place of business [1%:100 mg per day. See Clinical Pharmacology, Tables 8 and 9 . = increase; = decrease; = no effect Drugs with No Observed Clinically Significant Interactions with Mavyret No dose adjustment is required when Mavyret 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, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary No adequate human data are available to establish whether or not Mavyret poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when the components of Mavyret were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose of Mavyret [see Data] . No definitive conclusions regarding potential developmental effects of glecaprevir could be made in rabbits, since the highest achieved glecaprevir exposure in this species was only 7% (0.07 times) of the human exposure at the recommended dose. There were no effects with either compound in rodent pre/post-natal 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 [see Data] . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Glecaprevir Glecaprevir was administered orally to pregnant rats (up to 120 mg/kg/day) and rabbits (up to 60 mg/kg/day) during the period of organogenesis (gestation days (GD) 6 to 18, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed in rats at dose levels up to 120 mg/kg/day (53 times the exposures in humans at the recommended human dose (RHD)). In rabbits, the highest glecaprevir exposure achieved was 7% (0.07 times) of the exposure in humans at RHD. As such, data in rabbits during organogenesis are not available for glecaprevir systemic exposures at or above the exposures in humans at the RHD. In the pre/post-natal developmental study in rats, glecaprevir was administered orally (up to 120 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures 47 times the exposures in humans at the RHD. Pibrentasvir Pibrentasvir was administered orally to pregnant mice and rabbits (up to 100 mg/kg/day) during the period of organogenesis (GD 6 to 15, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed at any studied dose level in either species. The systemic exposures at the highest doses were 51 times (mice) and 1.5 times (rabbits) the exposures in humans at the RHD. In the pre/post-natal developmental study in mice, pibrentasvir was administered orally (up to 100 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures approximately 74 times the exposures in humans at the RHD. Lactation Risk Summary It is not known whether the components of Mavyret are excreted in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rodents, the components of Mavyret were present in milk, without effect on growth and development observed in the nursing pups [see Data] . The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for Mavyret and any potential adverse effects on the breastfed child from Mavyret or from the underlying maternal condition. Data No significant effects of glecaprevir or pibrentasvir on growth and post-natal development were observed in nursing pups at the highest doses tested (120 mg/kg/day for glecaprevir and 100 mg/kg/day for pibrentasvir). Maternal systemic exposure (AUC) to glecaprevir and pibrentasvir was approximately 47 or 74 times the exposure in humans at the RHD. Systemic exposure in nursing pups on post-natal day 14 was approximately 0.6 to 2.2 % of the maternal exposure for glecaprevir and approximately one quarter to one third of the maternal exposure for pibrentasvir. Glecaprevir or pibrentasvir was administered (single dose; 5 mg/kg oral) to lactating rats, 8 to 12 days post parturition. Glecaprevir in milk was 13 times lower than in plasma and pibrentasvir in milk was 1.5 times higher than in plasma. Parent drug (glecaprevir or pibrentasvir) represented the majority (>96%) of the total drug-related material in milk. Pediatric Use Safety and effectiveness of Mavyret in children less than 18 years of age have not been established. Geriatric Use In clinical trials of Mavyret, 328 subjects were age 65 years and over (14% of the total number of subjects in the Phase 2 and 3 clinical trials) and 47 subjects were age 75 and over (2%). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. No dosage adjustment of Mavyret is warranted in geriatric patients [see Clinical Pharmacology (12.3) ] . Renal Impairment No dosage adjustment of Mavyret is required in patients with mild, moderate or severe renal impairment, including those on dialysis [see Clinical Pharmacology (12.3) and Clinical Studies (14.5) ] . Hepatic Impairment No dosage adjustment of Mavyret is required in patients with mild hepatic impairment (Child-Pugh A). Mavyret is not recommended in patients with moderate hepatic impairment (Child-Pugh B). Safety and efficacy have not been established in HCV-infected patients with moderate hepatic impairment. Mavyret is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to higher exposures of glecaprevir and pibrentasvir [see Dosage and Administration (2.3) , Contraindications (4) , and Clinical Pharmacology (12.3) ] . Overdosage 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 are not significantly removed by hemodialysis. Mavyret Description Mavyret is a fixed-dose combination tablet containing glecaprevir and pibrentasvir for oral administration. Glecaprevir is a HCV NS3/4A PI, and pibrentasvir is a HCV NS5A inhibitor. Glecaprevir/Pibrentasvir Film-Coated Immediate Release Tablets Each tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. Glecaprevir and pibrentasvir are presented as a co-formulated, fixed-dose combination, immediate release bilayer tablet. The tablet contains the following inactive ingredients: colloidal silicon dioxide, copovidone (type K 28), croscarmellose sodium, hypromellose 2910, iron oxide red, lactose monohydrate, polyethylene glycol 3350, propylene glycol monocaprylate (type II), sodium stearyl fumarate, titanium dioxide, and vitamin E (tocopherol) polyethylene glycol succinate. The tablets do not contain gluten. Glecaprevir drug substance: The chemical name of glecaprevir is (3a R ,7 S ,10 S ,12 R ,21 E ,24a R )-7- tert -butyl- N -(1 R ,2 R )-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-1 H ,10 H -9,12-methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononadecino[11,12- b ]quinoxaline-10-carboxamide hydrate. The molecular formula is C 38 H 46 F 4 N 6 O 9 S (anhydrate) and the molecular weight for the drug substance is 838.87 g/mol (anhydrate). The strength of glecaprevir is based on anhydrous glecaprevir. Glecaprevir is a white to off-white crystalline powder with a solubility of less than 0.1 to 0.3 mg/mL across a pH range of 2 7 at 37 C and is practically insoluble in water, but is sparingly soluble in ethanol. Glecaprevir has the following molecular structure: Pibrentasvir drug substance: The chemical name of pibrentasvir is Methyl (2 S ,3 R )-1-[(2 S )-2-5-[(2 R ,5 R )-1-3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl-5-(6-fluoro-2-(2 S )-1-[ N -(methoxycarbonyl)- O -methyl-L-threonyl]pyrrolidin-2-yl-1 H -benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1 H -benzimidazol-2-ylpyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-ylcarbamate. The molecular formula is C 57 H 65 F 5 N 10 O 8 and the molecular weight for the drug substance is 1113.18 g/mol. Pibrentasvir is a white to off-white to light yellow crystalline powder with a solubility of less than 0.1 mg/mL across a pH range of 1 7 at 37 C and is practically insoluble in water, but is freely soluble in ethanol. Pibrentasvir has the following molecular structure: Mavyret - Clinical Pharmacology Mechanism of Action Mechanism of Action Mavyret is a fixed-dose combination of glecaprevir and pibrentasvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ] . Pharmacodynamics Cardiac Electrophysiology The effect of doses up to glecaprevir 600 mg (2 times the recommended dosage) with doses up to pibrentasvir 240 mg (2 times the recommended dosage) 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 to any clinically relevant extent. Pharmacokinetics The pharmacokinetic properties of the components of Mavyret in healthy subjects are provided in Table 6 . The steady-state pharmacokinetic parameters of glecaprevir and pibrentasvir in HCV-infected subjects without cirrhosis are provided in Table 7 . Table 6. Pharmacokinetic Properties of the Components of Mavyret in Healthy Subjects Glecaprevir Pibrentasvir Absorption T max (h) a 5.0 5.0 Effect of meal (relative to fasting) b 83-163% 40-53% Distribution % Bound to human plasma proteins 97.5 >99.9 Blood-to-plasma ratio 0.57 0.62 Elimination t 1/2 (h) 6 13 Metabolism secondary, CYP3A None Major route of excretion biliary-fecal biliary-fecal % of dose excreted in urine c 0.7 0 % of dose excreted in feces c 92.1 96.6 a. Median T max following single doses of glecaprevir and pibrentasvir in healthy subjects. b. Mean systemic exposures with moderate to high fat meals. c. Single dose administration of radiolabeled glecaprevir or pibrentasvir in mass balance studies. Table 7. Steady-State Pharmacokinetic Parameters of Glecaprevir and Pibrentasvir Following Administration of Mavyret in Non-Cirrhotic HCV-Infected Subjects Pharmacokinetic Parameter Glecaprevir b Pibrentasvir c C max (ng/mL) a 597 (114) 110 (49) AUC 24,ss (ng h/mL) a 4800 (122) 1430 (57) a Geometric mean (%CV) of individual-estimated C max and AUC 24,ss values b Relative to healthy subjects, glecaprevir C max was 51% lower and AUC 24,ss was similar (10% difference) in HCV-infected subjects without cirrhosis, respectively c Relative to healthy subjects, pibrentasvir C max and AUC 24,ss were 63% and 34% lower, respectively in HCV-infected subjects without cirrhosis, respectively Specific Populations Pediatric Patients The pharmacokinetics of Mavyret in pediatric patients has not been established. Subjects with Renal Impairment Glecaprevir and pibrentasvir AUC were increased 56% in non-HCV infected subjects with mild, moderate, severe, or end-stage renal impairment (GFR estimated using Modification of Diet in Renal Disease) not on dialysis compared to subjects with normal renal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis ( 18% difference) in dialysis-dependent non-HCV infected subjects. In HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observed for subjects with end stage renal disease, with or without dialysis, compared to subjects with normal renal function. Subjects with Hepatic Impairment Following administration of Mavyret in HCV infected subjects with compensated cirrhosis (Child-Pugh A), exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV infected subjects. At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC 100% higher in Child-Pugh B subjects, and increased to 11-fold in Child-Pugh C subjects. Pibrentasvir AUC was 26% higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects. Age/Gender/Race/Body Weight No clinically significant differences in the pharmacokinetics of glecaprevir or pibrentasvir were observed based on age [18-88 years], sex, race/ethnicity or body weight. 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. Tables 8 and 9 summarize the pharmacokinetic effects when glecaprevir/pibrentasvir was coadministered with other drugs which showed potentially clinically relevant changes. Significant interactions are not expected when Mavyret is coadministered with substrates of CYP3A, CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A1, or UGT1A4. Table 8. Drug Interactions: Changes in Pharmacokinetic Parameters of Glecaprevir (GLE) or Pibrentasvir (PIB) in the Presence of Coadministered Drug Co- administered Drug Regimen of Co- administered Drug (mg) Regimen of GLE/PIB (mg) N DAA Central Value Ratio (90% CI) C max AUC C min Atazanavir + ritonavir 300 + 100 once daily 300/120 once daily a 12 GLE 4.06 (3.15, 5.23) 6.53 (5.24, 8.14) 14.3 (9.85, 20.7) PIB 1.29 (1.15, 1.45) 1.64 (1.48, 1.82) 2.29 (1.95, 2.68) Carbamazepine 200 twice daily 300/120 single dose 10 GLE 0.33 (0.27, 0.41) 0.34 (0.28, 0.40) -- PIB 0.50 (0.42, 0.59) 0.49 (0.43, 0.55) -- Cyclosporine 100 single dose 300/120 once daily 12 GLE 1.30 (0.95, 1.78) 1.37 (1.13, 1.66) 1.34 (1.12, 1.60) PIB 1.26 (1.15, 1.37) 400 single dose 300/120 single dose 11 GLE 4.51 (3.63, 6.05) 5.08 (4.11, 6.29) -- PIB 1.93 (1.78, 2.09) -- Darunavir + ritonavir 800 + 100 once daily 300/120 once daily 8 GLE 3.09 (2.26, 4.20) 4.97 (3.62, 6.84) 8.24 (4.40, 15.4) PIB 1.66 (1.25, 2.21) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide 150/150/ 200/10 once daily 300/120 once daily 11 GLE 2.50 (2.08, 3.00) 3.05 (2.55, 3.64) 4.58 (3.15,6.65) PIB 1.57 (1.39, 1.76) 1.89 (1.63, 2.19) Omeprazole 20 once daily 300/120 single dose 9 GLE 0.78 (0.60, 1.00) 0.71 (0.58, 0.86) -- PIB -- 40 once daily (1 hour before GLE/PIB) 300/120 single dose 12 GLE 0.36 (0.21, 0.59) 0.49 (0.35, 0.68) -- PIB -- Rifampin 600 (first dose) 300/120 single dose 12 GLE 6.52 (5.06, 8.41) 8.55 (7.01, 10.4) -- PIB -- 600 once daily 300/120 single dose b 12 GLE 0.14 (0.11, 0.19) 0.12 (0.09, 0.15) -- PIB 0.17 (0.14, 0.20) 0.13 (0.11, 0.15) -- Lopinavir/ ritonavir 400/100 twice daily 300/120 once daily 9 GLE 2.55 (1.84, 3.52) 4.38 (3.02, 6.36) 18.6 (10.4, 33.5) PIB 1.40 (1.17, 1.67) 2.46 (2.07, 2.92) 5.24 (4.18, 6.58) = No change (central value ratio 0.80 to 1.25) a. Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported. b. Effect of rifampin on glecaprevir and pibrentasvir 24 hours after final rifampin dose. Table 9. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Combination of Glecaprevir/Pibrentasvir (GLE/PIB) Co- administered Drug Regimen of Co- administered Drug (mg) Regimen of GLE/PIB (mg) N Central Value Ratio (90% CI) C max AUC C min Abacavir ABC/DTG/3TC 600/50/300 once daily 300/120 once daily 12 1.31 (1.05, 1.63) Atorvastatin 10 once daily 400/120 once daily 11 22.0 (16.4, 29.6) 8.28 (6.06, 11.3) -- Caffeine 100 single dose 300/120 once daily 12 1.35 (1.23, 1.48) -- Dabigatran Dabigatran etexilate 150 single dose 300/120 once daily 11 2.05 (1.72, 2.44) 2.38 (2.11, 2.70) -- Darunavir DRV + RTV 800 + 100 once daily 300/120 once daily 12 1.30 (1.21, 1.40) 1.29 (1.18, 1.42) Ritonavir 2.03 (1.78, 2.32) 1.87 (1.74, 2.02) Dextro- methorphan Dextromethorphan hydrobromide 30 single dose 300/120 once daily 12 0.70 (0.61, 0.81) 0.75 (0.66, 0.85) -- Digoxin 0.5 single dose 400/120 once daily 12 1.72 (1.45, 2.04) 1.48 (1.40, 1.57) -- Ethinyl estradiol (EE) EE/ Norgestimate 35 µg/250 µg once daily 300/120 once daily 11 1.31 (1.24, 1.38) 1.28 (1.23, 1.32) 1.38 (1.25, 1.52) Norgestrel 1.54 (1.34, 1.76) 1.63 (1.50, 1.76) 1.75 (1.62, 1.89) Norgestromin 1.44 (1.34, 1.54) 1.45 (1.33, 1.58) Ethinyl estradiol EE/ Levonorgestrel 20 µg/100 µg once daily 300/120 once daily 12 1.30 (1.18, 1.44) 1.40 (1.33, 1.48) 1.56 (1.41, 1.72) Norgestrel 1.37 (1.23, 1.52) 1.68 (1.57, 1.80) 1.77 (1.58, 1.98) Elvitegravir EVG/COBI/FTC/ TAF 150/ 150/200/10 once daily 300/120 once daily 12 1.36 (1.24, 1.49) 1.47 (1.37, 1.57) 1.71 (1.50, 1.95) Tenofovir Felodipine 2.5 single dose 300/120 once daily 11 1.31 (1.05, 1.62) 1.31 (1.08, 1.58) -- Losartan 50 single dose 300/120 once daily 12 2.51 (2.00, 3.15) 1.56 (1.28, 1.89) -- Losartan carboxylic acid 2.18 (1.88, 2.53) -- Lovastatin Lovastatin 10 once daily 300/120 once daily 12 1.70 (1.40, 2.06) -- Lovastatin acid 5.73 (4.65, 7.07) 4.10 (3.45, 4.87) -- Midazolam 1 single dose 300/120 once daily 12 1.27 (1.11, 1.45) -- Omeprazole 20 single dose 300/120 once daily 12 0.57 (0.43, 0.75) 0.79 (0.70, 0.90) -- Pravastatin 10 once daily 400/120 once daily 12 2.23 (1.87, 2.65) 2.30 (1.91, 2.76) -- Raltegravir 400 twice daily 300/120 once daily 12 1.34 (0.89, 1.98) 1.47 (1.15, 1.87) 2.64 (1.42, 4.91) Rilpivirine 25 once daily 300/120 once daily 12 2.05 (1.73, 2.43) 1.84 (1.72, 1.98) 1.77 (1.59, 1.96) Rosuvastatin 5 once daily 400/120 once daily 11 5.62 (4.80, 6.59) 2.15 (1.88, 2.46) -- Simvastatin Simvastatin 5 once daily 300/120 once daily 12 1.99 (1.60, 2.48) 2.32 (1.93, 2.79) -- Simvastatin acid 10.7 (7.88, 14.6) 4.48 (3.11, 6.46) -- Sofosbuvir Sofosbuvir 400 once daily 400/120 once daily 8 1.66 (1.23, 1.22) 2.25 (1.86, 2.72) -- GS-331007 1.85 (1.67, 2.04) Tacrolimus 1 single dose 300/120 once daily 10 1.50 (1.24, 1.82) 1.45 (1.24, 1.70) -- Tenofovir EFV/FTC/TDF 300/200/300 once daily 300/120 once daily 12 1.29 (1.23, 1.35) 1.38 (1.31, 1.46) Valsartan 80 single dose 300/120 once daily 12 1.36 (1.17, 1.58) 1.31 (1.16, 1.49) -- = No change (central value ratio 0.80 to 1.25) 3TC lamivudine; ABC abacavir; COBI cobicistat; DRV darunavir; DTG dolutegravir; EFV efavirenz; EVG elvitegravir; FTC emtricitabine; RTV ritonavir; TAF tenofovir alafenamide; TDF tenofovir disoproxil fumarate Microbiology Mechanism of Action Glecaprevir Glecaprevir is an 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 IC 50 values ranging from 3.5 to 11.3 nM. Pibrentasvir Pibrentasvir is an 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. Antiviral Activity In HCV replicon assays, glecaprevir had median EC 50 values of 0.08-4.6 nM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a. Pibrentasvir had median EC 50 values of 0.5-4.3 pM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4b, 4d, 5a, 6a, 6e and 6p. Combination Antiviral Activity Evaluation of combination of glecaprevir and pibrentasvir showed no antagonism in antiviral activity in HCV genotype 1 replicon cell culture assays. Resistance In Cell Culture Selection of HCV genotype 1a, 1b, 2a, 3a, 4a or 6a replicons for reduced susceptibility to glecaprevir resulted in the emergence of amino acid substitutions most commonly at NS3 positions A156 or D/Q168. 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. Individual amino acid substitutions associated with resistance to other HCV protease inhibitors at positions 36, 43, 54, 55, 56, 155, 166, or 170 in NS3 generally did not reduce susceptibility to glecaprevir. Selection of HCV genotype 1a, 2a or 3a replicons for reduced susceptibility to pibrentasvir resulted in the emergence of amino acid substitutions at known NS5A inhibitor resistance-associated positions, including Q30D/deletion, Y93D/H/N or H58D +Y93H in genotype 1a replicons, F28S + M31I or P29S + K30G in genotype 2a replicons, and Y93H in genotype 3a replicons. The majority of individual amino acid substitutions associated with resistance to other HCV NS5A inhibitors at positions 24, 28, 30, 31, 58, 92, or 93 in NS5A did not reduce susceptibility to pibrentasvir. Individual NS5A amino acid substitutions that reduced susceptibility to pibrentasvir include M28G or Q30D in a genotype 1a replicon (244- and 94-fold, respectively), and P32-deletion in a genotype 1b replicon (1,036-fold). Some combinations of two or more NS5A inhibitor resistance-associated amino acid substitutions may result in greater reductions in pibrentasvir susceptibility. In Clinical Studies Studies in Treatment-Naïve and Peginterferon, Ribavirin and/or Sofosbuvir Treatment-Experienced Subjects with or without Cirrhosis In pooled analyses of NS3/4A PI- and NS5A inhibitor-naïve subjects who received Mavyret for 8, 12, or 16 weeks in Phase 2 and 3 clinical studies, treatment-emergent resistance analyses were conducted for 22 subjects who experienced virologic failure (2 with genotype 1, 2 with genotype 2, 18 with genotype 3 infection). No subjects with HCV genotype 4, 5 or 6 infection experienced virologic failure. Among the two genotype 1-infected subjects who experienced virologic failure, both subjects had a subtype 1a infection. One subject had treatment-emergent substitutions A156V in NS3, and Q30R, L31M and H58D in NS5A (Q30R and L31M were also detected at a low frequency at baseline). One subject had treatment-emergent Q30R and H58D (while Y93N was present at baseline and post-treatment) in NS5A. Among the two genotype 2-infected subjects who experienced virologic failure, both subjects had a subtype 2a infection, and no treatment-emergent substitutions were observed in NS3 or NS5A. Among the 18 genotype 3-infected subjects who experienced virologic failure, treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, or Q168L/R were observed in 11 subjects. A166S or Q168R were present at baseline and post-treatment in 5 subjects. Treatment-emergent NS5A substitutions M28G, A30G/K, L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n=9) or Y93H (n=5) at baseline and post-treatment. Studies in Subjects with or without Cirrhosis Who Were Treatment-Experienced to NS3/4A Protease and/or NS5A Inhibitors Treatment-emergent resistance analyses were conducted for 11 HCV genotype 1 infected subjects (10 genotype 1a, 1 genotype 1b) with prior NS3/4A PI or NS5A inhibitor treatment experience who experienced virologic failure with Mavyret with or without ribavirin in the MAGELLAN-1 study. Treatment-emergent NS3 substitutions V36A/M, Y56H, R155K/T, A156G/T/V, or D168A/T were observed in 73% (8/11) of subjects. Nine of 10 subjects (90%, not including one subject missing NS5A data at failure) had treatment-emergent NS5A substitutions M28A/G (or L28M for genotype 1b), P29Q/R, Q30K/R, H58D or Y93H/N. All 11 subjects also had NS5A inhibitor resistance-associated substitutions detected at baseline, and 7/11 had NS3 PI resistance-associated substitutions detected at baseline (see Cross-Resistance for the effect of baseline resistance-associated substitutions on treatment response for NS3/4A PI or NS5A inhibitor treatment-experienced patients). Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response (NS3/4A PI- and NS5A Inhibitor-Naïve Subjects) A pooled analysis of NS3/4A PI- and NS5A inhibitor-naïve subjects who received Mavyret in the Phase 2 and Phase 3 clinical studies was conducted to identify the HCV subtypes represented and explore the association between baseline amino acid polymorphisms and treatment outcome . Baseline polymorphisms relative to a subtype-specific reference sequence at resistance-associated 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. Among subjects who received Mavyret for 8-, 12-, or 16 weeks, baseline polymorphisms in NS3 were detected in 1% (9/845), 1% (3/398), 2% (10/613), 1% (2/164), 42% (13/31), and 3% (1/34) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively. No baseline polymorphisms were detected at NS3 amino acid position 156 across all genotypes. Baseline polymorphisms in NS5A were detected in 27% (225/841), 80% (331/415), 22% (136/615), 50% (80/161), 13% (4/31), and 54% (20/37) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively. Genotype 1, 2, 4, 5, and 6: Baseline HCV polymorphisms in genotypes 1, 2, 4, 5 and 6 had no impact on treatment outcome. Genotype 3: Among treatment-naïve, genotype 3-infected subjects without cirrhosis who received Mavyret for 8 weeks, an NS5A A30K polymorphism was detected in 10% (18/181) of subjects, of whom 78% (14/18) achieved SVR12. Insufficient data are available to characterize the impact of the A30K polymorphism in genotype 3-infected subjects with cirrhosis (n=1, SVR12) or prior treatment experience (n=1, relapse) who received the recommended Mavyret regimens. All genotype 3-infected subjects (100%, 16/16) with Y93H in NS5A at baseline who received the recommended Mavyret regimens achieved SVR12. Cross-resistance Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance is possible between glecaprevir and other HCV NS3/4A PIs, and between pibrentasvir and other HCV NS5A inhibitors. Cross-resistance is not expected between Mavyret and sofosbuvir, pegylated interferon or ribavirin. In the MAGELLAN-1 study, HCV genotype 1-infected subjects who had failed prior treatment with NS3/4A protease and/or NS5A inhibitors were treated with Mavyret for 12 or 16 weeks. Baseline sequences were analyzed by next generation sequencing at a 15% detection threshold. Among 23 NS3/4A PI-experienced/NS5A inhibitor-naïve subjects who received Mavyret for 12 weeks in MAGELLAN-1 (excluding 2 non-virologic failure subjects), 2 subjects each had baseline NS3 R155K or D168E/V substitutions; all 23 subjects achieved SVR12. Among NS5A inhibitor-experienced/PI-naïve subjects who received Mavyret for 16 weeks, baseline NS5A resistance-associated substitutions [R30Q (n=1), Y93H/N (n=5), M28A+Q30R (n=1), Q30H+Y93H (n=1), Q30R+L31M (n=2), L31M+H58P (n=1)], were detected in 73% (11/15) of subjects with available data, of whom 91% (10/11) achieved SVR12. The non-SVR12 subject experienced on-treatment virologic failure and had a genotype 1a infection with baseline NS5A Q30R and L31M substitutions. Persistence of Resistance-Associated Substitutions Data on the persistence of glecaprevir and pibrentasvir resistance-associated substitutions are not available. NS5A resistance-associated substitutions observed in patients treated with other NS5A inhibitors have been found to persist for longer than 1 year. In patients treated with other NS3/4A PI, viral populations with NS3 resistance-associated substitutions have been found to decline in some patients through post-treatment weeks 24 and 48. The long-term clinical impact of the emergence or persistence of virus containing glecaprevir or pibrentasvir resistance-associated substitutions is unknown. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis 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. Impairment of Fertility 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, than the exposure in humans at the recommended dose. Clinical Studies Description of Clinical Trials Table 10 summarizes the clinical trials conducted to support the effectiveness of Mavyret in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection and compensated liver disease (including Child-Pugh A cirrhosis) according to treatment history and cirrhosis status. Table 10. Clinical Trials Conducted with Mavyret in Adults With HCV Genotype 1, 2, 3, 4, 5 or 6 Infection and Compensated Liver Disease Genotype (GT) Clinical Trial Treatment Duration* TN and PRS-TE Subjects Without Cirrhosis GT1 ENDURANCE-1 Mavyret for 8 (n=351) or 12 weeks (n=352) GT2 SURVEYOR-2 Mavyret for 8 weeks (n=197) GT3 ENDURANCE-3 Mavyret for 8 (n=157) or 12 weeks (n=233) sofosbuvir + daclatasvir for 12 weeks (n=115) SURVEYOR-2 Mavyret for 16 (PRS-TE only) weeks (n=22) GT4, 5, 6 ENDURANCE-4 Mavyret for 12 weeks (n=26, GT5; n=19, GT6) SURVEYOR-1 Mavyret for 12 weeks (n=1, GT5; n=11, GT6) SURVEYOR-2 Mavyret for 8 weeks (n=46, GT4; n=2, GT5; n=10 GT6) TN and PRS-TE Subjects With Compensated Cirrhosis GT1, 2, 4, 5, 6 EXPEDITION-1 Mavyret for 12 weeks (n=146) GT3 SURVEYOR-2 Mavyret for 12 weeks (TN only) (n=40) or 16 weeks (PRS-TE only) (n=47) Subjects With CKD Stage 4 and 5 Without Cirrhosis or With Compensated Cirrhosis GT1-6 EXPEDITION-4 Mavyret for 12 weeks (n=104) NS5A Inhibitor or PI-Experienced Subjects Without Cirrhosis or With Compensated Cirrhosis GT1 MAGELLAN-1 Mavyret for 12 (n=25) or 16 weeks (n=17) TN=treatment naïve; PI=protease inhibitor; CKD=chronic kidney disease PRS-TE= defined as prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor. * Treatment durations for some trial arms shown in this table do not reflect recommended dosing for the respective genotypes, prior treatment history, and/or cirrhosis status. For recommended dosing in adults [see Dosage and Administration (2.2) ] . Serum HCV RNA values were measured during the clinical trials 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). The primary endpoint across all clinical trials was sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment. Relapse was defined as HCV RNA LLOQ after end-of-treatment response among subjects who completed treatment. Subjects with missing HCV RNA data, such as those who discontinued due to an adverse event, subject withdrawal or were lost to follow-up, were counted as SVR12 failures. Demographics and Baseline Characteristics of Clinical Trials in Treatment-Naïve or Treatment-Experienced the trail
undertaking Mavyret the trail
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