Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.    Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AP57 
Mechanism of action

Maviret is a fixed-dose combination of two pan-genotypic, direct acting antiviral agents, glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), targeting multiple steps in the HCV viral lifecycle.

Glecaprevir
Glecaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.

MAV API APR 22_CL                                                                             Page 11 of 25 Pibrentasvir
Pibrentasvir is a pan-genotypic inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been characterised based on cell culture antiviral activity and drug resistance mapping studies.

Antiviral activity

The EC50 values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding NS3 or NS5A from laboratory strains are presented in Table 5.

Table 5. Activity of glecaprevir and pibrentasvir against HCV genotypes 1-6 replicon cell lines 
HCV Subtype               Glecaprevir EC50, nM         Pibrentasvir EC50, nM 1a                          0.85                        0.0018
1b                          0.94                        0.0043
2a                           2.2                        0.0023
2b                           4.6                        0.0019
3a                           1.9                        0.0021
4a                           2.8                        0.0019
5a                          NA                          0.0014
6a                          0.86                        0.0028
NA = not available

The in vitro activity of glecaprevir was also studied in a biochemical assay, with similarly low IC50 values across genotypes.
EC50 values of glecaprevir and pibrentasvir against chimeric replicons encoding NS3 or NS5A from clinical isolates are presented in Table 6.

Table 6. Activity of glecaprevir and pibrentasvir against transient replicons containing NS3 or NS5A from HCV genotypes 1-6 clinical isolates


MAV API APR 22_CL                                                                             Page 12 of 25 Glecaprevir                                   Pibrentasvir
HCV
Number of clinical    Median EC50, nM          Number of clinical    Median EC50, nM subtype isolates                (range)                isolates                (range) 0.08                                          0.0009
1a               11                                             11
(0.05 – 0.12)                                (0.0006 – 0.0017)
0.29                                          0.0027
1b               9                                              8
(0.20 – 0.68)                                (0.0014 – 0.0035)
1.6                                          0.0009
2a               4                                              6
(0.66 – 1.9)                                (0.0005 – 0.0019)
2.2                                          0.0013
2b               4                                              11
(1.4 – 3.2)                                (0.0011 – 0.0019)
2.3                                          0.0007
3a               2                                              14
(0.71 – 3.8)                                (0.0005 – 0.0017)
0.41                                          0.0005
4a               6                                              8
(0.31 – 0.55)                                (0.0003 – 0.0013)
0.0012
4b               NA                      NA                     3
(0.0005 – 0.0018)
0.17                                         0.0014
4d                3                                             7
(0.13 – 0.25)                              (0.0010 – 0.0018)
5a                1                      0.12                   1                     0.0011 0.0007
6a               NA                      NA                     3
(0.0006 – 0.0010)
6e               NA                      NA                     1                     0.0008 6p               NA                      NA                     1                     0.0005 
NA = not available

Resistance
In cell culture
Amino acid substitutions in NS3 or NS5A selected in cell culture or important for the inhibitor class were phenotypically characterised in replicons.

Substitutions important for the HCV protease inhibitor class at positions 36, 43, 54, 55, 56, 155, 166, or 170 in NS3 had no impact on glecaprevir activity. Substitutions at amino acid position 168 in NS3 had no impact in genotype 2, while some substitutions at position 168 reduced glecaprevir susceptibility by up to 55-fold (genotypes 1, 3, 4), or reduced susceptibility by > 100-fold (genotype 6). Some substitutions at position 156 reduced susceptibility to glecaprevir (genotypes 1 to 4) by > 100-fold. Substitutions at amino acid position 80 did not reduce susceptibility to glecaprevir except for Q80R in genotype 3a, which reduced susceptibility to glecaprevir by 21-fold.

Single substitutions important for the NS5A inhibitor class at positions 24, 28, 30, 31, 58, 92, or 93 in NS5A in genotypes 1 to 6 had no impact on the activity of pibrentasvir. Specifically in genotype 3a, A30K or Y93H had no impact on pibrentasvir activity. Some combinations of substitutions in genotypes 1a and 3a (including A30K+Y93H in genotype 3a) showed reductions in susceptibility to pibrentasvir. In 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 genotype 3a replicon.

In clinical studies

Studies in treatment-naïve and peginterferon (pegIFN), ribavirin (RBV) and/or sofosbuvir treatment- experienced adult subjects with or without cirrhosis

Twenty-two of the approximately 2,300 subjects treated with Maviret for 8, 12, or 16 weeks in registrational Phase 2 and 3 clinical studies experienced virologic failure (2 with genotype 1, 2 with genotype 2, 18 with genotype 3 infection).


MAV API APR 22_CL                                                                             Page 13 of 25 Among the 2 genotype 1-infected subjects who experienced virologic failure, one had treatment- emergent substitutions A156V in NS3 and Q30R/L31M/H58D in NS5A, and one had Q30R/H58D (while Y93N was present at baseline and post-treatment) in NS5A.

Among the 2 genotype 2-infected subjects, no treatment-emergent substitutions were observed in NS3 or NS5A (the M31 polymorphism in NS5A was present at baseline and post-treatment in both subjects).

Among the 18 genotype 3-infected subjects treated with Maviret for 8, 12, or 16 weeks who experienced virologic failure, treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, or Q168L/R were observed in 11 subjects. A166S or Q168R were present at baseline and post-treatment in 5 subjects. Treatment-emergent NS5A substitutions M28G, A30G/K, L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n=9) or Y93H (n=5) at baseline and post- treatment.

Studies in adult subjects with or without compensated cirrhosis who were treatment-experienced to NS3/4A protease and/or NS5A inhibitors

Ten of 113 subjects treated with Maviret in the MAGELLAN-1 study for 12 or 16 weeks experienced virologic failure. Among the 10 genotype 1-infected subjects with virologic failure, treatment- emergent NS3 substitutions V36A/M, R155K/T, A156G/T/V, or D168A/T were observed in 7 subjects. Five of the 10 had combinations of V36M, Y56H, R155K/T, or D168A/E in NS3 at baseline and post-treatment. All of the genotype 1-infected virologic failure subjects had one or more NS5A substitutions L/M28M/T/V, Q30E/G/H/K/L/R, L31M, P32 deletion, H58C/D, or Y93H at baseline, with additional treatment-emergent NS5A substitutions M28A/G, P29Q/R, Q30K, H58D, or Y93H observed in 7 of the subjects at the time of failure.

Thirteen of the 177 subjects with chronic HCV GT1 infection (all virologic failures had GT1a infection) who were treatment-experienced with NS5A inhibitor + SOF treated with Maviret in study B16-439 for 12 weeks (9 out of 13) or 16 weeks (4 out of 13) experienced virologic failure. Among the 13 virologic failures, treatment-emergent NS3 substitutions were observed in 4 subjects at the time of failure: A156V (n = 2) or R155W + A156G (n = 2); 3 of these 4 subjects also had Q80K at baseline and at the time of failure. Twelve of 13 virologic failures had one or more NS5A polymorphisms detected at signature amino acid positions (M28V/T, Q30E/H/N/R, L31M/V, H58D, E62D/Q, or Y93H/N) at baseline, and 10 of 13 developed additional NS5A substitutions (M28A/S/T (n = 3), Q30N (n = 1), L31M/V (n = 2), P32del (n = 1), H58D (n = 4), E62D (n = 1)) at time of treatment failure.

Effect of baseline HCV amino acid polymorphisms on treatment response 
A pooled analysis of treatment-naïve and pegylated interferon, ribavirin and/or sofosbuvir treatment- experienced adult subjects receiving Maviret in the Phase 2 and Phase 3 clinical studies was conducted to explore the association between baseline polymorphisms and treatment outcome and to describe substitutions seen upon virologic failure. Baseline polymorphisms relative to a subtype-specific reference sequence at 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. Baseline polymorphisms in NS3 were detected in 1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% (1/34) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection,
respectively. Baseline polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415), 22.1% (136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV genotype 1,
2, 3, 4, 5, and 6 infection, respectively.

Genotype 1, 2, 4, 5, and 6: Baseline polymorphisms in genotypes 1, 2, 4, 5 and 6 had no impact on treatment outcome.

Genotype 3: For subjects who received the recommended regimen (n=313), baseline polymorphisms in NS5A (Y93H included) or NS3 did not have a relevant impact on treatment outcomes. All subjects 
MAV API APR 22_CL                                                                          Page 14 of 25 (15/15) with Y93H and 77% (17/22) with A30K in NS5A at baseline achieved SVR12. The overall prevalence of A30K and Y93H at baseline was 7.0% and 4.8%, respectively. The ability to assess the impact of baseline polymorphisms in NS5A was limited among treatment-naïve subjects with cirrhosis and treatment-experienced subjects due to low prevalence of A30K (3.0%, 4/132) or Y93H (3.8%, 5/132).

Cross-resistance

In vitro data indicate that the majority of the resistance-associated substitutions in NS5A at amino acid positions 24, 28, 30, 31, 58, 92, or 93 that confer resistance to ombitasvir, daclatasvir, ledipasvir, elbasvir, or velpatasvir remained susceptible to pibrentasvir. Some combinations of NS5A substitutions at these positions showed reductions in susceptibility to pibrentasvir. Glecaprevir was fully active against resistance-associated substitutions in NS5A, while pibrentasvir was fully active against resistance-associated substitutions in NS3. Both glecaprevir and pibrentasvir were fully active against substitutions associated with resistance to NS5B nucleotide and non-nucleotide inhibitors.

Clinical efficacy and safety
Table 7 summarizes clinical studies conducted with Maviret in adult and adolescent subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection.


MAV API APR 22_CL                                                                            Page 15 of 25 Table 7: Clinical studies conducted with Maviret in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 Infection

Genotype    Clinical study       Summary of study design
(GT)
TN and PRS-TE subjects without cirrhosis
GT1            ENDURANCE-1a         Maviret for 8 weeks (n=351) or 12 weeks (n=352) SURVEYOR-1           Maviret for 8 weeks (n=34)
GT2            ENDURANCE-2          Maviret (n=202) or Placebo (n=100) for 12 weeks SURVEYOR-2b          Maviret for 8 weeks (n=199) or 12 weeks (n=25)
GT3                                 Maviret for 8 weeks (n=157) or 12 weeks (n=233) ENDURANCE-3
Sofosbuvir + daclatasvir for 12 weeks (n=115)
Maviret for 8 weeks (TN only, n=29) or 12 weeks (n=76) or 16
SURVEYOR-2 weeks (TE only, n=22)
GT4, 5, 6      ENDURANCE-4          Maviret for 12 weeks (n=121)
ENDURANCE-5,6        Maviret for 8 weeks (n=75)
SURVEYOR-1           Maviret for 12 weeks (n=32)
SURVEYOR-2c          Maviret for 8 weeks (n=58)
GT1-6                              Maviret for 8 weeks (GT1, 2, 4, 5, and 6 and GT3 TN) (n=356) or 16 VOYAGE-1f weeks (GT3 TE only) (n=6)
TN and PRS-TE subjects with cirrhosis
GT1, 2, 4, 5,                    Maviret for 12 weeks (n=146)
EXPEDITION-1
6
GT3           SURVEYOR-2d        Maviret for 12 weeks (TN only, n=64) or 16 weeks (TE only, n=51) GT5, 6        ENDURANCE-5,6      Maviret for 12 weeks (n=9)
GT1-6                  f         Maviret for 12 weeks (GT1, 2, 4, 5, and 6 and GT3 TN) (n=157) or VOYAGE-2
16 weeks (GT3 TE only) (n=3)
GT1-6          EXPEDITION-8       Maviret for 8 weeks (n=343) (TN only) Subjects with CKD stage 3b, 4 and 5 with or without cirrhosis
GT1-6          EXPEDITION-4       Maviret for 12 weeks (n=104)
GT1-6          EXPEDITION-5       Maviret for 8 weeks (n=84) or 12 weeks (n=13) or 16 weeks (n=4) NS5A inhibitor and/or PI-experienced subjects with or without cirrhosis GT1, 4         MAGELLAN-1e        Maviret for 12 weeks (n=66) or 16 weeks (n=47) GT1                               Maviret for 12 weeks (n=78) or 16 weeks (n=78) or Maviret + RBV B16-439 for 12 weeks (n=21)g
HCV/HIV-1 co-infected subjects with or without cirrhosis
GT1-6            EXPEDITION-2        Maviret for 8 weeks (n=137) or 12 weeks (n=16) Liver or kidney transplant recipients
GT1-6            MAGELLAN-2          Maviret for 12 weeks (n=100)
Adolescent subjects (12 to <18 years)
GT1-6            DORA (Part 1)       Maviret for 8 weeks (n=44) or 16 weeks (n=3) TN=treatment-naïve, PRS TE=treatment experienced (includes previous treatment that included pegIFN (or IFN), and/or RBV and/or sofosbuvir), PI=Protease Inhibitor, CKD=chronic kidney disease a. ENDURANCE-1 included 33 subjects co-infected with HIV-1. DORA included 2 subjects coinfected with HIV-1.
b. GT2 from SURVEYOR-2 Parts 1 and 2 - Maviret for 8 weeks (n=54) or 12 weeks (n=25); GT2 from SURVEYOR-2 Part 4 - Maviret for 8 weeks (n=145).
c. GT3 without cirrhosis from SURVEYOR-2 Parts 1 and 2 - Maviret for 8 weeks (n=29) or 12 weeks (n=54); GT3 without cirrhosis from SURVEYOR-2 Part 3 - Maviret for 12 weeks (n=22) or 16 weeks (n=22).
d. GT3 with cirrhosis from SURVEYOR-2 Part 2 - Maviret for 12 weeks (n=24) or 16 weeks (n=4); GT3 with cirrhosis from SURVEYOR-2 Part 3 - Maviret for 12 weeks (n=40) or 16 weeks (n=47).
e. GT1, 4 from MAGELLAN-1 Part 1 - Maviret for 12 weeks (n=22); GT1, 4 from MAGELLAN-1 Part 2 - Maviret for 12 weeks (n=44) or 16 weeks (n=47).


MAV API APR 22_CL                                                                           Page 16 of 25 f. VOYAGE-1 and VOYAGE-2 were Asian regional studies.
g. Maviret is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or NS5A inhibitors (see section 4.4).

Serum HCV RNA values were measured during the clinical studies 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). Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the studies to determine the HCV cure rate.

Clinical studies in treatment-naïve or treatment-experienced subjects with or without cirrhosis Of the 2 409 adult subjects with compensated liver disease (with or without cirrhosis) treated who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir, the median age was 53 years (range: 19 to 88); 73.3% were treatment-naïve, 26.7% were treatment-experienced to a combination containing either sofosbuvir, ribavirin and/or peginterferon; 40.3% were HCV genotype 1; 19.8% were HCV genotype 2; 27.8% were HCV genotype 3; 8.1% were HCV genotype 4; 3.4% were HCV genotype 5-6; 13.1% were ≥ 65 years; 56.6% were male; 6.2% were Black; 12.3% had cirrhosis; 4.3% had severe renal impairment or end stage renal disease; 20.0% had a body mass index of at least 30 kg per m2; 7.7% had HIV-1 coinfection and the median baseline HCV RNA level was 6.2 log10 IU/mL.

Table 8: SVR12 in adult subjects treatment-naïve and treatment-experienceda to peginterferon, ribavirin and/or sofosbuvir with genotype 1, 2, 4, 5 and 6 infection who received the recommended duration (pooled data from ENDURANCE-1b, SURVEYOR-1, -2, and EXPEDITION-1, 2b, -4 and 8)

Genotype 1         Genotype 2       Genotype 4      Genotype      Genotype 6 5
SVR12 in subjects without cirrhosis
8 weeks                  99.2%             98.1%            95.2%        100%          92.3% (470/474)          (202/206)         (59/62)        (2/2)       (12/13) Outcome for subjects without SVR12
On-treatment               0.2%               0%               0%           0%            0% VF                         (1/474)           (0/206)           (0/62)        (0/2)        (0/13) Relapsec                   0%               1.0%              0%           0%            0% (0/471)           (2/204)           (0/61)        (0/2)        (0/13) Otherd                    0.6%              1.0%             4.8%          0%           7.7% (3/474)           (2/206)           (3/62)        (0/2)        (1/13) SVR12 in subjects with cirrhosis
8 weeks                  97.8%             100%             100%         100%          100% (226/231)           (26/26)          (13/13)        (1/1)         (9/9) 12 weeks                  96.8%             90.0%            100%           ---         100% (30/31)            (9/10)            (8/8)                      (1/1) Outcome for subjects without SVR12
On-treatment               0%                0%               0%           0%            0% VF                        (0/262)            (0/36)           (0/21)        (0/1)        (0/10) Relapsec                  0.4%               0%               0%           0%            0% (1/256)            (0/35)           (0/20)        (0/1)        (0/10) Otherd                   1.9%               2.8%              0%           0%            0% (5/262)            (1/36)           (0/21)        (0/1)        (0/10) VF=virologic failure a. Percent of subjects with prior treatment-experience to PRS is 26%, 14%, 24%, 0%, and 13% for genotypes 1, 2, 4, 5, and 6, respectively. None of the GT5 subjects were TE-PRS, and 3 GT6 subjects were TE-PRS.
b. Includes a total of 154 subjects coinfected with HIV-1 in ENDURANCE-1 and EXPEDITION-2 who received the recommended duration.
MAV API APR 22_CL                                                                         Page 17 of 25 c. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those who completed treatment.
d. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

Of the genotype 1-, 2-, 4-, 5-, or 6 infected subjects with end stage renal disease enrolled in EXPEDITION-4, 97.8% (91/93) achieved SVR12 with no virologic failures.

Clinical study in subjects with genotype 5 or 6 infection
ENDURANCE-5,6 was an open-label study in 84 HCV GT5 (N=23) or 6 infected (N=61) TN or TE- PRS adult subjects. Subjects without cirrhosis received Maviret for 8 weeks, and subjects with compensated cirrhosis received Maviret for 12 weeks. Of the 84 subjects treated, the median age was 59 years (range 24-79); 27% had HCV genotype 5, 73% had HCV genotype 6; 54% were female, 30% were White, 68% were Asian; 90% were HCV TN; 11% had compensated cirrhosis.

The overall SVR12 rate was 97.6% (82/84). The SVR12 rate was 95.7% (22/23) for GT5-infected subjects and 98.4% (60/61) for GT6-infected subjects. One TN GT5-infected subject without cirrhosis experienced relapse, and one TN GT6-infected subject with compensated cirrhosis experienced on- treatment virologic failure.

Subjects with genotype 1, 2, 4, 5, or 6 infection with cirrhosis who received 8 weeks of Maviret The safety and efficacy of Maviret given for 8 weeks in GT 1, 2, 4, 5 or 6 treatment-naïve adult subjects with compensated cirrhosis was evaluated in a single-arm, open-label study (EXPEDITION- 8).

Of the 280 subjects treated, the median age was 60 years (range: 34 to 88); 81.8% had HCV genotype 1, 10% had HCV genotype 2, 4.6% had HCV genotype 4, 0.4% had HCV genotype 5; 3.2% had HCV genotype 6; 60% were male; 9.6% were Black.

The overall SVR12 rate was 98.2% (275/280). There were no virologic failures.

Subjects with genotype 3 infection
The efficacy of Maviret in subjects who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir with genotype 3 chronic hepatitis C infection was demonstrated in the ENDURANCE-3 (treatment-naïve adults without cirrhosis), EXPEDITION-8 (treatment-naïve adults with cirrhosis), and SURVEYOR-2 Part 3 (adults with and without cirrhosis and/or treatment-experienced) clinical studies.

ENDURANCE-3 was a partially-randomised, open-label, active-controlled study in treatment-naïve genotype 3-infected subjects. Subjects were randomised (2:1) to either Maviret for 12 weeks or the combination of sofosbuvir and daclatasvir for 12 weeks; subsequently the study included a third arm (which was non-randomised) with Maviret for 8 weeks. EXPEDITION-8 was a single-arm, open-label study in treatment-naïve subjects with compensated cirrhosis and genotype 1, 2, 3, 4, 5 or 6 infection who received Maviret for 8 weeks. SURVEYOR-2 Part 3 was an open-label study that evaluated the efficacy of Maviret in treatment-experienced genotype 3-infected subjects without cirrhosis and with compensated cirrhosis for 16-weeks. Among treatment-experienced subjects, 46% (42/91) failed a previous regimen containing sofosbuvir.

Table 9: SVR12 in treatment-naïve, genotype 3-infected subjects without cirrhosis (ENDURANCE-3)

SVR                        Maviret 8 weeks         Maviret 12 weeks         SOF+DCV 12 weeks N=157                     N=233                     N=115
94.9% (149/157)          95.3% (222/233)           96.5% (111/115)
Treatment difference -1.2%;
95% confidence interval (-5.6% to 3.1%)
Treatment difference -0.4%;

MAV API APR 22_CL                                                                                 Page 18 of 25 97.5% confidence interval (-5.4% to 4.6%)
Outcome for subjects without SVR12
On-treatment VF         0.6% (1/157)            0.4% (1/233)                  0% (0/115) Relapsea                3.3% (5/150)            1.4% (3/222)                 0.9% (1/114) Otherb                  1.3% (2/157)            3.0% (7/233)                 2.6% (3/115) a. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those who completed treatment.
b. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

In a pooled analysis of treatment-naïve adult patients without cirrhosis (including Phase 2 and 3 data) where SVR12 was assessed according to the presence of baseline A30K, a numerically lower SVR12 rate was achieved in patients with A30K treated for 8 weeks as compared to those treated for 12 weeks [78% (14/18) vs 93% (13/14)].

Table 10: SVR12 in genotype 3-infected subjects with or without cirrhosis (SURVEYOR-2 Part 3 and EXPEDITION-8)

Treatment-naïve                                Treatment-experienced Treatment-naïve with cirrhosis                                   with or without with cirrhosis cirrhosis
Maviret                Maviret                   Maviret
8 weeks                12 weeks                 16 weeks
(N=63)                  (N=40)                   (N=69)
SVR                      95.2% (60/63)           97.5% (39/40)             95.7% (66/69) Outcome for subjects without SVR12
On-treatment VF           0% (0/63)              0% (0/40)                  1.4% (1/69) Relapsea                 1.6% (1/62)             0% (0/39)                  2.9% (2/68) Otherb                   3.2% (2/63)            2.5% (1/40)                  0% (0/69) SVR by cirrhosis status
No Cirrhosis                 NA                      NA                    95.5% (21/22) Cirrhosis              95.2% (60/63)           97.5% (39/40)               95.7% (45/47) a. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those who completed treatment.
b. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

Of the genotype 3-infected subjects with end stage renal disease enrolled in EXPEDITION-4, 100% (11/11) achieved SVR12.

Subjects with genotype 3b infection
GT3b is a subtype reported in a relatively small number of HCV infected patients in China and a few countries in South and Southeast Asia, but rarely outside of this region. Studies VOYAGE-1 and VOYAGE-2 were conducted in China, Singapore, and South Korea in HCV genotype 1-6 adult subjects without cirrhosis (VOYAGE-1) or with compensated cirrhosis (VOYAGE-2) that were treatment-naïve (TN) or treatment-experienced to combinations of interferon, peg interferon, ribavirin and/or sofosbuvir (TE-PRS). All subjects without cirrhosis or with compensated cirrhosis received 8 or 12 weeks of Maviret, respectively, except GT3 TE-PRS subjects who received 16 weeks of Maviret. The overall SVR12 rates were 97.2% (352/362) and 99.4% (159/160) in VOYAGE-1 and VOYAGE-2, respectively.

Among GT3b subjects without cirrhosis, a numerically lower SVR12 rate of 58.3% (7/12) [62.5% (5/8) for TN subjects and 50% (2/4) for TE-PRS subjects] was observed compared to GT3a subjects without cirrhosis (92.9% (13/14)). Three GT3b TN subjects experienced relapse and two GT3b TE- PRS subjects experienced on-treatment virologic failure. Among subjects with compensated cirrhosis, the overall SVR12 rate for GT3b infected subjects was 87.5% (7/8) [85.7% (6/7) for TN subjects and 100% (1/1) for TE-PRS subjects] and 100% (6/6) for GT3a infected subjects. One GT3b TN subject experienced relapse.

MAV API APR 22_CL                                                                          Page 19 of 25 Overall SVR12 rate from the clinical studies in treatment-naïve or treatment-experienced adult subjects with or without cirrhosis
In subjects who are treatment-naïve (TN) or treatment-experienced to combinations of interferon, peginterferon, ribavirin and/or sofosbuvir (TE-PRS) who received the recommended duration, 97.5% (1 395/1 431) achieved SVR12 overall, while 0.2% (3/1 431) experienced on-treatment virologic failure and 0.9% (12/1 407) experienced post-treatment relapse.

In TN or TE-PRS subjects with compensated cirrhosis who received the recommended duration, 97.1% (431/444) achieved SVR12 (among which 97.7% [335/343] of TN subjects achieved SVR12), while 0.2% (1/444) experienced on-treatment virologic failure and 0.9% (4/434) experienced post- treatment relapse.

In TN subjects without cirrhosis who received the recommended duration of 8 weeks, 97.5% (749/768) achieved SVR12, while 0.1% (1/768) experienced on-treatment virologic failure and 0.7% (5/755) experienced post-treatment relapse.

In TE-PRS subjects without cirrhosis who received the recommended duration, 98.2% (215/219) achieved SVR12, while 0.5% (1/219) experienced on-treatment virologic failure and 1.4% (3/218) experienced post-treatment relapse.

The presence of HIV-1 coinfection did not impact efficacy. The SVR12 rate in TN or TE-PRS HCV/HIV-1 co-infected subjects treated for 8 or 12 weeks (without cirrhosis and with compensated cirrhosis, respectively) was 98.2% (165/168) from ENDURANCE-1 and EXPEDITION-2. One subject experienced on-treatment virologic failure (0.6%, 1/168) and no subjects relapsed (0%, 0/166).

Clinical study in liver or kidney transplant recipients

MAGELLAN-2 was a single-arm, open-label study in 100 post-liver or -kidney transplant HCV GT1-6 infected adult subjects without cirrhosis who received Maviret for 12 weeks. The study included subjects who were HCV treatment-naïve or treatment-experienced to combinations of (peg) interferon, ribavirin, and/or sofosbuvir, with the exception of GT3-infected subjects who were all treatment-naïve.

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; 66% were HCV treatment-naïve; none had cirrhosis and 80% had a baseline fibrosis state of F0 or F1; 80% of subjects were post-liver transplant and 20% were post-kidney transplant. Immunosuppressants allowed for co-administration were ciclosporin ≤ 100 mg/day, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, and prednisolone.

The overall SVR12 rate in post-transplant subjects was 98.0% (98/100). There was one relapse and no on-treatment virologic failure.

Clinical study in renally impaired subjects

EXPEDITION-5 was an open-label study in 101 HCV GT1-6 infected adult subjects without cirrhosis or with compensated cirrhosis and chronic kidney disease (CKD) stage 3b, 4, or 5. Subjects were either treatment-naïve or treatment-experienced to combinations of (peg) interferon, ribavirin, and/or sofosbuvir and received Maviret for 8, 12, or 16 weeks per approved treatment durations.

Of the 101 subjects treated, the median age was 58 years (range 32-87); 53% had HCV genotype 1; 27% had HCV genotype 2; 15% had HCV genotype 3; 4% had HCV genotype 4; 59% were male;
73% were White; 80% were HCV treatment-naïve; 13% had cirrhosis and 65% had a baseline fibrosis state of F0 or F1; 7% were CKD stage 3b; 17% were CKD Stage 4, and 76% were CKD Stage 5 (all 

MAV API APR 22_CL                                                                          Page 20 of 25 receiving dialysis); 84 subjects received 8 weeks of treatment, 13 subjects received 12 weeks of treatment, and 4 subjects received 16 weeks of treatment.

The overall SVR12 rate was 97% (98/101). There were no virologic failures.

Durability of sustained virologic response
In a long-term follow-up study (M13-576), 99.5% (374/376) of adult subjects who had achieved SVR12 in prior clinical studies of Maviret maintained SVR up to their last follow-up visit (median duration of follow-up: 35.5 months): 100%, 99.6%, and 95.8% of subjects who had received 8, 12, and 16 weeks of Maviret therapy, respectively. Among the 2 subjects who did not maintain SVR, 1 experienced a late relapse 390 days after Maviret therapy, and the other subject experienced re- infection with a different HCV genotype.

Elderly
Clinical studies of Maviret included 328 patients aged 65 and over (13.8% of the total number of subjects). The response rates observed for patients ≥ 65 years of age were similar to that of patients < 65 years of age, across treatment groups.

Paediatric population

DORA (Part 1) was an open-label study to evaluate safety and efficacy in adolescents aged 12 years to less than 18 years who received Maviret 300 mg/120 mg (three 100 mg/40 mg film-coated tablets), for 8, or 16 weeks. 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; 11% were Black; 77% were HCV treatment-naïve; 23% were treatment-experienced to interferon; 4% had HIV-coinfection; none had cirrhosis; the mean weight was 59 kg (range: 32 to 109 kg).

The overall SVR12 rate was 100% (47/47). No subject experienced virologic failure 

Pharmacokinetic Properties

5.2.    Pharmacokinetic properties

The pharmacokinetic properties of the components of Maviret are provided in Table 11.


MAV API APR 22_CL                                                                            Page 21 of 25 Table 11: Pharmacokinetic properties of the components of Maviret in healthy adult 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 Biotransformation
Biotransformation                               secondary                 none Elimination
Major route of elimination                   Biliary excretion      Biliary excretion t1/2 (h) at steady-state                           6-9                   23 - 29 % of dose excreted in urinec                        0.7                     0 % of dose excreted in faecesc                      92.1d                  96.6 Transport
Substrate of transporter                     P-gp, BCRP, and            P-gp and not OATP1B1/3              excluded BCRP a. Median Tmax following single doses of glecaprevir and pibrentasvir in healthy subjects.
b. Mean systemic exposure with moderate to high fat meals.
c. Single dose administration of [14C]glecaprevir or [14C]pibrentasvir in mass balance studies.
d. Oxidative metabolites or their byproducts accounted for 26% of radioactive dose. No glecaprevir metabolites were observed in plasma.

In patients with chronic hepatitis C infection without cirrhosis, following 3 days of monotherapy with either glecaprevir 300 mg per day (N=6) or pibrentasvir 120 mg per day (N=8) alone, geometric mean AUC24 values were 13 600 ng∙h/mL for glecaprevir and 459 ng∙h/mL for pibrentasvir. Estimation of the pharmacokinetic parameters using population pharmacokinetic models has inherent uncertainty due to dose non-linearity and cross interaction between glecaprevir and pibrentasvir. Based on population pharmacokinetic models for Maviret in chronic hepatitis C patients, steady-state AUC24 values for glecaprevir and pibrentasvir were 4 800 and 1 430 ng∙h/mL in subjects without cirrhosis (N=1 804), and 10 500 and 1 530 ng∙h/mL in subjects with cirrhosis (N=280), respectively. Relative to healthy subjects (N=230), population estimates of AUC24, ss were similar (10% difference) for glecaprevir and 34% lower for pibrentasvir in HCV-infected patients without cirrhosis.

Linearity/non-linearity

Glecaprevir AUC increased in a greater than dose-proportional manner (1 200 mg QD had 516-fold higher exposure than 200 mg QD) which may be related to saturation of uptake and efflux transporters.

Pibrentasvir AUC increased in a greater than dose-proportional manner at doses up to 120 mg, (over 10-fold exposure increase at 120 mg QD compared to 30 mg QD), but exhibited linear pharmacokinetics at doses ≥ 120 mg. The non-linear exposure increase < 120 mg may be related to saturation of efflux transporters.

Pibrentasvir bioavailability when coadministered with glecaprevir is 3-fold of pibrentasvir alone.
Glecaprevir is affected to a lower extent by co-administration with pibrentasvir.

Pharmacokinetics in special populations
Race/ethnicity
No dose adjustment of Maviret is required based on race or ethnicity.


MAV API APR 22_CL                                                                           Page 22 of 25 Gender/weight
No dose adjustment of Maviret is required based on gender or body weight.

Elderly
No dose adjustment of Maviret is required in elderly patients. Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (12 to 88 years) analysed, age did not have a clinically relevant effect on the exposure to glecaprevir or pibrentasvir.

Paediatric population
No dose adjustment of Maviret is required in adolescents 12 years and older. Exposures of glecaprevir and pibrentasvir in adolescents aged 12 to < 18 years were comparable to those in adults from Phase 2/3 studies. The pharmacokinetics of glecaprevir and pibrentasvir have not been established in paediatric patients <12 years of age.

Renal impairment
Glecaprevir and pibrentasvir AUC were increased ≤ 56% in non-HCV infected subjects with mild, moderate, severe, or end stage renal impairment 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 population pharmacokinetic analysis of 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. Larger increases may be expected when unbound concentration is considered.

Overall, the changes in exposures of Maviret in HCV-infected subjects with renal impairment with or without dialysis were not clinically significant.

Hepatic impairment
At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC was 33% higher in Child-Pugh A subjects, 100% higher in Child-Pugh B subjects, and increased to 11-fold in Child-Pugh C subjects. Pibrentasvir AUC was similar in Child-Pugh A subjects, 26% higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects. Larger increases may be expected when unbound concentration is considered.

Population pharmacokinetic analysis demonstrated that following administration of Maviret in HCV- infected subjects with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV-infected subjects. The mechanism for the differences between glecaprevir exposure in chronic Hepatitis C patients with or without cirrhosis is unknown.