Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland
Pharmacotherapeutic group: Direct-acting antiviral
ATC code: J05AP51
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.
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 8. 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 8. Activity of ledipasvir and sofosbuvir against chimeric replicons:
| Genotype replicons | Ledipasvir activity (EC50, nM) | Sofosbuvir activity (EC50, nM) | ||
|---|---|---|---|---|
| Stable replicons | NS5A transient replicons Median (range)a | Stable replicons | NS5B transient replicons Median (range)a | |
| Genotype 1a | 0,031 | 0,018 (0,009-0,085) | 40 | 62 (29-128) |
| Genotype 1b | 0,004 | 0,006 (0,004-0,007) | 110 | 102 (45-170) |
| 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 4d | 0,60 | - | - | - |
| Genotype 5a | 0,15b | - | 15b | - |
| Genotype 6a | 1,1b | - | 14b | - |
| Genotype 6e | 264b | - | - | - |
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.
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 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).
Among post-transplant patients with compensated liver disease or patients with decompensated liver disease either pre- or post-transplant (SOLAR-1 and SOLAR-2 studies), relapse was associated with the detection of one or more of the following NS5A RAVs: K24R, M28T, Q30R/H/K, L31V, H58D and Y93H/C in 12/14 genotype 1a patients, and L31M, Y93H/N in 6/6 genotype 1b patients.
A NS5B substitution E237G was detected in 3 patients (1 genotype 1b and 2 genotype 1a) in the Phase 3 studies (ION-3, ION-1 and ION-2) and 3 patients with genotype 1a infection in the SOLAR-1 and SOLAR-2 studies at the time of relapse. The E237G substitution showed a 1.3-fold reduction in susceptibility to sofosbuvir in the genotype 1a replicon assay. The clinical significance of this substitution is currently unknown.
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]).
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. In the SOLAR-2 study, one patient with genotype 4d developed NS5B substitution E237G at the time of relapse. The clinical significance of this substitution is currently unknown.
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.
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 treatmentexperienced 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.
Among post-transplant patients with compensated liver disease (SOLAR-1 and SOLAR-2 studies), no relapse occurred in patients with baseline NS5A RAVs (n=23) following 12 weeks of treatment with ledipasvir/sofosbuvir + ribavirin. Among patients with decompensated liver disease (pre- and posttransplant), 4/16 (25%) patients with NS5A RAVs conferring >100-fold resistance relapsed after 12 weeks treatment with ledipasvir/sofosbuvir + ribavirin compared to 7/120 (6%) in those without any baseline NS5A RAVs or RAVs conferring a fold-change of ≤100.
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.
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.
The presence of pre-treatment NS5A and/or NS5B RAVs did not impact treatment outcome as all subjects with pre-treatment RAVs achieved SVR12 and SVR24. One 8-year-old subject infected with genotype 1a HCV who failed to achieve SVR12 had no NS5A or NS5B nucleoside inhibitor RAVs at baseline and had emergent NS5A RAV Y93H at relapse.
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.
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.
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 9. Demographics and baseline characteristics in study ION-3:
| Patient disposition | LDV/SOF 8 weeks (n=215) | LDV/SOF+RBV 8 weeks (n=216) | LDV/SOF 12 weeks (n=216) | TOTAL (n=647) |
|---|---|---|---|---|
| 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 American | 21% (45) | 17% (36) | 19% (42) | 19% (123) |
| 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 10. Response rates in study ION-3:
| LDV/SOF 8 weeks (n=215) | LDV/SOF+RBV 8 weeks (n=216) | LDV/SOF 12 weeks (n=216) | |
|---|---|---|---|
| SVR | 94% (202/215) | 93% (201/216) | 96% (208/216) |
| Outcome for patients without SVR | |||
| On-treatment virologic failure | 0/215 | 0/216 | 0/216 |
| 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 11. Relapse rates by baseline characteristics in the ION-3 study, virological failure population*:
| LDV/SOF 8 weeks (n=213) | LDV/SOF+RBV 8 weeks (n=210) | LDV/SOF 12 weeks (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
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 12. Demographics and baseline characteristics in study ION-1:
| Patient disposition | LDV/SOF 12 weeks (n=214) | LDV/SOF+RBV 12 weeks (n=217) | LDV/SOF 24 weeks (n=217) | LDV/SOF+RBV 24 weeks (n=217) | TOTAL (n=865) |
|---|---|---|---|---|---|
| Age (years): median (range) | 52 (18-75) | 52 (18-78) | 53 (22-80) | 53 (24-77) | 52 (18-80) |
| Male gender | 59% (127) | 59% (128) | 64% (139) | 55% (119) | 59% (513) |
| Race: Black/ African American | 11% (24) | 12% (26) | 15% (32) | 12% (26) | 12% (108) |
| White | 87% (187) | 87% (188) | 82% (177) | 84% (183) | 85% (735) |
| Genotype 1aa | 68% (145) | 68% (148) | 67% (146) | 66% (143) | 67% (582) |
| 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% (107) | 42% (91) | 46% (402) |
| 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 13. Response rates in study ION-1:
| LDV/SOF 12 weeks (n=214) | LDV/SOF+RBV 12 weeks (n=217) | LDV/SOF 24 weeks (n=217) | LDV/SOF+RBV 24 weeks (n=217) | |
|---|---|---|---|---|
| SVR | 99% (210/213) | 97% (211/217) | 98% (213/217) | 99% (215/217) |
| Outcome for patients without SVR | ||||
| On-treatment virologic failure | 0/213a | 0/217 | <1% (1/217) | 0/216 |
| Relapseb | <1% (1/212) | 0/217 | <1% (1/215) | 0/216 |
| Otherc | <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% (144/146) | 99% (141/143) |
| Genotype 1b | 100% (67/67) | 99% (67/68) | 97% (67/69) | 100% (72/72) |
| Cirrhosisd | ||||
| No | 99% (176/177) | 97% (177/183) | 98% (181/184) | 99% (178/180) |
| 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.
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 14. Demographics and baseline characteristics in study ION-2:
| Patient disposition | LDV/SOF 12 weeks (n=109) | LDV/SOF+RBV 12 weeks (n=111) | LDV/SOF 24 weeks (n=109) | LDV/SOF+RBV 24 weeks (n=111) | TOTAL (n=440) |
|---|---|---|---|---|---|
| Age (years): median (range) | 56 (24-67) | 57 (27-75) | 56 (25-68) | 55 (28-70) | 56 (24-75) |
| Male gender | 68% (74) | 64% (71) | 68% (74) | 61% (68) | 65% (287) |
| Race: Black/African American | 22% (24) | 14% (16) | 16% (17) | 18% (20) | 18% (77) |
| 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 |
| HCV protease inhibitor + PEG-IFN+RBV | 61% (66) | 58% (64) | 46% (50) | 46% (51) | 53% (231)a |
| 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 interpretable | 0% (0) | 0% (0) | 2% (2) | 0% (0) | <1% (2) |
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 15. Response rates in study ION-2:
| LDV/SOF 12 weeks (n=109) | LDV/SOF+RBV 12 weeks (n=111) | LDV/SOF 24 weeks (n=109) | LDV/SOF+RBV 24 weeks (n=111) | |
|---|---|---|---|---|
| SVR | 94% (102/109) | 96% (107/111) | 99% (108/109) | 99% (110/111) |
| Outcome for patients without SVR | ||||
| On-treatment virologic failure | 0/109 | 0/111 | 0/109 | <1% (1/111) |
| 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) |
| Yesd | 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 inhibitor + PEG-IFN+RBV | 94% (62/66) | 97% (62/64) | 98% (49/50) | 100% (51/51) |
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 16 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 16. Relapse rates for selected subgroups in study ION-2:
| LDV/SOF 12 weeks (n=109) | LDV/SOF+RBV 12 weeks (n=111) | LDV/SOF 24 weeks (n=109) | LDV/SOF+RBV 24 weeks (n=111) | |
|---|---|---|---|---|
| Number of responders at end of treatment | 108 | 111 | 109 | 110 |
| 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) |
| Presence of baseline NS5A resistance-associated substitutionsc | ||||
| 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.
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).
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.
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 17. 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) |
| Otherc | <1% (2/335) |
| SVR rates for selected subgroups | |
| Patients with cirrhosis | 94% (63/67) |
| Previously treated patients with cirrhosis | 98% (46/47) |
a 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).
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).
SOLAR-1 and SOLAR-2 were two open-label clinical studies that evaluated 12 and 24 weeks of treatment with ledipasvir/sofosbuvir in combination with ribavirin in genotype 1 and 4 HCV-infected patients who have undergone liver transplantation and/or who have decompensated liver disease. The two studies were identical in study design. Patients were enrolled in one of the seven groups based on liver transplantation status and severity of hepatic impairment (see Table 18). Patients with a CPT score >12 were excluded. Within each group, patients were randomized in a 1:1 ratio to receive ledipasvir/sofosbuvir + ribavirin for 12 or 24 weeks.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated patients, the median age was 59 years (range: 21 to 81 years); 77% of the patients were male; 91% were White; mean body mass index was 28 kg/m² (range: 18 to 49 kg/m²); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the patients failed a prior HCV therapy. Among the patients who had decompensated cirrhosis (pre- or post-transplant), 64% and 36% were CPT class B and C at screening, respectively, 24% had a baseline Model for End Stage Liver Disease (MELD) score greater than 15.
Table 18. Combined response rates (SVR12) in studies SOLAR-1 and SOLAR-2:
| LDV/SOF+RBV 12 weeks (n=307)a,b | LDV/SOF+RBV 24 weeks (n=307)a,b | |
|---|---|---|
| SVR | SVR | |
| Pre-transplant | ||
| CPT B | 87% (45/52) | 92% (46/50) |
| CPT C | 88% (35/40) | 83% (38/46) |
| Post-transplant | ||
| Metavir score F0-F3 | 95% (94/99) | 99% (99/100) |
| CPT Ac | 98% (55/56) | 96% (51/53) |
| CPT Bc | 89% (41/46) | 96% (43/45) |
| CPT Cc | 57% (4/7) | 78% (7/9) |
| FCH | 100% (7/7) | 100% (4/4) |
a Twelve patients transplanted prior to post-treatment Week 12 with HCV RNA< LLOQ at last measurement prior to transplant were excluded.
b Two patients who did not have decompensated cirrhosis and had also not received a liver transplant were excluded due to failure to meet the inclusion criteria for any of the treatment groups.
c CPT = Child-Pugh-Turcotte, FCH = Fibrosing cholestatic hepatitis. CPT A = CPT score 5-6 (compensated), CPT B = CPT score 7-9 (decompensated), CPT C = CPT score 10-12 (decompensated).
Forty patients with genotype 4 CHC were enrolled in SOLAR-1 and SOLAR-2 studies, SVR12 were 92% (11/12) and 100% (10/10) in post-transplant patients without decompensated cirrhosis and 60% (6/10) and 75% (6/8) in patients with decompensated cirrhosis (pre- and post-liver transplantation) treated for 12 or 24 weeks, respectively. Of the 7 patients who failed to achieve SVR12, 3 relapsed, all had decompensated cirrhosis and were treated with ledipasvir/sofosbuvir + ribavirin for 12 weeks.
Changes in MELD and CPT score from baseline to post-treatment Week 12 were analyzed for all patients with decompensated cirrhosis (pre- or post-transplant) who achieved SVR12 and for whom data were available (n=123) to assess the effect of SVR12 on hepatic function.
Change in MELD score: Among those who achieved SVR12 with 12 weeks treatment with ledipasvir/sofosbuvir + ribavirin, 57% (70/123) and 19% (23/123) had an improvement or no change in MELD score from baseline to post-treatment week 12, respectively; of the 32 patients whose MELD score was ≥ 15 at baseline, 59% (19/32) 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 score and class: Among those who achieved SVR12 with 12 weeks treatment with ledipasvir/sofosbuvir with ribavirin, 60% (74/123) and 34% (42/123) had an improvement or no change of CPT scores from baseline to post-treatment week 12, respectively; of the 32 patients who had CPT C cirrhosis at baseline, 53% (17/32) had CPT B cirrhosis at post-treatment Week 12; of the 88 patients who had CPT B cirrhosis at baseline, 25% (22/88) 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.
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 19). For genotype 3 infection, ledipasvir/sofosbuvir was given with or without ribavirin, also for 12 weeks (Table 20).
Table 19. 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% (22/44) | 93% (41/44) | 100% (10/10) | 7% (3/44) |
| Study 1119 | 5 | 41 | 49% (20/41) | 93% (38/41) | 89% (8/9) | 5% (2/40) |
| Study 0122 (ELECTRON-2) | 6 | 25 | 0% (0/25) | 96% (24/25) | 100% (2/2) | 4% (1/25) |
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 20. Response rates (SVR12) in patients with genotype 3 infection (ELECTRON-2):
| LDV/SOF+RBV 12 weeks | LDV/SOF 12 weeks | |||
|---|---|---|---|---|
| SVR | Relapsea | SVR | Relapsea | |
| Treatment-naïve | 100% (26/26) | 0% (0/26) | 64% (16/25) | 33% (8/24) |
| Patients without cirrhosis | 100% (20/20) | 0% (0/21) | 71% (15/21) | 25% (5/20) |
| Patients with cirrhosis | 100% (6/6) | 0% (0/5) | 25% (¼) | 75% (¾) |
| Treatment-experienced | 82% (41/50) | 16% (8/49) | NS | NS |
| Patients without cirrhosis | 89% (25/28) | 7% (2/27) | NS | NS |
| 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.
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.
The efficacy of ledipasvir/sofosbuvir in HCV infected patients aged 3 years and above was evaluated in a Phase 2, open label clinical study that enrolled 226 patients: 221 patients with genotype 1, 2 patients with genotype 3, and 3 patients with genotype 4 CHC (Study 1116) (see section 4.2 for information on paediatric use).
Ledipasvir/sofosbuvir was evaluated in 100 patients aged 12 to <18 years with genotype 1 HCV infection. A total of 80 patients (n=80) were treatment-naïve, while 20 patients (n=20) were treatment-experienced. All patients were treated with ledipasvir/sofosbuvir for 12 weeks.
Demographics and baseline characteristics were balanced across treatment-naïve and treatment-experienced patients. The median age was 15 years (range: 12 to 17); 63% of the patients were female; 91% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean weight was 61.3 kg (range: 33.0 to 126.0 kg); 55% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; and 1 patient who was treatment naïve was known to have cirrhosis. The majority of patients (84%) had been infected through vertical transmission.
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve patients and 100% [20/20] in treatment experienced patients). A total of 2 out of 100 patients (2%), both treatment- naïve, did not achieve SVR12 (due to loss to follow-up). No patient experienced virologic failure.
Ledipasvir/sofosbuvir was evaluated in 92 patients aged 6 to <12 years with genotype 1, 3, or 4 HCV-infection. A total of 72 patients (78%) were treatment-naïve and 20 patients (22%) were treatment-experienced. Eighty-nine of the patients (87 patients with genotype 1 HCV infection and 2 patients with genotype 4 HCV infection) were treated with ledipasvir/sofosbuvir for 12 weeks, 1 treatment experienced patient with genotype 1 HCV infection and cirrhosis was treated with ledipasvir/sofosbuvir for 24 weeks, and 2 treatment experienced patients with genotype 3 HCV infection were treated with ledipasvir/sofosbuvir plus ribavirin for 24 weeks.
The median age was 9 years (range: 6 to 11); 59% of the patients were male; 79% were White, 8% were Black, and 5% were Asian; 10% were Hispanic/Latino; mean weight was 32.8 kg (range: 17.5 to 76.4 kg); 59% had baseline HCV RNA levels greater than or equal to 800,000 IU/ mL; 84% had genotype 1a HCV infection; 2 patients (1 treatment-naïve, 1 treatment-experienced) had known cirrhosis. The majority of patients (97%) had been infected through vertical transmission.
The SVR rate was 99% overall (99% [88/89], 100% [1/1], and 100% [2/2] in patients treated with ledipasvir/sofosbuvir for 12 weeks, ledipasvir/sofosbuvir for 24 weeks, and ledipasvir/sofosbuvir plus ribavirin for 24 weeks, respectively). The one treatment-naïve patient with genotype 1 HCV infection and cirrhosis who was treated with Harvoni for 12 weeks did not achieve SVR12 and relapsed.
Ledipasvir/sofosbuvir was evaluated in 34 patients aged 3 to <6 years with genotype 1 (n=33) or genotype 4 (n=1) HCV-infection. All of the patients were treatment-naïve and treated with ledipasvir/sofosbuvir for 12 weeks. The median age was 5 years (range: 3 to 5); 71% of the patients were female; 79% were White, 3% were Black, and 6% were Asian; 18% were Hispanic/Latino; mean weight was 19.2 kg (range: 10.7 to 33.6 kg); 56% had baseline HCV RNA levels greater than or equal to 800,000 IU/ mL; 82% had genotype 1a HCV infection; no patients had known cirrhosis. All patients (100%) had been infected through vertical transmission.
The SVR rate was 97% overall (97% [32/33] in patients with genotype 1 HCV infection and 100% [1/1] in patients with genotype 4 HCV infection). One patient who prematurely discontinued study treatment after five days due to abnormal taste of the medication did not achieve SVR.
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.
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.
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.
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.
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.
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.
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.
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.
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 21.
Table 21. 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 (eGFR ≥50 and <80 ml/min/1,73 m²) | Moderate RI (eGFR ≥30 and <50 ml/min/1,73 m²) | Severe RI (eGFR <30 ml/min/1,73 m²) | ESRD Requiring Dialysis | Severe RI (eGFR <30 ml/min/1,73 m²) | ESRD Requiring Dialysis | ||
| Dosed 1 hr Before Dialysis | Dosed 1 hr After Dialysis | ||||||
| Sofosbuvir | 1.6-fold ↑ | 2.1-fold ↑ | 2.7-fold ↑ | 1.3-fold ↑ | 1.6-fold ↑ | ~2-fold ↑ | 1.9-fold ↑ |
| GS-331007 | 1.6-fold ↑ | 1.9-fold ↑ | 5.5-fold ↑ | ≥10-fold ↑ | ≥20-fold ↑ | ~6-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 adult 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 studed in HCV negative adult patients with mild (eGFR ≥50 and <80 mL/min/1.73m2), moderate (eGFR ≥30 and <50 mL/min/1.73m2), severe renal impairment (eGFR <30 mL/min/1.73m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir,relative to patients with normal renal function (eGFR >80 mL/min/1.73m2). 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 adult 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 adult 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 ⅔ trials.
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative adult 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 adult 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 adult 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 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.
Ledipasvir, sofosbuvir, and GS-331007 exposures in paediatric patients aged 3 years and above were similar to those in adults from Phase ⅔ studies, following administration of ledipasvir/sofosbuvir. The 90% confidence intervals of geometric least-squares mean ratios for all PK parameters of interest were contained within the predetermined similarity bounds of less than 2-fold (50% to 200%) with the exception of ledipasvir Ctau in paediatric patients 12 years and above which was 84% higher (90%CI: 168% to 203%) and was not considered clinically relevant.
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in paediatric patients aged <3 years (see section 4.2).
No target organs of toxicity were identified in rat and dog studies with ledipasvir at AUC exposures approximately 7 times the human exposure at the recommended clinical dose.
Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.
Ledipasvir was not carcinogenic in the 26-week rasH2 transgenic mouse and the 2-year rat carcinogenicity studies at exposures up to 26-times in mice and 8-times in rats higher than human exposure.
Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were slightly reduced at maternal exposures 6-fold the exposure in humans at the recommended clinical dose. At the no observed effect level, AUC exposure to ledipasvir was approximately 7- and 3-fold, in males and females, respectively, the human exposure at the recommended clinical dose.
No teratogenic effects were observed in rat and rabbit developmental toxicity studies with ledipasvir.
In a rat pre- and postnatal study, at a maternally toxic dose, the developing rat offspring exhibited mean decreased body weight and body weight gain when exposed in utero (via maternal dosing) and during lactation (via maternal milk) at a maternal exposure 4 times the exposure in humans at the recommended clinical dose. There were no effects on survival, physical and behavioural development and reproductive performance in the offspring at maternal exposures similar to the exposure in humans at the recommended clinical dose.
When administered to lactating rats, ledipasvir was detected in plasma of suckling rats likely due to excretion of ledipasvir via milk.
Environmental risk assessment studies have shown that ledipasvir has the potential to be very persistent and very bioaccumulative (vPvB) in the environment (see section 6.6).
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity; however, exposure to the major metabolite GS-331007 at doses which cause adverse effects was 16 times (rat) and 71 times (dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic toxicity studies at exposures 5 times (rat) and 16 times (dog) higher than the clinical exposure. No liver or heart findings were observed in the 2-year carcinogenicity studies at exposures 17 times (mouse) and 9 times (rat) higher than the clinical exposure.
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to GS-331007 in these studies was up to 17 times (mouse) and 9 times (rat) higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat and rabbit development studies. No adverse effects on behaviour, reproduction or development of offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 6 times the expected clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure margins based on the major human metabolite was approximately 5 times higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of lactating rats.
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