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Approval of Sovaldi (sofosbuvir) tablets for the treatment of chronic hepatitis C

On December 6, 2013, FDA approved SOVALDI (sofosbuvir) tablets for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

Sovaldi is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon, andis the second drug approved by the FDA in the past two weeks to treat chronic HCV infection. On November 22, the FDA approved Olysio (simeprevir)..

Below is a summary of the basis of approval and highlights from the prescribing information for Sovaldi. Please refer to the full prescribing information for all the information needed to use Sovaldi safely and effectively.

INDICATIONS AND USAGE

SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

  • SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection

The following points should be considered when initiating treatment with SOVALDI:

  • Monotherapy of SOVALDI is not recommended for treatment of CHC.
  • Treatment regimen and duration are dependent on both viral genotype and patient population
  • Treatment response varies based on baseline host and viral factors

DOSAGE AND ADMINISTRATION

The recommended dose of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food
SOVALDI should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults. The recommended regimen and treatment duration for SOVALDI combination therapy is provided in Table 1.

Table 1           Recommended Regimens and Treatment Duration for SOVALDI Combination Therapy in HCV Mono-infected and HCV/HIV-1 Co-infected Patients

 

Treatment

Duration

Patients with genotype 1 or 4 CHC

 SOVALDI + peginterferon alfaa + ribavirinb

12 weeks

Patients with genotype 2 CHC

 SOVALDI + ribavirinb

12 weeks

Patients with genotype 3 CHC

 SOVALDI + ribavirinb

24 weeks

a.   See peginterferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 CHC.
b.   Dose of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dose of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤ 50 mL/min) require ribavirin dose reduction; refer to ribavirin prescribing information.

SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient.< p/>

Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
SOVALDI in combination with ribavirin is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection.

Severe Renal Impairment and End Stage Renal Disease
No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.

WARNINGS AND PRECAUTIONS

Use with Potent P-gp Inducers
Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of SOVALDI.  Rifampin and St. John’s wort should not be used with SOVALDI.

ADVERSE REACTIONS
The most common adverse events (≥ 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

DRUG INTERACTIONS
Potential for Drug Interactions
After oral administration of SOVALDI, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.

Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent 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 should not be used with SOVALDI.  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. 

7.2       Potentially Significant Drug Interactions
Drug interaction information for SOVALDI with potential concomitant drugs is summarized in Table 5. The drug interactions described are based on potential drug interactions that may occur with SOVALDI. The table is not all-inclusive.

Table 5  Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interactiona


Concomitant Drug Class: Drug Name

Effect on Concentrationb

Clinical Comment

Anticonvulsants:
carbamazepine                    phenytoin                            phenobarbital                     oxcarbazepine

↓ sofosbuvir
↓ GS-331007

Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital or oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.

Antimycobacterials:
rifabutin             rifampin                           rifapentine

↓ sofosbuvir
↓ GS-331007

Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.
SOVALDI should not be used with rifampin, a potent intestinal P-gp inducer [See Warnings and Precautions (5.2)].

Herbal Supplements:
St. John’s wort (Hypericum perforatum)

↓ sofosbuvir
↓ GS-331007

SOVALDI should not be used with St. John’s wort, a potent intestinal P-gp inducer [See Warnings and Precautions (5.2)].

HIV Protease Inhibitors:
tipranavir/ritonavir

↓ sofosbuvir
↓ GS-331007

Coadministration of SOVALDI with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI.  Coadministration is not recommended.

a.         This table is not all inclusive.
b.         ↓ = decrease.
Drugs without Clinically Significant Interactions with SOVALDI
In addition to the drugs included in Table 5, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

USE IN SPECIFIC POPULATIONS

Renal Impairment
No dose adjustment of SOVALDI 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 (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dose recommendation can be given for patients with severe renal impairment or ESRD. Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl <50 mL/min.

Hepatic Impairment
No dose adjustment of SOVALDI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of SOVALDI have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.

Patients with HCV/HIV-1 Co-infection
The safety and efficacy of SOVALDI was assessed in 223 HCV/HIV-1 co-infected subjects [See Clinical Studies (14.4)]. See Dosage and Administration (2.1) for dosing recommendations in HCV/HIV-1 co-infected patients. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials.

Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
SOVALDI was studied in HCV-infected subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of SOVALDI and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA < lower limit of quantification (LLOQ) at 12 weeks post-transplant.  HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg SOVALDI and weight-based 1000-1200 mg ribavirin daily for 24-48 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who received SOVALDI and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score ≤14. Of these 61 subjects, 41 subjects underwent liver transplantation following up to 48 weeks of treatment with SOVALDI and ribavirin; 37 had HCV RNA < LLOQ at the time of transplantation. Of the 37 subjects, the post-transplant virologic response (pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week post-transplant time point. The safety profile of SOVALDI and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials.

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-naïve 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-naïve 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-naïve 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.

14.2     Clinical Trials in Subjects with Genotype 1 or 4 CHC

Treatment-Naïve 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-naïve 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-Naïve 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-naïve 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

Peg-IFN alfa + RBV 24 weeks

 

N=256a

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

Placebo 12 weeks

 

N=207

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

Genotype 3

 

N=109

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              

SOVALDI + RBV
 16 weeks          

 

N= 103a

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

SOVALDI + RBV                              16 weeks

SOVALDI + RBV                              12 weeks

SOVALDI + RBV                             16 weeks

 

N=39

N=35

N=64

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-Naïve and Previously Treated Adults ─ VALENCE (Study 133)

The VALENCE trial evaluated sofosbuvir in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naïve 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

Genotype 3 SOVALDI + RBV 24 weeks

 

N=73

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-naïve

3% (1/32)

5% (5/105)

Treatment-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. 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

Genotype 3    SOVALDI + RBV         24 weeks

 

N=73

N=250

Treatment-naïve

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-naïve or experienced, whereas genotype 1 subjects were all treatment-naïve. 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

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-naïve; 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.

The complete label will be posted at Drug@FDA.

FDA Press Release

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration