Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Cardiac Electrophysiology
Thorough QT studies have been conducted for elbasvir and grazoprevir.
The effect of elbasvir 700 mg on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 42 healthy subjects. At a concentration 3 to 4 times the therapeutic concentration, elbasvir does not prolong QTc to any clinically relevant extent.
The effect of grazoprevir 1600 mg (16 times the approved dose) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 41 healthy subjects. At a concentration 40 times the therapeutic concentration, grazoprevir does not prolong QTc to any clinically relevant extent.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetic properties of elbasvir and grazoprevir have been evaluated in non-HCV- infected adult subjects and in HCV-infected adult subjects. Elbasvir pharmacokinetics were similar in healthy subjects and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose- proportional manner over the range of 10-800 mg once daily in HCV-infected subjects. Ribavirin co- administration with ZEPATIER had no clinically relevant impact on plasma AUC and Cmax of elbasvir and grazoprevir compared to administration of ZEPATIER alone. The geometric mean steady-state pharmacokinetic parameter values for elbasvir and grazoprevir in non-cirrhotic HCV-infected subjects are provided in Table 7. Following once daily administration of ZEPATIER to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days.

Table 7: Geometric Mean (90% Confidence Interval) for Elbasvir and Grazoprevir Steady State Pharmacokinetic Parameter Values in Non-Cirrhotic HCV-Infected Subjects Estimated Based on Population Pharmacokinetic Modeling

Geometric Mean (90% Confidence Interval)


AUC0-24 (ng•hr/mL)              Cmax (ng/mL)                  C24 (ng/mL) 
Elbasvir           1920 (1880, 1960)             121 (118, 123)               48.4 (47.3, 49.6) Grazoprevir          1420 (1400, 1530)             165 (161, 176)               18.0 (17.8,19.9) 
Absorption
Following administration of ZEPATIER to HCV-infected subjects, elbasvir peak concentrations occur at a median Tmax of 3 hours (range of 3 to 6 hours); grazoprevir peak concentrations occur at a median Tmax of 2 hours (range of 30 minutes to 3 hours). The absolute bioavailability of elbasvir is estimated to be 32%, and grazoprevir is estimated to be 27%.

Effect of Food
Relative to fasting conditions, the administration of a single dose of ZEPATIER with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food [see Dosage and Administration (2.2)].

Distribution
Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and α1-acid glycoprotein. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively, based on population pharmacokinetic modeling.
In preclinical distribution studies, elbasvir distributes into most tissues including the liver; whereas grazoprevir distributes predominantly to the liver likely facilitated by the active transport through the OATP1B1/3 liver uptake transporter.

Elimination
The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.

Metabolism
Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma.

Excretion
The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine.

Specific Populations
Pediatric Population
The pharmacokinetics of ZEPATIER in pediatric patients less than 18 years of age have not been established.

Geriatric Population
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age compared to subjects less than 65 years of age.

Gender
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males.

Weight/BMI


In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics.
Grazoprevir AUC is estimated to be 15% higher in a 53-kg subject compared to a 77-kg subject. This change is not clinically relevant for grazoprevir.

Race/Ethnicity
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans.

Renal Impairment
In population pharmacokinetic analyses, elbasvir AUC was 25% higher in hemodialysis-dependent subjects and 46% higher in non-dialysis-dependent subjects with severe renal impairment compared to elbasvir AUC in subjects without severe renal impairment. In population pharmacokinetic analysis in HCV- infected subjects, grazoprevir AUC was 10% higher in hemodialysis-dependent subjects and 40% higher in non-dialysis-dependent subjects with severe renal impairment compared to grazoprevir AUC in subjects without severe renal impairment. Elbasvir and grazoprevir are not removed by hemodialysis. Elbasvir and grazoprevir are unlikely to be removed by peritoneal dialysis as both are highly protein bound.
Overall, changes in exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant [see Use in Specific Populations (8.8)].

Hepatic Impairment
The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV-infected subjects with mild hepatic impairment (Child-Pugh Category A [CP-A], score of 5-6), moderate hepatic impairment (Child- Pugh Category B [CP-B], score of 7-9) and severe hepatic impairment (Child-Pugh Category C [CP-C], score of 10-15). In addition, the pharmacokinetics of elbasvir and grazoprevir were also evaluated in HCV- infected subjects including CP-A subjects with compensated cirrhosis.
Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. In population pharmacokinetic analyses, elbasvir steady-state AUC was similar in HCV- infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.
Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. In population pharmacokinetic analyses, grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.

Drug Interaction Studies
Drug interaction studies were performed in healthy adults with elbasvir, grazoprevir, or co- administered elbasvir and grazoprevir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. Table 8 summarizes the effects of co-administered drugs on the exposures of the individual components of ZEPATIER (elbasvir and grazoprevir). Table 9 summarizes the effects of the individual components of ZEPATIER on the exposures of the co-administered drugs. For information regarding clinical recommendations, [see Contraindications (4), Warnings and Precautions (5), and Drug Interactions (7)].
Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate and strong CYP3A inducers with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of strong CYP3A4 inhibitors with ZEPATIER may increase elbasvir and grazoprevir plasma concentrations.
Grazoprevir is a substrate of OATP1B1/3. Co-administration of ZEPATIER with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.
Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co- administration with grazoprevir resulted in a 34% increase in plasma exposure of midazolam and a 43% increase in plasma exposure of tacrolimus (see Tables 6 and 9). Elbasvir inhibited P-gp in vitro, but no clinically relevant increases in concentrations of digoxin (a P-gp substrate; see Table 9) were observed by co-administration of elbasvir. Grazoprevir is not a P-gp inhibitor in vitro. Elbasvir and grazoprevir are 

inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates.
Clinically significant drug interactions with ZEPATIER as an inhibitor of other CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6), UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporter (OCT)2, are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolized by CYP1A2, CYP2B6, or CYP3A based on in vitro data.



Table 8: Drug Interactions: Changes in Pharmacokinetics of Elbasvir or Grazoprevir in the Presence of Co-Administered Drug
Regimen of                           Geometric Mean Ratio [90% CI] of EBR and GZR PK with/without Co-                          Regimen of
Co-                                          Co-Administered Drug (No Effect=1.00) Administered                    EBR or/and    N
Administered
Drug                            GZR                                    AUC*            Cmax            C24 Drug
Antifungal
400 mg once      EBR 50 mg                               1.80 (1.41,    1.29 (1.00,     1.89 (1.37,
7          EBR daily        single-dose                                2.29)          1.66)           2.60) Ketoconazole
400 mg once      GZR 100 mg                              3.02 (2.42,    1.13 (0.77,     2.01 (1.49,
8          GZR daily        single-dose                                3.76)          1.67)           2.71) Antimycobacterial
600 mg single-   EBR 50 mg                               1.22 (1.06,    1.41 (1.18,     1.31 (1.12, 14         EBR dose IV       single-dose                                1.40)          1.68)           1.53) 600 mg single-   EBR 50 mg                               1.17 (0.98,    1.29 (1.06,     1.21 (1.03, 14         EBR dose PO        single-dose                                1.39)          1.58)           1.43) 600 mg PO       GZR 200 mg                              0.93 (0.75,    1.16 (0.82,     0.10 (0.07, Rifampin                                    12         GZR once daily      once daily                                1.17)          1.65)           0.13) 600 mg IV      GZR 200 mg                             10.21 (8.68,    10.94 (8.92,    1.77 (1.40, 12         GZR single-dose     single-dose                              12.00)          13.43)           2.24) 600 mg PO       GZR 200 mg                              8.35 (7.38,    6.52 (5.16,     1.62 (1.32, 12         GZR single-dose      once daily                               9.45)†          8.24)           1.98) HCV Antiviral
20 mg once      GZR 200 mg                              0.90 (0.63,    0.87 (0.50,     0.94 (0.77,
EBR                                       10         GZR daily         once daily                                1.28)          1.52)           1.15)                200 mg once      EBR 20 mg                               1.01 (0.83,    0.93 (0.76,     1.02 (0.83,
GZR                                       10         EBR daily        once daily                                 1.24)          1.13)           1.24) HIV Protease Inhibitor
300 mg/
EBR 50 mg                               4.76 (4.07,    4.15 (3.46,     6.45 (5.51, 100 mg once                    10         EBR once daily                                 5.56)          4.97)           7.54) Atazanavir/       daily ritonavir      300 mg/
GZR 200 mg                             10.58 (7.78,    6.24 (4.42,    11.64 (7.96, 100 mg once                    12         GZR once daily                              14.39)           8.81)         17.02) daily
600 mg/
EBR 50 mg                               1.66 (1.35,    1.67 (1.36,     1.82 (1.39, 100 mg twice                   10         EBR once daily                                 2.05)          2.05)           2.39) Darunavir/        daily ritonavir      600 mg/
GZR 200 mg                              7.50 (5.92,    5.27 (4.04,     8.05 (6.33, 100 mg twice                   13         GZR once daily                                9.51)          6.86)          10.24) daily
400 mg/
EBR 50 mg                               3.71 (3.05,    2.87 (2.29,     4.58 (3.72, 100 mg twice                   10         EBR once daily                                 4.53)          3.58)           5.64) Lopinavir/        daily ritonavir      400 mg/
GZR 200 mg                             12.86 (10.25,   7.31 (5.65,    21.70 (12.99, 100 mg twice                   13         GZR once daily                               16.13)          9.45)          36.25) daily
100 mg twice     GZR 200 mg                              2.03 (1.60,    1.15 (0.60,     1.88 (1.65, Ritonavir‡                                   10         GZR daily        single-dose                                2.56)          2.18)           2.14) 


HIV Integrase Strand Transfer Inhibitor
EBR 50 mg
50 mg single-       + GZR                               0.98 (0.93,     0.97 (0.89,    0.98 (0.93, 12        EBR dose         200 mg once                               1.04)           1.05)          1.03) daily
Dolutegravir
EBR 50 mg
50 mg single-       + GZR                               0.81 (0.67,     0.64 (0.44,    0.86 (0.79, 12        GZR dose         200 mg once                               0.97)           0.93)          0.93) daily
400 mg single-   EBR 50 mg                              0.81 (0.57,     0.89 (0.61,    0.80 (0.55,
10        EBR dose         single-dose                               1.17)           1.29)          1.16) Raltegravir
400 mg twice     GZR 200 mg                             0.89 (0.72,     0.85 (0.62,    0.90 (0.82,
11        GZR daily         once daily                               1.09)           1.16)          0.99) HIV Non-Nucleoside Reverse Transcriptase Inhibitor
600 mg once      EBR 50 mg                              0.46 (0.36,     0.55 (0.41,    0.41 (0.28, 10        EBR daily        once daily                                0.59)           0.73)          0.59) Efavirenz
600 mg once      GZR 200 mg                             0.17 (0.13,     0.13 (0.09,    0.31 (0.25, 12        GZR daily         once daily                               0.24)           0.19)          0.38) EBR 50 mg
25 mg once         + GZR                               1.07 (1.00,     1.07 (0.99,    1.04 (0.98,
19        EBR daily        200 mg once                               1.15)           1.16)          1.11) daily
Rilpivirine
EBR 50 mg
25 mg once         + GZR                               0.98 (0.89,     0.97 (0.83,    1.00 (0.93,
19        GZR daily        200 mg once                               1.07)           1.14)          1.07) daily
HIV Nucleotide Reverse Transcriptase Inhibitor
300 mg once      EBR 50 mg                              0.93 (0.82,     0.88 (0.77,    0.92 (0.81, Tenofovir                                      10        EBR daily        once daily                                1.05)           1.00)          1.05) disoproxil fumarate       300 mg once      GZR 200 mg                             0.86 (0.65,     0.78 (0.51,    0.89 (0.78, 12        GZR daily         once daily                               1.12)           1.18)          1.01) HIV Fixed-Dose Combination Regimen
EBR 50 mg/
Elvitegravir/                                                           2.18 (2.02,     1.91 (1.77,    2.38 (2.19, 150 mg/        GZR 100 mg     21        EBR cobicistat/                                                               2.35)           2.05)          2.60) 150 mg/         once daily emtricitabine/
200 mg/        EBR 50 mg/ tenofovir                                                             5.36 (4.48,     4.59 (3.70,    2.78 (2.48, 300 mg once disoproxil                      GZR 100 mg     21        GZR daily                                                  6.43)           5.69)          3.11) fumarate                        once daily
Immunosuppressant
EBR 50 mg
400 mg single-      + GZR                               1.98 (1.84,     1.95 (1.84,    2.21 (1.98,
14        EBR dose         200 mg once                               2.13)           2.07)          2.47) daily
Cyclosporine
EBR 50 mg
400 mg single-      + GZR                              15.21 (12.83,   17.00 (12.94,   3.39 (2.82,
14        GZR dose         200 mg once                              18.04)          22.34)          4.09) daily
Mycophenolate      1000 mg        EBR 50 mg                              1.07 (1.00,     1.07 (0.98,    1.05 (0.97, 14        EBR mofetil        single-dose       + GZR                                   1.14)           1.16)          1.14) 


200 mg once daily
EBR 50 mg
1000 mg           + GZR                                0.74 (0.60,   0.58 (0.42,   0.97 (0.89, 14        GZR single-dose     200 mg once                                0.92)         0.82)         1.06) daily
EBR 50 mg
40 mg single-      + GZR                                1.17 (1.11,   1.25 (1.16,   1.04 (0.97,
14        EBR dose        200 mg once                                1.24)         1.35)         1.12) daily
Prednisone
EBR 50 mg
40 mg single-      + GZR                                1.09 (0.95,   1.34 (1.10,   0.93 (0.87,
14        GZR dose        200 mg once                                1.25)         1.62)         1.00) daily
EBR 50 mg
2 mg single-       + GZR                                0.97 (0.90,   0.99 (0.88,   0.92 (0.83,
16        EBR dose         200 mg once                                1.06)         1.10)         1.02) daily
Tacrolimus
EBR 50 mg
2 mg single-       + GZR                                1.12 (0.97,   1.07 (0.83,   0.94 (0.87,
16        GZR dose         200 mg once                                1.30)         1.37)         1.02) daily
Opioid-Substitution Therapy
8 mg/2 mg       EBR 50 mg                               1.22 (0.98,   1.13 (0.87,   1.22 (0.99, 15        EBR single-dose     single-dose                                1.52)         1.46)         1.51) Buprenorphine
8-24 mg/
/naloxone                     GZR 200 mg                              0.86 (0.63,   0.80 (0.54,   0.97 (0.77,                 2-6 mg once                     12§       GZR once daily                                1.18)         1.20)         1.22) daily
20-120 mg      EBR 50 mg                               1.20 (0.94,   1.23 (0.94,   1.32 (1.03,
10§       EBR once daily     once daily                                 1.53)         1.62)         1.68) Methadone
20-150 mg      GZR 200 mg                              1.03 (0.76,   0.89 (0.60,   0.98 (0.79,
12§       GZR once daily      once daily                                1.41)         1.32)         1.23) Acid-Reducing Agent
EBR 50 mg/
20 mg single-                                           1.05 (0.92,   1.11 (0.98,   1.03 (0.91,
GZR 100 mg      16        EBR dose                                                   1.18)         1.26)         1.17) single-dose
Famotidine
EBR 50 mg/
20 mg single-                                           1.10 (0.95,   0.89 (0.71,   1.12 (0.97,
GZR 100 mg      16        GZR dose                                                   1.28)         1.11)         1.30) single-dose
EBR 50 mg/
40 mg once                                              1.05 (0.93,   1.02 (0.92,   1.03 (0.92,
GZR 100 mg      16        EBR daily                                                   1.18)         1.14)         1.17) single-dose
Pantoprazole
EBR 50 mg/
40 mg once                                              1.12 (0.96,   1.10 (0.89,   1.17 (1.02,
GZR 100 mg      16        GZR daily                                                   1.30)         1.37)         1.34) single-dose
Phosphate Binder
EBR 50 mg
Calcium        2668 mg           + GZR                                0.92 (0.75,   0.86 (0.71,   0.87 (0.70, 12        EBR acetate       single-dose       100 mg                                   1.14)         1.04)         1.09) single-dose


EBR 50 mg
2668 mg           + GZR                               0.79 (0.68,        0.57 (0.40,       0.77 (0.61,
12        GZR single-dose       100 mg                                  0.91)              0.83)             0.99) single-dose
EBR 50 mg
2400 mg           + GZR                               1.13 (0.94,        1.07 (0.88,       1.22 (1.02,
12        EBR single-dose       100 mg                                  1.37)              1.29)             1.45) Sevelamer                        single-dose carbonate                        EBR 50 mg
2400 mg           + GZR                               0.82 (0.68,        0.53 (0.37,       0.84 (0.71,
12        GZR single-dose       100 mg                                  0.99)              0.76)             0.99) single-dose
Statin
20 mg single-   GZR 200 mg                              1.26 (0.97,        1.26 (0.83,       1.11 (1.00,
Atorvastatin                                      9        GZR dose         once daily                                1.64)              1.90)             1.23) 1 mg single-    GZR 200 mg                              0.81 (0.70,        0.72 (0.57,       0.91 (0.82, Pitavastatin                                      9        GZR dose          once daily                                0.95)              0.92)             1.01) EBR 50 mg
40 mg single-      + GZR                                0.98 (0.93,        0.97 (0.89,       0.97 (0.92,
12        EBR dose        200 mg once                                1.02)              1.05)             1.02) daily
Pravastatin
EBR 50 mg
40 mg single-      + GZR                                1.24 (1.00,        1.42 (1.00,       1.07 (0.99,
12        GZR dose        200 mg once                                1.53)              2.03)             1.16) daily
EBR 50 mg
10 mg single-       + GZR                               1.09 (0.98,        1.11 (0.99,       0.96 (0.86, 11        EBR dose           200 mg                                  1.21)              1.26)             1.08) single-dose
10 mg single-   GZR 200 mg                              1.16 (0.94,        1.13 (0.77,       0.93 (0.84, Rosuvastatin                                     11        GZR dose         once daily                                1.44)              1.65)             1.03) EBR 50 mg
10 mg single-      + GZR                                1.01 (0.79,        0.97 (0.63,       0.95 (0.87, 11        GZR dose        200 mg once                                1.28)              1.50)             1.04) daily
Abbreviations: EBR, elbasvir; GZR, grazoprevir; IV, intravenous; PO, oral; EBR + GZR, administration of EBR and GZR as separate pills; EBR/GZR, administration of EBR and GZR as a single fixed-dose combination tablet.
*AUC0-inf for single-dose, AUC0-24 for once daily.
†AUC
0-24
‡Higher doses of ritonavir have not been tested in a drug interaction study with GZR.

§The reference (EBR or GZR alone) for the analysis consisted of subjects pooled across Phase I studies.



Table 9: Drug Interactions: Changes in Pharmacokinetics for Co-Administered Drug in the Presence of Elbasvir, Grazoprevir, or Co-Administered Elbasvir and Grazoprevir Regimen of                                                     Geometric Mean Ratio [90% CI] of Co- Co-                           EBR or/and                                     Administered Drug PK with/without Co-                                EBR or/and GZR
Administered                        GZR                                   N      EBR or/and GZR (No Effect=1.00) Administered                              Regimen
Drug                         Administration
Drug                                                           AUC*           Cmax        Ctrough† P-gp Substrate
Digoxin
1.11 (1.02,   1.47 (1.25,
Digoxin         0.25 mg           EBR               50 mg once daily    18                                   -- 1.22)         1.73) single-dose
CYP3A Substrate
Midazolam
1.34 (1.29,   1.15 (1.01,
Midazolam      2 mg single-        GZR              200 mg once daily    11                                   -- 1.39)         1.31) dose
CYP2C8 Substrate
Montelukast
1.11 (1.01,   0.92 (0.81,   1.39 (1.25,
Montelukast    10 mg single-        GZR              200 mg once daily    23 1.20)         1.06)         1.56) dose
HCV Antiviral
Sofosbuvir
50 mg + 200 mg once        1.13 (1.05,   0.87 (0.78,   1.53 (1.43,
GS-331007     400 mg single-    EBR + GZR                                16 daily                 1.21)         0.96)         1.63) dose
Sofosbuvir
50 mg + 200 mg once        2.43 (2.12,   2.27 (1.72,
Sofosbuvir    400 mg single-    EBR + GZR                                16                                   -- daily                2.79)‡         2.99) dose
HIV Protease Inhibitor
Atazanavir
300 mg/
1.07 (0.98,   1.02 (0.96,   1.15 (1.02,
ritonavir          EBR               50 mg once daily    8
1.17)         1.08)         1.29)
100 mg once
Atazanavir/        daily ritonavir     Atazanavir
300 mg/
1.43 (1.30,   1.12 (1.01,   1.23 (1.13,
ritonavir          GZR              200 mg once daily    11
1.57)         1.24)         1.34)
100 mg once daily
Darunavir
600 mg/
0.95 (0.86,   0.95 (0.85,   0.94 (0.85,
ritonavir          EBR               50 mg once daily    8
1.06)         1.05)         1.05)
100 mg twice
Darunavir/         daily ritonavir     Darunavir
600 mg/
1.11 (0.99,   1.10 (0.96,   1.00 (0.85,
ritonavir          GZR              200 mg once daily    13
1.24)         1.25)         1.18)
100 mg twice daily
Lopinavir
400 mg/
Lopinavir/                                                                    1.02 (0.93,   1.02 (0.92,   1.07 (0.97, ritonavir          EBR               50 mg once daily    9 ritonavir                                                                       1.13)         1.13)         1.18) 100 mg twice daily



Lopinavir
400 mg/
1.03 (0.96,   0.97 (0.88,   0.97 (0.81,
ritonavir         GZR             200 mg once daily       13
1.16)         1.08)         1.15)
100 mg twice daily
HIV Integrase Strand Transfer Inhibitor
Dolutegravir
50 mg + 200 mg once            1.16 (1.00,   1.22 (1.05,   1.14 (0.95, Dolutegravir     50 mg single-    EBR + GZR                                  12 daily                     1.34)         1.40)         1.36) dose
Raltegravir
1.02 (0.81,   1.09 (0.83,   0.99 (0.80,
400 mg single-      EBR             50 mg single-dose       10
1.27)         1.44)        1.22)§ dose
Raltegravir
Raltegravir
1.43 (0.89,   1.46 (0.78,   1.47 (1.09,
400 mg twice        GZR             200 mg once daily       11
2.30)         2.73)         2.00) daily
HIV Non-Nucleoside Reverse Transcriptase Inhibitor
Efavirenz
0.82 (0.78,   0.74 (0.67,   0.91 (0.87,
600 mg once         EBR             50 mg once daily        7
0.86)         0.82)         0.96) daily
Efavirenz
Efavirenz
1.00 (0.96,   1.03 (0.99,   0.93 (0.88,
600 mg once         GZR             200 mg once daily       11
1.05)         1.08)         0.98) daily
Rilpivirine
50 mg + 200 mg once            1.13 (1.07,   1.07 (0.97,   1.16 (1.09, Rilpivirine      25 mg once      EBR + GZR                                  19 daily                     1.20)         1.17)         1.23) daily
HIV Nucleotide Reverse Transcriptase Inhibitor
Tenofovir disoproxil
1.34 (1.23,   1.47 (1.32,   1.29 (1.18,
fumarate          EBR             50 mg once daily        10
1.47)         1.63)         1.41)
300 mg once
Tenofovir          daily disoproxil fumarate        Tenofovir disoproxil
1.18 (1.09,   1.14 (1.04,   1.24 (1.10,
fumarate          GZR             200 mg once daily       12
1.28)         1.25)         1.39)
300 mg once daily
Tenofovir disoproxil
50 mg + 100 mg once             1.27 (1.20,   1.14 (0.95,   1.23 (1.09, fumarate        EBR/GZR                                   13
Daily                      1.35)         1.36)         1.40)
300 mg once daily
HIV Fixed-Dose Combination Regimen
Elvitegravir
50 mg / 100 mg once            1.10 (1.00,   1.02 (0.93,   1.31 (1.11, Elvitegravir/   150 mg once       EBR/GZR                                   22 Daily                     1.21)         1.11)         1.55) cobicistat/        daily emtricitabine/    Cobicistat
50 mg / 100 mg once            1.49 (1.42,   1.39 (1.29,
tenofovir     150 mg once       EBR/GZR                                   22                                   -- Daily                     1.57)         1.50) disoproxil         daily fumarate                                        50 mg / 100 mg once            1.07 (1.03,   0.96 (0.90,   1.19 (1.13, Emtricitabine     EBR/GZR                                   22
Daily                     1.10)         1.02)         1.25)


                 200 mg once daily
Tenofovir disoproxil
50 mg / 100 mg once          1.18 (1.13,   1.25 (1.14,   1.20 (1.15,
fumarate       EBR/GZR                                 22
Daily                   1.24)         1.37)         1.26)
300 mg once daily
Immunosuppressant
Cyclosporine
50 mg + 200 mg once           0.96 (0.90,   0.90 (0.85,   1.00 (0.92, Cyclosporine     400 mg single-   EBR + GZR                               14 daily                    1.02)         0.97)        1.08)§ dose
Mycophenolate
Mycophenolic         mofetil                     50 mg + 200 mg once           0.95 (0.87,   0.85 (0.67, EBR + GZR                               14                                   -- acid           1000 mg                               daily                    1.03)         1.07) single-dose
Prednisone
50 mg + 200 mg once           1.08 (1.01,   1.04 (0.99,
Prednisolone     40 mg single-    EBR + GZR                               14                                   -- daily                    1.16)         1.09) dose
Prednisone
50 mg + 200 mg once           1.08 (1.00,   1.05 (1.00,
Prednisone      40 mg single-    EBR + GZR                               14                                   -- daily                    1.17)         1.10) dose
Tacrolimus
50 mg + 200 mg once           1.43 (1.24,   0.60 (0.52,   1.70 (1.49, Tacrolimus       2 mg single-    EBR + GZR                               16 daily                    1.64)         0.69)        1.94)§ dose
Oral Contraceptive
1.01 (0.97,   1.10 (1.05,
EBR             50 mg once daily      20                                   -- Ethinyl                                                                       1.05)         1.16) estradiol (EE)                                                                 1.10 (1.05,   1.05 (0.98, 0.03 mg EE/        GZR            200 mg once daily      20                                   -- 1.14)         1.12)
0.15 mg LNG single-dose                                                  1.14 (1.04,   1.02 (0.95, EBR             50 mg once daily      20                                   -- Levonorgestrel                                                                    1.24)         1.08) (LNG)                                                                      1.23 (1.15,   0.93 (0.84, GZR            200 mg once daily      20                                   -- 1.32)         1.03)
Opioid Substitution Therapy
Buprenorphine
8 mg/Naloxone                                                 0.98 (0.89,   0.94 (0.82,   0.98 (0.88, EBR             50 mg once daily      15
2 mg single-                                                    1.08)         1.08)         1.09) dose
Buprenorphine    Buprenorphine
8-24 mg/
0.98 (0.81,   0.90 (0.76,
Naloxone         GZR            200 mg once daily      12                                   -- 1.19)         1.07)
2-6 mg once daily
Methadone
1.03 (0.92,   1.07 (0.95,   1.10 (0.96,
20-120 mg         EBR             50 mg once daily      10
1.15)         1.20)         1.26) once daily
R-Methadone
Methadone
1.09 (1.02,   1.03 (0.96,
20-150 mg         GZR            200 mg once daily      12                                   --
1.17)         1.11) once daily



Methadone
1.09 (0.94,    1.09 (0.95,    1.20 (0.98,
20-120 mg              EBR              50 mg once daily        10
1.26)          1.25)          1.47) once daily
S-Methadone
Methadone
1.23 (1.12,    1.15 (1.07,
20-150 mg              GZR              200 mg once daily       12                                       --
1.35)          1.25) once daily
Statin
Atorvastatin
50 mg + 200 mg once             1.94 (1.63,    4.34 (3.10,    0.21 (0.17, Atorvastatin     10 mg single-       EBR + GZR                                    16 daily                      2.33)          6.07)          0.26) dose
Pitavastatin
1.11 (0.91,    1.27 (1.07,
Pitavastatin      1 mg single-           GZR              200 mg once daily        9                                       -- 1.34)          1.52) dose
Pravastatin
50 mg + 200 mg once             1.33 (1.09,    1.28 (1.05,
Pravastatin      40 mg single-       EBR + GZR                                    12                                       -- daily                     1.64)¶          1.55) dose
Rosuvastatin
50 mg + 200 mg once             2.26 (1.89,    5.49 (4.29,    0.98 (0.84, Rosuvastatin     10 mg single-       EBR + GZR                                    12 daily                     2.69)#          7.04)          1.13) dose
Abbreviations: EBR, elbasvir; GZR, grazoprevir; EBR + GZR, administration of EBR and GZR as separate tablets; EBR/GZR, administration of EBR and GZR as a single fixed-dose combination tablet *AUC0-inf for single-dose administration; AUC0-24 for once daily administration; AUC0-12 for twice daily administration †C24 for once daily administration; C12 for twice daily administration.

‡N=14

§C12
¶N=10

#N=8


12.4 Microbiology
Mechanism of Action
ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and non- overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.
Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly.
The mechanism of action of elbasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.
Grazoprevir 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, grazoprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a, 1b, and 4a NS3/4A protease enzymes with IC50 values of 7 pM, 4 pM, and 62 pM, respectively.

Antiviral Activity
In HCV replicon assays, the EC50 values of elbasvir against full-length replicons from genotypes 1a, 1b, and 4, were 4 pM, 3 pM, and 0.3 pM, respectively. The median EC50 values of elbasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 5 pM for genotype 1a (range 3-9 pM; N=5), 9 pM for genotype 1b (range 5-10 pM; N=4), 0.2 pM for genotype 4a (range 0.2-0.2 pM; N=2), 3,600 pM for genotype 4b (range 17 pM-34,000 pM; N=3), 0.45 pM for genotype 4d (range 0.4-0.5 pM; N=2), 1.9 pM for genotype 4f (N=1), 36.3 pM for genotype 4g (range 0.6-72 pM; N=2), 0.6 pM for genotype 4m (range 0.4-0.7 pM; N=2), 2.2 pM for genotype 4o (N=1), and 0.5 pM for genotype 4q (N=1).
In HCV replicon assays, the EC50 values of grazoprevir against full-length replicons from genotypes 1a, 1b, and 4, were 0.4 nM, 0.5 nM, and 0.3 nM, respectively. The median EC50 values of grazoprevir against chimeric replicons encoding NS3/4A sequences from clinical isolates were 0.8 nM for genotype 1a 

(range 0.4-5.1 nM; N=10), 0.3 nM for genotype 1b (range 0.2-5.9 nM; N=9), 0.3 nM for genotype 4a (N=1), 0.16 nM for genotype 4b (range 0.11-0.2 nM; N=2), and 0.24 nM for genotype 4g (range 0.15-0.33 nM; N=2).

Combination Antiviral Activity
Evaluation of elbasvir in combination with grazoprevir or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Evaluation of grazoprevir in combination with ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance
In Cell Culture
HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell culture for genotypes 1a, 1b, and 4 which resulted in the emergence of resistance-associated amino acid substitutions in NS5A or NS3, respectively. The majority of amino acid substitutions in NS5A or NS3 selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in genotype 1a, 1b, or 4 replicons.
For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions M28A/G/T, Q30D/E/H/K/R, L31M/V, H58D, and Y93C/H/N reduced elbasvir antiviral activity by 1.5- to 2,000-fold. In genotype 1b replicons, single NS5A substitutions L28M, L31F, and Y93H reduced elbasvir antiviral activity by 2- to 17- fold. In genotype 4 replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3- to 23-fold. In general, in HCV genotype 1a, 1b, or 4 replicons, combinations of elbasvir resistance-associated substitutions further reduced elbasvir antiviral activity.
For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions Y56H, R155K, A156G/T/V, and D168A/E/G/N/S/V/Y reduced grazoprevir antiviral activity by 2- to 81-fold; V36L/M, Q80K/R, or V107I single substitutions had no impact on grazoprevir antiviral activity in cell culture. In genotype 1b replicons, single NS3 substitutions F43S, Y56F, V107I, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 1.5- to 375-fold. In genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold. In general, in HCV genotype 1a, 1b, or 4 replicons, combinations of grazoprevir resistance-associated substitutions further reduced grazoprevir antiviral activity.

In Clinical Studies
In a pooled analysis of subjects treated with regimens containing ZEPATIER or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials, resistance analyses of both drug targets were conducted for 50 subjects who experienced virologic failure and had sequence data available (6 with on- treatment virologic failure, 44 with post-treatment relapse). Treatment-emergent substitutions observed in the viral populations of these subjects based on HCV genotypes and subtypes are shown in Table 10.
Treatment-emergent NS5A substitutions were detected in 30/37 (81%) genotype 1a-, 7/8 (88%) genotype 1b-, and 5/5 (100%) genotype 4-infected subjects. The most common treatment-emergent NS5A substitutions in genotype 1a were at position Q30 (n=22). Treatment-emergent NS3 substitutions were detected in 29/37 (78%) genotype 1a-, 2/8 (25%) genotype 1b-, and 2/5 (40%) genotype 4-infected subjects. The most common treatment-emergent NS3 substitutions in genotype 1a were at position D168 (n=18). Treatment-emergent substitutions were detected in both HCV drug targets in 23/37 (62%) genotype 1a-, 1/8 (13%) genotype 1b-, and 2/5 (40%) genotype 4-infected subjects.



Table 10: Treatment-Emergent Amino Acid Substitutions Among Virologic Failures in the Pooled Analysis of ZEPATIER with and without Ribavirin Regimens in Phase 2 and Phase 3 Clinical Trials 


Genotype 1a                 Genotype 1b                Genotype 4
Target                   N = 37                       N=8                       N=5 M28A/G/T,
Q30H/K/R/Y,                                       L28S/T, M31I/V, P58D, NS5A                                           L28M, L31F/V, Y93H
L31F/M/V, H58D,                                             Y93H
Y93H/N/S
V36L/M, Y56H, V107I,
A156M/T/V, D168A/G,
NS3               R155I/K, A156G/T/V,         Y56F, V107I, A156T
V170I
V158A, D168A/G/N/V/Y

Persistence of Resistance-Associated Substitutions
The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A, and NS3, respectively, was assessed in HCV genotype 1-infected subjects in Phase 2 and 3 trials whose virus had treatment-emergent resistance-associated substitutions in the drug target, and with available data through at least 24 weeks post-treatment using population nucleotide sequence analysis.
Viral populations with treatment-emergent NS5A resistance-associated substitutions were generally more persistent than those with NS3 resistance-associated substitutions. Among genotype 1a-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels at follow-up week 12 in 95% (35/37) of subjects and in 100% (9/9) of subjects with follow-up week 24 data. Among genotype 1b- infected subjects, NS5A resistance-associated substitutions persisted at detectable levels in 100% (7/7) of subjects at follow-up week 12 and in 100% (3/3) of subjects with follow-up week 24 data.
Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (1/2) of subjects.
Due to the limited number of genotype 4-infected subjects with treatment-emergent NS5A and NS3 resistance-associated substitutions, trends in persistence of treatment-emergent substitutions in this genotype could not be established.
The lack of detection of a virus containing a resistance-associated substitution does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment. The long-term clinical impact of the emergence or persistence of virus containing ZEPATIER-resistance-associated substitutions is unknown.

Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response in Genotype 1-Infected Subjects
Analyses using population nucleotide sequencing were conducted to explore the association between NS5A or NS3 amino acid polymorphisms and treatment response among treatment-naïve and treatment- experienced genotype 1-infected subjects. Baseline NS5A polymorphisms at resistance-associated positions (focusing on any change from subtype reference at NS5A amino acid positions 28, 30, 31, or 93) were evaluated. Baseline NS3 polymorphisms at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175 were evaluated. Analyses of SVR12 rates pooled data from subjects naïve to direct-acting antivirals and who received ZEPATIER with or without ribavirin in Phase 3 clinical trials, and censored subjects who did not achieve SVR12 for reasons unrelated to virologic failure.

Genotype 1a
In Clinical Studies
In genotype 1a-infected subjects, the presence of one or more HCV NS5A amino acid polymorphisms at position M28, Q30, L31, or Y93 was associated with reduced efficacy of ZEPATIER for 12 weeks (Table 11), regardless of prior treatment history or cirrhosis status. The prevalence of polymorphisms at any of these positions in genotype 1a-infected subjects was 11% (62/561) overall, and 12% (37/309) specifically for subjects in the U.S. across Phase 2 and Phase 3 clinical trials evaluating ZEPATIER for 12 weeks or ZEPATIER plus ribavirin for 16 weeks. The prevalence of polymorphisms at these positions in genotype 1a-infected subjects was 6% (35/561) at position M28, 2% (11/561) at position Q30, 3% (15/561) at position L31, and 2% (10/561) at position Y93. Polymorphisms at NS5A position H58 were common (10%) and were 


not associated with reduced ZEPATIER efficacy, except for a single virologic failure subject whose virus had baseline M28V and H58D polymorphisms.
The SVR12 rates for subjects treated with ZEPATIER for 12 weeks were 88% (29/33) for subjects with M28V/T/L polymorphisms (n=29, 3, and 1, respectively), 40% (4/10) for subjects with Q30H/R/L polymorphisms (n=5, 3, and 2, respectively), 38% (5/13) for subjects with an L31M polymorphism, and 63% (5/8) for subjects with Y93C/H/N/S polymorphisms (n=3, 3, 1, and 1, respectively). Although clinical trial data are limited, among genotype 1a-infected subjects with these NS5A polymorphisms who received ZEPATIER plus ribavirin for 16 weeks, six out of six subjects achieved SVR12. The specific NS5A polymorphisms observed in subjects treated with ZEPATIER plus ribavirin for 16 weeks included M28V (n=2), Q30H (n=1), L31M (n=2), or Y93C/H (n=1 each).

Table 11: Clinical Trial Data: SVR12 in HCV Genotype 1a-Infected Subjects without or with Baseline NS5A Polymorphisms
ZEPATIER 12 Weeks        ZEPATIER + RBV 16 Weeks
NS5A Polymorphism Status
SVR12 % (n/N)                SVR12 % (n/N)
Without baseline NS5A polymorphism
(M28, Q30, L31, or Y93)                       98% (441/450)                100% (49/49) With baseline NS5A polymorphism
(M28*, Q30*, L31*, or Y93*)                    70% (39/56)                  100% (6/6) *Any change from GT1a reference.

There are insufficient clinical trial data to determine the impact of HCV NS5A amino acid polymorphisms in treatment-experienced subjects who failed prior PegIFN + RBV + HCV protease inhibitor therapy and received ZEPATIER with ribavirin.

In genotype 1a-infected subjects, the NS3 Q80K polymorphism did not impact treatment response.
Polymorphisms at other NS3 resistance-associated positions were uncommon and were not associated with reduced treatment efficacy.
In Postmarketing Observational Studies
Effectiveness (SVR12 rates) in observational studies can be subject to certain biases and confounding factors that cannot be accounted for in the analyses, in part due to the nature of the study designs and populations under study.

Protocol 095
In Protocol 095, a sub-study of a prospective, observational comparative study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 29 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93.
Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 93% (27/29). 23 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 100% (14/14), 100% (1/1), 33% (1/3), and 100% (5/5), respectively. Six patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 100% (6/6).

VA NS5A Cohort Study
In a retrospective Veterans Administration (VA) NS5A cohort study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 93 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93. Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 81% (75/93). 65 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 94% (16/17), 100% (8/8), 84% (16/19), and 81% (17/21), respectively. 28 patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 64% (18/28).

Genotype 1b

In Clinical Studies
In genotype 1b-infected subjects treated with ZEPATIER for 12 weeks, SVR12 rates (non-virologic failure-censored) were 94% (48/51) and 99% (247/248) for those with and without one or more NS5A polymorphisms at position 28, 30, 31, or 93.
In genotype 1b-infected subjects, baseline NS3 polymorphisms did not impact treatment response.

Effect of Baseline HCV Polymorphisms on Treatment Response in Genotype 4-Infected Subjects Phylogenetic analysis of HCV sequences from genotype 4-infected subjects (n=71) in the pooled analyses of subjects (non-virologic failure-censored) treated with regimens containing ZEPATIER or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials identified 4 HCV genotype 4 subtypes (4a, 4d, 4k, 4o). Most subjects were infected with either subtype 4a (42%) or 4d (51%); 1 to 2 subjects were infected with each of the other genotype 4 subtypes. Among subjects enrolled at U.S. study sites, 11/13 (85%) were infected with HCV subtype 4a. There were two subjects infected with HCV subtype 4d who experienced virologic failure with the regimen containing grazoprevir and elbasvir.
In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS5A polymorphisms (any change from reference at NS5A amino acid positions 28, 30, 31, 58, and 93 by population nucleotide sequencing) were 100% (28/28) and for subjects without baseline NS5A polymorphisms were 95% (41/43).
In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS3 polymorphisms (any change from reference at NS3 amino acid positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175 by population nucleotide sequencing) were 100% (18/18) and for subjects without baseline NS3 polymorphisms were 96% (51/53).

Cross Resistance
Cross resistance is possible among NS5A inhibitors and NS3/4A protease inhibitors by class.
Elbasvir and grazoprevir are fully active against viral populations with substitutions conferring resistance to NS5B inhibitors.
In the C-SALVAGE trial, subjects with genotype 1 infection who had failed prior treatment with boceprevir (n=28), simeprevir (n=8), or telaprevir (n=43) in combination with PegIFN + RBV received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. There are limited data to determine the impact of HCV NS3 resistance-associated substitutions detected at baseline in treatment-experienced subjects who failed prior PegIFN + RBV + HCV protease inhibitor therapy and received ZEPATIER with ribavirin. SVR was achieved in 88% (21/24) of genotype 1a and genotype 1b infected subjects with NS3 resistance-associated substitutions detected at baseline. Specific NS3 substitutions observed at baseline included one or more of the following: V36L/M (n=8), T54S (n=4), S122G/T (n=9), R155K/T (n=9), A156S/T (n=1), and D168E/N (n=3). SVR was 100% (55/55) in subjects without baseline NS3 resistance substitutions. The 3 virologic failure subjects had the following NS3 or NS5A substitutions/polymorphisms at baseline: NS3 R155T/D168N, NS3 R155K plus NS5A H58D, and NS3 T54S plus NS5A L31M.
The efficacy of ZEPATIER has not been established in patients who have previously failed treatment with other regimens that included an NS5A inhibitor.