Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP51 
Mechanism of action

Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. Biochemical confirmation of NS5A inhibition by ledipasvir is not currently possible as NS5A has no enzymatic function. In vitro resistance selection and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action.

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.
GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral activity

The EC50 values of ledipasvir and sofosbuvir against full-length or chimeric replicons encoding NS5A and NS5B sequences from clinical isolates are detailed in Table 5. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir but reduced the anti-HCV activity of ledipasvir by 12-fold against genotype 1a HCV replicons.

Table 5: Activity of ledipasvir and sofosbuvir against chimeric replicons 
Genotype           Ledipasvir activity (EC50, nM)           Sofosbuvir activity (EC50, nM) replicons       Stable replicons      NS5A transient      Stable replicons    NS5B transient replicons                                replicons
Median (range)a                          Median (range)a
Genotype 1a         0.031                0.018                40                  62 (29-128) (0.009-0.085)
Genotype 1b         0.004                0.006                110                    102 (45-170) (0.004-0.007)
Genotype 2a         21-249               -                    50                     29 (14-81) Genotype 2b         16-530b              -                    15b                    - Genotype 3a         168                  -                    50                     81 (24-181) Genotype 4a         0.39                 -                    40                     - Genotype            Ledipasvir activity (EC50, nM)          Sofosbuvir activity (EC50, nM) replicons       Stable replicons       NS5A transient     Stable replicons     NS5B transient replicons                               replicons
Median (range)a                         Median (range)a
Genotype 4d      0.60                  -                  -                    - Genotype 5a      0.15b                 -                  15b                  - Genotype 6a      1.1b                  -                  14b                  - Genotype 6e      264 b
-                  -                    - a Transient replicons carrying NS5A or NS5B from patient isolates.
b The chimeric replicons carrying NS5A genes from genotype 2b, 5a, 6a and 6e were used for testing ledipasvir while the chimeric replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing sofosbuvir.

Resistance

In cell culture
HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotype 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A substitution Y93H in both genotype 1a and 1b. Additionally a Q30E substitution developed in genotype 1a replicons. Site-directed mutagenesis of NS5A RAVs showed that substitutions conferring a fold-change > 100 and ≤ 1,000 in ledipasvir susceptibility are Q30H/R, L31I/M/V, P32L and Y93T in genotype 1a and P58D and Y93S in genotype 1b; and substitutions conferring a fold-change > 1,000 are M28A/G, Q30E/G/K, H58D, Y93C/H/N/S in genotype 1a and A92K and Y93H in genotype 1b.

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the viral replication capacity by 89% to 99% compared to the corresponding wild-type.

In clinical studies – Genotype 1
In a pooled analysis of patients who received ledipasvir/sofosbuvir in Phase 3 studies (ION-3, ION-1 and ION-2), 37 patients (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis due to virologic failure or early study drug discontinuation and having HCV RNA > 1,000 IU/mL.
Post-baseline NS5A and NS5B deep sequencing data (assay cut off of 1%) were available for 37/37 and 36/37 patients, respectively.

NS5A resistance-associated variants (RAVs) were observed in post-baseline isolates from 29/37 patients (22/29 genotype 1a and 7/8 genotype 1b) not achieving sustained virologic response
(SVR). Of the 29 genotype 1a patients who qualified for resistance testing, 22/29 (76%) patients harboured one or more NS5A RAVs at positions K24, M28, Q30, L31, S38 and Y93 at failure, while the remaining 7/29 patients had no NS5A RAVs detected at failure. The most common variants were Q30R, Y93H and L31M. Of the 8 genotype 1b patients who qualified for resistance testing, 7/8 (88%) harboured one or more NS5A RAVs at positions L31 and Y93 at failure, while 1/8 patients had no NS5A RAVs at failure. The most common variant was Y93H. Among the 8 patients who had no NS5A RAVs at failure, 7 patients received 8 weeks of treatment (n = 3 with ledipasvir/sofosbuvir; n = 4 with ledipasvir/sofosbuvir + ribavirin) and 1 patient received ledipasvir/sofosbuvir for 12 weeks.
In phenotypic analyses, post-baseline isolates from patients who harboured NS5A RAVs at failure showed 20- to at least a 243-fold (the highest dose tested) reduced susceptibility to ledipasvir.
Site-directed mutagenesis of the Y93H substitution in both genotype 1a and 1b as well as the Q30R and L31M substitution in genotype 1a conferred high levels of reduced susceptibility to ledipasvir (fold-change in EC50 ranging from 544-fold to 1,677-fold).

The sofosbuvir resistance-associated substitution S282T in NS5B was not detected in any virologic failure isolate from the Phase 3 studies. However, the NS5B S282T substitution in combination with NS5A substitutions L31M, Y93H and Q30L were detected in one patient at failure following 8 weeks of treatment with ledipasvir/sofosbuvir from a Phase 2 study (LONESTAR). This patient was subsequently retreated with ledipasvir/sofosbuvir + ribavirin for 24 weeks and achieved SVR following retreatment.

In the SIRIUS study (see “Clinical efficacy and safety”, below) 5 patients with genotype 1 infection relapsed after treatment with ledipasvir/sofosbuvir with or without ribavirin. NS5A RAVs were seen at relapse in 5/5 patients (for genotype 1a: Q30R/H + L31M/V [n = 1] and Q30R [n = 1]; for genotype 1b: Y93H [n = 3]).

In the SOLAR-1 study (see “Clinical efficacy and safety”, below) 13 patients with genotype 1 infection relapsed after treatment with ledipasvir/sofosbuvir with ribavirin. NS5A RAVs were seen at the time of relapse in 11/13 patients (for genotype 1a: Q30R alone [n = 2], Y93C [n = 1], Y93H/C [n = 2], Q30R + H58D [n = 1], M28T + Q30H [n = 1]; for genotype 1b: Y93H [n = 3], Y93H/C [n = 1]).

In clinical studies – Genotype 2, 3, 4, 5 and 6
NS5A RAVs: No genotype 2 infected patients experienced relapse in the clinical study and therefore there are no data regarding NS5A RAVs at the time of failure.

In genotype 3 infected patients experiencing virologic failure, development of NS5A RAVs (including enrichment of RAVs present at baseline) was typically not detected at the time of failure (n = 17).

In genotype 4, 5 and 6 infection, only small numbers of patients have been evaluated (total of 5 patients with failure). The NS5A substitution Y93C emerged in the HCV of 1 patient (genotype 4), while NS5A RAVs present at baseline were observed at the time of failure in all patients.

NS5B RAVs: The NS5B substitution S282T emerged in the HCV of 1/17 genotype 3-failures, and in the HCV of 1/3, 1/1 and 1/1 of genotype 4-, 5- and 6-failures, respectively.

Effect of baseline HCV resistance-associated variants on treatment outcome 
Genotype 1
Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome. In the pooled analysis of the Phase 3 studies, 16% of patients had baseline NS5A RAVs identified by population or deep sequencing irrespective of subtype. Baseline NS5A RAVs were overrepresented in patients who experienced relapse in the Phase 3 studies (see “Clinical efficacy and safety”).

Following 12 weeks of treatment with ledipasvir/sofosbuvir (without ribavirin) in treatment- experienced patients (arm 1 of ION-2 study) 4/4 patients with baseline NS5A RAVs conferring a ledipasvir fold-change of ≤ 100 achieved SVR. For the same treatment arm, patients with baseline NS5A RAVs conferring a fold-change of > 100, relapse occurred in 4/13 (31%), as compared to 3/95 (3%) in those without any baseline RAVs or RAVs conferring a fold-change of ≤ 100.

Following 12 weeks of treatment with ledipasvir/sofosbuvir with ribavirin in treatment-experienced patients with compensated cirrhosis (SIRIUS, n = 77), 8/8 patients with baseline NS5A RAVs conferring > 100-fold reduced susceptibility to ledipasvir achieved SVR12.

The group of NS5A RAVs that conferred > 100-fold shift and was observed in patients were the following substitutions in genotype 1a (M28A, Q30H/R/E, L31M/V/I, H58D, Y93H/N/C) or in genotype 1b (Y93H). The proportion of such baseline NS5A RAVs seen with deep sequencing varied from very low (cut off for assay = 1%) to high (main part of the plasma population).

The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any patient in Phase 3 studies by population or deep sequencing. SVR was achieved in all 24 patients (n = 20 with L159F+C316N; n = 1 with L159F; and n = 3 with N142T) who had baseline variants associated with resistance to NS5B nucleoside inhibitors.

Following treatment with ledipasvir/sofosbuvir with ribavirin for 12 weeks in post-liver transplant patients with compensated liver disease (SOLAR-1), none (n = 8) of the patients with baseline NS5A RAVs conferring a ledipasvir fold-change of > 100 relapsed. Following treatment with ledipasvir/sofosbuvir with ribavirin for 12 weeks in patients with decompensated disease (irrespective of liver transplantation status), 3/7 patients with baseline NS5A RAVs conferring > 100-fold reduced susceptibility to ledipasvir relapsed, as compared to 4/68 in those without any baseline RAVs or RAVs conferring ≤ 100-fold reduced susceptibility to ledipasvir.

Genotype 2, 3, 4, 5 and 6
Due to the limited size of studies, the impact of baseline NS5A RAVs on treatment outcome for patients with genotype 2, 3, 4, 5 or 6 CHC has not been fully evaluated. No major differences in outcomes were observed by the presence or absence of baseline NS5A RAVs.

Cross-resistance

Ledipasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all ledipasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir.
Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to ledipasvir may reduce the antiviral activity of other NS5A inhibitors.

Clinical efficacy and safety

The efficacy of ledipasvir [LDV]/sofosbuvir [SOF] was evaluated in three open-label Phase 3 studies with data available for a total of 1,950 patients with genotype 1 CHC. The three Phase 3 studies included one study conducted in non-cirrhotic treatment-naïve patients (ION-3); one study in cirrhotic and non-cirrhotic treatment-naïve patients (ION-1); and one study in cirrhotic and non-cirrhotic patients who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor (ION-2). Patients in these studies had compensated liver disease. All three Phase 3 studies evaluated the efficacy of ledipasvir/sofosbuvir with or without ribavirin.

Treatment duration was fixed in each study. Serum HCV RNA values were measured during the clinical studies using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System.
The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. SVR was the primary endpoint to determine the HCV cure rate which was defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment.

Treatment-naïve adults without cirrhosis – ION-3 (study 0108) – Genotype 1 ION-3 evaluated 8 weeks of treatment with ledipasvir/sofosbuvir with or without ribavirin and 12 weeks of treatment with ledipasvir/sofosbuvir in treatment-naïve non-cirrhotic patients with genotype 1 CHC. Patients were randomised in a 1:1:1 ratio to one of the three treatment groups and stratified by HCV genotype (1a versus 1b).

Table 6: Demographics and baseline characteristics in study ION-3

Patient disposition          LDV/SOF         LDV/SOF+RB             LDV/SOF            TOTAL 8 weeks                V              12 weeks
(n = 215)            8 weeks           (n = 216)         (n = 647)
(n = 216)
Age (years): median (range)     53 (22-75)        51 (21-71)          53 (20-71)         52 (20-75) Male gender                     60% (130)         54% (117)           59% (128)          58% (375) Race: Black/ African            21% (45)          17% (36)            19% (42)           19% (123) American
Patient disposition          LDV/SOF        LDV/SOF+RB            LDV/SOF            TOTAL 8 weeks              V              12 weeks
(n = 215)          8 weeks           (n = 216)          (n = 647)
(n = 216)
White                  76% (164)         81% (176)       77% (167)           78% (507) Genotype 1a                    80% (171)         80% (172)       80% (172)           80% (515)a IL28CC genotype                26% (56)          28% (60)        26% (56)            27% (172) FibroTest-Determined Metavir scoreb
F0-F1                       33% (72)       38% (81)           33% (72)            35% (225) F2                          30% (65)       28% (61)           30% (65)            30% (191) F3-F4                       36% (77)       33% (71)           37% (79)            35% (227) Not interpretable           < 1% (1)       1% (3)             0% (0)              < 1% (4) a One patient in the LDV/SOF 8-week treatment arm did not have a confirmed genotype 1 subtype.
b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 0.59-1.00 = F3-F4.

Table 7 : Response rates in study ION-3

LDV/SOF            LDV/SOF+RBV             LDV/SOF
8 weeks              8 weeks             12 weeks
(n = 215)            (n = 216)            (n = 216)
SVR                                94% (202/215)         93% (201/216)        96% (208/216) Outcome for patients without SVR
On-treatment virologic          0/215                 0/216              0/216 failure
Relapsea                        5% (11/215)           4% (9/214)         1% (3/216) Otherb                          < 1% (2/215)          3% (6/216)         2% (5/216) Genotype
Genotype 1a                     93% (159/171)         92% (159/172)      96% (165/172) Genotype 1b                     98% (42/43)           95% (42/44)        98% (43/44) a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.
b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g.
lost to follow-up).

The 8-week treatment of ledipasvir/sofosbuvir without ribavirin was non-inferior to the 8-week treatment of ledipasvir/sofosbuvir with ribavirin (treatment difference 0.9%; 95% confidence interval: -3.9% to 5.7%) and the 12-week treatment of ledipasvir/sofosbuvir (treatment difference -2.3%; 97.5% confidence interval: -7.2% to 3.6%). Among patients with a baseline HCV RNA < 6 million IU/mL, the SVR was 97% (119/123) with 8-week treatment of ledipasvir/sofosbuvir and 96% (126/131) with 12-week treatment of ledipasvir/sofosbuvir.
Table 8 : Relapse rates by baseline characteristics in the ION-3 study, virological failure population*

LDV/SOF         LDV/SOF+RBV             LDV/SOF
8 weeks           8 weeks              12 weeks
(n = 213)         (n = 210)             (n = 211)
Gender
Male                                   8% (10/129)       7% (8/114)    2% (3/127) Female                                 1% (1/84)         1% (1/96)     0% (0/84) IL28 genotype
CC                                     4% (2/56)         0% (0/57)     0% (0/54) Non-CC                                 6% (9/157)        6% (9/153)    2% (3/157) Baseline HCV RNAa
HCV RNA < 6 million IU/mL              2% (2/121)        2% (3/136)    2% (2/128) HCV RNA ≥ 6 million IU/mL              10% (9/92)        8% (6/74)     1% (1/83) * Patients lost to follow-up or who withdrew consent excluded.
a HCV RNA values were determined using the Roche TaqMan Assay; a patient’s HCV RNA may vary from visit to visit.

Treatment-naïve adults with or without cirrhosis – ION-1 (study 0102) – Genotype 1 ION-1 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment with ledipasvir/sofosbuvir with or without ribavirin in 865 treatment-naïve patients with genotype 1 CHC including those with cirrhosis (randomised 1:1:1:1). Randomisation was stratified by the presence or absence of cirrhosis and HCV genotype (1a versus 1b).

Table 9: Demographics and baseline characteristics in study ION-1

Patient disposition        LDV/SOF        LDV/SOF        LDV/SO      LDV/SOF          TOTAL 12 weeks         + RBV            F         + RBV
(n = 214)       12 weeks      24 weeks     24 weeks        (n = 865)
(n = 217)     (n = 217)    (n = 217)
Age (years): median           52 (18-75)      52 (18-78)    53           53 (24-77)     52 (18-80) (range)                                                     (22-80)
Male gender                   59% (127)       59% (128)     64%          55% (119)      59% (513) (139)
Race: Black/ African          11% (24)        12% (26)      15% (32)     12% (26)       12% (108) American
White                   87% (187)       87% (188)     82%          84% (183)      85% (735) (177)
Genotype 1aa                  68% (145)       68% (148)     67%          66% (143)      67% (582) (146)
IL28CC genotype            26% (55)           35% (76)      24% (52)     34% (73)       30% (256) FibroTest-Determined Metavir scoreb
F0-F1                   27% (57)           26% (56)   29% (62) 30% (66)           28% (241) F2                      26% (56)           25% (55)   22% (47) 28% (60)           25% (218) F3-F4                   47% (100)          48% (104)  49%          42% (91)       46% (402) (107)
Not interpretable         < 1% (1)      1% (2)        < 1% (1)     0% (0)         < 1% (4) a Two patients in the LDV/SOF 12-week treatment arm, one patient in the LDV/SOF+RBV 12-week treatment arm, two patients in the LDV/SOF 24-week treatment arm, and two patients in the LDV/SOF+RBV 24-week treatment arm did not have a confirmed genotype 1 subtype.
b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 0.59-1.00 = F3-F4.
Table 10: Response rates in study ION-1

LDV/SOF         LDV/SOF+RBV            LDV/SOF       LDV/SOF+RBV
12 weeks           12 weeks             24 weeks        24 weeks
(n = 214)          (n = 217)            (n = 217)       (n = 217)
SVR                       99% (210/213)     97% (211/217)         98%            99% (215/217) (213/217)
Outcome for patients without SVR
On-treatment              0/213a          0/217                 < 1% (1/217)   0/216 virologic failure
Relapseb                  < 1% (1/212)    0/217                 < 1% (1/215)   0/216 Other c
< 1% (2/213)    3% (6/217)            < 1% (2/217)   < 1% (2/217)
SVR rates for selected subgroups
Genotype
Genotype 1a               98% (142/145)   97% (143/148)         99%            99% (141/143) (144/146)
Genotype 1b            100% (67/67)      99% (67/68)           97% (67/69)    100% (72/72) Cirrhosisd
No                     99% (176/177)     97% (177/183)         98%             99% (178/180) (181/184)
Yes                       94% (32/34)       100% (33/33)        97% (32/33) 100% (36/36) a    One patient was excluded from the LDV/SOF 12-week treatment arm and one patient was excluded from the LDV/SOF+RBV 24-week treatment arm as both patients were infected with genotype 4 CHC.
b    The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on- treatment assessment.
c    Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g.
lost to follow-up).
d    Patients with missing cirrhosis status were excluded from this subgroup analysis.

Previously treated adults with or without cirrhosis – ION-2 (study 0109) – Genotype 1 ION-2 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment with ledipasvir/sofosbuvir with or without ribavirin (randomised 1:1:1:1) in genotype 1 HCV-infected patients with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Randomisation was stratified by the presence or absence of cirrhosis, HCV genotype (1a versus 1b) and response to prior HCV therapy (relapse/breakthrough versus non-response).

Table 11: Demographics and baseline characteristics in study ION-2

Patient           LDV/SOF        LDV/SOF+        LDV/SOF          LDV/SOF+          TOTAL disposition         12 weeks          RBV          24 weeks            RBV (n = 109)       12 weeks       (n = 109)         24 weeks         (n = 440) (n = 111)                        (n = 111)
Age (years):        56 (24-67)       57 (27-75)      56 (25-68)       55 (28-70)     56 (24-75) median (range)
Male gender         68% (74)         64% (71)        68% (74)         61% (68)       65% (287) Race: Black/        22% (24)         14% (16)        16% (17)         18% (20)       18% (77) African
American
White         77% (84)         85% (94)        83% (91)         80% (89)       81% (358) Genotype 1a         79% (86)         79% (88)        78% (85)         79% (88)       79% (347) Prior HCV therapy
PEG-IFN+RBV      39% (43)         42% (47)        53% (58)         53% (59)       47% (207)a Patient           LDV/SOF         LDV/SOF+         LDV/SOF         LDV/SOF+         TOTAL disposition         12 weeks           RBV           24 weeks           RBV (n = 109)        12 weeks        (n = 109)        24 weeks        (n = 440) (n = 111)                        (n = 111)
HCV protease       61% (66)         58% (64)        46% (50)         46% (51)       53% (231)a inhibitor +
PEG-IFN+RBV
IL28CC genotype       9% (10)         10% (11)         14% (16)        16% (18)        13% (55) FibroTest-Determined Metavir scoreb
F0-F1              14% (15)        10% (11)         12% (13)        16% (18)        13% (57) F2                 28% (31)        26% (29)         28% (31)        30% (33)        28% (124) F3-F4              58% (63)        64% (71)         58% (63)        54% (60)        58% (257) Not                0% (0)          0% (0)           2% (2)          0% (0)          < 1% (2) interpretable a One patient in the LDV/SOF 24-week treatment arms and one patient in the LDV/SOF+RBV    24-week treatment arm were prior treatment failures of a non-pegylated interferon-based regimen.
b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 0.59-1.00 = F3-F4.

Table 12: Response rates in study ION-2

LDV/SOF          LDV/SOF+RB            LDV/SOF         LDV/SOF+RB
12 weeks                V              24 weeks               V
(n = 109)           12 weeks           (n = 109)          24 weeks
(n = 111)                             (n = 111)
SVR                         94% (102/109)       96% (107/111)      99% (108/109)      99% (110/111) Outcome for patients without SVR
On-treatment virologic 0/109                 0/111              0/109              < 1% (1/111) failure
Relapsea                 6% (7/108)          4% (4/111)         0/109              0/110 Otherb                   0/109               0/111              < 1% (1/109)       0/111 SVR rates for selected subgroups
Genotype
Genotype 1a              95% (82/86)         95% (84/88)        99% (84/85)        99% (87/88) Genotype 1b              87% (20/23)         100% (23/23)       100% (24/24)       100% (23/23) Cirrhosis
No                       95% (83/87)         100% (88/88)c      99% (85/86)c       99% (88/89) Yes d
86% (19/22)         82% (18/22)        100% (22/22)       100% (22/22) Prior HCV therapy
PEG-IFN+RBV              93% (40/43)         96% (45/47)        100% (58/58)       98% (58/59) HCV protease             94% (62/66)         97% (62/64)        98% (49/50)        100% (51/51) inhibitor +
PEG-IFN+RBV a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.
b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g.
lost to follow-up).
c Patients with missing cirrhosis status were excluded from this subgroup analysis.
d Metavir score = 4 or Ishak score ≥ 5 by liver biopsy, or FibroTest score of > 0.75 and (APRI) of > 2.

Table 13 presents relapse rates with the 12-week regimens (with or without ribavirin) for selected subgroups (see also previous section “Effect of baseline HCV resistance-associated variants on treatment outcome”). In non-cirrhotic patients relapses only occurred in the presence of baseline NS5A RAVs, and during therapy with ledipasvir/sofosbuvir without ribavirin. In cirrhotic patients relapses occurred with both regimens, and in the absence and presence of baseline NS5A RAVs.
Table 13: Relapse rates for selected subgroups in study ION-2

LDV/SOF       LDV/SOF+RBV     LDV/SOF               LDV/SOF+RBV
12 weeks          12 weeks    24 weeks                  24 weeks
(n = 109)         (n = 111)   (n = 109)                 (n = 111)
Number of responders at       108            111           109                     110 end of treatment
Cirrhosis
No                        5% (4/86)a     0% (0/88)b          0% (0/86)b       0% (0/88) Yes                       14% (3/22)     18% (4/22)          0% (0/22)        0% (0/22) c
Presence of baseline NS5A resistance-associated substitutions
No                        3% (3/91)d     2% (2/94)           0% (0/96)        0% (0/95)f Yes                       24% (4/17)  e
12% (2/17)          0% (0/13)        0% (0/14) a These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms.
b Patients with missing cirrhosis status were excluded from this subgroup analysis.
c Analysis (by deep sequencing) included NS5A resistance-associated polymorphisms that conferred > 2.5-fold change in EC50 (K24G/N/R, M28A/G/T, Q30E/G/H/L/K/R/T, L31I/F/M/V, P32L, S38F, H58D, A92K/T, and Y93C/F/H/N/S for genotype 1a and L31I/F/M/V, P32L, P58D, A92K, and Y93C/H/N/S for genotype 1b HCV infection).
d 3/3 of these patients had cirrhosis.
e 0/4 of these patients had cirrhosis.
f One patient who achieved a viral load < LLOQ at end of treatment had missing baseline NS5A data and was excluded from the analysis.

Previously treated adults with cirrhosis – SIRIUS – Genotype 1
SIRIUS included patients with compensated cirrhosis who first failed therapy with pegylated interferon (PEG-IFN) + ribavirin, and then failed a regimen consisting of a pegylated interferon + ribavirin + an NS3/4A protease inhibitor. Cirrhosis was defined by biopsy, Fibroscan (> 12.5 kPa) or FibroTest > 0.75 and an AST:platelet ratio index (APRI) of > 2.

The study (double-blind and placebo-controlled) evaluated 24 weeks of treatment ledipasvir/sofosbuvir (with ribavirin placebo) versus 12 weeks of treatment with ledipasvir/sofosbuvir with ribavirin. Patients in the latter treatment arm received placebo (for ledipasvir/sofosbuvir and ribavirin) during the first 12 weeks, followed by active blinded therapy during the subsequent 12 weeks. Patients were stratified by HCV genotype (1a versus 1b) and prior treatment response (whether HCV RNA < LLOQ had been achieved).

Demographics and baseline characteristics were balanced across the two treatment groups. The median age was 56 years (range: 23 to 77); 74% of patients were male; 97% were white; 63% had genotype 1a HCV infection; 94% had non-CC IL28B alleles (CT or TT).

Of the 155 patients enrolled, 1 patient discontinued treatment whilst on placebo. Of the remaining 154 patients, a total of 149 achieved SVR12 across both treatment groups; 96% (74/77) of patients in the ledipasvir/sofosbuvir with ribavirin 12-week group and 97% (75/77) of patients in the ledipasvir/sofosbuvir 24-week group. All 5 patients who did not achieve SVR12 relapsed after having end-of-treatment response (see section “Resistance” – “In clinical studies” above).

Previously treated adults who have failed on sofosbuvir + ribavirin ± PEG-IFN The efficacy of ledipasvir/sofosbuvir in patients who had previously failed treatment with sofosbuvir + ribavirin ± PEG-IFN is supported by two clinical studies. In study 1118, 44 patients with genotype 1 infection, including 12 cirrhotic patients, who had previously failed treatment with sofosbuvir + ribavirin + PEG-IFN or with sofosbuvir + ribavirin were treated with ledipasvir/sofosbuvir + ribavirin for 12 weeks; the SVR was 100% (44/44). In study ION-4, 13 HCV/HIV-1 co-infected patients with genotype 1, including 1 cirrhotic patient, who had failed a sofosbuvir + ribavirin regimen were enrolled; the SVR was 100% (13/13) after 12 weeks of treatment with ledipasvir/sofosbuvir.
HCV/HIV co-infected adults – ION-4
ION-4 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks of treatment with ledipasvir/sofosbuvir without ribavirin in HCV treatment-naïve and treatment-experienced patients with genotype 1 or 4 CHC who were co-infected with HIV-1. Treatment-experienced patients had failed prior treatment with PEG-IFN + ribavirin ± an HCV protease inhibitor or sofosbuvir + ribavirin ± PEG-IFN. Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine or raltegravir.

The median age was 52 years (range: 26 to 72); 82% of the patients were male; 61% were white; 34% were black; 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-CC IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the patients were treatment-experienced.

Table 14: Response rates in study ION-4

LDV/SOF
12 weeks
(n = 335)
SVR                                              96% (321/335)a
Outcome for patients without SVR
On-treatment virologic failure                 < 1% (2/335)
Relapseb                                       3% (10/333)
Other  c
< 1% (2/335)
SVR rates for selected subgroups
Patients with cirrhosis                        94% (63/67)
Previously treated patients with cirrhosis 98% (46/47) a 8 patients with genotype 4 HCV infection were enrolled in the study with 8/8 achieving SVR12.
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on- treatment assessment.
c Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g.
lost to follow-up).

HCV/HIV co-infected adults – ERADICATE
ERADICATE was an open-label study to evaluate 12 weeks of treatment with ledipasvir/sofosbuvir in 50 patients with genotype 1 CHC co-infected with HIV. All patients were treatment-naïve to HCV therapy without cirrhosis, 26% (13/50) of patients were HIV antiretroviral naïve and 74% (37/50) of patients were receiving concomitant HIV antiretroviral therapy. At the time of the interim analysis 40 patients have reached 12 weeks post treatment and SVR12 was 98% (39/40).

Patients awaiting liver transplantation and post-liver transplant – SOLAR-1 SOLAR-1 is an open-label, multicentre study evaluating 12 and 24 weeks of treatment with ledipasvir/sofosbuvir + ribavirin in patients with genotype 1 or 4 CHC who have advanced liver disease and/or who have undergone liver transplantation. Seven patient populations are being evaluated (patients with decompensated cirrhosis [CPT B and C] pre-transplant; post-transplant, no cirrhosis; post-transplant CPT A; post-transplant CPT B; post-transplant CPT C; post-transplant fibrosing cholestatic hepatitis [FCH]). Patients with a CPT score > 12 were excluded.
Table 15: Response rates (SVR12) in study SOLAR-1

LDV/SOF+RBV                          LDV/SOF+RBV
12 weeks                             24 weeks
(n = 168)a                           (n = 163)a
SVR                 Relapse          SVR                Relapse
Pre-transplant
CPT B                  87% (26/30)       10.3% (3/29)     89% (24/27)    4.0% (1/25) CPT C                  86% (19/22)       5.0% (1/20)      87% (20/23)    9.1% (2/22) Post-transplant
Metavir score          96% (53/55)       3.6% (2/55)      98% (55/56)    0% (0/55) F0-F3
CPT Ab                 96% (25/26)       0% (0/25)        96% (24/25)    0% (0/24) CPT Bb                 85% (22/26)       4.3% (1/23)      88% (23/26)    0% (0/23) CPT Cb                 60% (3/5)         40.0% (2/5)      75% (3/4)      25% (1/4) FCH                    100% (4/4)        0% (0/4)         100% (2/2)     0% (0/2) a. Six patients (1 in the 12-week, 5 in the 24-week treatment group) with HCV RNA < LLOQ at last measurement prior to transplant, were transplanted prior to SVR12 and were excluded from SVR12 and relapse analyses. Only patients who demonstrated SVR12 or relapse were included in relapse analyses.
b. CPT = Child-Pugh-Turcotte. CPT A = CPT score 5-6 (compensated), CPT B = CPT score 7-9 (decompensated), CPT C = CPT score 10-12 (decompensated).

Of 169 patients with decompensated cirrhosis (pre- or post-transplant CPT B or C), those patients who achieved SVR12 and had post-treatment week 12 laboratory data available (e.g. excluding patients who died, were transplanted, or had missing data at this time-point) were assessed for changes in their MELD and CPT scores.

Change in MELD score: 53% (72/135) and 21% (28/135) had an improvement or no change of MELD score from baseline to post-treatment week 4, respectively; of the 35 patientswhose MELD score was ≥ 15 at baseline, 63% (22/35) had a MELD score < 15 at post-treatment week 12. The improvement in MELD scores observed was driven largely by improvements in total bilirubin.

Change in CPT: 59% (79/133) and 34% (45/133) had an improvement or no change of CPT scores from baseline to post-treatment week 12, respectively; of the 39 patientswho had CPT C cirrhosis at baseline, 56% (22/39) had CPT B cirrhosis at post-treatment week 12; of the 99 patientswho had CPT B cirrhosis at baseline, 29% (27/92) had CPT A cirrhosis at post-treatment week 12. The improvement in CPT scores observed was driven largely by improvements in total bilirubin and albumin.

Clinical efficacy and safety in genotype 2, 3, 4, 5 and 6 (see also section 4.4) Ledipasvir/sofosbuvir has been evaluated for the treatment of non-genotype 1 infection in small Phase 2 studies, as summarised below.

The clinical studies enrolled patients with or without cirrhosis, who were treatment-naïve or with prior treatment failure after therapy with PEG-IFN + ribavirin +/- an HCV protease inhibitor.

For genotype 2, 4, 5 and 6 infection, therapy consisted of ledipasvir/sofosbuvir without ribavirin, given for 12 weeks (Table 16). For genotype 3 infection, ledipasvir/sofosbuvir was given with or without ribavirin, also for 12 weeks (Table 17).
Table 16: Response rates (SVR12) with ledipasvir/sofosbuvir for 12 weeks in patients with genotype 2, 4, 5 and 6 HCV infection

Study               GT     n        TEa                  SVR12                  Relapseb Overall      Cirrhosis
Study 1468 (LEPTON)           2     26     19% (5/26)    96% (25/26) 100% (2/2)          0% (0/25) Study 1119                    4     44     50%           93% (41/44) 100%                7% (3/44) (22/44)                    (10/10)
Study 1119                    5     41     49%           93% (38/41) 89% (8/9)           5% (2/40) (20/41)
Study 0122                  6     25       0% (0/25)  96% (24/25) 100% (2/2)     4% (1/25) (ELECTRON-2) a TE: number of treatment-experienced patients.
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

Table 17: Response rates (SVR12) in patients with genotype 3 infection (ELECTRON-2) 
LDV/SOF+RBV                           LDV/SOF
12 weeks                           12 weeks
SVR           Relapsea             SVR          Relapsea
Treatment-naïve              100% (26/26)   0% (0/26)           64% (16/25)    33% (8/24) Patients without            100% (20/20)   0% (0/21)           71% (15/21)    25% (5/20) cirrhosis
Patients with cirrhosis   100% (6/6)       0% (0/5)          25% (1/4)   75% (3/4) Treatment-experienced      82% (41/50)      16% (8/49)        NS          NS Patients without          89% (25/28)      7% (2/27)         NS          NS cirrhosis
Patients with cirrhosis   73% (16/22)      27% (6/22)        NS          NS NS: not studied.
a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

Patients with renal impairment
Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks of treatment with ledipasvir/sofosbuvir in 18 genotype 1 HCV-infected patients with severe renal impairment not requiring dialysis. At baseline, two patients had cirrhosis and the mean eGFR was 24.9 mL/min (range: 9.0-39.6). SVR12 was achieved in 18/18 patients.

Study 4063 was an open-label three-arm clinical study that evaluated 8, 12, and 24 weeks of treatment with ledipasvir/sofosbuvir in a total of 95 patients with genotype 1 (72%), 2 (22%), 4 (2%), 5 (1%), or 6 (2%) CHC and ESRD requiring dialysis: 45 treatment-naïve genotype 1 HCV-infected patients without cirrhosis received ledipasvir/sofosbuvir for 8 weeks; 31 treatment-experienced genotype 1 HCV-infected patients and treatment-naïve or treatment-experienced patients with genotype 2, 5, and 6 infection without cirrhosis received ledipasvir/sofosbuvir for 12 weeks; and 19 genotype 1, 2, and 4 HCV-infected patients with compensated cirrhosis received ledipasvir/sofosbuvir for 24 weeks. Of the 95 total patients, at baseline, 20% of patients had cirrhosis, 22% were treatment experienced, 21% had received a kidney transplant, 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 11.5 years (range: 0.2 to 43.0 years). The SVR rates for the 8, 12, and 24 week ledipasvir/sofosbuvir treatment groups were 93% (42/45), 100% (31/31), and 79% (15/19),
respectively. Of the seven patients who did not achieve SVR12, none experienced virologic failure or relapsed.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients, ledipasvir median peak plasma concentration was observed at 4.0 hours post-dose. Sofosbuvir was absorbed quickly and the median peak plasma concentrations were observed ~ 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed at 4 hours post-dose.

Based on the population pharmacokinetic analysis in HCV-infected patients, geometric mean steady-state AUC0-24 for ledipasvir (n = 2,113), sofosbuvir (n = 1,542), and GS-331007 (n = 2,113) were 7,290, 1,320 and 12,000 ng•h/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir and GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (n = 191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected patients. Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.

Effects of food
Relative to fasting conditions, the administration of a single dose of ledipasvir/sofosbuvir with a moderate fat or high fat meal increased the sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect the sofosbuvir Cmax. The exposures to GS-331007 and ledipasvir were not altered in the presence of either meal type. Harvoni can be administered without regard to food.

Distribution

Ledipasvir is > 99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.51 and 0.66.

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity was approximately 0.7.

Biotransformation

In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure was almost exclusively due to the parent drug (> 98%). Unchanged ledipasvir is also the major species present in faeces.

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analogue triphosphate GS-461203. The active metabolite is not observed. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Within ledipasvir/sofosbuvir, GS-331007 accounts for approximately 85% of total systemic exposure.

Elimination

Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in faeces and urine was 87%, with most of the radioactive dose recovered from faeces (86%).
Unchanged ledipasvir excreted in faeces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary excretion of unchanged ledipasvir is a major route of elimination with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir in healthy volunteers following administration of ledipasvir/sofosbuvir in the fasted state was 47 hours.

Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major elimination pathway for GS-331007 with a large part actively secreted. The median terminal half-lives of sofosbuvir and GS-331007 following administration of ledipasvir/sofosbuvir were 0.5 and 27 hours, respectively.

Neither ledipasvir nor sofosbuvir are substrates for hepatic uptake transporters, organic cation transporter (OCT) 1, organic anion-transporting polypeptide (OATP) 1B1 or OATP1B3. GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or OAT3, or OCT2.

In vitro potential for ledipasvir/sofosbuvir to affect other medicinal products 
At concentrations achieved in the clinic, ledipasvir is not an inhibitor of hepatic transporters including the OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxic compound extrusion (MATE) 1 transporter, multidrug resistance protein (MRP) 2 or MRP4. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1 and GS-331007 is not an inhibitor of OAT1, OCT2 and MATE1.

Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes.

Pharmacokinetics in special populations

Race and gender
No clinically relevant pharmacokinetic differences due to race have been identified for ledipasvir, sofosbuvir or GS-331007. No clinically relevant pharmacokinetic differences due to gender have been identified for sofosbuvir or GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant.

Elderly
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 80 years) analysed, age did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir or GS-331007. Clinical studies of ledipasvir/sofosbuvir included 235 patients (8.6% of total number of patients) aged 65 years and over.

Renal impairment
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the components of Harvoni compared to subjects with normal renal function, as described in the text below, are provided in Table 18.

Table 18: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir, GS-331007, and Ledipasvir Compared to Subjects with Normal Renal Function

HCV-Negative Subjects                                                HCV-Infected Subjects Mild RI      Moderate RI     Severe RI      ESRD Requiring           Severe RI    ESRD (eGFR ≥      (eGFR ≥30       (eGFR <30      Dialysis                 (eGFR        Requiring 50 and       and <50         mL/min/1.73    Dosed 1    Dosed 1       <30          Dialysis <80          mL/min/1.73     m2)            hr Before  hr After      mL/min/1.
mL/min/1.    m2)                            Dialysis   Dialysis      73m2) 73m2)
Sofosbuvir       1.6-fold↑      2.1-fold↑          2.7-fold↑         1.3-fold↑   1.6-fold↑   ~2-fold↑   1.9-fold↑ GS-331007                                                            ≥10-fold    ≥20-fold    ~6-fold↑ 1.6-fold↑      1.9-fold↑          5.5-fold↑                                            23-fold↑ ↑           ↑
Ledipasvir       -              -                  ↔                 -           -           -          1.6-fold↑ ↔ indicates no clinically relevant change in the exposure of Ledipasvir.

The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault, median [range] CrCl 22 [17-29] mL/min)..

The pharmacokinetics of sofosbuvir were studied in HCV negative patients with mild (eGFR ≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvirrelative to patients with normal renal function (eGFR
> 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered sofosbuvir dose.

In HCV-infected patients with severe renal impairment treated with ledipasvir/sofosbuvir for 12 weeks (n = 18), the pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were consistent with that observed in HCV negative patients with severe renal impairment.

The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected patients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n=94) for 8, 12, or 24 weeks, and compared to patients without renal impairment in the ledipasvir/sofosbuvir Phase 2/3 trials.

Hepatic impairment
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative patients with severe hepatic impairment (CPT class C). Ledipasvir plasma exposure (AUCinf) was similar in patients with severe hepatic impairment and control patients with normal hepatic function. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to ledipasvir.

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected patients with moderate and severe hepatic impairment (CPT class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively.
Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir and GS-331007.

Body weight
Body weight did not have a significant effect on sofosbuvir exposure according to a population pharmacokinetic analysis. Exposure to ledipasvir decreases with increasing body weight but the effect is not considered to be clinically relevant.

Paediatric population
The pharmacokinetics of ledipasvir, sofosbuvir and GS-331007 in paediatric patients have not been established (see section 4.2).