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2014年10月10日，美国食品和药品监督管理局(FDA)批准新复方片剂ledipasvir/sofosbuvir(商标名Harvoni 吉利德抗产品)治疗慢性丙型肝炎病毒(HCV)基因型1感染，
INFORMATION
3 DOSAGE FORMS AND STRENGTHS HARVONI is available as an orange colored, diamond shaped, film-coated tablet debossed with "GSI" on one side and "7985" on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Reduced Therapeutic Effect Due to P-gp InducersThe concomitant use of HARVONI and P-gp inducers (e.g., rifampin, St. John's wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of HARVONI. Therefore, the use of HARVONI with P-gp inducers (e.g., rifampin or St. John's wort) is not recommended [see Drug Interactions (7.2)]. 5.2 Related Products Not RecommendedThe use of HARVONI with other products containing sofosbuvir (SOVALDI®) is not recommended. 6 ADVERSE REACTIONS 6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety assessment of HARVONI was based on pooled data from three Phase 3 clinical trials of subjects with genotype 1 chronic hepatitis C (CHC) with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received HARVONI for 8, 12 and 24 weeks, respectively [see Clinical Studies (14)]. The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, <1%, and 1% for subjects receiving HARVONI for 8, 12, and 24 weeks, respectively. The most common adverse reactions (≥10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of HARVONI. Table 2 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in ≥5% of subjects receiving 8, 12, or 24 weeks treatment with HARVONI in clinical trials. The majority of adverse reactions presented in Table 2 occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 2 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with HARVONI
Laboratory Abnormalities
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies with HARVONI in pregnant women. Because animal reproduction studies are not always predictive of human response, HARVONI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ledipasvir: No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to ledipasvir was approximately 4- and 2-fold, respectively, the exposure in humans at the recommended clinical dose. Sofosbuvir: No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 3- to 6-fold and 7- to 17-fold the exposure in humans at the recommended clinical dose, respectively. 8.3 Nursing MothersIt is not known whether HARVONI and its metabolites are present in human breast milk. When administered to lactating rats, ledipasvir was detected in the plasma of suckling rats likely due to the presence of ledipasvir in milk. Ledipasvir had no clear effects on the nursing pups. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HARVONI and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. 8.4 Pediatric UseSafety and effectiveness of HARVONI have not been established in pediatric patients. 8.5 Geriatric UseClinical trials of HARVONI included 117 subjects aged 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of HARVONI is warranted in geriatric patients [see Clinical Pharmacology (12.3)]. 8.6 Renal ImpairmentNo dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. The safety and efficacy of HARVONI have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.7 Hepatic ImpairmentNo dosage adjustment of HARVONI is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). Safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific antidote is available for overdose with HARVONI. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with HARVONI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis is unlikely to result in significant removal of ledipasvir since ledipasvir is highly bound to plasma protein. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. 11 DESCRIPTION HARVONI is a fixed-dose combination tablet containing ledipasvir and sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Ledipasvir: The IUPAC name for ledipasvir is Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate. It has a molecular formula of C49H54F2N8O6 and a molecular weight of 889.00. It has the following structural formula: Ledipasvir is practically insoluble (<0.1 mg/mL) across the pH range of 3.0–7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL). Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥2 mg/mL across the pH range of 2–7.7 at 37°C and is slightly soluble in water.
Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes. The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are shown in Table 5 [see Drug Interactions (7.2)]. Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or HARVONI*
12.4 Microbiology Mechanism of Action Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 µM. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Antiviral Activity In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 0.018 nM for genotype 1a (range 0.009–0.085 nM; N=30) and 0.006 nM for genotype 1b (range 0.004–0.007 nM; N=3). Ledipasvir has less antiviral activity compared to genotype 1 against genotypes 4a, 5a, and 6a, with EC50 values of 0.39 nM, 0.15 nM, and 1.1 nM, respectively. Ledipasvir has substantially lower activity against genotypes 2a, 2b, 3a, and 6e with EC50 values of 21–249 nM, 16–530 nM, 168 nM, and 264 nM, respectively. In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, 2a, 3a, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 2b, 5a, or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29–128 nM; N=67), 102 nM for genotype 1b (range 45–170 nM; N=29), 29 nM for genotype 2 (range 14–81 nM; N=15), and 81 nM for genotype 3a (range 24–181 nM; N=106). In replication competent virus assays, the EC50 values of sofosbuvir against genotypes 1a and 2a were 30 nM and 20 nM, respectively. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance In Cell Culture HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotypes 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b. Additionally, a Q30E substitution emerged in genotype 1a replicons. Site-directed mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E substitution in genotype 1a, conferred high levels of reduced susceptibility to ledipasvir (fold change in EC50 greater than 1000-fold). HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir. In Clinical Trials In a pooled analysis of subjects who received HARVONI in Phase 3 trials, 37 subjects (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis due to virologic failure (35 with virologic relapse, 2 with breakthrough on-treatment due to documented non-adherence). Post-baseline NS5A and NS5B deep sequencing data (assay cutoff of 1%) were available for 37/37 and 36/37 subjects' viruses, respectively. Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects also had baseline NS5A polymorphisms at resistance-associated amino acid positions. The most common substitutions detected at failure were Q30R, Y93H or N, and L31M. Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Three of these 7 subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most common substitution detected at failure was Y93H. At failure, 38% (14/37) of virologic failure subjects had 2 or more NS5A substitutions at resistance-associated positions. In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A resistance-associated substitutions at failure showed 20- to >243-fold reduced susceptibility to ledipasvir. Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously associated with sofosbuvir failure were detected in the Phase 3 trials. In addition, NS5B substitutions at highly conserved positions D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) were detected at low frequency by next generation sequencing in treatment failure subjects infected with HCV GT1a. The D61G substitution was previously described in subjects infected with HCV GT1a in a liver pre-transplant trial. The clinical significance of these substitutions is currently unknown. The sofosbuvir-associated resistance substitution S282T in NS5B was not detected in any failure isolate from the Phase 3 trials. NS5B substitutions S282T, L320V/I, and V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected in one subject at failure following 8 weeks of treatment with HARVONI in a Phase 2 trial. Cross Resistance Ledipasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all ledipasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to ledipasvir may reduce the antiviral activity of other NS5A inhibitors. The efficacy of ledipasvir/sofosbuvir has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor. Persistence of Resistance-Associated Substitutions No data are available on the persistence of ledipasvir or sofosbuvir resistance-associated substitutions. NS5A resistance-associated substitutions for other NS5A inhibitors have been found to persist for >1 year in some patients. Effect of Baseline HCV Polymorphisms on Treatment Response Analyses were conducted to explore the association between pre-existing baseline NS5A polymorphisms at resistance-associated positions and relapse rates. In the pooled analysis of the Phase 3 trials, 23% (370/1589) of subjects' virus had baseline NS5A polymorphisms at resistance-associated positions (any change from reference at NS5A amino acid positions 24, 28, 30, 31, 58, 92, or 93) identified by population or deep sequencing. In treatment-naïve subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions in Studies ION-1 and ION-3, relapse rates were 6% (3/48) after 8 weeks and 1% (1/113) after 12 weeks of treatment with HARVONI. Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks treatment with HARVONI. In treatment-experienced subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions, relapse rates were 22% (5/23) after 12 weeks and 0% (0/19) after 24 weeks of treatment with HARVONI. The specific baseline NS5A resistance-associated polymorphisms observed among subjects with relapse were M28T/V, Q30H, Q30R, L31M, H58P, Y93H, and Y93N in genotype 1a, and L28M, A92T, and Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-associated positions appeared to have higher relapse rates. SVR was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F; and N=3 with N142T) who had baseline polymorphisms associated with resistance to NS5B nucleoside inhibitors. The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any subject in Phase 3 trials by population or deep sequencing. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays. Carcinogenicity studies of ledipasvir in mice and rats are ongoing. Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. Two-year carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in females, while rats were administered doses of up to 750 mg/kg/day in males and females. No increase in the incidence of drug-related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC exposure to the predominant circulating metabolite GS-331007 of approximately 4- and 18-fold (in mice) and 8- and 10-fold (in rats), in males and females respectively, the exposure in humans at the recommended clinical dose. Impairment of Fertility Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were reduced slightly at maternal exposures approximately 3-fold the exposure in humans at the recommended clinical dose. At the highest dose levels without effects, AUC exposure to ledipasvir was approximately 5- and 2-fold, in males and females, respectively, the exposure in humans at the recommended clinical dose. Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 5-fold the exposure in humans at the recommended clinical dose. 13.2 Animal Toxicology and/or Pharmacology Sofosbuvir: Heart degeneration and inflammation were observed in rats following GS-9851 (a stereoisomeric mixture containing approximately 50% sofosbuvir) doses of 2,000 mg/kg/day for up to 5 days. At this dose, AUC exposure to the predominant circulating metabolite GS-331007 is approximately 17-fold higher than human exposure at the recommended clinical dose. No heart degeneration or inflammation was observed in mice, rats, or dogs in studies up to 3 months, 6 months, or 9 months at GS-331007 AUC exposures approximately 24-, 5-, or 17-fold higher, respectively, than human exposure at the recommended clinical dose. In addition, no heart degeneration or inflammation was observed in rats following sofosbuvir doses of up to 750 mg/kg/day in the 2-year carcinogenicity study at GS-331007 AUC exposure approximately 9-fold the exposure in humans at the recommended clinical dose. 14 CLINICAL STUDIES 14.1 Overview of Clinical TrialsThe efficacy of HARVONI was evaluated in three Phase 3 trials of 1518 subjects with genotype 1 chronic hepatitis C (CHC) with compensated liver disease: Study ION-3: noncirrhotic treatment-naïve subjects [see Clinical Studies (14.2)], Study ION-1: cirrhotic and noncirrhotic treatment-naïve subjects [see Clinical Studies (14.2)], and Study ION-2: cirrhotic and noncirrhotic subjects who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor [see Clinical Studies (14.3)]. All three Phase 3 trials evaluated efficacy of HARVONI (one fixed-dose tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir administered once daily) with or without ribavirin. Treatment duration was fixed in each trial. Serum 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/mL. Sustained virologic response (SVR) was the primary endpoint and was defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment. 14.2 Clinical Trials in Treatment-Naïve Subjects Treatment-Naïve Adults without Cirrhosis — ION-3 (Study 0108) ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 CHC. Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks, HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks. Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT). Table 6 presents the response rates for the HARVONI treatment groups in the ION-3 trial after 8 and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 6. Table 6 Study ION-3: Response Rates after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 CHC
Relapse rates by baseline viral load are presented in Table 7. Table 7 Study ION-3: Relapse Rates by Baseline Viral Load after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 CHC
ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1 CHC including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b). The interim primary endpoint analysis for SVR included all subjects enrolled in the 12-week treatment groups (N=431). SVR rates for all subjects enrolled in the 24-week treatment groups (N=434) were not available at the time of interim analysis. Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis. Table 8 presents the response rates for the treatment group of HARVONI for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 8. Table 8 Study ION-1: Response Rates after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 CHC with and without Cirrhosis
Table 9 Study ION-1: SVR Rates for Selected Subgroups after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 CHC with and without Cirrhosis
Previously-Treated Adults with or without Cirrhosis — ION-2 (Study 0109) ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse). Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis. Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were non-responder. Fifty-three percent (53%) of the subjects failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these subjects, 62% were relapse/breakthrough and 38% were non-responder. Table 10 presents the response rates for the HARVONI treatment groups in the ION-2 trial. Ribavirin was not shown to increase response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arms are not presented in Table 10. Table 10 Study ION-2: Response Rates after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC with or without Cirrhosis who Failed Prior Therapy
Response rates and relapse rates for selected subgroups are presented in Tables 11 and 12. Table 11 Study ION-2: SVR Rates for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC who Failed Prior Therapy
These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms. NS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 93. Close 16 HOW SUPPLIED/STORAGE AND HANDLING HARVONI tablets are orange, diamond-shaped, film-coated, debossed with "GSI" on one side and "7985" on the other side of the tablet. Each bottle contains 28 tablets (NDC 61958-1801-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure. Store at room temperature below 30°C (86°F). Dispense only in original container. Do not use if seal over bottle opening is broken or missing. New Drugs Online Report for sofosbuvir + ledipasvir Information Generic Name: sofosbuvir + ledipasvir Trade Name: Harvoni Synonym: GS-7977, GS-5855 Entry Type: New formulation Developmental Status UK: Launched EU: Launched US: Approved (Licensed) UK launch Plans: Available only to registered users Actual UK launch date: November 2014 Comments Nov 14: Launched in the UK. NHS list price of 28 tabs of Harvoni (90mg ledipasvir/400mg sofosbuvir) is £12,993.33 [20]. 27/11/2014 15:43:43 Nov 14: Marketed authorisation granted by European Commission allowing for marketing of Harvoni in all 28 countries of the EU [19]. 19/11/2014 08:40:11 Oct 14: Approved in the US for HCV genotype 1 infection. Approval is based on three PIII studies which showed that Harvoni achieved cure rates (SVR 12) of 94%-99% [17]. 13/10/2014 11:15:54 Sep 14: EU positive opinion for treatment of chronic hepatitis C infection in adults [16]. 29/09/2014 14:24:50 Apr 14: Granted priority review in the US. A decision on approval is expected by 10 Oct [14] 07/04/2014 19:33:19 Feb 14: EU CHMP issues an opinion on the use of a fixed-dose combination of ledipasvir and sofosbuvir in the treatment of chronic HCV infection in a compassionate use programme. The assessment report and conditions of use of the combination of ledipasvir and sofosbuvir with or without ribavirin in this setting will be published shortly on the EMA´s website [13]. 24/02/2014 11:44:21 Feb 14: Filed in the EU for treatment of chronic hepatitis C genotype 1 infection in adults [12]. 13/02/2014 10:57:02 Feb 14: Filed in the US as a once-daily fixed-dose combination of ledipasvir 90mg and sofosbuvir 400mg for the treatment of chronic hepatitis C genotype 1 infection in adults [11] 11/02/2014 15:45:52 Dec 13: Company plans to file in US Q1 2014,where it has been award Breakthrough designation [10] 19/12/2013 21:51:52 Oct 12: PIII study starts in US, EU & UK [2]. 08/10/2012 17:57:03 Trial or other data Nov 14: Gilead announce results from several PII & PIII studies. In a pooled analysis of PII & PIII open-label studies (Oral #82) in more than 500 genotype 1 HCV infected pts with compensated cirrhosis who received Harvoni alone or with ribavirin (RBV) for 12 or 24 weeks, 96% of pts achieved SVR12. Pts who achieve SVR12 are considered cured of HCV infection. Two prospective analyses from a PII open-label study (Study GS-US-337-0123) evaluating pts with decompensated cirrhosis and those with HCV recurrence following liver transplantation also are being presented. In the first subgroup (Oral #239), 108 genotype 1 and 4 infected pts with decompensated cirrhosis, including those with moderate hepatic impairment (Child-Pugh-Turcotte (CPT) Class B) and severe hepatic impairment (CPT Class C), received Harvoni plus RBV for 12 or 24 weeks. Overall, SVR12 rates were 87% in the 12-week arm and 89% in the 24-week arm. The second subgroup (Oral #8) evaluated 12 or 24 weeks of Harvoni plus RBV among 223 genotype 1 and 4 pts who developed HCV recurrence following liver transplantation. Among non-cirrhotic pts, SVR12 rates were 96% & 98% following 12 and 24 weeks of treatment, respectively. For pts with compensated cirrhosis, SVR12 rates were 96% for both 12 weeks & 24 weeks of therapy. SVR12 rates among pts with decompensated cirrhosis were 81% for both 12 weeks & 24 weeks of therapy. Study GS-US-337-0121 (Late Breaker Oral #LB-6) evaluated 155 genotype 1 pts with compensated cirrhosis who had failed prior treatment with pegylated interferon (PegIFN)/RBV and subsequently PegIFN/RBV plus a protease inhibitor. In this study, pts were randomized (1:1) to receive Harvoni plus RBV for 12 weeks or Harvoni alone for 24 weeks. 96% of those receiving Harvoni plus RBV for 12 weeks and 97% of those receiving Harvoni for 24 weeks achieved SVR12. In a second study (Oral #235), 51 genotype 1 pts who previously failed SOF/PegIFN/RBV, SOF/RBV or a SOF placebo/PegIFN/RBV treatment regimen received Harvoni plus RBV for 12 weeks. 29% of pts had cirrhosis. 98% achieved SVR12 following 12 weeks of treatment with Harvoni plus RBV. In all of these studies, Harvoni was well tolerated and its safety profile was generally consistent with that observed in clinical trials of Harvoni. Adverse events included fatigue, headache, nausea and anemia, which was more common among patients taking RBV. Grade 3/4 laboratory abnormalities were infrequent and included decreases in hemoglobin, which is consistent with RBV-associated anaemia [18]. 14/11/2014 12:03:55 Apr 14: NHS England commissioned. Patients eligible for treatment are those with significant risk of death or irreversible damage within the next 12 months, irrespective of genotype [15] 22/04/2014 09:17:03 Apr 14: Results from three PIII studies published early on-line in the NEJM: ION-1 (http://www.nejm.org/doi/full/10.1056/NEJMoa1402454), ION-2 (http://www.nejm.org/doi/full/10.1056/NEJMoa1316366) and ION-3 (http://www.nejm.org/doi/full/10.1056/NEJMoa1402355) 14/04/2014 08:37:45 Feb 14: Results of the PII LONESTAR study (n=100) published in the Lancet Feb 8 2014: 383: 515-23. The study found that the fixed dose-combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV irrespective of treatment history or presence of compensated cirrhosis. 11/02/2014 15:10:32 Dec 13: Topline results announced from three PIII clinical trials (ION-1, ION-2 and ION-3) of the once-daily fixed-dose combination of sofosbuvir 400mg ledipasvir 90mg, with and without ribavirin, for the treatment of genotype 1 chronic HCV infection. 1,952 patients were enrolled across the 3 studies; of these, 1,512 were treatment-naïve, 440 were treatment experienced and 224 had compensated cirrhosis. Of the 1,518 patients randomized to the 12-week arms of ION-1 and to all arms of ION-2 and ION-3, 1,456 patients (95.9%) achieved the primary efficacy endpoint of SVR12. Of the 62 patients (4.1%) who failed to achieve SVR12, 36 patients (2.4%) experienced virologic failure: 35 due to relapse and only one patient due to on-treatment breakthrough (with documented noncompliance). Twenty-six patients (1.7%) were lost to follow-up or withdrew consent [10]. 19/12/2013 21:49:46 May 13: NCT01851330 (ION-3) starts May 13 and is due to complete Dec 14 [9]. 13/05/2013 09:13:20 May 13: Company is to start a 3rd PIII trial (ION-3) of the once daily fixed-dose combination tablet of sofosbuvir and ledipasvir in 600 non-cirrhotic, treatment-naïve genotype 1 HCV-infected patients. The design of ION-3 is based on interim results from the PII LONESTAR study, which evaluated 8- and 12-week courses of therapy in 60 treatment-naïve, non-cirrhotic patients. In this study, 19/19 patients in the 12-week arm had a sustained virologic response four weeks after completing therapy (SVR4) and 40/41 in the 8-week arms had a SVR8, with one relapse occurring in the arm receiving sofosbuvir/ledipasvir without RBV. In ION-3, participants will be randomized to receive sofosbuvir and ledipasvir for 8 weeks (n=200), sofosbuvir and ledipasvir + RBV for 8 weeks (n=200), or sofosbuvir and ledipasvir for 12 weeks (n=200). The primary endpoint is SVR12, defined as maintaining undetectable HCV RNA 12 weeks post-treatment and considered a cure for HCV infection. The study is designed to assess non-inferiority of the 8-week treatment duration arms to the 12-week treatment duration arm [8]. 03/05/2013 08:43:40 Mar 13: A planned review by the study´s Data and Safety Monitoring Board (DSMB) of safety data from 200 pts in all four arms and of SVR4 rates (sustained virologic response four weeks after completion of therapy) from 100 pts in the two 12-week duration arms concluded that the ION-1 trial should continue without modification [7]. 05/04/2013 09:35:12 Jan 13: NCT01768286 (ION-2) is a PIII, multicentre, randomized, open-label study to investigate the efficacy and safety of sofosbuvir/GS-5885 fixed-dose combination (400/90 mg) ± ribavirin for 12 and 24 weeks in 400 treatment-experienced subjects with chronic Genotype 1 HCV Infection. The primary outcomes are SVR12 and safety and tolerability. The study starts Jan 13 and is due to complete Nov 14 [4]. 24/01/2013 17:22:13 Oct 12: NCT01701401 is a PIII, multicentre, randomized, open-label study to investigate the efficacy and safety of sofosbuvir/GS-5885 fixed-dose combination (400/90 mg) +/- ribavirin for 12 and 24 weeks in 800 treatment-naive subjects with chronic genotype 1 HCV Infection. The primary outcome is sustained virologic response (SVR) 12 weeks after discontinuing therapy. The study starts Oct 12 and is due to complete Dec 14 [2]. 08/10/2012 17:56:34 Jul 12: Gilead is planning to start a PIII study of the combination of GS-7977 + GS-5855 in a single pill to treat hepatitis C in a trial of 800 patients by Q4 2012. If the combination is effective, the company could apply for regulatory approval in the middle of 2014 [1]. 31/07/2012 08:41:11 Evidence Based Evaluations EPAR http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003850/WC500177996.pdf NICE scope http://www.nice.org.uk/guidance/indevelopment/gid-tag484/documents NHSC/NIHR http://www.hsc.nihr.ac.uk/topics/sofosbuvir-with-ledipasvir-for-hepatitis-c-genotyp/ References Available only to registered users Category BNF Category: Viral hepatitis (05.03.03) Pharmacology: Epidemiology: ~200,000 to 500,000 people are infected with HCV in England and Wales [5], and around 45% of these are of genotype 1 [6] Indication: Hepatitis C infection Additional Details: Method(s) of Administration Oral Company Information Name: Gilead Sciences US Name: Gilead Sciences NICE Information Anticipated Commissioning route (England) - In timetable: Yes When: Jun / 2015 Note: www.nice.org.uk/guidance/indevelopment/gid-tag484 PBR Likely specified high cost drug. 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