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Sovaldi

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Sovaldi

CLINICAL PHARMACOLOGY

Mechanism Of Action

Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus [See Microbiology].

Pharmacodynamics

Effect On Electrocardiogram

The effect of sofosbuvir 400 and 1200 mg on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, SOVALDI does not prolong QTc to any clinically relevant extent.

Pharmacokinetics

Absorption

The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5-2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or without pegylated interferon), geometric mean steady state sofosbuvir (N=838) and GS- 331007 (N=1695) AUC0-24 were 828 ng•hr/mL and 6790 ng•hr/mL, respectively. Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0-24 was 39% higher and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg.

Effect Of Food

Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0-inf. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, SOVALDI can be administered without regard to food.

Distribution

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.

Metabolism

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) 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.

After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and > 90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.

Elimination

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, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.

Specific Populations

Race

Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.

Gender

No clinically relevant pharmacokinetic differences have been observed between men and women for sofosbuvir and GS-331007.

Pediatric Patients

The pharmacokinetics of sofosbuvir in pediatric patients have not been established [See Use in Specific Populations].

Geriatric Patients

Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007 [See Use In Specific Populations].

Patients with Renal Impairment

The pharmacokinetics of sofosbuvir were studied in HCV negative subjects 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 subjects with end stage renal disease (ESRD) requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR > 80 mL/min/1.73m²), the sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment or ESRD. No dose recommendation can be given for patients with severe renal impairment or ESRD [See DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Patients with Hepatic Impairment

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of SOVALDI is recommended for patients with mild, moderate and severe hepatic impairment [See Use in Specific Populations].

Assessment of Drug Interactions

The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 6. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 7 [See DRUG INTERACTIONS].

Table 6 : Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Druga

Co-administered Drug Dose of Coadministered Drug
(mg)
Sofosbuvir Dose
(mg)
N Mean Ratio (90% CI) of Sofosbuvir and GS-331007 PK With/Without Coadministered Drug
No Effect=1.00
  Cmax AUC Cmin
Cyclosporine 600 single dose 400 single dose 19 sofosbuvir 2.54
(1.87, 3.45)
4.53
(3.26, 6.30)
NA
GS-331007 0.60
(0.53, 0.69)
1.04
(0.90, 1.20)
NA
Darunavir
(boosted with ritonavir)
800/100 once daily 400 single dose 18 sofosbuvir 1.45
(1.10, 1.92)
1.34
(1.12, 1.59)
NA
GS-331007 0.97
(0.90, 1.05)
1.24
(1.18, 1.30)
NA
Efavirenzc 600 once daily 400 single dose 16 sofosbuvir 0.81
(0.60, 1.10)
0.94
(0.76, 1.16)
NA
Emtricitabinec 200 once daily GS-331007 0.77
(0.70, 0.84)
0.84
(0.76, 0.92)
NA
Tenofovir disoproxil fumaratec 300 once daily
Methadone 30 to 130 once daily 400 once daily 14 sofosbuvir 0.95b
(0.68, 1.33)
1.30b
(1.00, 1.69)
NA
GS-331007 0.73b
(0.65, 0.83)
1.04b
(0.89, 1.22)
NA
Rilpivirine 25 once daily 400 single dose 17 sofosbuvir 1.21
(0.90, 1.62)
1.09
(0.94, 1.27)
NA
GS-331007 1.06
(0.99, 1.14)
1.01
(0.97, 1.04)
NA
Tacrolimus 5 single dose 400 single dose 16 sofosbuvir 0.97
(0.65, 1.43)
1.13
(0.81, 1.57)
NA
GS-331007 0.97
(0.83, 1.14)
1
(0.87, 1.13)
NA
NA = not available/not applicable
a All interaction studies conducted in healthy volunteers
b Comparison based on historic control
c Administered as ATRIPLA

No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with raltegravir.

Table 7 : Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvira

Coadministered Drug Dose of Coadministered Drug
(mg)
Sofosbuvir Dose
(mg)
N Mean Ratio (90% CI) of Coadministered drug PK With/Without Coadministered Drug
No Effect=1.00
Cmax AUC Cmin
Tenofovir disoproxil fumarateb 300 once daily 400 single dose 16 1.25
(1.08, 1.45)
0.98
(0.91, 1.05)
0.99
(0.91, 1.07)
Raltegravir 400 once daily 400 single dose 19 0.57
(0.44, 0.75)
0.73
(0.59, 0.91)
0.95
(0.81, 1.12)
Tacrolimus 5 single dose 400 single dose 16 0.73
(0.59, 0.90)
1.09
(0.84, 1.40)
NA
NA = not available/not applicable
a All interaction studies conducted in healthy volunteers
b Administered as ATRIPLA

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone or rilpivirine.

Microbiology

Mechanism Of Action

Sofosbuvir is an 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 analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 μM. GS-461203 is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral Activity

In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 μM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 μM for genotype 1a (range 0.029-0.128 μM; N=67), 0.102 μM for genotype 1b (range 0.045-0.170 μM; N=29), 0.029 μM for genotype 2 (range 0.014-0.081 μM; N=15) and 0.081 μM for genotype 3a (range 0.024-0.181 μM; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 μM, respectively. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance

In Cell Culture

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. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types.

In Clinical Trials

In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials, 224 subjects had post-baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%).

Treatment-emergent substitutions L159F (n= 6) and V321A (n= 5) were detected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977-0523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cut off of 1%.

In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and relapse post-transplant in multiple subjects infected with GT1b HCV. In addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a subject infected with GT1a HCV with a partial treatment response.

The clinical significance of these substitutions is not known.

Cross Resistance

HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin-associated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir was active against HCV replicons with NS3/4A protease inhibitor, NS5B non-nucleoside inhibitor and NS5A inhibitor resistant variants.

Animal Toxicology And/Or Pharmacology

Heart degeneration and inflammation were observed in rats following GS-9851 (a stereoisomeric mixture containing approximately 50% sofosbuvir) doses of 2000 mg/kg/day for up to 5 days. At this dose, AUC exposure to the predominant metabolite GS-331007 is approximately 29-fold higher than human exposure at the recommended clinical dose. No heart degeneration or inflammation was observed in rats following sofosbuvir doses of up to 500 mg/kg/day for 6 months at a GS-331007 AUC exposure approximately 9-fold higher than human exposure at the recommended clinical dose. In dogs and mice, heart degeneration and inflammation were not observed following sofosbuvir doses of up to 500 and 1000 mg/kg/day for 9 and 3 months, respectively, the highest doses tested. At these doses, GS-331007 AUC exposures are approximately 27- and 41-fold higher, respectively, than human exposure at the recommended clinical dose.

Clinical Studies

Description Of Clinical Trials

The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of 1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C (CHC) and one Phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 CHC. Among the five trials in HCV mono-infected subjects, one was conducted in treatment-na´ve subjects with genotype 1, 4, 5 or 6 CHC in combination with peginterferon alfa 2a and ribavirin and the other four were conducted in subjects with genotype 2 or 3 CHC in combination with ribavirin, including one in treatment-na´ve subjects, one in interferon intolerant, ineligible or unwilling subjects, one in subjects previously treated with an interferon-based regimen, and one in all subjects irrespective of prior treatment history or ability to take interferon. The trial in HCV/HIV-1 co-infected subjects was conducted in combination with ribavirin in treatment-na´ve subjects with genotype 1 CHC and all subjects with genotype 2 or 3 CHC irrespective of prior treatment history or ability to take interferon. Subjects in these trials had compensated liver disease including cirrhosis. SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dose was weight-based at 1000-1200 mg daily administered in two divided doses when used in combination with SOVALDI, and the peginterferon alfa 2a dose, where applicable, was 180 micrograms per week. Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials 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 per mL. Sustained virologic response (SVR) was the primary endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment.

Clinical Trials In Subjects With Genotype 1 Or 4 CHC

Treatment-Na´ve Adults - NEUTRINO (Study 110)

NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with SOVALDI in combination with peginterferon alfa 2a and ribavirin in treatment-na´ve subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical control.

Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m² (range: 18 to 56 kg/m²); 78% had baseline HCV RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9% had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 8 presents the response rates for the treatment group of SOVALDI + peginterferon alfa + ribavirin.

Table 8 : Response Rates in Study NEUTRINO

  SOVALDI + Peg-IFN alfa + RBV 12 weeks
N=327a
Overall SVR 90% (295/327)
  Genotype 1b 89% (261/292)
     Genotype 1a 92% (206/225)
     Genotype 1b 82% (54/66)
  Genotype 4 96% (27/28)
Outcome for subjects without SVR
  On-treatment virologic failure 0/327
  Relapsec 9% (28/326)
  Otherd 1% (4/327)
a Including seven subjects with genotype 5 or 6 infection.
b One subject had genotype 1a/1b mixed infection.
c The denominator for relapse is the number of subjects with HCV RNA < LLOQ at their last on-treatment assessment.
d Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

Response rates for selected subgroups are presented in Table 9.

Table 9 : SVR Rates for Selected Subgroups in NEUTRINO

  SOVALDI + Peg-IFN alfa + RBV 12 weeks
Cirrhosis
  No 92% (252/273)
  Yes 80% (43/54)
Race
  Black 87% (47/54)
  Non-black 91% (248/273)
Multiple Baseline Factors
  Genotype 1, Metavir F3/F4 fibrosis, IL28B non-C/C, HCV RNA > 800,000 IU/mL 71% (37/52)

SVR rates were 98% (93/95) in subjects with baseline IL28B C/C allele and 87% (202/232) in subjects with baseline IL28B non-C/C alleles.

It is estimated that the response rate in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed response rate in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 9). The SVR rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA > 800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52).

Clinical Trials In Subjects With Genotype 2 Or 3 CHC

Treatment-Na´ve Adults - FISSION (Study 1231)

FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of treatment with SOVALDI and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-na´ve subjects with genotype 2 and 3 HCV. The ribavirin doses used in the SOVALDI + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1000-1200 mg per day and 800 mg per day regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA level ( < 6 log10IU/mL vs. ≥ 6 log10IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio.

Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28 kg/m² (range: 17 to 52 kg/m²); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3. Table 10 presents the response rates for the treatment groups of SOVALDI + ribavirin and peginterferon alfa + ribavirin.

Table 10 : Response Rates in Study FISSION

  SOVALDI + RBV 12 weeks
N=256a
Peg-IFN alfa + RBV 24 weeks
N=243a
Overall SVR 67% (171/256) 67% (162/243)
  Treatment differenceb 0.3% (95% CI: -7.5% to 8.0%)
  Genotype 2 95% (69/73) 78% (52/67)
  Genotype 3 56% (102/183) 63% (110/176)
Outcome for subjects without SVR
  On-treatment virologic failure < 1% (1/256) 7% (18/243)
  Relapsec 30% (76/252) 21% (46/217)
    Genotype 2 5% (4/73) 15% (9/62)
    Genotype 3 40% (72/179) 24% (37/155)
  Otherd 3% (8/256) 7% (17/243)
a Including three subjects with recombinant genotype 2/1 HCV infection.
b Adjusted for pre-specified stratification factors.
c. The denominator for relapse is the number of subjects with HCV RNA < LLOQ at their last on-treatment assessment.
d Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

Response rates for subjects with cirrhosis at baseline are presented in Table 11 by genotype.

Table 11 : SVR Rates by Cirrhosis and Genotype in Study FISSION

  Genotype 2 Genotype 3
SOVALDI + RBV 12 weeks Peg-IFN alfa + RBV 24 weeks SOVALDI + RBV 12 weeks Peg-IFN alfa + RBV 24 weeks
N=73 N=67 N=183 N=176
Cirrhosis
  No 97% (59/61) 81% (44/54) 61% (89/145) 71% (99/139)
  Yes 83% (10/12) 62% (8/13) 34% (13/38) 30% (11/37)

Interferon Intolerant, Ineligible Or Unwilling Adults - POSITRON (Study 107)

POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks of treatment with SOVALDI and ribavirin (N=207) compared to placebo (N=71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and stratified by cirrhosis (presence vs. absence).

Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the subjects were male; 91% were White, 5% were Black; 11% were Hispanic or Latino; mean body mass index was 28 kg/m² (range: 18 to 53 kg/m²); 70% had baseline HCV RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype 3. The proportions of subjects who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment (81%). Table 12 presents the response rates for the treatment groups of SOVALDI + ribavirin and placebo.

Table 12 : Response Rates in Study POSITRON

  SOVALDI + RBV 12 weeks
N=207
Placebo 12 weeks
N=71
Overall SVR 78% (161/207) 0/71
  Genotype 2 93% (101/109) 0/34
  Genotype 3 61% (60/98) 0/37
Outcome for subjects without SVR
  On-treatment virologic failure 0/207 97% (69/71)
  Relapsea 20% (42/205) 0/0
    Genotype 2 5% (5/107) 0/0
    Genotype 3 38% (37/98) 0/0
  Otherb 2% (4/207) 3% (2/71)
a The denominator for relapse is the number of subjects with HCV RNA < LLOQ at their last on-treatment assessment.
b Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

Table 13 presents the subgroup analysis by genotype for cirrhosis and interferon classification.

Table 13 :SVR Rates for Selected Subgroups by Genotype in POSITRON

  SOVALDI + RBV 12 weeks
Genotype 2
N=109
Genotype 3
N=98
Cirrhosis
No 92% (85/92) 68% (57/84)
Yes 94% (16/17) 21% (3/14)
Interferon Classification
Ineligible 88% (36/41) 70% (33/47)
Intolerant 100% (9/9) 50% (4/8)
Unwilling 95% (56/59) 53% (23/43)

Previously Treated Adults - FUSION (Study 108)

FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of treatment with SOVALDI and ribavirin in subjects who did not achieve SVR with prior interferon-based treatment (relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence) and HCV genotype (2 vs. 3).

Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the subjects were male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 29 kg/m² (range: 19 to 44 kg/m²); 73% had baseline HCV RNA levels greater than 6log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 14 presents the response rates for the treatment groups of SOVALDI + ribavirin for 12 weeks and 16 weeks.

Table 14 : Response Rates in Study FUSION

  SOVALDI + RBV 12 weeks
N= 103a
SOVALDI + RBV 16 weeks
N=98a
Overall SVR 50% (51/103) 71% (70/98)
  Genotype 2 82% (32/39) 89% (31/35)
  Genotype 3 30% (19/64) 62% (39/63)
Outcome for subjects without SVR
On-treatment virologic failure 0/103 0/98
  Relapseb 48% (49/103) 29% (28/98)
    Genotype 2 18% (7/39) 11% (4/35)
    Genotype 3 66% (42/64) 38% (24/63)
  Otherc 3% (3/103) 0/98
a Including six subjects with recombinant genotype 2/1 HCV infection.
b The denominator for relapse is the number of subjects with HCV RNA < LLOQ at their last on-treatment assessment.
c Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

Table 15 presents the subgroup analysis by genotype for cirrhosis and response to prior HCV treatment.

Table 15 : SVR Rates for Selected Subgroups by Genotype in Study FUSION

  Genotype 2 Genotype 3
SOVALDI + RBV 12 weeks
N=39
SOVALDI + RBV 16 weeks
N=35
SOVALDI + RBV 12 weeks
N=64
SOVALDI + RBV 16 weeks
N=63
Cirrhosis
  No 90% (26/29) 92% (24/26) 37% (14/38) 63% (25/40)
  Yes 60% (6/10) 78% (7/9) 19% (5/26) 61% (14/23)
Response to prior HCV treatment
  Relapser/ breakthrough 86% (25/29) 89% (24/27) 31% (15/49) 65% (30/46)
  Nonresponder 70% (7/10) 88% (7/8) 27% (4/15) 53% (9/17)

Treatment-Na´ve And Previously Treated Adults - VALENCE (Study 133)

The VALENCE trial evaluated SOVALDI in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-na´ve subjects or subjects who did not achieve SVR with prior interferon-based treatment, including subjects with compensated cirrhosis. The original trial design was a 4 to 1 randomization to SOVALDI + ribavirin for 12 weeks or placebo. Based on emerging data, this trial was unblinded and all genotype 2 HCV-infected subjects continued the original planned treatment and received SOVALDI + ribavirin for 12 weeks, and duration of treatment with SOVALDI + ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven genotype 3 subjects had already completed SOVALDI + ribavirin for 12 weeks at the time of the amendment.

Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the subjects were male; mean body mass index was 26 kg/m² (range: 17 to 44 kg/m²); the mean baseline HCV RNA level was 6.4 log10 IU per mL; 78% had HCV genotype 3; 58% of the subjects were treatment-experienced and 65% of those subjects experienced relapse/breakthrough to prior HCV treatment.

Table 16 presents the response rates for the treatment groups of SOVALDI + ribavirin for 12 weeks and 24 weeks.

Table 16 : Response Rates in Study VALENCEa

  Genotype 2 SOVALDI + RBV 12 weeks
N=73
Genotype 3 SOVALDI + RBV 24 weeks
N=250
Overall SVR 93% (68/73) 84% (210/250)
Outcome for subjects without SVR
  On-treatment virologic failure 0% (0/73) < 1% (1/250)
  Relapseb 7% (5/73) 14% (34/249)
     Treatment-na´ve 3% (1/32) 5% (5/105)
     Treatment-experienced 10% (4/41) 20% (29/144)
  Otherc 0% (0/73) 2% (5/250)
aPlacebo subjects (N=85) were not included as none achieved SVR12. Eleven genotype 3 subjects who received SOVALDI + ribavirin for 12 weeks were not included.
b The denominator for relapse is the number of subjects with HCV RNA < LLOQ at their last on treatment assessment.
c Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow up).

Table 17 presents the subgroup analysis by genotype for cirrhosis and prior HCV treatment experience.

Table 17 : SVR Rates for Selected Subgroup by Genotype in Study VALENCE

  Genotype 2 SOVALDI + RBV 12 weeks
N=73
Genotype 3 SOVALDI + RBV 24 weeks
N=250
Treatment-na´ve 97% (31/32) 93% (98/105)
  Non-cirrhotic 97% (29/30) 93% (86/92)
  Cirrhotic 100% (2/2) 92% (12/13)
Treatment-experienced 90% (37/41) 77% (112/145)
  Non-cirrhotic 91% (30/33) 85% (85/100)
  Cirrhotic 88% (7/8) 60% (27/45)

Clinical Trials in Subjects Co-infected With HCV And HIV-1

SOVALDI was studied in an open-label clinical trial (Study PHOTON-1) evaluating the safety and efficacy of 12 or 24 weeks of treatment with SOVALDI and ribavirin in subjects with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 subjects were either HCV treatment-na´ve or experienced, whereas genotype 1 subjects were all treatment-na´ve. Subjects received 400 mg SOVALDI and weight-based ribavirin (1000 mg for subjects weighing < 75 kg or 1200 mg for subjects weighing ≥ 75kg) daily for 12 or 24 weeks based on genotype and prior treatment history. Subjects were either not on antiretroviral therapy with a CD4+ cell count > 500 cells/mm³ or had virologically suppressed HIV-1 with a CD4+ cell count > 200 cells/mm³. Efficacy data 12 weeks post treatment are available for 210 subjects (see Table 18).

Table 18 : Response Rates in Study PHOTON-1a

  HCV genotype 1 SOVALDI + RBV 24 weeks TN
(N=114)
HCV genotype 2 SOVALDI + RBV 12 weeks TN
(N=26)
HCV genotype 3 SOVALDI + RBV 24 weeks TE
(N=13)
Overall 76% (87/114) 88% (23/26) 92% (12/13)
Outcome for subjects without SVR12
  On-treatment virologic failure 1% (1/114) 4% (1/26) 0/13
  Relapseb 22% (25/113) 0/25 8% (1/13)
  Otherc 1% (1/114) 8% (2/26) 0/13
TN = Treatment-na´ve; TE = Treatment-experienced
a Subjects with genotype 2 CHC treated with SOVALDI + RBV for 24 weeks (N=15) and subjects with genotype 3 CHC treated with SOVALDI + RBV for 12 weeks (N=42) are not included in the table.
b The denominator for relapse is the number of subjects with HCV RNA < LLOQ at their last on treatment assessment.
c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow up).

In subjects with HCV genotype 1 infection, the SVR rate was 82% (74/90) in subjects with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with relapse accounting for the majority of treatment failures. SVR rates in subjects with HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele and 75% (62/83) in subjects with baseline IL28B non-C/C alleles.

In the 223 CHC subjects with HIV-1 co-infection, the percentage of CD4+ cells did not change during treatment. Median CD4+ cell count decreases of 85 cells/mm³ and 84 cells/mm³ were observed at the end of treatment with SOVALDI + ribavirin for 12 or 24 weeks, respectively. HIV-1 rebound during SOVALDI + ribavirin treatment occurred in 2 subjects (0.9%) on antiretroviral therapy.

Last reviewed on RxList: 12/18/2013
This monograph has been modified to include the generic and brand name in many instances.

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