12 CLINICAL PHARMACOLOGY

12.1 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)].

12.2 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.

12.3 Pharmacokinetics

The pharmacokinetic properties of the components of MAVYRET in healthy subjects are provided in Table 7. The steady-state pharmacokinetic parameters of glecaprevir and pibrentasvir in HCV-infected subjects without cirrhosis are provided in Table 8. For pellets relative to tablets in healthy adult subjects under non-fasting conditions, geometric mean ratios (GMRs) of glecaprevir and pibrentasvir Cmax were 0.664 and 1.137, AUCinf were 0.795 and 1.219, and C24 were 0.917 and 1.174. These differences were not considered clinically significant.

Table 7. Pharmacokinetic Properties of the Components of MAVYRET in Healthy Subjects
	Glecaprevir	Pibrentasvir
Absorption
Tmax (h)a of tablets	5.0	5.0
Tmax (h)a of oral pellets	3.0	5.0
Effect of meal (relative to fasting)b on tablets	↑ 83-163%	↑ 40-53%
Effect of meal (relative to fasting)b on oral pellets	↑ 131-167%	↑ 56-114%
Distribution
% Bound to human plasma proteins	97.5	>99.9
Blood-to-plasma ratio	0.57	0.62
Elimination
t1/2 (h)	6	13
Metabolism	secondary,	None
	CYP3A
Major route of excretion	biliary-fecal	biliary-fecal
% of dose excreted in urinec	0.7	0
% of dose excreted in fecesc	92.1	96.6
a. Median Tmax following single doses of glecaprevir and pibrentasvir in healthy subjects. b. Mean systemic exposures with low/moderate to high fat meals. c. Single dose administration of radiolabeled glecaprevir or pibrentasvir in mass balance studies.

Table 8. Steady-State Pharmacokinetic Parameters of Glecaprevir and Pibrentasvir Following Administration of MAVYRET in Non-Cirrhotic HCV-Infected Subjects
Pharmacokinetic Parameter	Glecaprevirb	Pibrentasvirc
Cmax (ng/mL)a	597 (114)	110 (49)
AUC24,ss (ng•h/mL)a	4800 (122)	1430 (57)
Ctrough,ss (ng/mL)a	13.0 (334)	18.9 (92)
a Geometric mean (%CV) of individual-estimated Cmax, AUC24,ss and Ctrough,ss values b Relative to healthy subjects, glecaprevir Cmax was 51% lower, AUC24,ss was similar (10% difference), and Ctrough,ss was 157% higher in HCV-infected subjects without cirrhosis c Relative to healthy subjects, pibrentasvir Cmax was 63% lower, AUC24,ss was 34% lower, and Ctrough,ss was 37% lower in HCV-infected subjects without cirrhosis

Specific Populations

Pediatric Patients

The pharmacokinetics of glecaprevir and pibrentasvir were determined in HCV-infected pediatric subjects 3 years of age and older receiving a daily dose of MAVYRET as described below in Table 9. GMRs of glecaprevir and pibrentasvir Cmax and AUC24 in HCV-infected pediatrics vs. adults ranged from 1.58-2.68 and 0.965-1.64, respectively. GMRs of glecaprevir Ctrough ranged from 0.292-0.954 and GMRs of pibrentasvir Ctrough ranged from 0.794-1.93. All pediatric glecaprevir and pibrentasvir PK parameter values fell within the range observed in adult subjects. These differences were not considered clinically significant. The pharmacokinetics of glecaprevir and pibrentasvir have not been established in children less than 3 years of age.

Table 9. Pharmacokinetic Parameters of Glecaprevir (GLE) and Pibrentasvir (PIB) in HCV Infected Pediatric Subjects
Age and Weight (kg)	N	Total Daily Dose of GLE/PIB (mg)	PK Parameter	Geometric Mean (%CV)
				GLE	PIB
12 to < 18 years, ≥ 45 kg	14	300/120	AUC24 (ng•h/mL)	4790 (72)	1380 (40)
			Cmax (ng/mL)	1040 (86)	174 (36)
			Ctrough (ng/mL)	3.79 (82)	15.0 (61)
9 to < 12 years, 30 to < 45 kg	13	250/100	AUC24 (ng•h/mL)	7870 (209)	2200 (99)
			Cmax (ng/mL)	1370 (169)	225 (72)
			Ctrough (ng/mL)	12.4 (856)	36.5 (164)
6 to < 9 years, 20 to < 30 kg	13	200/80	AUC24 (ng•h/mL)	6860 (142)	1640 (63)
			Cmax (ng/mL)	1600 (155)	197 (52)
			Ctrough (ng/mL)	7.44 (383)	19.4 (103)
3 to < 6 years, 12 to < 20 kg	12	150/60	AUC24 (ng•h/mL)	7520 (205)	1790 (58)
			Cmax (ng/mL)	1530 (280)	233 (48)
			Ctrough (ng/mL)	6.58 (318)	17.9 (119)

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 was 100% higher in Child-Pugh B subjects, and increased 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 (12-88 years), sex, race/ethnicity or body weight (45 kg or greater). Patients under the age of 12 and weighing less than 45 kg are dosed based on body weight [see Dosage and Administration (2.4)].

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 10 and 11 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 10. 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)
					Cmax	AUC	Cmin
Atazanavir + ritonavir	300 + 100 once daily	300/120 once dailya	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	GLEb	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 dosec	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. HCV-infected transplant recipients who received cyclosporine dose of 100 mg or less per day had mean glecaprevir exposures 2.4-fold of those not receiving cyclosporine. c. Effect of rifampin on glecaprevir and pibrentasvir 24 hours after final rifampin dose.

Table 11. 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)
				Cmax	AUC	Cmin
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

12.4 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 IC50 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 EC50 values of 0.08-4.6 nM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4d, 5a, and 6a. Pibrentasvir had median EC50 values of 0.5-15.6 pM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 3b, 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 a 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 a genotype 3a replicon. Introduction of an NS5A Y93H substitution into a genotype 3b replicon further reduced susceptibility to pibrentasvir by 6336-fold.

In Clinical Studies

Studies in Treatment-Naïve and (peg)Interferon, 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 the registrational Phase 2 and 3 clinical studies (including EXPEDITION-2 and MAGELLAN-2), treatment-emergent resistance analyses were conducted for 24 subjects who experienced virologic failure (2 with genotype 1, 2 with genotype 2, 20 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 20 genotype 3-infected subjects who experienced virologic failure, treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, or Q168L/R were observed in 13 subjects. A166S or Q168R were present at baseline and post-treatment in 5 subjects. Treatment-emergent NS5A substitutions S24F, M28G/K, A30G/K, L31F, P58T, or Y93H were observed in 17 subjects, and 14 subjects had A30K (n=9) or Y93H (n=6) 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: In registrational trials, HCV subtype 3a was the predominant genotype 3 subtype overall and was detected in >99% of U.S. genotype 3-infected subjects. Among treatment-naïve, genotype 3a-infected subjects without cirrhosis who received MAVYRET for 8 weeks, an NS5A A30K polymorphism was detected in 10% (18/179) of subjects, of whom 78% (14/18) achieved SVR12. Limited data are available to characterize the impact of the A30K polymorphism in genotype 3a-infected subjects with cirrhosis (n=3 who received MAVYRET for 8 weeks, all achieved SVR12) or prior treatment experience (n=1 who received MAVYRET for 16 weeks, relapse). In the pooled Phase 2 and Phase 3 trials, including post-registrational trials EXPEDITION-8, VOYAGE-1 and VOYAGE-2, 94% (15/16) of genotype 3a-infected subjects with Y93H in NS5A at baseline who received the recommended MAVYRET regimens achieved SVR12. In MAGELLAN-2 (post-transplant subjects), SVR12 was achieved in 2 of 3 (67%) genotype 3-infected subjects with the NS5A Y93H baseline polymorphism. In the VOYAGE-1 and VOYAGE-2 trials conducted in China, Singapore, and South Korea, 50% (20/40) of genotype 3-infected subjects had subtype 3b, of whom 14 (70%) achieved SVR12 with MAVYRET durations of 8, 12 or 16 weeks [see Clinical Studies (14.4)]. The naturally occurring NS5A K30 and M31 polymorphisms were detected in 95% (19/20) and 100% (20/20) of genotype 3b-infected subjects.

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, (peg)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.