July 30, 2016
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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

Cardiac Electrophysiology

The effect of sofosbuvir 400 and 1200 mg (three times the recommended dosage) 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 dosage three times the maximum recommended dosage, 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 AUC0-24 was 969 ng•hr/mL for sofosbuvir (N=838), and 6790 ng•hr/mL for GS-331007 (N=1695). Relative to healthy subjects administered sofosbuvir alone (N=272), the sofosbuvir AUC0-24 was 60% 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 microgram/mL to 20 microgram/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 greater than 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 between 50 to less than 80 mL/min/1.73m²), moderate (eGFR between 30 to less than 50 mL/min/1.73m²), severe renal impairment (eGFR less than 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 greater than 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 AUC0inf 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 dosage 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 dosage 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 dosage adjustment of SOVALDI is recommended for patients with mild, moderate or severe hepatic impairment [see Use in Specific Populations].

Assessment of Drug Interactions

Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not recommended [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters.

The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs.

The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 5. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 6 [see DRUG INTERACTIONS].

Table 5 : 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
Tenofovir disoproxil fumaratec 300 once daily GS-331007 0.77
(0.70, 0.84)
0.84
(0.76, 0.92)
NA
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)
1.00
(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 efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet

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

Table 6 : 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 Sofosbuvir No Effect=1.00
Cmax AUC Cmin
Norelgestromin norgestimate 0.18/0.215/0.25/ ethinyl estradiol 0.025 once daily 400 once daily 15 1.07
(0.94, 1.22)
1.06
(0.92, 1.21)
1.07
(0.89, 1.28)
Norgestrel 1.18
(0.99, 1.41)
1.19
(0.98, 1.45)
1.23
(1.00, 1.51)
Ethinyl estradiol 1.15
(0.97, 1.36)
1.09
(0.94, 1.26)
0.99
(0.80, 1.23)
Raltegravir 400 twice 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
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)
NA = not available/not applicable
a All interaction studies conducted in healthy volunteers
b Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet

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 micromolar. GS-461203 is neither 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 micromolar. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 micromolar for genotype 1a (range 0.029–0.128 micromolar; N=67), 0.102 micromolar for genotype 1b (range 0.045–0.170 micromolar; N=29), 0.029 micromolar for genotype 2 (range 0.014–0.081 micromolar; N=15) and 0.081 micromolar for genotype 3a (range 0.024–0.181 micromolar; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 micromolar, 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 P79770523 [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 cutoff 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 ribavirinassociated 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.

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 virus and one Phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 HCV, as summarized in Table 7.

Table 7 : Trials Conducted with SOVALDI with Peginterferon Alfa and/or Ribavirin in Subjects with Chronic HCV Genotype 1, 2, 3, or 4 Infection

Trial Population Study Arms (Number of Subjects Treated)
NEUTRINO Treatment naive (TN) (GT1, 4, 5 or 6) SOVALDI+Peg-IFN alfa+RBV 12 weeks (327)
FISSION TN (GT2 or 3) SOVALDI+RBV 12 Weeks (256) Peg-IFN alfa+RBV 24 weeks (243)
POSITRON Interferon intolerant, ineligible or unwilling subjects (GT2 or 3) SOVALDI+RBV 12 Weeks (207) Placebo 12 weeks (71)
FUSION Previous interferon relapsers or nonresponders (GT2 or 3) SOVALDI+RBV 12 Weeks (103) SOVALDI+RBV 16 Weeks (98)
VALENCE TN or previous interferon relapsers or nonresponders (GT2 or 3) SOVALDI+RBV 12 Weeks for GT2 (73) SOVALDI+RBV 12 Weeks for GT3 (11) SOVALDI+RBV 24 Weeks for GT3 (250) Placebo for 12 weeks (85)
PHOTON-1
  • HCV/HIV-1 co-infected TN (GT1)
  • HCV/HIV-1 co-infected TN or previous interferon relapsers or nonresponders (GT2 or 3)
SOVALDI+RBV 24 Weeks for GT1 (114) SOVALDI+RBV 12 Weeks for GT2 or 3 TN (68) SOVALDI+RBV 24 Weeks for GT2 or 3 previous interferon relapsers or nonresponders (41)

Subjects in these trials had compensated liver disease including cirrhosis. SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dosage was weight-based at 1000-1200 mg daily administered in two divided doses when used in combination with SOVALDI, and the peginterferon alfa 2a dosage, 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 (SVR12) 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 HCV

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 SVR12 for the treatment group of SOVALDI + peginterferon alfa + ribavirin in subjects with genotype 1 or 4 HCV. Available data on subjects with genotype 5 or 6 HCV treated with SOVALDI + peginterferon alfa + ribavirin for 12 weeks were insufficient for dosing recommendations; therefore these results are not presented in Table 8 [see Use in Specific Populations].

Table 8 : Study NEUTRINO: SVR12 for Treatment-Na´ve Subjects with Genotype 1 or 4 HCV

  SOVALDI + Peg-IFN alfa + RBV 12 weeks
  N=320
Overall SVR 90% (289/320)
  Genotype 1a 90% (262/292)
     Genotype 1a 92% (206/225)
     Genotype 1b 83% (55/66)
  Genotype 4 96% (27/28)
Outcome for subjects without SVR
  On-treatment virologic failure 0/320
  Relapseb 9% (28/319)
  Otherc 1% (3/320)
a One subject had genotype 1a/1b mixed 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).

SVR12 for selected subgroups are presented in Table 9.

Table 9 : SVR12 Rates for Selected Subgroups in NEUTRINO in Subjects with Genotype 1 or 4 HCV

  SOVALDI + Peg-IFN alfa + RBV 12 weeks
Cirrhosis
  No 93% (247/267)
  Yes 79% (42/53)
Race
  Black 87% (47/54)
  Non-black 91% (242/266)
Multiple Baseline Factors
  Genotype 1, Metavir F3/F4 fibrosis, IL28B non-C/C, HCV RNA > 800,000 IU/mL 71% (37/52)

SVR12 rates were 99% (89/90) in subjects with genotype 1 or 4 HCV and baseline IL28B C/C allele and 87% (200/230) in subjects with genotype 1 or 4 HCV and baseline IL28B non-C/C alleles.

It is estimated that the SVR12 in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed SVR12 in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 9). The SVR12 rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA greater than 800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52).

Clinical Trials In Subjects With Genotype 2 Or 3 HCV

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 dosage 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 (less than 6 log10 IU/mL vs. at least 6 log10 IU/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 11 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and peginterferon alfa + ribavirin in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these results are not presented in Table 10.

Table 10 : Study FISSION: SVR12 in Treatment-Na´ve Subjects with Genotype 2 HCV

  SOVALDI + RBV 12 weeks
N=73a
Peg-IFN alfa + RBV 24 weeks
N=67a
SVR12 95% (69/73) 78% (52/67)
Outcome for subjects without SVR12
  On-treatment virologic failure 0/73 4% (3/67)
  Relapseb 5% (4/73) 15% (9/62)
  Otherc 0/73 4% (3/67)
a Including three 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).

SVR12 for genotype 2 HCV infected subjects with cirrhosis at baseline are presented in Table 11.

Table 11 : SVR12 Rates by Cirrhosis in Study FISSION in Subjects with Genotype 2 HCV

  SOVALDI + RBV 12 weeks
N=73
Peg-IFN alfa + RBV 24 weeks
N=67
Cirrhosis
  No 97% (59/61) 81% (44/54)
  Yes 83% (10/12) 62% (8/13)

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 13 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and placebo in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these results are not presented in Table 12.

Table 12 : Study POSITRON: SVR12 in Interferon Intolerant, Ineligible or Unwilling Subjects with Genotype 2 HCV

  SOVALDI + RBV 12 weeks
N=109
Placebo 12 weeks
N= 34
SVR12 93% (101/109) 0/34
Outcome for subjects without SVR12
On-treatment virologic failure 0/109 97% (33/34)
Relapsea 5% (5/107) 0/0
Otherb 3% (3/109) 3% (1/34)
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 for cirrhosis and interferon classification in subjects with genotype 2 HCV.

Table 13 : SVR12 Rates for Selected Subgroups in POSITRON in Subjects with Genotype 2 HCV

  SOVALDI + RBV 12 weeks
N=109
Cirrhosis
  No 92% (85/92)
  Yes 94% (16/17)
Interferon Classification
  Ineligible 88% (36/41)
  Intolerant 100% (9/9)
  Unwilling 95% (56/59)

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 6 log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 15 presents the SVR12 for the treatment groups of SOVALDI + ribavirin for 12 weeks in subjects with genotype 2 HCV. Treatment of 16 weeks in subjects with genotype 2 HCV was not shown to increase the SVR12 observed with 12 weeks of treatment. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 or 16 weeks was suboptimal; therefore these results are not presented in Table 14.

Table 14 : Study FUSION: SVR12 in Previous Interferon Relapsers and Nonresponders with Genotype 2 HCV

  SOVALDI + RBV 12 weeks
N=39a
SVR12 82% (32/39)
Outcome for subjects without SVR12
  On-treatment virologic failure 0/39
  Relapseb 18% (7/39)
  Otherc 0/39
a Including three 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 for cirrhosis and response to prior HCV treatment in subjects with genotype 2 HCV.

Table 15 : SVR12 Rates for Selected Subgroups in Study FUSION in Subjects with Genotype 2 HCV

  SOVALDI + RBV 12 weeks
N=39
Cirrhosis
  No 90% (26/29)
  Yes 60% (6/10)
Response to prior HCV treatment
  Relapser/ breakthrough 86% (25/29)
  Nonresponder 70% (7/10)

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 SVR12 for the treatment groups of SOVALDI + ribavirin for 12 weeks and 24 weeks.

Table 16 : Study VALENCEa: SVR12 in Subjects with Genotype 2 or 3 HCV Who were Treatment-Na´ve or Who Did Not Achieve SVR12 with Prior Interferon-Based Treatment

  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-naive 3% (1/32) 5% (5/105)
     T reatment-experienced 10% (4/41) 20% (29/144)
  Otherc 0% (0/73) 2% (5/250)
a Placebo subjects (N=85) were not included as none achieved SVR12.
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 SVR12 Rates for Selected Subgroups by Genotype in Study VALENCE in Subjects with Genotype 2 or 3 HCV

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

  Genotype 2 SOVALDI + RBV 12 weeks
N=73
Genotype 3 SOVALDI + RBV 24 weeks
N=250
Treatment-naive 97% (31/32) 93% (98/105)
  Non-cirrhotic 97% (29/30) 93% (86/92)
  Cirrhotic 100% (2/2) 92% (12/13)
T reatment-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 less than 75 kg or 1200 mg for subjects weighing at least 75 kg) 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 greater than 500 cells/mm³ or had virologically suppressed HIV-1 with a CD4+ cell count greater than 200 cells/mm³. Efficacy data 12 weeks post treatment are available for 210 subjects (see Table 18).

Table 18 : Study PHOTON-1a: SVR12 in Treatment-Na´ve or Treatment-Experienced Subjects with Genotype 1, 2, or 3 HCV

  HCV genotype 1 HCV genotype 2 HCV genotype 3
SOVALDI + RBV 24 weeks TN
(N=114)
SOVALDI + RBV 12 weeks TN
(N=26)
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 HCV treated with SOVALDI + RBV for 24 weeks (N=15) and subjects with genotype 3 HCV 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 SVR12 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. SVR12 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 HCV 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: 3/31/2016
This monograph has been modified to include the generic and brand name in many instances.

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