Sovaldi (sofosbuvir) - Summary of the basis of approval and highlights from prescribing information

Sovaldi  (sofosbuvir) - Summary of the basis of approval and highlights from prescribing  information

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, and is 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

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 Interaction^a

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 VALENCE^a

	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-1^a

	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

Hepatitis C- Gilead's Sovaldi (Sofosbuvir) Is Now FDA Approved

 Related:
Gilead said Friday it would price the drug at $84,000 for one 12-week supply. Patients with a less common subtype of the disease may need to take the drug for 24 weeks, raising the cost to $168,000 for one course of treatment. Drugs already on the market run between $25,000 and $50,000 for a course of treatment. 

Food and Drug Administration Approves Gilead’s Sovaldi™ (Sofosbuvir) for the Treatment of Chronic Hepatitis C

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– Sovaldi Approved for Use in Genotypes 1, 2, 3 or 4 –

– High Cure Rates (SVR12) and Shortened, 12-Week Course of Therapy for Many Patients –

– First Ever Oral Treatment Regimen for Genotypes 2 or 3 –

– First Regimen for Patients Awaiting Liver Transplantation to Prevent HCV Recurrence –

FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 6, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Sovaldi™ (sofosbuvir) 400 mg tablets, a once-daily oral nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

Sovaldi’s efficacy has been established in subjects with hepatitis C virus (HCV) genotypes 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. Recommended regimens and treatment duration for Sovaldi combination therapy in HCV mono-infected or HCV/HIV-1 co-infected patients follows:

Sovaldi Product Photo

					Treatment					Duration
Genotype 1 or 4					Sovaldi + peg-interferon alfa + ribavirin					12 weeks
Genotype 2					Sovaldi + ribavirin					12 weeks
Genotype 3					Sovaldi + ribavirin					24 weeks

Sovaldi in combination with ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who are interferon ineligible. Additionally, Sovaldi should be used in combination with ribavirin for treatment of CHC patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation to prevent post-transplant HCV infection. Treatment regimen, duration and response to Sovaldi are dependent on viral genotype and patient population, and associated baseline factors. Monotherapy is not recommended. Full Prescribing Information will be available on www.Gilead.com.

The FDA granted Sovaldi Priority Review and Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options.
“I believe that Sovaldi will have a major impact on public health by significantly increasing the number of Americans who are cured of hepatitis C,” said Ira Jacobson, MD, Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York City and a principal investigator in the Sovaldi clinical trials. “In clinical studies, Sovaldi in combination with other agents achieved very high cure rates while shortening the duration of treatment to as little as 12 weeks and reducing or completely eliminating the need for interferon injections, depending on the viral genotype.”

Chronic hepatitis C affects an estimated 4 million people in the United States, the majority of whom are “baby boomers” – individuals born between 1945 and 1965. The disease is the nation’s leading cause of liver cancer and liver transplantation, and in recent years has surpassed HIV/AIDS as a cause of death. The current standard of care for HCV involves up to 48 weeks of therapy with a pegylated interferon (peg-IFN)/ribavirin (RBV)-containing regimen, which may not suitable for certain types of patients.

“It is our hope that Sovaldi will mark the beginning of a new era in hepatitis C treatment. Gilead is proud to have played a role in bringing about this important therapeutic advance and we would like to extend our thanks to the many patients and physicians who partnered with us on Sovaldi’s clinical studies,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences.

Sovaldi’s approval is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, which evaluated 12 or 16 weeks of treatment with Sovaldi combined with either RBV or RBV plus peg-IFN. Three of these studies evaluated Sovaldi plus RBV in genotype 2 or 3 patients who were either treatment-naïve (FISSION), treatment-experienced (FUSION) or peg-IFN intolerant, ineligible or unwilling (POSITRON). NEUTRINO evaluated Sovaldi in combination with Peg-IFN/RBV in treatment naïve patients with genotypes 1, 4, 5 or 6. In these studies, Sovaldi-based therapy was found to be superior to historical controls (NEUTRINO and FUSION) or to placebo (POSITRON), or non-inferior to currently available treatment options (FISSION) based on the proportion of patients who had a sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV. Trial participants taking Sovaldi-based therapy achieved SVR12 rates of 50-90 percent. For full study details, see the Clinical Studies section of the full Prescribing Information.

During the FDA’s review, data from two additional Phase 3 studies, VALENCE and PHOTON-1, were added to the NDA as a result of the Breakthrough Designation status. In the VALENCE study, patients with genotype 3 HCV infection were treated with Sovaldi and RBV for 24 weeks. Eighty-four percent of patients in this trial achieved SVR12. The PHOTON-1 study evaluated Sovaldi and RBV for 12 weeks in patients with genotype 2 HCV infection co-infected with HIV-1 and for 24 weeks in patients with genotypes 1 or 3 HCV co-infected with HIV-1. Trial participants achieved SVR12 rates of 76-92 percent. In all Phase 3 studies of Sovaldi, no viral resistance to the drug was detected among patients who relapsed following completion of therapy.

To date, nearly 3,000 patients have received at least one dose of Sovaldi in Phase 2 or 3 studies. Sovaldi combination therapy was well tolerated in clinical studies. Adverse events were generally mild and there were few treatment discontinuations due to adverse events. The most common adverse events occurring in at least 20 percent of patients receiving Sovaldi in combination with Peg-IFN/RBV were fatigue, headache, nausea, insomnia and anemia; see below for Important Safety Information regarding contraindications, warnings and precautions, adverse reactions and drug interactions.

On November 22, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion on Gilead’s application for marketing authorization for Sovaldi. The CHMP opinion was adopted following an accelerated review procedure, which is reserved for medicinal products that are expected to be of major public health interest. This assessment does not guarantee marketing authorization by the European Commission. If approved, Sovaldi could be available in the European Union in the first quarter of 2014. Applications for marketing approval of Sovaldi are also pending in Australia, Canada, New Zealand, Switzerland and Turkey.

Dr. Jacobson is a paid consultant to Gilead.
The Wholesaler Acquisition Cost (WAC) of a 28-tablet bottle of Sovaldi in the United States is $28,000.

U.S. Patient Assistance Program
Gilead is committed to ensuring that people with hepatitis C can access Sovaldi and has launched Support Path™ (www.MySupportPath.com) to provide assistance to patients who are uninsured, underinsured or who need financial assistance to pay for the medicine. The program consists of an integrated offering of support services for patients and providers, including:

• Access to dedicated case managers to help patients and their providers with insurance-related needs, including identifying alternative coverage options such as federally-insured programs (e.g., Medicaid, Medicare) and health exchanges.
• Education and support, including a 24/7 nursing support service line and the ability to schedule an onsite visit from a clinical educator.
• The Sovaldi Co-pay Coupon Program, which provides co-pay assistance for eligible patients with private insurance who need assistance paying for out-of-pocket medication costs. Most patients will pay no more than $5 per co-pay. Co-pay assistance can also be applied toward deductibles and co-insurance obligations.
• Gilead will provide support to the Patient Access Network (PAN) Foundation, an independent non-profit organization that provides assistance for eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs.
• The Support Path Patient Assistance Program will provide Sovaldi at no charge for eligible patients with no other insurance options.

Information about how to apply for any of these forms of assistance can be found at www.MySupportPath.com or by calling 1-855-7MyPath (1-855-769-7284) between 9 a.m. - 8 p.m. EST.

Global Availability
Gilead is committed to helping ensure access to Sovaldi in resource-limited settings. The company is developing a hepatitis C treatment access program, focusing on those countries with the greatest HCV burden. Full program details will be announced in the coming months.

About Sovaldi
Sovaldi is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. Sovaldi is a direct-acting agent, meaning that it interferes directly with the HCV life cycle by suppressing viral replication. Treatment regimen and duration for Sovaldi are dependent on both viral genotype and patient population. Treatment response varies based on baseline host and viral factors. Monotherapy is not recommended for treatment of CHC.

IMPORTANT SAFETY INFORMATION

Contraindications
Sovaldi combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to Sovaldi combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

Warnings and Precautions

• Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.
• Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (≥20%, all grades) adverse reactions for:

• Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia
• Sovaldi + ribavirin combination therapy were fatigue, and headache

Drug Interactions
In addition to rifampin and St. John’s wort, coadministration of Sovaldi is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that physicians and patients may not see advantages of Sovaldi over other therapies and may therefore be reluctant to prescribe the product, and the risk that public payers may be reluctant to approve or provide reimbursement for the product. In addition, pending marketing applications for Sovaldi in the European Union and other territories may not be approved in the currently anticipated timelines or at all, and marketing approval, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at www.Gilead.com

Sovaldi and Support Path are trademarks or registered trademarks of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Photos/Multimedia Gallery Available: http://www.businesswire.com/multimedia/home/20131206005775/en/

Source: Gilead Sciences, Inc.
Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

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Gilead's Sofosbuvir Is FDA Approved

FDA NEWS RELEASE

For Immediate Release: Dec. 6, 2013
Media Inquiries: Stephanie Yao, 301-796-0394, stephanie.yao@fda.hhs.gov 

Consumer Inquiries: 888-INFO-FDA

FDA approves Sovaldi for chronic hepatitis C

Drug is third with breakthrough therapy designation to receive FDA approval

The U.S. Food and Drug Administration today approved Sovaldi (sofosbuvir) to treat chronic hepatitis C virus (HCV) infection. Solvadi 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.

“Today’s approval represents a significant shift in the treatment paradigm for some patients with chronic hepatitis C,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Sovaldi is 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).

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with HCV.

Sovaldi is a nucleotide analog inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. Sovaldi is to be used as a component of a combination antiviral treatment regimen for chronic HCV infection. There are several different types of HCV infection. Depending on the type of HCV infection a patient has, the treatment regimen could include Sovaldi and ribavirin or Sovaldi, ribavirin and peginterferon-alfa. Ribavirin and peginterferon-alfa are two drugs also used to treat HCV infection.

Sovaldi’s effectiveness was evaluated in six clinical trials consisting of 1,947 participants who had not previously received treatment for their disease (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants co-infected with HCV and HIV. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s HCV infection has been cured.

Results from all clinical trials showed a treatment regimen containing Sovaldi was effective in treating multiple types of the hepatitis C virus. Additionally, Sovaldi demonstrated efficacy in participants who could not tolerate or take an interferon-based treatment regimen and in participants with liver cancer awaiting liver transplantation, addressing unmet medical needs in these populations.

The most common side effects reported in clinical study participants treated with Sovaldi and ribavirin were fatigue and headache. In participants treated with Sovaldi, ribavirin and peginterferon-alfa, the most common side effects reported were fatigue, headache, nausea, insomnia and anemia.

Sovaldi is the third drug with breakthrough therapy designation to receive FDA approval. The FDA can designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may demonstrate a substantial improvement over available therapies for patients with serious or life-threatening diseases. Sovaldi was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.

Sovaldi is marketed by Gilead, based in Foster City, Calif. Olysio is marketed by Raritan, N.J.-based Janssen Pharmaceuticals.

For more information:

FDA: Approved Drugs: Questions and Answers

FDA: Drug Innovation

FDA: What’s New at FDA in Hepatitis

CDC: Hepatitis C Information for the Public


The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Sofosbuvir - Novel antiviral for chronic hepatitis C backed for approval

Oct 25 - Related @ Family Practice News Digital Network
FDA panel backs approval of new protease inhibitor for hepatitis C
A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C........

 

Infectious Diseases

Novel antiviral for chronic hepatitis C backed for approval
October 28 2013
By: ELIZABETH MECHCATIE, Family Practice News Digital Network

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.
 

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

 

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

 

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

 

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

 

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.
 

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

 

 http://www.familypracticenews.com/news/infectious-diseases/single-article/novel-antiviral-for-chronic-hepatitis-c-backed-for-approval/9d3d2c8ccfe4ffe7086f359765c9a569.html

FDA panel unanimously backs Gilead's hepatitis C drug sofosbuvir

The FDA Antiviral Drugs Advisory Committee  reviewed  Gilead's Sofosbuvir on October 25 and Johnson & Johnson's Simeprevir on October 24.  Both drugs have won support from the committee for approval by U.S. health regulators. The FDA is scheduled to decide whether to approve sofosbuvir by Dec. 8, and simeprevir by Nov. 27.

Panel recommends FDA approve sofosbuvir for hepatitis C

Oct 25

The FDA’s Antiviral Drugs Advisory Committee today recommended approval of sofosbuvir, a first-in-class, once-daily oral nucleotide inhibitor from Gilead Sciences, for treatment of chronic hepatitis C virus genotypes 1, 2, 3 and 4.

The panel voted unanimously and enthusiastically in support of approving sofosbuvir in combination with ribavirin for treatment of HCV GT 2 and 3 in adult patients.

“This is a game-changer,” committee member Marc G. Ghany, MD, MHSc, staff physician with the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said.

The panel also voted 15-0 but offered more reservations in support of approving sofosbuvir in combination with pegylated interferon and ribavirin (PR) for treatment of HCV GT 1 and 4 in treatment-naive patients.

“I was hesitant to give approval for a one-arm study,” committee member Dean Follmann, PhD, chief, biostatistics research branch, National Institute of Allergy and Infectious Diseases, said. “The 90% success rate is what really made me comfortable with this.”

The votes followed a discussion on a series of phase 3 studies of a sofosbuvir-based regimen, generally of 12 to 16 weeks, that demonstrated similar or superior effectiveness to current treatment options at primary endpoint of sustained virologic response (SVR) at 12 weeks.

The committee also discussed, but did not vote, on whether evidence supported sofosbuvir in combination with PR for treatment of chronic hepatitis C in patients with GT 1 infection who are nonresponders to a prior course of PR.

Studies did not directly analyze this patient population, but the FDA presented extrapolated data that suggested about 75% of treatment-experienced patients might respond positively to the therapy.

Several committee members expressed concern over the lack of real data, while others suggested it was a risk worth taking.

Thomas P. Giordano, MD, MPH, associate professor of medicine at Baylor College of Medicine, questioned whether voicing approval was appropriate.

“Clinicians are going to do what they have to do to take care of their patients, but the agency’s responsibility is at a different level,” he said.

On the discussion of whether evidence supported use of sofosbuvir in combination with ribavirin in hepatocellular carcinoma patients meeting Milan criteria awaiting liver transplantation, panel Chairman Yoshihiko Murata, MD, PhD, division of infectious diseases, University of Rochester School of Medicine and Dentistry, said there was a consensus among the panel on the need to treat this population.

“It’s work in progress, but it’s work that has to be done,” Donald J. Alcendor, PhD, associate professor, department of microbiology and immunology at Meharry Medical College, said.
Source - Healio

FDA Advisory Committee Supports Approval of Gilead's Sofosbuvir for Chronic Hepatitis C Infection

Date(s): 25-Oct-2013 4:43 PM

- Final FDA Decision on Sofosbuvir Anticipated by December 8, 2013

FOSTER CITY, Calif.--(BUSINESS WIRE)--Oct. 25, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) has voted unanimously (15-0) that the available data support approval of the once-daily nucleotide analogue sofosbuvir in combination with ribavirin for the treatment of chronic hepatitis C in adult patients with genotype 2 and 3 infection. Committee members also voted unanimously (15-0) that the available data support approval of sofosbuvir in combination with pegylated interferon and ribavirin for the treatment of chronic hepatitis C in treatment-naïve adult patients with genotype 1 and 4 infection.

   
The recommendations of the Advisory Committee are not binding, but will be considered by FDA as the agency completes its review of Gilead's New Drug Application (NDA) for sofosbuvir. Gilead submitted the NDA on April 8, 2013 and was granted a priority review. The FDA also granted sofosbuvir a Breakthrough Therapy designation. The FDA grants Breakthrough Therapy designation and priority review status to drug candidates that may offer major advances in treatment over existing options. A target review date of December 8, 2013 has been set under the Prescription Drug User Fee Act (PDUFA). Applications for marketing approval of sofosbuvir are also pending in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey.
   
The sofosbuvir NDA is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, in which 12 or 16 weeks of sofosbuvir-based therapy was found to be superior or non-inferior to currently available treatment options or historical controls, based on the proportion of patients who had a sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). During the review, data from an additional Phase 3 study, VALENCE, were filed to the NDA. In this study, patients with genotype 3 HCV infection were treated with sofosbuvir and ribavirin for 24 weeks. Patients who achieve SVR12 are considered cured of HCV.
   
About Sofosbuvir
Sofosbuvir is a nucleotide analogue inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. Sofosbuvir is a direct-acting agent, meaning that it interferes directly with the HCV life cycle by suppressing viral replication. Sofosbuvir is an investigational product and its safety and efficacy have not been established.
   
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.
   
Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that FDA, EMA and other regulatory agencies may not approve sofosbuvir in the currently anticipated timelines or at all, and that any marketing approvals, if granted, may have significant limitations on their use. In addition, future studies of sofosbuvir, including in combination with other products, may not produce favorable results. Further, even if approved, Gilead may not be able to successfully commercialize sofosbuvir, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
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FDA panel unanimously backs Gilead's hepatitis C drug sofosbuvir

By Toni Clarke

WASHINGTON Oct 25 (Reuters) - A federal advisory panel recommended on Friday that the U.S. Food and Drug Administration approve Gilead Sciences Inc's experimental hepatitis C drug sofosbuvir, paving the way for a treatment that is more effective than current therapies and takes less time.

The FDA advisory panel voted 15 to 0 in favor of approval of the drug in patients with two variants of the liver-damaging disease - genotype 2 and genotype 3 - in combination with an existing treatment, ribavirin.

If approved, it will be the first all-oral treatment for genotypes 2 and 3, obviating the need for the injectable drug interferon, which can cause debilitating side effects. Panelists called the vote "historic" and a "game-changer."

"Our patients have been waiting for this for a long time," said Dr. Curt Hagedorn, chief of medicine service at the Central Arkansas Veterans Healthcare Service.

The panel also voted unanimously to approve the drug in patients with genotype 1 and genotype 4 variants in combination with ribavirin and interferon in patients who have not received prior therapy.
Genotype 1 accounts for roughly 70 percent of hepatitis C cases. The FDA is not bound to follow the advice of its panels but typically does so.

"We'd already built in 100 percent chance of approval into our valuation for the company," said Karen Andersen, an analyst at Morningstar. "Gilead is still really in the prime position looking ahead in the hepatitis C market."

Panelists also appeared to support the use of sofosbuvir in patients who failed prior treatment, even though the company has little hard data to support such a claim.
"I did think there was a surprise upside result by the end of the panel," said Michael Yee, an analyst at RBC Capital Markets.

Bristol-Myers Squibb Co and Abbvie Inc have advanced all-oral clinical trial programs in late-stage development, using a variety of so-called direct acting antivirals, which directly interfere with the virus's ability to replicate. But Gilead is widely seen to be in the lead.

Chronic hepatitis C affects at least 3 million people in the United States, according to the U.S. Centers for Disease Control.

Analysts on average expect Gilead's drug to generate sales of $1.73 billion in 2014, according to Thomson Reuters data.

Current standard treatments for genotype 1 often include a protease inhibitor. These are oral drugs that include Merck & Co Inc's Victrelis and Vertex Inc's Incivek.
Gilead acquired sofosbuvir, known as a nucleotide analogue inhibitor, with its $11 billion purchase of Pharmasset Inc in 2012.

Panelists urged Gilead to make the drug available to other companies to study in combination with other oral regimens waiting in the wings.
Bristol-Myers is expected to present data from a late-stage clinical trial of its interferon-free treatment of genotype 1 patients at next month's meeting of the American Association for the Study of Liver Diseases in Washington, D.C.

The FDA is due to rule on whether to approve the drug by Dec. 8.
http://www.reuters.com/article/2013/10/25/gilead-hepatitisc-idUSL1N0IF1JN20131025

Hepatitis C: CHMP Backs 'Compassionate Use' of Sofosbuvir

Miriam E. Tucker

The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) has issued a "compassionate use" opinion for Gilead Sciences Inc's antiviral drug sofosbuvir in patients who have chronic hepatitis C virus (HCV) infection and who are awaiting a liver transplant or have already received one.

This is the third time the CHMP has used the compassionate use designation for a drug. Set up at the national level, compassionate use programs aim to give patients with life-threatening, chronic, or seriously disabling disease who do not have other treatment options access to drugs that are still under development or consideration and that have not yet been authorized for wider use.

Sofosbuvir, an NS5B polymerase inhibitor, is currently under evaluation by the EMA for wider use in patients with chronic HCV. In the meantime, Sweden had requested a CHMP opinion for use of the antiviral in combination with other agents specifically in patients before or after liver transplantation.

In the United States, sofosbuvir is being discussed today at a US Food and Drug Administration advisory committee hearing for the treatment of chronic HCV infection in combination with other agents in adult patients with genotypes 1 to 6 and/or adult patients awaiting liver transplantation.

HCV infection occurs in 0.4% to 3.5% of the population in different EU member states and is the most common single cause of liver transplantation in the European Union. There is currently no standard therapy for patients with chronic HCV who are awaiting transplantation or who have already received a liver transplant, and there are no approved treatments for most of these patients.

"Many patients with HCV infection in the pre- and post-transplant setting are therefore in urgent medical need of therapy to prevent graft reinfection or to treat recurrent HCV infection in the graft," the EMA said in a statement.

The CHMP opinion is intended to ensure a common approach for member states that are considering setting up a compassionate use program. It is not mandatory. An assessment report and conditions of use of sofosbuvir in this setting will be published shortly on the agency's Web site, the EMA says.
Medscape Medical News

FDA Panel Backs HCV Drugs

Published: Oct 25, 2013

By Michael Smith, North American Correspondent, MedPage Today

An FDA committee has unanimously supported approval of both simeprevir and sofosbuvir, drugs that act directly against hepatitis C (HCV).

The Antiviral Drugs Advisory Committee voted 19-0 to recommend approval of simeprevir, in combination with pegylated interferon and ribavirin, as suitable for treatment of patients with genotype 1 HCV.

The committee voted 15-0 to support approval of sofosbuvir in combination with ribavirin for treatment of patients with genotype 2 and 3 HCV.
And, by the same margin, the committee supported approval of the drug, in combination with pegylated interferon and ribavirin, for patients with genotype 1 and 4 infection.
If the agency agrees with the advice, simeprevir and sofosbuvir will be the first new HCV drugs approved since 2011.

The FDA is not bound to take the advisory committee's advice but usually does so.
The two drugs are the first in an anticipated wave of second-generation, direct-acting agents for the disease, which chronically afflicts about 3.2 million Americans.

For years, the standard therapy for hepatitis C was a combination of pegylated interferon-alfa and ribavirin, drugs that are regarded as both difficult and dangerous to take.
In 2011, the FDA approved the first agents that act directly against the virus itself -- the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).

Simeprevir, another protease inhibitor, would be the third drug in the class, while sofosbuvir -- a nucleotide analog NS5B polymerase inhibitor -- would be the first in its class to get the nod.
The simeprevir application was based on efficacy results from three placebo-controlled phase III trials, two in treatment-naive patients and one in patients who had relapsed after interferon-based therapy.

In all three trials, the primary endpoint was the proportion of patients with undetectable virus 12 weeks after the end of therapy -- the so-called SVR₁₂.
Among treatment-naive patients, the SVR₁₂ rate was 80% among those getting all three drugs and 50% among those in the control group, who got placebo along with interferon and ribavirin.
Among relapsers, the SVR₁₂ rates were 79% in the simeprevir group and 36% among placebo patients.

In genotypes 2 and 3, regarded as relatively easy to treat, the sofosbuvir application was based on several studies of the drug in combination with ribavirin, a general anti-viral medication.
In some cases, the study evaluated efficacy over different treatment durations, while in others, the combination was compared with placebo or peginterferon and ribavirin.
An open-label trial evaluated the drug in patients with other genotypes, including the difficult-to-treat genotype 1, using sofosbuvir in combination with ribavirin and peginterferon, an immune system booster.

FDA reviewers, summarizing the data for genotypes 2 and 3 in briefing documents before the advisory committee meeting, said the combination of sofosbuvir and ribavirin was both efficacious and safe and would be the first all-oral, interferon-free treatment for HCV, if approved.

As well as efficacy, the combination offers a shorter treatment duration and improved safety profile compared with interferon-based regimens, the current standard of care, the reviewers concluded.
On the other hand, sofosbuvir appeared to offer better efficacy in patients with genotype 2 than in those with genotype 3, they noted.

It would also address an unmet need -- therapy for patients ineligible for, intolerant of, or unwilling to take interferon-based regimens.

Among those with HCV genotypes 1 and 4, the reviewers argued, sofosbuvir plus pegylated interferon and ribavirin would offer increased efficacy and shorter treatment than currently approved regimens.

But the available data were not sufficient to make definite dosing recommendations for patients with genotypes 5 or 6, the reviewers concluded.
Source

Related Links:

Download FDA Review Information For Sofosbuvir And Simeprevir.

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FDA Revised Draft Guidance on Hepatitis C Drug Development
The US Food and Drug Administration (FDA) released a new guidance document on 16 October 2013 detailing its preferred methods of developing applications in support of drugs to treat chronic infections caused by the hepatitis C virus.