High SVR12 rates were achieved in patients who failed a prior treatment containing NS5A inhibitors (ledipasvir or daclatasvir) and in patients with pre-existing NS5A substitutions (while PI-naïve and without pre-existing treatment emergent NS3 substitutions in positions 155, 156 and 168) treated with MAVIRET for the recommended duration (16 weeks). High SVR12 rates were achieved in patients with prior failure to a protease inhibitor only (while NS5A-inhibitor naïve) treated for the recommended duration (12 weeks). Lower efficacy was observed in patients who previously failed both NS5A inhibitors and NS3/4A PIs and had pre-existing treatment emergent substitutions in both NS5A and NS3.

Clinical Study in Liver or Kidney Transplant Recipients

MAGELLAN-2 was a single-arm, open-label study in post-liver or -kidney transplant HCV infected patients without cirrhosis.

In this study, the immunosuppressants allowed for co-administration were cyclosporine ≤ 100 mg, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, and prednisolone.

The demographic and disease characteristics of the patient population in MAGELLAN-2 are summarized in Table 30.

Table 30. Demographic and Other Baseline Characteristics of the Liver or Kidney Transplant Recipient Patient Population with Chronic HCV Infection with or without Cirrhosis (MAGELLAN-2)

The response rates in post-liver or kidney transplant patients are presented in Table 31.

Table 31. Sustained Virologic Response (SVR12) in Post-Liver or Kidney Transplant Recipient Patients with Chronic HCV Infection (MAGELLAN-2)

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

The efficacy of MAVIRET in PWID and patients on MAT with HCV genotype 1, 2, 3, 4, 5 or 6 infection is based on data from Phase 2 and 3 trials in 4,655 adults and adolescents who received MAVIRET; 1,373 patients were identified as PWID based on self-reported history of injection drug use at trial enrollment, 3,282 patients did not report injection drug use (non-PWID), 225 patients reported concomitant use of MAT for opioid use disorder, and 4,098 patients reported no use of MAT (332 patients were not included in the analysis due to missing assessment of MAT).

PWID

In the PWID population, 62 patients were considered current/recent PWID (defined as self-reported injection drug use within the last 12 months prior to starting MAVIRET), 959 patients were considered former PWID (defined as self-reported injection drug use more than 12 months prior to starting

MAVIRET), and 352 patients did not specify current/recent PWID versus former PWID and were not included in the analysis. Compared to former/non-PWID patients (n = 4,241), the current/recent PWID patients were more frequently male (79%), White (73%), younger (median age [range]: 40 years [19 to 64]), treatment-naïve (94%), and had higher proportions of HCV genotype 3 infection (44%) and HIV co-infection (24%). Similar to the former/non-PWID patients, the majority of current/recent PWID patients were non-cirrhotic (73%).

The overall SVR12 rate was 97.8% (4,147/4,241) in former/non-PWID patients and 88.7% (55/62) in current/recent PWID patients; the difference between the two groups was primarily due to missing data at the time of the SVR12 measurement window in the current/recent PWID group. Virologic failure rates, however, were similar in both groups: 1.6% (1/62) in the current/recent PWID patients and 1.2% (50/4,241) in former/non-PWID patients.

MAT

Patients on MAT were more frequently male (70%), White (92%), younger (median age [range]: 47 years [23 to 76]), treatment-naïve (89%), and had a higher proportion of HCV genotype 3 infection (50%) as compared to patients not on MAT. Among the patients on MAT, 74% were non-cirrhotic, and 7% were co-infected with HIV, similar to those not on MAT.

The SVR12 rates were also similar between patients on MAT (95.6% [215/225]) and those not on MAT (97.7% [4,002/4,098]), with low rates of virologic failure in both groups (0.4% [1/225] and 1.3% [52/4,098], respectively).

Durability of Sustained Virologic Response

In a long-term follow-up study (M13-576), 99.5% (374/376) of adult patients who had achieved SVR12 in prior clinical studies of MAVIRET maintained SVR up to their last follow-up visit (median duration of follow-up: 35.5 months): 100%, 99.6%, and 95.8% of patients who had received 8, 12, and 16 weeks of MAVIRET therapy, respectively. Among the 2 patients who did not maintain SVR, 1 experienced a late relapse 390 days after MAVIRET therapy, and the other patient experienced re-infection with a different HCV genotype.

Clinical Study in Pediatric Patients (3 to less than 18 years of age and weighing at least 12 kg)

DORA (Part 1 and Part 2) was an open-label study to evaluate the safety and efficacy of MAVIRET in pediatric patients 3 to less than 18 years of age.

DORA Part 1 evaluated the safety and efficacy in 47 adolescent patients (age range: 12 to 17 years old; weight range: 32 to 109 kg) without cirrhosis who received MAVIRET tablets for 8 weeks (44 patients) or 16 weeks (3 patients).

The demographic and disease characteristic of the patient population in DORA Part 1 are summarized in Table 32.

Table 32. Demographic and Other Baseline Characteristics of the Adolescent Patient Population with Chronic HCV Infection (DORA Part 1)

DORA Part 2 evaluated the safety and efficacy in 80 pediatric patients aged 3 years to less than 12 years who received weight based MAVIRET granules in sachets for 8, 12 or 16 weeks. 18 patients received the initial lower dose, and 62 patients received the final recommended dose. The median age was 7 years (range: 3 to 11).

The demographic and disease characteristics of the patient population in DORA Part 2 are summarized in Table 33.

Table 33. Demographic and Other Baseline Characteristics of the Pediatric Patient Population with Chronic HCV Infection (DORA Part 2)

The response rates in adolescent patients with chronic HCV infection are presented in Table 34. No patients experienced virologic failure.

Table 34. Sustained Virologic Response (SVR12) in HCV-Infected Adolescent Patients with Chronic HCV Infection (DORA Part 1)

The response rates in pediatric patients with chronic HCV infection are presented in Table 35. The overall SVR12 rate for the patients who received the final recommended dose ratio was 98.4% (61/62). No patients taking the final recommended dose ratio experienced virologic failure.

Table 35. Sustained Virologic Response (SVR12) in HCV-Infected Pediatric Patients with Chronic HCV Infection (DORA Part 2)

Acute HCV Infection

The efficacy and safety of MAVIRET in patients with documented acute HCV infection was evaluated in Study M20-350, a single-arm, open-label study of 286 adults who were treatment-naïve for the current infection and received MAVIRET for 8 weeks (Table 36).

Table 36. Clinical Study Conducted with MAVIRET in Patients with Acute HCV Genotype 1, 2, 3 or 4 Infection

This study design included adults and adolescents with physician-diagnosed acute HCV infection, who had not received prior treatment for the current infection. Diagnosis of acute HCV infection at screening was based on physician diagnosis, quantifiable HCV RNA, and one or more of the following criteria: a negative anti-HCV antibody, HCV RNA or HCV core antigen testing result followed by positive HCV RNA or HCV core antigen testing, clinical signs of liver disease associated with acute HCV infection, and recent risk behaviours associated with HCV transmission. Eighty-four percent of enrolled subjects had evidence of clinical hepatitis at screening in the absence of other causes of liver disease, recent risk behavior for HCV transmission, and a confirmed HCV RNA or HCV core antigen positivity within 8 months prior to screening. At baseline, 96% of subjects had quantifiable HCV RNA, of whom 39% had a documented result of negative HCV antibody or unquantifiable HCV RNA within the previous year, and 4% of subjects had unquantifiable HCV RNA possibly reflecting spontaneous clearance of the HCV infection during the pre-treatment period.

Although the design of study M20-350 included adolescents, none were enrolled. Eligible participants had no cirrhosis or had compensated cirrhosis and were required to have no evidence of chronic HCV or hepatitis B infection. Individuals with HIV-1 co-infection and current people who inject drugs (PWID) were permitted to participate. Patients received oral tablets of GLE/PIB once daily for eight weeks and were followed for 12 weeks after the end of treatment. The primary endpoint was the percentage of patients with sustained virologic response 12 weeks post-treatment (SVR12) in the intention-to-treat (ITT) population. Secondary endpoints included the percentage of patients achieving SVR12 in the Modified ITT-Virologic Failure (mITT-VF) population, and the percentage of patients with on-treatment virologic failure and post-treatment relapse in the ITT population.

The median age was 43 years (range: 20 to 78); 82% had no history of a prior HCV infection; 64% were HCV genotype 1, 4% were HCV genotype 2, 13% were HCV genotype 3, 19% were HCV genotype 4; 6% were ≥ 65 years; 89% were male; 11% were Black; 2% had cirrhosis; 50% had HIV co-infection; 14% were current/recent PWID; 8% reported ongoing use of MAT for opioid use disorder; 9% had a body mass index of at least 30 kg per m2; and median baseline HCV RNA level was 5.4 log10 IU/mL.

The overall SVR12 rate was 96.2% (275/286); no patients experienced virologic failure. The SVR12 rates were similar across subgroups (including HIV-1 co-infection, PWID, MAT). The SVR12 rate was 97.2% (138/142) for patients with HCV/HIV-1 co-infection and 95.1% (137/144) for patients with HCV mono-infection. The response rates for MAVIRET in patients with acute HCV genotype 1, 2, 3 or 4 infection treated for 8 weeks are shown in Table 37. Two subjects who did not achieve SVR12 were reinfected with HCV, based on differences in HCV genotypes or subtype clades between the baseline and follow-up periods.

Table 37. Sustained Virologic Response (SVR12) in Patients Infected with Acute HCV Genotypes 1, 2, 3 or 4 Infection (M20-350)

Pediatric Population

Although the design of Study M20-350 included adolescents, none were enrolled. Use of MAVIRET in pediatric patients with acute HCV infection is supported by extrapolation of the totality of evidence, including safety and efficacy from adult patients with acute HCV infection and from both adult and pediatric patients with chronic HCV infection (See Pharmacokinetics 10.3).

15. Microbiology

MAVIRET (glecaprevir/pibrentasvir) is a fixed-dose bilayer tablet (3X) combination regimen of glecaprevir and pibrentasvir.

Antiviral Activity in vitro

Glecaprevir

Glecaprevir is a pangenotypic inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, glecaprevir inhibited the proteolytic activity of recombinant NS3/4A enzymes from clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a with IC₅₀ value ranging from 3.5 to 11.3 nM.

Pibrentasvir

Pibrentasvir is a pangenotypic inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.

Combination Activity

Evaluation of combination of glecaprevir and pibrentasvir showed no antagonism in antiviral activity in HCV genotype 1 replicon cell culture assays.

Antiviral Activity in Cell Culture

The EC₅₀ values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding NS3 or NS5A from laboratory strains are presented in Table 38.

Table 38. Activity of Glecaprevir and Pibrentasvir Against HCV Genotypes 1 to 6 Replicon Cell Lines

The EC₅₀ values of glecaprevir and pibrentasvir against chimeric replicons encoding NS3 or NS5A from clinical isolates are presented in Table 39.

Table 39. Activity of Glecaprevir and Pibrentasvir against Transient Replicons Containing NS3 or NS5A from HCV Genotypes 1 to 6 Clinical Isolates

Resistance

In Cell Culture

Amino acid substitutions in NS3 or NS5A selected in cell culture or important for the inhibitor class were phenotypically characterized in replicons.

Substitutions important for the HCV protease inhibitor class at positions 36, 43, 54, 55, 56, 155, 166, or 170 in NS3 had no impact on glecaprevir activity. Individual substitutions at NS3 amino acid position A156 introduced into HCV replicons by site-directed mutagenesis generally caused the greatest reductions (> 100-fold) in susceptibility to glecaprevir. Individual substitutions at NS3 position D/Q168 had varying effects on glecaprevir susceptibility depending on HCV genotype/subtype and specific amino acid change, with the greatest reductions (>30-fold) observed in genotypes 1a (D168F/Y), 3a (Q168R) and 6a (D168A/G/H/V/Y). Combinations of NS3 Y56H plus D/Q168 substitutions resulted in greater reductions in glecaprevir susceptibility. An NS3 Q80R substitution in genotype 3a caused a 21-fold reduction in glecaprevir susceptibility, while Q80 substitutions in genotypes 1a and 1b (including genotype 1a Q80K) did not reduce glecaprevir susceptibility.

Single substitutions important for the NS5A inhibitor class at positions 24, 28, 30, 31, 58, 92, or 93 in NS5A in genotypes 1 to 6 had no impact on the activity of pibrentasvir. Amino acid substitutions resulting from multiple nucleotide changes reduced susceptibility to pibrentasvir in a genotype 1a replicon (M28G or Q30D, 244- and 94-fold, respectively), and in a genotype 1b replicon (P32-deletion, 1,036-fold). Some combinations of two or more NS5A inhibitor resistance-associated amino acid substitutions may result in greater reductions in pibrentasvir susceptibility. Specifically in genotype 3a, A30K or Y93H had no impact on pibrentasvir activity. Some combinations of substitutions in genotypes 1a and 3a (including A30K+Y93H in genotype 3a) showed reductions in susceptibility to pibrentasvir. In genotype 3b replicon, the presence of naturally occurring polymorphisms K30 and M31 in NS5A reduced susceptibility to pibrentasvir by 24-fold relative to the activity of pibrentasvir in genotype 3a replicon.

In Clinical Studies of Patients with Chronic HCV Infection

Studies in Treatment-Naïve and (Peg)interferon, Ribavirin and/or Sofosbuvir Treatment-Experienced Patients with or without Cirrhosis

Twenty-two of the approximately 2,300 patients treated with MAVIRET for 8, 12, or 16 weeks in the registrational Phase 2 and 3 clinical studies experienced virologic failure (2 with genotype 1, 2 with genotype 2, 18 with genotype 3 infection). In addition, 1 genotype 3-infected patient experiencing virologic failure was determined to be reinfected with a genotype 3 virus distinct from the one present at baseline. Among the 22 patients experiencing virologic failure, treatment-emergent substitutions were detected in 54.5% (12/22) of patients in NS3 and 81.8% (18/22) of patients in NS5A.

Among the 2 genotype 1-infected patients who experienced virologic failure, one had treatment-emergent substitutions A156V in NS3 and Q30R/L31M/H58D in NS5A, and 1 had Q30R/H58D (while Y93N was present at baseline and post-treatment) in NS5A.

Among the 2 genotype 2-infected patients, no treatment-emergent substitutions were observed in NS3 or NS5A (the M31 polymorphism in NS5A was present at baseline and post-treatment in both patients).

Among the 18 genotype 3-infected patients treated with MAVIRET for 8, 12, or 16 weeks who experienced virologic failure, treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, or Q168L/R were observed in 11 patients. A166S or Q168R were present at baseline and post-treatment in 5 patients. Treatment-emergent NS5A substitutions M28G, A30G/K, L31F, P58T, or Y93H were observed in 16 patients, and 13 patients had A30K (n = 9) or Y93H (n = 5) at baseline and post-treatment.

Studies in Patients with or without Cirrhosis Who Were Treatment-Experienced to NS3/4A Protease and/or NS5A Inhibitors

Ten of 113 patients treated with MAVIRET in the MAGELLAN-1 study for 12 or 16 weeks experienced virologic failure.

Among the 10 genotype 1-infected patients with virologic failure, treatment-emergent NS3 substitutions V36A/M, R155K/T, A156G/T/V, or D168A/T were observed in 7 patients. Five of the 10 had combinations of V36M, Y56H, R155K/T, or D168A/E in NS3 at baseline and post-treatment. All of the genotype 1-infected virologic failure patients had one or more NS5A substitutions L/M28M/T/V, Q30E/G/H/K/L/R, L31M, P32 deletion, H58C/D, or Y93H at baseline, with additional treatment-emergent NS5A substitutions M28A/G, P29Q/R, Q30K, H58D, or Y93H observed in 7 of the patients at the time of failure.

In Clinical Studies of Patients with Acute HCV Infection

In patients who received MAVIRET for 8 weeks in the Phase 3b clinical study (M20-350), baseline polymorphisms in NS3 and/or NS5A had no impact on treatment outcome; no patients experienced virologic failure.

Effect of Baseline HCV Substitutions/Polymorphisms on Treatment Response

A pooled analysis of treatment-naïve and (peg)interferon, ribavirin and/or sofosbuvir treatment-experienced patients with chronic HCV infection receiving MAVIRET in the Phase 2 and Phase 3 clinical studies was conducted to explore the association between baseline polymorphisms and treatment outcome and to describe substitutions seen upon virologic failure. Baseline polymorphisms relative to a subtype-specific reference sequence at amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 92, and 93 in NS5A were evaluated at a 15% detection threshold by next-generation sequencing. Baseline polymorphisms in NS3 at any of the above-listed amino acid positions were detected in 1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% (1/34) of patients with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively. Baseline polymorphisms in NS5A at any of the above-listed amino acid positions were detected in 26.8% (225/841), 79.8% (331/415), 22.1% (136/615), 49.7% (80/161), 12.9 % (4/31), and 54.1% (20/37) of patients with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively. The prevalence of baseline polymorphisms in NS3 was higher in genotype 5 as compared to other genotypes; the high prevalence in genotype 5 was due to the common D168E polymorphism, which remains susceptible to glecaprevir. In general, with the exception of genotype 5, the prevalence of baseline polymorphisms was higher in NS5A than in NS3.

Genotype 1, 2, 4, 5, and 6: The presence of baseline polymorphism in NS3 and NS5A did not have an impact on SVR12 rates for genotype 1, 2, 4, 5 and 6.

Genotype 3: Among 313 genotype 3-infected patients receiving the recommended duration, baseline NS3 polymorphisms had no impact on treatment outcome. All patients 100% (15/15) with Y93H in NS5A at baseline achieved SVR12. Among patients receiving the recommended duration, 77% (17/22) with A30K in NS5A at baseline achieved SVR12. Among genotype 3-infected patients without cirrhosis receiving the recommended regimen, 91.4% (53/58) who had polymorphisms in NS5A at baseline achieved SVR12. Among genotype 3-infected patients with compensated cirrhosis receiving the recommended regimen, 100% (21/21) who had polymorphisms in NS5A at baseline achieved SVR12.

Cross-resistance

In vitro

In vitro data indicate that the majority of the resistance-associated substitutions in NS5A at amino acid positions 24, 28, 30, 31, 58, 92, or 93 that confer resistance to ombitasvir, daclatasvir, ledipasvir, elbasvir, or velpatasvir remained susceptible to pibrentasvir. Glecaprevir was fully active against resistance-associated substitutions in NS5A, while pibrentasvir was fully active against resistance-associated substitutions in NS3. Both glecaprevir and pibrentasvir were fully active against substitutions associated with resistance to NS5B nucleotide and non-nucleotide inhibitors.

Clinical Studies

In the MAGELLAN-1 study, patients with chronic HCV infection who had failed prior treatment with NS3/4A protease and/or NS5A inhibitors were treated with MAVIRET for 12 or 16 weeks. Baseline sequences were analyzed by next generation sequencing at 15% detection threshold. One or more of the following NS3 polymorphisms were detected at baseline in 16% (17/105) of patients with genotype 1 infection: R155K/T (n = 8) or D168A/E/N/T/V (n = 10). One or more of the following NS5A substitutions were detected in 60% (63/105) of the genotype 1-infected patients: K24Q/R (n = 4), L/M28A/M/T/V (n = 11), Q/R30E/G/H/K/L/Q/R (n = 29), L31I/M/V (n = 14), H/P58C/D/P/Q/S/T/Y (n = 17), A92E/T (n = 2), or Y93H/N/S (n = 23). The number of genotype 4-infected patients enrolled in the study was small, and did not allow for analysis of resistance.

Among 23 PI-experienced/NS5A inhibitor-naïve patients receiving 12 weeks of treatment, 2 patients each had baseline polymorphisms in NS3-only, NS5A-only, or NS3+NS5A; all 23 patients achieved SVR12. Among 32 NS5A inhibitor-experienced patients (with or without PI-experience) receiving 16 weeks of treatment, SVR12 rate was 100% (1/1), 95.0% (19/20), 25.0% (1/4), and 100% (7/7) in patients with baseline polymorphisms in NS3-only, NS5A-only, NS3+NS5A, or without any polymorphisms in NS3 or NS5A, respectively.

16. Non-Clinical Toxicology

General toxicology

Glecaprevir

Glecaprevir was well tolerated without adverse effects in studies for up to 1-month (mouse), 6-months (rat) and 9-months (dog). Maximum achieved glecaprevir plasma exposures in the longest duration studies were approximately 70 times (mice and rats) and 137 times (dog) higher when compared to human exposure at the recommended dose.

Pibrentasvir

Pibrentasvir was well tolerated without adverse effects in studies for up to 6-months (rat), 3-months (mouse) and 9-months (dog). Maximum achieved pibrentasvir plasma exposures in the longest duration studies were approximately 85 times (mice), 6 times (rat) and 17 times (dog) higher when compared to human exposure at the recommended dose.

Carcinogenicity

Glecaprevir and pibrentasvir were 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 rodent micronucleus assays.

Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted.

Reproductive and developmental toxicology

No effects on mating, female or male fertility, or early embryonic development were observed in rodents at up to the highest dose tested. Systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 63 and 102 times higher, respectively, the exposure in humans at the recommended dose.