Summary Basis of Decision for Maviret

 

Clinical Pharmacology

Maviret is a fixed-dose combination of two direct-acting antiviral agents for the treatment of hepatitis C virus (HCV); glecaprevir, a non-structural 3/4A (NS3/4A) protease inhibitor, and pibrentasvir, an NS5A inhibitor. Both of these drug substances have been shown to have potent in vitro antiviral activity against the main HCV genotypes 1 to 6.

Glecaprevir is a pan-genotypic 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.

Pibrentasvir is a pan-genotypic inhibitor of HCV NS5A, which is essential for viral ribonucleic acid (RNA) replication and virion assembly.

The clinical pharmacology report submitted included reports on the human pharmacodynamic and pharmacokinetic studies. The following items were noted:

Pharmacodynamics

QT Prolongation

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.

Pharmacokinetics

Hepatic Impairment

Hepatic impairment studies were conducted with a single dose of the glecaprevir 300 mg and pibrentasvir 120 mg combination in HCV-negative patients under non-fasting conditions. Compared to patients with normal hepatic function, glecaprevir exposures were higher in patients with Child-Pugh A (↑ 33% area under the curve [AUC]), Child-Pugh B (↑38% maximum plasma drug concentration [C_max], ↑2-fold AUC), and Child-Pugh C (↑5-fold C_max, ↑11-fold AUC) hepatic impairment. Pibrentasvir exposures were similar in patients with Child-Pugh A (≤20% difference in C_max or AUC), but higher in patients 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 HCV infected patients with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV infected patients.

Given the data, no dose adjustment of Maviret is required in patients with mild hepatic impairment (Child-Pugh A). However, use of Mavriet is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C).

Renal Impairment

Renal impairment studies were conducted with a single dose of the glecaprevir 300 mg and pibrentasvir 120 mg combination in HCV-negative patients with mild (estimated glomerular filtration rate [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 end-stage renal disease not on dialysis (eGFR <15 mL/min/1.73 m²). Compared to patients with normal renal function, glecaprevir plasma concentration time curve (AUC) values were similar in patients with mild renal impairment (13% difference), but higher in patients with moderate renal impairment (↑30%), severe renal impairment (↑45%), or end-stage renal disease not on dialysis (↑56%). Compared to patients with normal renal function, pibrentasvir AUC values were similar in patients with mild (11% difference) or moderate (25% difference) renal impairment, but higher in patients with severe renal impairment ↑37%), or end-stage renal disease not on dialysis (↑46%). Maximum plasma concentration (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 patients 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 HCV-infected patients with renal impairment with or without dialysis were not considered clinically significant.

Effects of Food on Oral Absorption

Intake of food along with Maviret has been shown to increase the bioavailability of Maviret. Increases in glecaprevir C_max and area under the plasma concentration-time curve from time zero to time t (AUC_T) was observed when a single 300 mg/120 mg dose of Maviret was 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 C_max and AUC_T and 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.

Drug-Drug Interactions

One prominent risk associated with use of Maviret is the potential for drug-drug interactions with sensitive substrates of P-glycoprotein (P-gp) and OATP1B1/3, strong inducers of P-gp/CYP3A. Coadministration of Maviret with atorvastatin, atazanavir, dabigatran etexilate, ethinyl estradiol-containing products, rifampin and simvastatin are contraindicated. Drugs that are not recommended to be used with Maviret include carbamazepine, St. John's wort, boosted protease inhibitors such as darunavir + ritonavir (DRV/rtv) and lopinavir + ritonavir (LPV/rtv), and lovastatin.

For further details, please refer to the Maviret Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Maviret was evaluated in nine Phase II-III clinical trials, in over 2,300 patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and with compensated liver disease (with or without cirrhosis). These nine Phase II-III clinical trials included open-labelled, placebo-controlled, and active-controlled clinical trials.

For all nine studies, the primary efficacy endpoint was based upon the sustained virologic response (SVR; defined as hepatitis C virus ribonucleic acid [HCV RNA] less than the lower limit of quantification [LLOQ]) observed after cessation of treatment through post treatment week 12 (SVR12).

Serum HCV RNA values were measured using the Roche COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a LLOQ of 15 IU/mL (except for SURVEYOR-1 and SURVEYOR-2 clinical trials which used the Roche COBAS TaqMan real-time reverse transcriptase-PCR [RT-PCR] assay v. 2.0 with an LLOQ of 25 IU/mL).

Across all nine studies, the patient demographics and baseline characteristics were comparable between the treatment arms. The studies are described below.

Treatment-Naïve and Treatment-Experienced-(Peg)interferon/Ribavirin/Sofosbuvir Patients with or without Cirrhosis Infected with Genotypes 1, 2, 4, 5 or 6

ENDURANCE-1 (Trial M13-590)

Clinical trial ENDURANCE-1 was a Phase III, randomized, open-label, multicentre trial which evaluated the efficacy and safety of Maviret (glecaprevir/pibrentasvir) in HCV treatment-naïve or prior treatment-experienced (i.e., interferon [IFN] or pegylated interferon [pegIFN] with or without ribavirin [RBV], or sofosbuvir [SOF] + RBV with or without pegIFN) chronic HCV genotype 1-infected or HCV genotype 1/Human Immunodeficiency Virus-1(HIV-1) co-infected patients without cirrhosis for 8- and 12-week treatment durations.

Hepatitis C virus genotype 1-infected treatment-naïve or prior treatment-experienced patients without cirrhosis were randomized in a 1:1 ratio into one of two treatment arms:

• Arm A: Maviret 300 mg/120 mg once daily (QD) for 12 weeks;
• Arm B: Maviret 300 mg/120 mg QD for 8 weeks.

Randomization was stratified by screening viral load (< or ≥6 million IU/mL) and by HCV genotype 1 subtype (1b or non-1b). Safety and efficacy were assessed throughout the study. In the Post-Treatment Period, all patients administered at least one dose of study drug were to be followed for 24 weeks post-treatment to monitor for safety, HCV RNA, plasma HIV-1 RNA (if applicable), HIV resistance (if applicable), and the emergence and/or persistence of HCV resistance-associated viral variants.

SURVEYOR-1 (Trial M14-867)

Clinical trial SURVEYOR-1 was a Phase II open-label, multicentre trial, consisting of two parts (Part 1 and Part 2) which evaluated the efficacy, safety, and pharmacokinetics of administration of Maviret in patients with HCV genotype 1, 4, 5, or 6 infection with compensated cirrhosis (genotype 1 only) or without cirrhosis (genotype 1, 4, 5, and 6). Part 1 enrolled patients who received Maviret for 12 weeks. Part 2 enrolled patients who received Maviret for 8 or 12 weeks. Patients who completed or prematurely discontinued the Treatment Period were followed for 24 weeks to monitor HCV RNA to evaluate efficacy and the emergence and persistence of viral variants.

For Part 1, genotype 1 treatment-naïve or pegIFN/RBV -null responder patients without cirrhosis were enrolled sequentially into one of two treatment arms:

• Arm A: Maviret 200 mg/120 mg QD for 12 weeks;
• Arm B: Maviret 200 mg/40 mg QD for 12 weeks.

Part 2 of the study was initiated based on the evaluation of efficacy and safety results from Part 1, as follows:

• Genotype 1-infected treatment-naïve or pegIFN/RBV experienced patients without cirrhosis were enrolled into Arm K;
• Genotype 1-infected treatment-naïve or pegIFN/RBV experienced patients with compensated cirrhosis were enrolled into Arm F.
• Genotype 4, 5, and 6-infected treatment-naïve or pegIFN/RBV experienced patients without cirrhosis were enrolled into Arm I.

The regimens corresponding to each of those arms were:

• Arm K: Maviret 300 mg/120 mg QD for 8 weeks;
• Arm F: Maviret 200 mg/120 mg QD for 12 weeks;
• Arm I: Maviret 300 mg/120 mg QD for 12 weeks.

Post-treatment relapse, defined as HCV RNA <LLOQ at the end of treatment followed with a confirmed HCV RNA ≥LOQ (defined as two consecutive HCV RNA measurements ≥LOQ) in the Post-Treatment Period, was monitored throughout the study to determine if the treatment duration was optimal. Within each arm, if the proportion of patients with relapse had exceeded 10% of patients who completed the assigned therapy (minimum of 10 patients who completed treatment as assigned evaluated), all remaining patients or a subset of patients (e.g., treatment-experienced) enrolled in the same or the related arm who had not reached the end of assigned treatment, would be offered an additional four weeks of study drug treatment.

ENDURANCE-2 (Trial M15-464)

Clinical trial ENDURANCE-2 was a Phase III, randomized, double-blind, placebo-controlled multicentre trial which evaluated the efficacy and safety of Maviret in HCV genotype 2-infected patients without cirrhosis, who were either HCV treatment-naïve or prior treatment-experienced (i.e., with IFN or pegIFN ± RBV, or SOF + RBV ± pegIFN).

Chronic HCV genotype 2-infected adults without underlying cirrhosis meeting all eligibility criteria were randomized in a 2:1 ratio into Arm A or Arm B:

• Arm A: Maviret 300 mg/120 mg QD for 12 weeks;
• Arm B: Matching placebo QD for 12 weeks followed by open-label Maviret 300 mg/120 mg QD for 12 weeks.

The study consisted of three periods:

• Double-Blind Treatment Period: Patients were randomized in a 2:1 ratio to receive either 12 weeks of Maviret (Arm A) or 12 weeks of matching placebo (Arm B), respectively.
• Open-Label Treatment Period: Patients randomized to placebo in the Double-Blind Treatment Period received subsequently open-label Maviret for 12 weeks.
• Post-Treatment Period: Patients randomized to active drug (Arm A) who completed or prematurely discontinued study drug during the Double-Blind Treatment Period and patients randomized to placebo (Arm B) who completed the Open-Label Treatment Period or prematurely discontinued study drug in the Open-Label Treatment Period were followed for 24 weeks post-treatment to monitor HCV RNA levels and to evaluate safety, efficacy, and the emergence and persistence of resistant viral variants.

Randomization of patients was stratified into three strata by type of previous treatment experience (i.e., HCV treatment-naïve or the last treatment regimen that the patient had received either IFN or pegIFN ± RBV or SOF + RBV ± pegIFN).

SURVEYOR-2 (Trial M14-868)

Clinical trial SURVEYOR-2 was an expanded Phase II, randomized, open-label, multipart, multicentre trial. The trial design consisted of four independent parts, with Parts 1 and 2 representing the supportive/exploratory parts of the trial and Parts 3 and 4 representing the confirmatory/registrational parts of the trial.

In Part 1, genotype 2-infected treatment-naïve and treatment-experienced patients without cirrhosis were randomized into one of three treatment arms:

• Arm A: Maviret 300 mg/120 mg QD for 12 weeks;
• Arm B: Maviret 200 mg/120 mg QD for 12 weeks;
• Arm C: Maviret 200 mg/120 mg QD + RBV 1,000 mg or 1,200 mg (weight based) divided twice daily (BID) for 12 weeks.

In Part 1, genotype 3-infected treatment-naïve and treatment-experienced patients without cirrhosis were randomized in a 1:1:1:1 ratio into one of four treatment arms:

• Arm D: Maviret 300 mg/120 mg QD for 12 weeks;
• Arm E: Maviret 200 mg/120 mg QD for 12 weeks;
• Arm F: Maviret 200 mg/120 mg QD + RBV 1,000 mg or 1,200 mg (weight based) divided BID for 12 weeks;
• Arm G: Maviret 200 mg/40 mg QD for 12 weeks.

Patients were stratified in Part 1 by prior HCV treatment history (naïve or experienced).

Arms in Part 2 were enabled for enrollment based on prespecified safety and efficacy criteria for data from Part 1 Arms A to G, once all patients in Part 1 had reached Post-Treatment Week 4.

In Part 2, genotype 2-infected treatment-naïve and treatment-experienced patients without cirrhosis were enrolled into:

• Arm J: Maviret 300 mg/120 mg QD for 8 weeks.

In Part 2, genotype 3-infected treatment-naïve and treatment-experienced patients without cirrhosis were enrolled into:

• Arm L: Maviret 300 mg/120 mg QD for 8 weeks (treatment-naïve) or 12 weeks (treatment-experienced).

In Part 2, genotype 3-infected treatment-naïve patients with cirrhosis were randomized in a 1:1 ratio into one of two treatment arms:

• Arm O: Maviret 300 mg/120 mg QD for 12 weeks;
• Arm P: Maviret 300 mg/120 mg QD + RBV 800 mg QD for 12 weeks.

Arms in Part 3 were enabled for enrollment of genotype 3-infected patients based on prespecified criteria for efficacy data from Part 2 Arms L (treatment-experienced group) and O (treatment-naïve group) once all applicable patients in Arms L and O had reached Post-Treatment Week 4.

Non-cirrhotic and/or cirrhotic patients meeting all eligibility criteria were randomized in a 1:1 ratio into one of two treatment arms in Part 3 with randomization stratified by presence or absence of cirrhosis and by prior HCV treatment history (naïve or experienced) for cirrhotic patients.

Arms Q and R in Part 3 for all genotype 3 cohorts (non-cirrhotic and cirrhotic) were enabled based on the supporting data from Part 2 and the prespecified efficacy criteria.

In Part 3, genotype 3-infected treatment-naïve patients with cirrhosis were only enrolled into:

• Arm Q: Maviret 300 mg/120 mg QD for 12 weeks.

In Part 3, genotype 3-infected treatment-experienced patients without cirrhosis were randomized in a 1:1 ratio into 1 of 2 treatment arms:

• Arm Q: Maviret 300 mg/120 mg QD for 12 weeks;
• Arm R: Maviret 300 mg/120 mg QD for 16 weeks.

In Part 3, genotype 3-infected treatment-experienced patients with cirrhosis were only enrolled into:

• Arm R: Maviret 300 mg/120 mg QD for 16 weeks.

In Part 4, genotype 2-infected and genotype 4 to 6-infected treatment-naïve and treatment-experienced patients without cirrhosis were enrolled into:

• Arm S: Maviret 300 mg/120 mg QD for 8 weeks.

Safety and efficacy were assessed throughout the study. In the Post-Treatment Period, all patients administered at least one dose of study drug were followed for 24 weeks to monitor for safety, HCV RNA, and the emergence and/or persistence of resistance-associated variants.

ENDURANCE-4 (Trial M13-583)

Clinical trial ENDURANCE-4 was a Phase III, single arm, open-label, multicentre study which evaluated the efficacy and safety of Maviret in HCV genotype 4 to 6-infected patients without cirrhosis, who were either HCV treatment-naïve or treatment-experienced (i.e., had failed prior IFN ± RBV, pegIFN ± RBV, or SOF + RBV ± pegIFN).

The study consisted of a Screening Period (confirming patient eligibility), Treatment Period, and Post-Treatment Period. During the Treatment Period, patients received 12 weeks of Maviret 300 mg/120 mg. In the Post-Treatment Period, all patients administered at least one dose of study drug were followed for 24 weeks post-treatment to monitor for safety, HCV RNA, and the emergence and/or persistence of resistance-associated viral variants.

EXPEDITION-1 (Trial M14-172)

Clinical trial EXPEDITION-1 was a Phase III, single-arm, open-label, multicentre study which evaluated the efficacy and safety of Maviret in chronic HCV genotype 1, 2 and 4 to 6-infected patients with cirrhosis who were either HCV treatment-naïve or prior treatment-experienced (i.e., IFN or pegINF± RBV, or SOF + RBV ± pegIFN).

The study consisted of a Screening Period (confirming patient eligibility), Treatment Period, and Post-Treatment Period. During the Treatment Period, patients received 12 weeks of Maviret 300 mg/120 mg. In the Post-Treatment Period, all patients administered at least one dose of study drug were followed for 24 weeks post-treatment to monitor for safety, HCV RNA, and the emergence and/or persistence of resistance-associated viral variants.

Genotype 3 Infected Patients

The efficacy of Maviret in patients who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir with genotype 3 chronic hepatitis C infection was demonstrated in the ENDURANCE-3 (treatment-naïve without cirrhosis) and SURVEYOR-2 Parts 1-3 (patients with and without cirrhosis and treatment-naïve and/or treatment-experienced) clinical studies. A description of the ENDURANCE-3 study is provided below. For Parts 1-3 of the SURVEYOR-2 study, a description has been provided above in the SURVEYOR-2 (Trial M14-868).

ENDURANCE-3 (Trial M13-594)

Clinical trial ENDURANCE-3 was a Phase III, randomized, open-label, active-controlled, multicentre study which compared efficacy and safety of Maviret for 12 weeks to SOF coadministered with daclatasvir (DCV) for 12 weeks and to Maviret for 8 weeks in adults with chronic HCV in treatment-naïve chronic HCV genotype 3-infected patients without cirrhosis.

Hepatitis C virus genotype 3-infected treatment-naïve patients without cirrhosis were enrolled into one of three treatment arms:

• Arm A: Maviret 300 mg/120 mg QD for 12 weeks;
• Arm B: SOF 400 mg + DCV 60 mg QD for 12 weeks;
• Arm C: Maviret 300 mg/120 mg QD for 8 weeks.

Patients meeting all eligibility criteria were initially randomized in a 2:1 ratio to Arms A or B. After enrollment in Arms A and B was completed, patients were assigned to Arm C.

Patients with Chronic Kidney Disease Stage 4 and 5 with or without Cirrhosis

EXPEDITION-4 (Trial M15-462)

Clinical trial EXPEDITION-4 was a Phase III, single arm, open-label, multicentre trial which evaluated the efficacy and safety of Maviret for 12 weeks in HCV genotype 1 to 6-infected treatment-naïve or prior treatment-experienced (i.e., had failed prior IFN or pegIFN with or without RBV, pegIFN/RBV + SOF, or SOF + RBV) patients with or without cirrhosis, who had severe renal impairment or end-stage renal disease, including those on dialysis.

Patients were categorized during screening as having chronic kidney disease Stage 4 or Stage 5. Among HCV genotype 3-infected patients, only treatment-naïve patients with or without cirrhosis were eligible for enrollment.

The study consisted of a Screening Period (confirming patient eligibility), Treatment Period, and Post-Treatment Period. During the Treatment Period, patients received 12 weeks of Maviret 300 mg/120 mg. In the Post-Treatment Period, all patients administered at least one dose of study drug were followed for 24 weeks post-treatment to monitor for safety, HCV RNA, and the emergence and/or persistence of resistance-associated viral variants.

Nonstructural 5A and/or Protease Inhibitor-Experienced Patients with or without Cirrhosis

MAGELLAN-1 (Trial M15-410)

Clinical trial MAGELLAN-1 was a Phase II randomized, open-label, multicentre trial, which consisted of two parts (Part 1 and Part 2), to evaluate the efficacy, safety, and pharmacokinetics of the co-administration of Maviret with or without RBV in patients with chronic genotype 1 (Parts 1 and 2) or genotype 4 to 6 (Part 2) HCV infection who failed a prior anti-HCV direct-acting antiviral agent-containing regimen.

For Part 1, patients were randomized in a 1:1:1 ratio to one of three treatment arms:

• Arm A: Maviret 200 mg/80 mg QD for 12 weeks;
• Arm B: Maviret 300 mg/120 mg QD + RBV 800 mg QD for 12 weeks;
• Arm C: Maviret 300 mg/120 mg QD for 12 weeks.

Enrollment in Arm A was stopped with Amendment 3 based upon the decision not to pursue development of the doses in Arm A (glecaprevir/pibrentasvir 200 mg/80 mg QD). Patients were subsequently randomized in a 1:1 ratio to Arms B or C.

Randomization in Part 1 was stratified by HCV genotype 1 subtype (1b or non-1b) and by previous experience to any of the three following direct-acting antiviral regimen classes:

1. Any experience with a NS5A inhibitor ± protease inhibitors (e.g., daclatasvir [DCV] + SOF, DCV + asunaprevir, DCV + simeprevir [SMV], ledipasvir [LDV] + SOF, ombitasvir + paritaprevir/ritonavir); or
2. NS5A inhibitor-naïve/protease inhibitor-experienced (e.g., SMV + SOF, SMV + pegylated interferon and RBV [PR], telaprevir + PR, boceprevir + PR); or
3. All other previous direct-acting antiviral agent-containing regimens not captured above (e.g., SOF + PR, SOF + RBV).

Part 2 of the study was initiated based on meeting efficacy and safety criteria in Part 1. Approximately 80 HCV genotype 1 or genotype 4 to 6-infected, direct-acting antiviral agent treatment-experienced patients with compensated liver disease with or without cirrhosis were randomized in a 1:1 ratio to one of 2 treatment arms:

• Arm D: Maviret 300 mg/120 mg QD for 12 weeks;
• Arm E: Maviret 300 mg/120 mg QD for 16 weeks.

Randomization in Part 2 was stratified by HCV genotype (genotype 1 or genotype 4 to 6) and by previous experience to the following two direct-acting antiviral regimen classes:

1. NS5A inhibitor (± protease inhibitor)-experienced, limited to DCV-, ledipasvir-, or ombitasvir-containing combination regimens; or
2. NS5A inhibitor-naïve/NS3/4A protease inhibitor-experienced, limited to: paritaprevir/ritonavir-, SMV-, telaprevir (TVR)-, or boceprevir (BOC)-containing combination regimens.

Efficacy Results and Discussion

Based on the nine clinical trials described above, overall Maviret achieved high SVR12 rates (97.4%) with low virologic failure rates (1.4%) in 2,369 patients across all HCV genotypes 1 to 6, treatment durations, prior treatment history, including patients with baseline polymorphism or patients with comorbidities (cirrhosis, renal impairment, and HIV-1 co-infection).

Among the largest treatment group of treatment-naïve patients and treatment-experienced (i.e., peg(IFN), RBV or SOF-experienced) patients infected with genotypes 1 to 6 without compensated cirrhosis, an 8-week treatment with Maviret achieved SVR12 rates (97.5 %) similar to the combination of SOF and velpatasvir (VEL) therapy (99%), the only other approved pan-genotypic HCV regimen. Maviret therapy, however, achieved similar efficacy at significantly lower treatment duration, 8-weeks instead of 12-weeks. This lower treatment duration may represent a more convenient form of treatment thereby improving patients' adherence to medication treatment. Treatment-naïve and treatment-experienced patients with compensated cirrhosis were assigned a longer treatment duration of 12 weeks. All subgroups of patients with or without cirrhosis were associated with low relapse rates for all genotypes (1 to 6) following 8 or 12 weeks of treatment.

Maviret also demonstrated a high SVR12 rate (95%) in genotype 3-infected treatment-naïve patients without cirrhosis in the Endurance -3 study following 8 and 12 weeks of treatment with an associated low relapse rates (3.3% and 1.4%, respectively). In addition, at both treatment durations, Maviret showed a comparable SVR12 rate to the currently approved regimen of DCV + SOF. As a result, Maviret treatment-naïve patients without cirrhosis have been assigned an 8-week treatment duration.

Among genotype 3-infected treatment-experienced patients treated for 12 and 16 weeks, the SVR rates were 89.8% after 12 weeks and 95.7% after 16 weeks of treatment with low relapse rates. As a result, a 16-week treatment was assigned to treatment-experienced patients. The high efficacy rates, with reduced treatment duration for treatment-naïve patients and the high efficacy rate in treatment-experienced after 16 weeks of therapy, represent a significant improvement over the existing therapies for genotype 3-infected patients who are currently supported by suboptimal efficacy rates, longer treatment for TN patients without cirrhosis, and/or associated with significant relapse rates.

In Study M15-410, the efficacy of Maviret was not affected by prior treatment history with protease inhibitors (e.g., BOC/TLV + PR) in the absence of NS5A inhibitor experience (e.g., ledipasvir/sofosbuvir [LDV/SOF], DCV regimens). No virologic failures occurred among the 38 protease inhibitor-experienced (NS5A inhibitor-naïve) patients, including 12 with cirrhosis. Seven of the cirrhotic patients were treated with 12 weeks of Maviret, the recommended treatment duration for treatment-experienced patients with cirrhosis. As such, similar efficacy is expected in protease inhibitor-experienced (NS5A inhibitor-naïve) non-cirrhotic and treatment-experienced patients treated with peginterferon/ribavirin/sofosbuvir (TE-PRS) non-cirrhotic patients treated for 8 weeks. As SOF and Maviret had non-overlapping resistance profiles, patients who failed SOF-based regimens (SOF + PR or SOF/RBV) were grouped with pegIFN/RBV failures or treatment-experienced group on the basis that SOF failures responded similarly as pegIFN/RBV failures. These groups of patients received similar treatment duration. Among the more difficult-to-treat patient population, the genotype 1-infected patients who previously failed NS3 inhibitors received a treatment duration indication of 12 weeks on the basis of high SVR12 (100%) and the no effects of baseline substitutions.

Patients previously treated with NS5A inhibitors (e.g., SOF + LDV or DCV + SOF) received longer treatment duration (16 weeks) on the basis of treatment response (SVR12, 94.4%) and the absence of effects by baseline substitutions. In contrast, patients who previously received both NS5A and protease inhibitors reported a somewhat lower SVR12 rate (81%) after 16 weeks of treatment and treatment outcomes were severely impacted by key baseline substitutions (SVR12, 25% after 16 weeks of treatment). This later group of patients received no genotype 1 treatment indication.

Although baseline polymorphism has been detected within the NS3 and NS5A proteins of all genotypes, being rare in the NS3 protein and significantly more prevalent in the NS5A-protein, the presence of baseline polymorphism in NS3 and/or NS5A did not reveal any impact on SVR12 rates in genotype 1, 2, and 4 to 6-infected patients.

The efficacy rate reported in a limited number of co-infected patients with HCV genotype 1 and HIV-1 was similar to that in HCV genotype 1 mono-infected patients. This is consistent with previous studies which demonstrated that the presence of HIV-1 co-infection does not adversely impact efficacy with the use of highly effective direct-acting antiviral agent-based regimens.

Results from Study M15-462 confirmed that the presence of severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²), including dialysis, had no impact on the efficacy rate. Based on these results, treatment duration has been proposed without regard to any degree of renal impairment and without the need for dose adjustment. The Maviret regimen, therefore, fulfills the unmet need of a safe and effective RBV-free regimen for patients infected with HCV genotype 2, 3, 5, or 6 with severe renal impairment, including those on dialysis who currently have no other treatment option available to them.

The efficacy in genotype 5- and 6-infected patients could not be formally assessed using powered comparisons given the very low prevalence of infection with these genotypes. There were no virologic failures among 80 patients infected with genotype 5 or genotype 6 in the clinical program. The in vitro potency of Maviret against NS3 and NS5A in genotype 5 and genotype 6 was similar to that in genotype 1 to genotype 4. Furthermore, early viral kinetics in genotype 5- and genotype 6-infected patients demonstrated that HCV RNA was suppressed as quickly as in patients infected with other genotypes. Also, exposure-response analysis showed that genotype 5- and genotype 6-infected patients achieved SVR regardless of glecaprevir or pibrentasvir exposure, demonstrating that exposures were significantly above the threshold to suppress these genotypes. Therefore, the duration of treatment recommended for genotype 5- and genotype 6-infected patients are the same as for the other genotypes.

 

 

Indication

The New Drug Submission for Maviret was filed by the sponsor with the following indication:

Maviret is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection.

Based on the review of submitted data, Health Canada approved the following indication:

Maviret is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection with or without compensated cirrhosis. This includes patients with HCV genotype 1 infection who were previously treated with either a regimen of NS5A inhibitor or with a NS3/4A protease inhibitor but not both classes of inhibitors.

For more information, refer to the Maviret Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Maviret was primarily evaluated in nine Phase II-III clinical trials (ENDURANCE-1, 2, 3, 4; SURVEYOR-1 and 2; EXPEDITION -1 and 4; and MAGELLAN-1) previously described in the Clinical Efficacy section. Based on the nine clinical trials, Maviret (glecaprevir/pibrentasvir) in fixed-dose combination has been shown to have a favourable safety profile in HCV-infected patients treated for 8, 12, or 16 weeks, across all subpopulations. The overall safety profile was similar to that reported for patients receiving placebo or an active-controlled product (SOF + DCV).

The most common direct-acting antiviral agent related adverse events (≥3%) reported in the studies were headache (13.2%), fatigue (11.4%), nausea (7.6%), diarrhea (3.8%) and pruritus (3.3%). The majority of the direct-acting antiviral (DAA) related adverse events were of Grade 1 (mild) in severity. Direct-acting antiviral related Grade 3 or higher adverse events and serious adverse events were uncommon and found to occur at a rate of 0.2% and <0.1%, respectively, of all 2,265 Phase II and III patients. Adverse events which led to premature discontinuation of study drug were infrequent, and occurred at a rate of 0.1% of all these patients. The type, frequency, and severity of adverse events in patients with cirrhosis were similar to those in patients without cirrhosis.

There were no hematological or blood chemistry findings of concern. While there were elevations in total bilirubin the patients were asymptomatic. The bilirubin elevations were predominantly indirect, consistent with the known inhibition of bilirubin metabolism UDP-glucuronosyltransferase 1-1 (also known as UGT1A1) and/or transporters by one of the components of Maviret, glecaprevir. There were no cases consistent with drug-induced liver injury. Additional clinical and safety laboratory assessments during treatment beyond standard practice are not considered necessary.

Maviret also demonstrated a favourable safety profile in patients with renal insufficiency, including patients on dialysis.

Currently no data are available on the safety and efficacy of Maviret for use in the following populations: patients with moderate and severe hepatic impairment (Child-Pugh B and Child-Pugh C), patients awaiting liver transplant or having a liver transplant, pregnant and nursing women, pediatric patients and patients with hepatitis B virus. The needs of these subgroups of patients remain unmet since the efficacy and safety of Maviret in these subgroups are unknown. Therefore, Maviret should not be used in these patients.

Identified Risks Associated with Maviret

The risks either known to be or potentially associated with Maviret and/or DAAs as a class have been identified and the labelling language in the Maviret Product Monograph is considered an adequate risk management strategy to prevent or reduce the occurrences of these risks. In addition, a risk management plan was submitted to Health Canada by the sponsor to monitor the known risks or other developing safety concerns and has been considered acceptable.

Some of the more prominent risks associated with use of Maviret are as follows:

• Drug-Drug Interaction information where drugs that are not recommended to be used with Maviret include carbamazepine, St. John's Wort, boosted protease inhibitors such as darunavir/ritonavir and lopinavir/ritonavir, and lovastatin;
• Risk of HBV reactivation and risk of early recurrence of hepatocellular carcinoma in patients treated with the direct-acting antiviral agents class;
• Information on the safety and efficacy of Maviret in HIV/HCV co-infected patients is limited;
• The risk of development of resistance of the HCV to treatment.

The risks associated with the use of Maviret were dealt with proper labelling in the Maviret Product Monograph, to either use with caution or restrict the use in special groups of patients.

Overall Risk-Benefit Assessment

Treatment of HCV genotype 1- to 6- infected patients with the Maviret regimen resulted in high SVR12 rates across all populations studied, including direct-acting antiviral agents-experienced patients, patients with compensated cirrhosis, severe renal impairment, or co-infection with HIV-1, regardless of baseline host and viral factors. These results represent a significant advance over currently approved treatment regimens for HCV.

Overall, the risks associated with Maviret are limited.

Adverse drug reactions and laboratory abnormalities reported in the clinical studies were generally mild. Virologic failures and development of resistance for the regimen are considered to be low.

An assessment of potential drug-drug interactions identified a number of interactions which are likely to be of clinical significance. Appropriate recommendations for dose adjustments, avoidance of co-administration, or contraindications have been included in the prescribing information of Maviret.

The overall benefit-risk profile for Maviret is favourable when used as directed in the prescribing information for the treatment of adult patients across all HCV genotypes 1 to 6, treatment durations (8, 12, or 16-weeks), prior treatment history, including patients with baseline polymorphism and patients with comorbidities (e.g., compensated cirrhosis, renal impairment, etc.).

For more information, refer to the Maviret Product Monograph, approved by Health Canada and available through the Drug Product Database.