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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].

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
Tmax (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
t½ (h) 6 13
Metabolism secondary, CYP3A None
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 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 Glecaprevirb Pibrentasvirc
Cmax (ng/mL)a 597 (114) 110 (49)
AUC24,ss (ng•h/mL)a 4800 (122) 1430 (57)
a Geometric mean (%CV) of individual-estimated Cmax and AUC24,ss values
b Relative to healthy subjects, glecaprevir Cmax was 51% lower and AUC24,ss was similar (10% difference) in HCV-infected subjects without cirrhosis, respectively
c Relative to healthy subjects, pibrentasvir Cmax and AUC24,ss were 63% and 34% lower, respectively in HCV-infected subjects without cirrhosis, respectively

Specific Populations

Pediatric Patients

Exposures [geometric mean (%CV)] of glecaprevir and pibrentasvir in 14 pediatric patients 12 years of age and older receiving a daily dose of MAVYRET (300 mg glecaprevir and 120 mg pibrentasvir) were 4790 (72) and 1380 (40) ng•h/mL for AUC24,ss, and 1040 (86) and 174 (36) ng/mL for Cmax, respectively, and were comparable to those in adults who received the same dose. The pharmacokinetics of glecaprevir and pibrentasvir have not been established in children less than 12 years of age.

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 [12-88 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)
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 d 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 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)
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

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, 4a, 4d, 5a, and 6a. Pibrentasvir had median EC50 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-Naive and (peg)Interferon, Ribavirin and/or Sofosbuvir Treatment-Experienced Subjects with or without Cirrhosis

In pooled analyses of NS3/4A PI- and NS5A inhibitor-naive subjects who received MAVYRET for 8, 12, or 16 weeks in 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-Naive Subjects)

A pooled analysis of NS3/4A PI- and NS5A inhibitor-naive 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-naive, 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. In the pooled Phase 2 and Phase 3 trials, all genotype 3-infected subjects (100% 16/16) 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.

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-naive 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-naive 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.

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 Subjects 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)
HCV/HIV-1 Co-Infected Subjects without Cirrhosis or with Compensated Cirrhosis
GT1, 2, 3, 4, 6 EXPEDITION-2 MAVYRET for 8 (n=137) or 12 weeks (n=16)
Liver or Kidney Transplant Recipients without Cirrhosis
GT1, 2, 3, 4, 6 MAGELLAN-2 MAVYRET for 12 weeks (n=100)
Adolescent Subjects (12 years to less than 18 years)
GT1, 2, 3, 4 DORA (Part 1) MAVYRET for 8 weeks (n=44) or 16 weeks (n=3)
TN=treatment naive; PI=protease inhibitor; CKD=chronic kidney disease PRS-TE= defined as prior treatment experience with regimens containing (peg)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 and pediatric patients 12 years and older or weighing at least 45 kg [see DOSAGE AND ADMINISTRATION].

** ENDURANCE-1 included 33 subjects co-infected with HIV-1.

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-Naive Or Treatment-Experienced Adults To (peg)Interferon, Ribavirin And/Or Sofosbuvir (PRS) Without Cirrhosis Or With Compensated Cirrhosis (Child-Pugh A)

Of the 2,152 treated subjects without cirrhosis or with compensated cirrhosis who were treatment-naive or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir (PRS), excluding EXPEDITION-4 (NCT02651194) and MAGELLAN-1 (NCT02446717), the median age was 54 years (range: 19 to 88); 73% were treatment-naive, 27% were PRS treatment-experienced; 39% were HCV genotype 1; 21% were HCV genotype 2; 29% were HCV genotype 3; 7% were HCV genotype 4; 4% were HCV genotype 5-6; 13% were ≥65 years; 54% were male; 5% were Black; 12% had cirrhosis; 20% had a body mass index of at least 30 kg per m2; and median baseline HCV RNA level was 6.2 log10 IU/mL.

Treatment-Naive Or PRS Treatment-Experienced Adults With HCV Genotype 1, 2, 4, 5, Or 6 Infection Without Cirrhosis

The efficacy of MAVYRET in subjects who were treatment-naive or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir (PRS) with genotype 1, 2, 4, 5 or 6 chronic HCV infection without cirrhosis was studied in four trials using 8- or 12-week durations: ENDURANCE-1 (NCT02604017), ENDURANCE-4 (NCT02636595), SURVEYOR-1 [(Part 2) NCT02243280], and SURVEYOR-2 [(Part 2 and Part 4) NCT02243293].

ENDURANCE-1 was a randomized (1:1), open-label, multi-national trial comparing the efficacy of 8 weeks of treatment with MAVYRET versus 12 weeks of treatment in subjects without cirrhosis with genotype 1 infection with or without HIV-1 co-infection (n=33 co-infected). Table 11 presents SVR12 in MAVYRET-treated genotype 1-infected subjects for the 8 week treatment arm. Due to numerically similar efficacy, MAVYRET is recommended for 8 weeks for treatment-naive and PRS treatment-experienced genotype 1 subjects without cirrhosis, rather than 12 weeks [see DOSAGE AND ADMINISTRATION].

Table 11. ENDURANCE-1: Efficacy in Treatment-Naive and PRS Treatment-Experienced with HCV Genotype 1 Infection and without Cirrhosis








  Genotype 1
MAVYRET
8 Weeks
(N=351)
SVR12 99% (348/351)
Outcome for Subjects without SVR12
  On-treatment VF <1% (1/351)
  Relapse 0/349
  Other* <1% (2/351)
VF= virologic failure

* Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

The SVR12 data from the open-label trials SURVEYOR-2 (Parts 2 and 4), ENDURANCE-4 and SURVEYOR-1 (Part 2) are pooled by genotype, where appropriate, in Table 12 for ease of display.

Table 12. SURVEYOR-2 (Part 2 and Part 4), ENDURANCE-4 and SURVEYOR-1 (Part 2): Efficacy in Treatment-Naive and PRS Treatment-Experienced Adults with HCV Genotypes 2, 4, 5 or 6 Infection without Cirrhosis









  SURVEYOR-2 MAVYRET 8 Weeks ENDURANCE-4 and SURVEYOR-1 MAVYRET 12 Weeks
GT2
N=197
GT4
N=46
GT5
N=2
GT6
N=10
GT5
N=27
GT6
N=30
SVR 12 98%
(193/197)
93%
(43/46)
100%
(2/2)
100%
(10/10)
100%
(27/27)
100%
(30/30)
Outcome for Subjects without SVR12
  On Treatment VF 0/197 0/46 0/2 0/10 0/27 0/30
  Relapse 1%
(2/195)
0/45 0/2 0/10 0/26 0/29
  Other* 1%
(2/197)
7%
(3/46)
0/2 0/10 0/27 0/30
GT=genotype; VF= virologic failure

* Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

Treatment-Naive Or PRS Treatment-Experienced Adults With HCV Genotype 1, 2, 4, 5, Or 6 Infection With Compensated Cirrhosis

The efficacy of MAVYRET in subjects who were treatment-naive or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir (PRS) with genotype 1, 2, 4, 5 or 6 chronic hepatitis C virus infection with compensated cirrhosis (Child-Pugh A) was studied in the single-arm, open-label EXPEDITION-1 (NCT02642432) trial, which included 146 subjects treated with MAVYRET for 12 weeks.

Table 13. EXPEDITION-1: Efficacy in Treatment-Naive and PRS Treatment-Experienced Adults with HCV Genotype 1, 2, 4, 5 or 6 Infection with Compensated Cirrhosis








  MAVYRET 12 Weeks
(N=146)
Total
(all GTs)
(N=146)
GT1
(N=90)
GT2
(N=31)
GT4
(N=16)
GT5
(N=2)
GT6
(N=7)
SVR12 99%
(145/146)
99%
(89/90)
100%
(31/31)
100%
(16/16)
100%
(2/2)
100%
(7/7)
Outcome for Subjects without SVR12
  On-treatment VF 0/146 0/90 0/31 0/16 0/2 0/7
  Relapse <1%
(1/144)
1%
(1/88)
0/31 0/16 0/2 0/7
GT = genotype; VF = virologic failure

Treatment-Naive Or PRS Treatment-Experienced Adults With HCV Genotype 3 Infection Without Cirrhosis Or With Compensated Cirrhosis

The efficacy of MAVYRET in subjects without cirrhosis or with compensated cirrhosis who were treatment-naive or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir (PRS) with genotype 3 chronic HCV infection was studied in ENDURANCE-3 (NCT02640157) and in SURVEYOR-2 Part 3.

ENDURANCE-3 was a partially-randomized, open-label, active-controlled trial in treatment-naive subjects. Subjects were randomized (2:1) to either MAVYRET for 12 weeks or to the combination of sofosbuvir and daclatasvir for 12 weeks; subsequently the trial included a third non-randomized arm with MAVYRET for 8 weeks. The SVR12 data are summarized in Table 14. Due to numerically similar efficacy MAVYRET is recommended for 8 weeks for treatment-naive genotype 3 subjects without cirrhosis, rather than 12 weeks [see DOSAGE AND ADMINISTRATION].

Table 14. ENDURANCE-3: Efficacy in Treatment-Naive, HCV Genotype 3-Infected Subjects without Cirrhosis








  MAVYRET1 8 Weeks (N=157) MAVYRET 12 Weeks* (N=233) DCV+SOF 12 W`eeks (N=115)
SVR12 94.9% (149/157) 95.3% (222/233)* 96.5% (111/115)
Outcome for Subjects without SVR12
  On-treatment VF 1% (1/157) <1% (1/233) 0/115
  Relapse 3% (5/150) 1% (3/222) 1% (1/114)
  Other2 1% (2/157) 3% (7/233) 3% (3/115)
VF=virologic failure
1 MAVYRET 8 weeks was a non-randomized treatment arm.
2 Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

* Data for MAVYRET 12-week treatment is displayed to reflect the original randomized study design. The treatment difference (95% confidence interval) was -1.2% (-5.6, 3.1) between the randomized arms of MAVYRET 12 weeks and DCV + SOF 12 weeks.

SURVEYOR-2 Part 3 was an open-label trial randomizing PRS treatment-experienced subjects with genotype 3 infection without cirrhosis to 12- or 16-weeks of treatment. In addition, the trial evaluated the efficacy of MAVYRET in genotype 3-infected subjects with compensated cirrhosis in two dedicated treatment arms using 12-week (treatment-naive only) and 16-week (PRS treatment-experienced only) durations. Among PRS treatment-experienced subjects treated with MAVYRET for 16 weeks, 49% (34/69) had failed a previous regimen containing sofosbuvir.

Table 15. SURVEYOR-2 Part 3: Efficacy in Treatment-Naive or PRS Treatment-Experienced, HCV Genotype 3-Infected Adults without Cirrhosis or with Compensated Cirrhosis












  Treatment-Naive with Compensated Cirrhosis PRS Treatment-Experienced without Cirrhosis or with Compensated Cirrhosis
MAVYRET
12 Weeks
(N=40)
MAVYRET
16 Weeks
(N=69)
SVR12 98% (39/40) 96% (66/69)
Outcome for Subjects without SVR12    
  On-treatment VF 0/40 1% (1/69)
  Relapse 0/39 3% (2/68)
  Other* 3% (1/40) 0/69
SVR12 by Cirrhosis Status    
  Without Cirrhosis NA 95% (21/22)
  With Compensated Cirrhosis 98% (39/40) 96% (45/47)
VF=virologic failure

* Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

Treatment-Naive And PRS Treatment-Experienced Adults With CKD Stage 4 And 5 And Chronic HCV Infection Without Cirrhosis Or With Compensated Cirrhosis

EXPEDITION-4 was an open-label, single-arm, multicenter trial to evaluate safety and efficacy in subjects with severe renal impairment (CKD Stages 4 and 5) with compensated liver disease (with and without Child-Pugh A cirrhosis). There were 104 subjects enrolled, 82% were on hemodialysis, and 53%, 15%, 11%, 19%, 1% and 1% were infected with HCV genotypes 1, 2, 3, 4, 5 and 6; respectively. Overall, 19% of subjects had compensated cirrhosis and 81% of subjects were non-cirrhotic; 58% and 42% of subjects were treatment-naive and PRS treatment-experienced, respectively. The overall SVR12 rate was 98% and no subjects experienced virologic failure. The presence of renal impairment did not affect efficacy; no dose-adjustments were required during the trial.

Adults Who Are NS5A Inhibitor Or NS3/4A-Protease Inhibitor (PI)-Experienced, Without Cirrhosis Or With Compensated Cirrhosis

MAGELLAN-1 was a randomized, multipart, open-label trial in 141 genotype 1- or 4-infected subjects who failed a previous regimen containing an NS5A inhibitor and/or NS3/4A PI. Part 1 (n=50) was a randomized trial exploring 12 weeks of glecaprevir 200 mg and pibrentasvir 80 mg, glecaprevir 300 mg and pibrentasvir 120 mg, with and without ribavirin (only data from glecaprevir 300 mg plus pibrentasvir 120 mg without ribavirin are included in these analyses).

Part 2 (n=91) randomized genotype 1- or 4-infected subjects without cirrhosis or with compensated cirrhosis to 12- or 16-weeks of treatment with MAVYRET.

Of the 42 genotype 1-infected subjects treated in Parts 1 and 2, who were either NS5A inhibitor-experienced only (and treated for 16 weeks), or NS3/4A PI-experienced only (and treated for 12 weeks), the median age was 58 years (range: 34 to 70); 40% of the subjects were NS5A-treatment experienced only and 60% were PI experienced only; 24% had cirrhosis; 19% were ≥65 years, 69% were male; 26% were Black; 43% had a body mass index ≥ 30 kg/m2; 67% had baseline HCV RNA levels of at least 1,000,000 IU per mL; 79% had subtype 1a infection, 17% had subtype 1b infection and 5% had non-1a/1b infection.

Due to higher rates of virologic failure and treatment-emergent drug resistance, the data do not support labeling for treatment of HCV genotype 1-infected patients who are both NS3/4A PI and NS5A inhibitor-experienced.

Table 16. MAGELLAN-1: Efficacy in HCV Genotype 1-Infected Adults Who Are NS3/4A PI-Experienced or NS5A Inhibitor-Experienced, without Cirrhosis or with Compensated Cirrhosis









  PI-Experienced1
(NS5A Inhibitor- naive)
NS5A Inhibitor- Experienced2
(PI-naive)
MAVYRET
12 Weeks
(N=25)
MAVYRET
16 Weeks
(N=17)
SVR12 92% (23/25) 94% (16/17)
Outcome for Subjects without SVR
  On-treatment Virologic Failure 0/25 6% (1/17)
  Relapse 0/25 0/16
  Other3 8% (2/25) 0/17
PI= protease inhibitor
1 Includes subjects who were treated with a regimen containing an NS3/4A PI (simeprevir with sofosbuvir, or simeprevir, boceprevir, or telaprevir with (peg)interferon and ribavirin) and without prior treatment with an NS5A inhibitor.
2 Includes subjects who were treated with a regimen containing an NS5A inhibitor (ledipasvir with sofosbuvir or daclatasvir with (peg)interferon and ribavirin) and without prior treatment with an NS3/4A PI.
3 Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

Treatment-Naive Or PRS Treatment-Experienced Adults With HCV/HIV-1 Coinfection Without Cirrhosis Or With Compensated Cirrhosis

EXPEDITION-2 (NCT02738138) was an open-label study in 153 HCV/HIV-1-coinfected subjects. Subjects without cirrhosis received MAVYRET for 8 weeks and subjects with compensated cirrhosis received MAVYRET for 12 weeks. The study included subjects who were HCV treatment-naive or treatment-experienced to combinations of (peg)interferon, ribavirin, and/or sofosbuvir, with the exception of GT3-infected subjects who were all treatment naive.

Of the 153 subjects treated, the median age was 45 years (range: 23 to 74); 63% had HCV genotype 1, 7% had HCV genotype 2, 17% had HCV genotype 3, 11% had HCV genotype 4, 2% had HCV genotype 6; 11% had cirrhosis; 84% were male; and 16% were Black.

In EXPEDITION-2, the SVR12 rate in HCV/HIV-1 co-infected subjects was 98% (150/153). One subject experienced on-treatment virologic failure and no subjects relapsed.

Treatment-Naive Or PRS Treatment-Experienced Adults With Liver Or Kidney Transplant Without Cirrhosis

MAGELLAN-2 (NCT02692703) was a single-arm, open-label study in 100 post-liver or -kidney transplant HCV GT 1, 2, 3, 4, or 6 infected subjects without cirrhosis who received MAVYRET for 12 weeks. The study included subjects who were HCV treatment-naive or treatment-experienced to combinations of (peg)interferon, ribavirin, and/or sofosbuvir, with the exception of GT3-infected subjects who were all treatment-naive.

Of the 100 subjects treated, the median age was 60 years (range: 39 to 78); 57% had HCV genotype 1, 13% had HCV genotype 2, 24% had HCV genotype 3, 4% had HCV genotype 4, 2% had HCV genotype 6; 75% were male; 8% were Black; 80% of subjects were post-liver transplant and 20% were post-kidney transplant. Immunosuppressants allowed for co-administration were cyclosporine ≤100 mg, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, and prednisolone.

The overall SVR12 rate in post-transplant subjects was 98% (98/100). There was one relapse and no on-treatment virologic failures.

Clinical Trial In Pediatric Subjects (12 Years To Less Than 18 Years)

The efficacy of MAVYRET was evaluated in an open-label study (DORA [Part 1]) (NCT03067129) that evaluated adolescent subjects 12 years to less than 18 years without cirrhosis who received MAVYRET for 8 or 16 weeks. Treatment duration was chosen to match approved adult durations based on HCV genotype and prior treatment experience.

47 subjects were enrolled in DORA (Part 1). The median age was 14 years (range: 12 to 17); 79% had HCV genotype 1, 6% had HCV genotype 2, 9% had HCV genotype 3, 6% had HCV genotype 4; 55% were female; 9% were Black; 77% were HCV treatment-naive; 23% were treatment-experienced to interferon; 4% had HIV-coinfection; none had cirrhosis; the mean weight was 59 kg (range: 32 kg to 109 kg).

The overall SVR12 rate was 100% (47/47).

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