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新型丙型肝炎病毒药物Olysio（simeprevir hard capsules）获批上市
Treatment discontinuation in patients with inadequate on-treatment virologic response Use with peginterferon alfa and ribavrin It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained virologic response (SVR), therefore discontinuation of treatment is recommended in these patients. The HCV RNA thresholds that trigger discontinuation of treatment (i.e., treatment stopping rules) are presented in table 2.
There are no virologic treatment stopping rules that apply to the combination of OLYSIO with sofosbuvir. Dosage adjustment or interruption of OLYSIO treatment To prevent treatment failure, the dose of OLYSIO must not be reduced or interrupted. If treatment with OLYSIO is discontinued because of adverse reactions or inadequate on-treatment virologic response, OLYSIO treatment must not be reinitiated. Dosage adjustment or interruption of medicinal products used in combination with OLYSIO for the treatment of CHC If adverse reactions, potentially related to the medicinal products that are used in combination with OLYSIO for the treatment of CHC, require dosage adjustment or interruption of the medicinal product(s), refer to the instructions outlined in the respective Summary of Product Characteristics for these medicinal products. If the other medicinal products that are used in combination with OLYSIO for the treatment of CHC are permanently discontinued for any reason, OLYSIO must also be discontinued. When ribavirin has been added to the combination of OLYSIO and sofosbuvir, and ribavirin needs to be discontinued, consideration can be given to continue treatment of OLYSIO with sofosbuvir alone (see section 5.1). Missed dose If a dose of OLYSIO is missed, and the patient notices within 12 hours of the usual dosing time, the patient should take the missed dose of OLYSIO with food as soon as possible and then take the next dose of OLYSIO at the regularly scheduled time. If a dose of OLYSIO is missed by more than 12 hours after the usual dosing time, the patient should not take the missed dose of OLYSIO and should resume dosing of OLYSIO with food at the regularly scheduled time. Special populations Elderly (over 65 years of age) There are limited data on the safety and efficacy of OLYSIO in patients older than 65 years. There are no safety and efficacy data of OLYSIO in patients over the age of 75 years. No dose adjustment of OLYSIO is required in elderly patients (see section 5.2). Renal impairment No dose adjustment of OLYSIO is required in patients with mild or moderate renal impairment. Increased simeprevir exposures have been observed in individuals with severe renal impairment. OLYSIO has not been studied in HCV infected patients with severe renal impairment (creatinine clearance below 30 ml/min) or end stage renal disease, including patients requiring haemodialysis. As exposure may be increased in HCV infected patients with severe renal impairment, caution is recommended when prescribing OLYSIO to these patients (see section 5.2). Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with OLYSIO regarding their use in patients with renal impairment. Hepatic impairment No dose adjustment of OLYSIO is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Simeprevir exposure is significantly increased in subjects with severe hepatic impairment (Child-Pugh class C) and no dose recommendation can be given for those patients (see section 5.2). The safety and efficacy of OLYSIO have not been studied in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C); therefore particular caution is recommended when prescribing OLYSIO to HCV infected patients with moderate or severe hepatic impairment. Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with OLYSIO regarding their use in patients with decompensated cirrhosis (Child-Pugh class B or C). Race Given limited data, the potential risks and benefits of OLYSIO 150 mg should be carefully considered prior to use in East Asian patients (see section 5.2). Paediatric population The safety and efficacy of OLYSIO in children aged below 18 years have not yet been established. No data are available. HCV/Human immunodeficiency virus type 1 (HIV-1) co-infection No dose adjustment of OLYSIO is required in HCV/HIV-1 co-infected patients (see sections 4.8, 5.1 and 5.2). OLYSIO in combination with peginterferon alfa and ribavirin: HCV/HIV-1 co-infected patients, irrespective of prior HCV treatment history, should be treated in the same way as HCV mono-infected patients, except for co-infected patients with cirrhosis who should receive 36 weeks of treatment with peginterferon alfa and ribavirin after completing 12 weeks of treatment with OLYSIO, peginterferon alfa and ribavirin (total treatment duration of 48 weeks). Please refer to sections 4.4 and 4.5 for relevant interactions with antiretroviral agents. Method of administration OLYSIO must be taken orally once a day with food (see section 5.2). The capsule should be swallowed as a whole. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use General The efficacy of OLYSIO has not been studied in patients with HCV genotypes 2, 3, 5 or 6; therefore OLYSIO should not be used in these patients (see section 5.1). OLYSIO must not be administered as monotherapy and must be prescribed in combination with other medicinal products for the treatment of CHC. Consult the Summary of Product Characteristics of the co-prescribed medicinal products before starting therapy with OLYSIO. Warnings and precautions related to these medicinal products also apply to their use in OLYSIO combination treatment. There are no clinical data on the use of OLYSIO in re-treating patients who have failed an HCV NS3-4A protease inhibitor-based therapy (see sections 5.1 and 5.3). Use of simeprevir in patients infected with HCV genotype 1a Simeprevir efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in patients infected with hepatitis C genotype 1a with the NS3 Q80K polymorphism at baseline compared to patients with hepatitis C genotype 1a without the Q80K polymorphism (see section 5.1). Testing for the presence of the Q80K polymorphism in patients with HCV genotype 1a is strongly recommended when considering therapy with OLYSIO in combination with peginterferon alfa and ribavirin. Alternative therapy should be considered for patients infected with HCV genotype 1a with the Q80K polymorphism or in cases where testing is not accessible. Data are too limited to evaluate whether the presence of Q80K polymorphism in HCV genotype 1a patients reduces the efficacy of simeprevir when OLYSIO is used in combination with other direct acting antivirals against HCV (see section 5.1). Until confirmatory data becomes available, testing for the presence of the Q80K polymorphism should be considered before initiating OLYSIO in combination with sofosbuvir in patients infected with HCV genotype 1a. Interferon-free therapy Interferon-free regimens with OLYSIO have not been investigated in phase 3 studies (see section 5.1). The optimal regimen and treatment duration have not been established. Interferon-free therapy with OLYSIO should only be used in patients who are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment. Co-administration with other direct acting antivirals against HCV OLYSIO should only be co-administered with other direct acting antiviral medicinal products if the benefits are considered to outweigh the risks based upon available data. There are no data to support the co-administration of OLYSIO and telaprevir or boceprevir. These HCV protease inhibitors are anticipated to be cross-resistant, and co-administration is not recommended (see also section 4.5). OLYSIO in combination with peginterferon alfa-2b In the clinical studies, patients randomised to simeprevir in combination with peginterferon alfa-2b and ribavirin obtained numerically lower SVR12 rates and also experienced viral breakthrough and viral relapse more frequently than those treated with simeprevir in combination with peginterferon alfa-2a and ribavirin (see section 5.1). Pregnancy and contraception OLYSIO should only be used during pregnancy or in women of childbearing potential if the benefit justifies the risk. Female patients of childbearing potential must use an effective form of contraception (see section 4.6). The contraindications and warnings regarding pregnancy and contraception requirements applicable to the co-administered medicinal products also apply to their use in OLYSIO combination treatment. Ribavirin may cause birth defects and/or death of the exposed foetus. Therefore, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients (see section 4.6). Photsensitivity Photosensitivity reactions have been observed with OLYSIO combination treatment (see section 4.8). Patients should be informed of the risk of photosensitivity reactions and on the importance of applying appropriate sun protective measures during treatment with OLYSIO. Excess exposure to sun and use of tanning devices during treatment with OLYSIO should be avoided. If photosensitivity reactions occur, discontinuation of OLYSIO should be considered and patients should be monitored until the reaction has resolved. Rash Rash has been observed with OLYSIO combination treatment (see section 4.8). Patients with mild to moderate rashes should be monitored for possible progression of rash, including the development of mucosal signs or systemic symptoms. In case of severe rash, OLYSIO and other co-administered medicinal products for the treatment of CHC should be discontinued and the patients should be monitored until the symptoms have resolved. Hepatic impairment Simeprevir plasma exposure is significantly increased in subjects with severe hepatic impairment (Child-Pugh class C). The safety and efficacy of OLYSIO have not been studied in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or in decompensated patients; therefore particular caution is recommended when prescribing OLYSIO to these patients (see sections 4.2 and 5.2). Laboratory testing during treatment with OLYSIO, peginterferon alfa and ribavirin HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated (see also guidelines for treatment duration and stopping rules; section 4.2). Use of a sensitive quantitative HCV RNA assay for monitoring HCV RNA levels during treatment is recommended. Refer to the Summary of Product Characteristics of peginterferon alfa and ribavirin for baseline, on-treatment and post-treatment laboratory testing requirements including haematology, biochemistry (including hepatic enzymes and bilirubin), and pregnancy testing requirements. Interactions with medicinal products Co-administration of OLYSIO with substances that moderately or strongly induce or inhibit cytochrome P450 3A (CYP3A4) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively. Please refer to section 4.5 for information on interactions with medicinal products. Hepatitis B Virus (HBV) co-infection The safety and efficacy of OLYSIO for the treatment of HCV infection in patients co-infected with HBV have not been studied. Organ transplant patients Co-administration of OLYSIO with ciclosporin is not recommended as this leads to significantly higher exposure of simeprevir based on interim data from an ongoing phase 2 study in HCV infected post-liver transplant patients (see section 4.5). Excipient of OLYSIO capsules OLYSIO capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Medicinal products that affect simeprevir exposure The primary enzyme involved in the biotransformation of simeprevir is CYP3A4 (see section 5.2) and clinically relevant effects of other medicinal products on simeprevir pharmacokinetics via CYP3A4 may occur. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A4 may significantly increase the plasma exposure of simeprevir, while co-administration with moderate or strong inducers of CYP3A4 may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see table 3). Therefore, co-administration of OLYSIO with substances that moderately or strongly inhibit or induce CYP3A4 is not recommended. Hepatic uptake of simeprevir is mediated by OATP1B1. Inhibitors of OATP1B1 such as eltrombopag or gemfibrozil may result in mild increases in simeprevir plasma concentrations. Medicinal products that are affected by the use of simeprevir Simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Co-administration of OLYSIO with medicinal products that are primarily metabolised by CYP3A4 may result in increased plasma concentrations of such medicinal products (see table 3). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir inhibits OATP1B1 and P-gp transporters. Co-administration of OLYSIO with medicinal products that are substrates for OATP1B1 and P-gp transport may result in increased plasma concentrations of such medicinal products (see table 3). Interaction table Established and theoretical interactions between simeprevir and selected medicinal products are listed in table 3 (least square mean ratios with 90% confidence intervals (90% CI) are presented, increase is indicated as “↑”, decrease as “↓”, no change as “↔”). Interaction studies have been performed in healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted.
Pregnancy There are no adequate and well-controlled studies with simeprevir in pregnant women. Studies in animals have shown reproductive effects (see section 5.3). OLYSIO should only be used during pregnancy or in women of childbearing potential if the benefit justifies the risk. Female patients of childbearing potential must use an effective form of contraception. Because OLYSIO must be co-administered with other medicinal products, for the treatment of CHC, the contraindications and warnings applicable to those medicinal products also apply to their use in combination treatment with OLYSIO (see section 4.3). Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Female patients of childbearing potential and male patients with female partners of childbearing potential must use an effective form of contraception during treatment with ribavirin and after completion of ribavirin treatment for a duration as specified in the Summary of Product Characteristics for ribavirin. Breast-feeding It is not known whether simeprevir or its metabolites are excreted in human milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk (see section 5.3). A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from OLYSIO therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother. Fertility There are no data on the effect of simeprevir on human fertility. No effects on fertility were observed in animal studies (see section 5.3). 4.7 Effects on ability to drive and use machines OLYSIO has no or negligible influence on the ability to drive and use machines. Combination treatment of OLYSIO with other medicinal products for the treatment of CHC may affect a patient's ability to drive and use machines. Refer to the Summary of Product Characteristics for these co-administered medicinal products regarding their potential effect on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Use with peginterferon alfa and ribavirin The overall safety profile of simeprevir in combination with peginterferon alfa and ribavirin in patients with HCV genotype 1 infection who were treatment-naïve or who failed prior interferon therapy with or without ribavirin is based on the pooled data from 2 clinical phase 2 studies (studies C205 and C206) and 3 clinical phase 3 studies (studies C208, C216 and HPC3007). The pooled data from these phase 2 and phase 3 studies included 1,486 patients who received simeprevir in combination with peginterferon alfa and ribavirin (of which 924 patients were to receive simeprevir 150 mg once daily for 12 weeks) and 540 patients who received placebo with peginterferon alfa and ribavirin. In the pooled phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with simeprevir were grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 3.1% of patients receiving simeprevir with peginterferon alfa and ribavirin versus 0.5% of patients receiving placebo with peginterferon alfa and ribavirin. Serious adverse reactions were reported in 0.3% of simeprevir-treated patients (2 photosensitivity events requiring hospitalisation) and in none of the patients receiving placebo with peginterferon alfa and ribavirin. During the first 12 weeks of treatment, the most frequently reported adverse reactions (incidence ≥ 5%) were nausea, rash, pruritus, dyspnoea, blood bilirubin increase and photosensitivity reaction (see section 4.4). Discontinuation of simeprevir due to adverse reactions occurred in 0.9% of patients receiving simeprevir with peginterferon alfa and ribavirin. The safety profile of simeprevir is comparable between patients with HCV genotype 4 infection and genotype 1 infection. Tabulated list of adverse reactions Adverse reactions are reported in table 4. The adverse reactions are listed by system organ class (SOC) and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).
Rash and pruritus During the 12 weeks treatment with simeprevir, rash and pruritus were observed in 21.8% and 21.9% of simeprevir-treated patients, compared to 16.6% and 14.6% in patients treated with placebo, peginterferon alfa and ribavirin, respectively (all grades; pooled phase 3). Most of the rash and pruritus events in simeprevir-treated patients were of mild or moderate severity (grade 1 or grade 2). Grade 3 rash or pruritus occurred in 0.5% and 0.1% of simeprevir-treated patients, respectively. Discontinuation of simeprevir due to rash or pruritus occurred in 0.8% and 0.1% of simeprevir-treated patients, compared to 0.3% and no patients treated with placebo, peginterferon alfa and ribavirin, respectively. Blood bilirubin increased During the 12 weeks treatment with simeprevir, 'blood bilirubin increased' was reported in 7.4% of simeprevir-treated patients, compared to 2.8% in patients treated with placebo, peginterferon alfa and ribavirin (all grades; pooled phase 3). In 2% and 0.3% of the simeprevir-treated patients grade 3 or grade 4 'blood bilirubin increased' was reported, respectively (pooled phase 3 studies). Discontinuation of simeprevir due to 'blood bilirubin increased' was rare (0.1%; n=1). During administration of simeprevir with peginterferon alfa and ribavirin, the elevations in direct and indirect bilirubin were generally not associated with elevations in liver transaminases and normalised after end of treatment. Photosensitivity reactions During the 12 weeks treatment with simeprevir, photosensitivity reactions were reported in 4.7% of simeprevir-treated patients compared to 0.8% in patients treated with placebo, peginterferon alfa and ribavirin (all grades; pooled phase 3). Most photosensitivity reactions in simeprevir-treated patients were of mild or moderate severity (grade 1 or 2); 0.3% of the simeprevir-treated patients experienced serious reactions leading to hospitalisation (see section 4.4). Dyspnoea During the first 12 weeks treatment with simeprevir, dyspnoea was reported in 11.8% of simeprevir-treated patients, compared to 7.6% in patients treated with placebo, peginterferon alfa and ribavirin (all grades; pooled phase 3). Only grade 1 and 2 events were reported and there were no events leading to discontinuation of any of the study drugs. In patients aged > 45 years, dyspnoea was reported in 16.4% of simeprevir-treated patients compared to 9.1% in patients treated with placebo, peginterferon alfa and ribavirin (all grades; pooled phase 3). Laboratory abnormalities There were no differences in haemoglobin, neutrophils or platelets between both treatment groups. Treatment-emergent laboratory abnormalities that were observed at a higher incidence in simeprevir-treated patients than in patients treated with placebo, peginterferon alfa and ribavirin are given in table 5.
In study HPC2002, assessing simeprevir in combination with sofosbuvir with or without ribavirin, no new safety findings were identified other than those observed with simeprevir in combination with peginterferon alfa and ribavirin. The most common (> 10%) adverse events reported during 12 weeks treatment with simeprevir in combination with sofosbuvir were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Other selected adverse events of interest (grouped term) reported during 12 weeks treatment with simeprevir were rash (11% in patients receiving simeprevir in combination with sofosbuvir without ribavirin versus 20% in patients receiving simeprevir in combination with sofosbuvir and ribavirin), anemia (0% versus 13%, respectively), photosensitivity reactions (7% versus 6%, respectively) and increased bilirubin (0% versus 9%, respectively). Other special populations Patients co-infected with HIV-1 The safety profile of simeprevir in combination with peginterferon alfa and ribavirin is comparable between HCV genotype 1 infected patients with and without HIV-1 co-infection. Hepatic impairment Simeprevir exposure is significantly increased in patients with severe hepatic impairment (see sections 4.2 and 5.2). A trend for a higher incidence of increased bilirubin levels with increasing simeprevir plasma exposure was observed. These increases in bilirubin levels were not associated with any adverse liver safety finding. A higher incidence of anaemia in patients with advanced fibrosis has been reported. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard. Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie E-mail: medsafety@hpra.ie 4.9 Overdose Human experience of overdose with simeprevir is limited. In healthy adult subjects receiving single doses up to 600 mg or once daily doses up to 400 mg for 5 days, and in HCV infected adult patients receiving 200 mg once daily for 4 weeks, adverse reactions were consistent with those observed in clinical studies at the recommended dose (see section 4.8). There is no specific antidote for overdose with OLYSIO. In the event of an overdose with OLYSIO, it is recommended to employ the usual supportive measures and observe the patient's clinical status. Simeprevir is highly protein bound, therefore dialysis is unlikely to result in significant removal of simeprevir (see section 5.2). 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AE14. Mechanism of action Simeprevir is a specific inhibitor of the HCV NS3/4A serine protease, which is essential for viral replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively. Antiviral activity in vitro The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 nM (7.05 ng/ml) and 19 nM (14.25 ng/ml), respectively. Chimeric replicons carrying NS3 sequences derived from HCV PI treatment-naïve genotype 1a and genotype 1b patients displayed median fold change (FC) in simeprevir EC50 values of 1.4 (N=78) and 0.4 (N=59) compared to reference genotype 1b replicon, respectively. Genotype 1a and 1b isolates with a baseline Q80K polymorphism resulted in median FC in simeprevir EC50 of 11 (N=33) and 8.4 (N=2), respectively. Median simeprevir FC values against genotype 2, genotype 3, and genotype 4 baseline isolates tested were 25 (N=4), 1,014 (N=2), and 0.3 (N=8), respectively. The presence of 50% human serum reduced simeprevir replicon activity by 2.4-fold. In vitro combination of simeprevir with interferon, ribavirin, NS5A or NS5B inhibitors resulted in additive or synergistic effects. Antiviral activity in vivo Short term monotherapy data of simeprevir from studies C201 (genotype 1) and C202 (genotype 2, 3, 4, 5 and 6) in patients receiving 200 mg once daily simeprevir for 7 days is presented in table 6.
Resistance in cell culture Resistance to simeprevir was characterised in HCV genotype 1a and 1b replicon-containing cells. Ninety-six percent of simeprevir-selected genotype 1 replicons carried one or multiple amino acid substitutions at NS3 protease positions 43, 80, 155, 156, and/or 168, with substitutions at NS3 position D168 being most frequently observed (78%). Additionally, resistance to simeprevir was evaluated in HCV genotype 1a and 1b replicon assays using site-directed mutants and chimeric replicons carrying NS3 sequences derived from clinical isolates. Amino acid substitutions at NS3 positions 43, 80, 122, 155, 156, and 168 reduced in vitro simeprevir activity. Substitutions such as D168V or A, and R155K were usually associated with large reductions in susceptibility to simeprevir in vitro (FC in EC50 > 50), whereas other substitutions such as Q80K or R, S122R, and D168E displayed in vitro low level resistance (FC in EC50 between 2 and 50). Other substitutions such as Q80G or L, S122G, N or T did not reduce simeprevir activity (FC in EC50 ≤ 2). Amino acid substitutions at NS3 positions 80, 122, 155, and/or 168, associated with in vitro low level resistance to simeprevir when occurring alone, reduced simeprevir activity by more than 50-fold when present in combination. Resistance in clinical studies In a pooled analysis of patients treated with 150 mg simeprevir in combination with peginterferon alfa and ribavirin who did not achieve SVR in the controlled phase 2 and phase 3 clinical studies, emerging amino acid substitutions at NS3 positions 80, 122, 155 and/or 168 were observed in 180 out of 197 (91%) patients. Substitutions D168V and R155K alone or in combinations with other mutations at these positions emerged most frequently (table 7). Most of these emerging substitutions have been shown to reduce simeprevir anti-HCV activity in cell culture replicon assays. HCV genotype 1 subtype-specific patterns of simeprevir treatment-emergent amino acid substitutions were observed in patients not achieving SVR. Patients with HCV genotype 1a predominantly had emerging R155K alone or in combination with amino acid substitutions at NS3 positions 80, 122 and/or 168, while patients with HCV genotype 1b had most often an emerging D168V substitution (table 7). In patients with HCV genotype 1a with a baseline Q80K amino acid substitution an emerging R155K substitution was observed most frequently at failure.
In study HPC2002 in genotype 1 infected patients treated with simeprevir in combination with sofosbuvir with or without ribavirin, 5 out of 6 patients (83%) with relapse had emerging amino acid substitutions R155K or D168E. No emerging amino acid substitutions associated with sofosbuvir resistance were observed. Persistence of resistance–associated substitutions The persistence of simeprevir-resistant NS3 amino acid substitutions was assessed following treatment failure. In the pooled analysis of patients receiving 150 mg simeprevir in combination with peginterferon alfa and ribavirin in the controlled phase 2 and phase 3 studies, treatment-emergent simeprevir-resistance variants were no longer detectable in 90 out of 180 patients (50%) at the end of the studies after a median follow-up of 28 weeks (range 0-70 weeks). In 32 out of 48 patients (67%) with emerging single D168V and in 34 out of 66 (52%) patients with emerging single R155K, the respective emerging variants were no longer detected at end of the studies. Data from an ongoing, long-term follow-up study (study HPC3002) in patients who did not achieve SVR with a simeprevir-based regimen in a previous phase 2 study showed that in 70% (16/23) of these patients emerging mutations were no longer detected after a median follow-up of 88 weeks (range 47-147 weeks). The long-term clinical impact of the emergence or persistence of simeprevir-resistance-associated substitutions is unknown. Effect of baseline HCV polymorphisms on treatment response Analyses were conducted to explore the association between naturally-occurring baseline NS3/4A amino acid substitutions (polymorphisms) and treatment outcome. Baseline polymorphisms at NS3 positions 43, 80, 122, 155, 156, and/or 168, associated with reduced simeprevir activity in vitro were generally uncommon (1.3%) in patients with HCV genotype 1 infection in the controlled phase 2 and phase 3 studies (n=2,007; studies C208, C216, HPC3007, C206, C205), with exception of the substitution Q80K in HCV genotype 1a patients. The observed prevalence of Q80K polymorphism at baseline in the overall HCV genotype 1 population of the phase 2 and phase 3 studies was 14%, 30% in patients with HCV genotype 1a and 0.5% in patients with HCV genotype 1b. In Europe, the observed prevalence of Q80K polymorphism in genotype 1 overall was 6% (76/1,254), 19% (73/377) in patients with HCV genotype 1a and 0.3% (3/877) in genotype 1b. The Q80K polymorphism was not observed in patients with genotype 4 (study HPC3011). In the pooled analysis of the phase 3 studies C208 and C216, and in study HPC3007, the presence of Q80K at baseline was associated with lower SVR rates in HCV genotype 1a patients treated with simeprevir in combination with peginterferon alfa and ribavirin compared to HCV genotype 1a patients treated with simeprevir in combination with peginterferon alfa and ribavirin without Q80K (table 8).
In study HPC3007, 80% (24/30) of the HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism at baseline were eligible for a total treatment duration of 24 weeks by meeting the protocol-defined RGT criteria (HCV RNA < 25 IU/ml detectable or undetectable at week 4 and undetectable HCV RNA at week 12); in these patients the SVR12 rate was 58%. Forty-three percent (13/30) of HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism at baseline had undetectable HCV RNA at week 4 (RVR); in these patients the SVR12 rate was 77%. Thirteen percent (4/30) of HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism had HCV RNA ≥ 25 IU/ml at week 4; none of these patients achieved a SVR12. Cross-resistance Some of the treatment-emergent NS3 amino acid substitutions detected in simeprevir-treated patients who did not achieve SVR in clinical studies (e.g., R155K) have been shown to reduce anti-HCV activity of telaprevir, boceprevir, and other NS3/4A PIs. The impact of prior exposure to simeprevir in patients not achieving SVR on the efficacy of subsequent HCV NS3/4A PI-based treatment regimens has not been established. There are no clinical data on the efficacy of simeprevir in patients with a history of exposure to the NS3/4A PIs telaprevir or boceprevir. Simeprevir-resistant variants studied remained susceptible to representative HCV nucleoside and non-nucleoside polymerase inhibitors, and NS5A inhibitors. Variants carrying amino-acid substitutions conferring reduced susceptibility to NS5A inhibitors (L31F/V, Y93C/H), nucleoside inhibitors (S96T, S282T) and non-nucleoside inhibitors (C316N, M414I/L, P495A) remained susceptible to simeprevir in vitro. Clinical efficacy and safety The efficacy of simeprevir in combination with peginterferon alfa and ribavirin in patients with HCV genotype 1 infection was evaluated in two phase 3 studies in treatment-naïve patients (studies C208 and C216), one phase 3 study in patients who relapsed after prior interferon-based therapy (study HPC3007), one phase 2 study in patients who failed prior therapy with peginterferon and ribavirin (including prior relapsers, partial and null responders) (study C206), and one phase 3 study in patients with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naïve or failed previous HCV therapy (study C212). The efficacy of simeprevir in combination with peginterferon alfa and ribavirin in patients with HCV genotype 4 infection was evaluated in one phase 3 study in treatment-naïve patients or patients who failed previous therapy with peginterferon and ribavirin (study HPC3011). The efficacy of simeprevir as part of an interferon-free regimen with or without ribavirin was evaluated in a phase 2a study in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0-F2, or treatment-naïve and prior null responder patients with METAVIR fibrosis score F3-F4 and compensated liver disease (study HPC2002). Prior relapsers were patients who had undetectable HCV RNA at the end of prior interferon-based therapy and detectable HCV RNA during follow-up; prior partial responders were patients with prior on-treatment ≥ 2 log10 reduction in HCV RNA from baseline at week 12 and detectable HCV RNA at the end of prior therapy with peginterferon and ribavirin; and null responders were patients with prior on-treatment < 2 log10 reduction in HCV RNA from baseline at week 12 during prior therapy with peginterferon and ribavirin. Patients in these studies had compensated liver disease (including cirrhosis), HCV RNA of at least 10,000 IU/ml, and liver histopathology consistent with CHC. In treatment-naïve and prior relapser patients, the overall duration of treatment with peginterferon alfa and ribavirin in the phase 3 studies was response-guided. In these patients, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA < 25 IU/ml detectable or undetectable at week 4 AND undetectable HCV RNA at week 12. Plasma HCV RNA levels were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System (25 IU/ml LLOQ and 15 IU/ml limit of detection). Treatment stopping rules for HCV therapy were used to ensure that patients with inadequate on-treatment virologic response discontinued treatment in a timely manner. In the phase 3 study C212 in HCV/HIV-1 co-infected patients, the overall duration of treatment with peginterferon alfa and ribavirin in treatment-naïve and prior relapser patients with cirrhosis was not response-guided; these patients received a fixed total duration of HCV treatment of 48 weeks. The total duration of treatment with peginterferon alfa and ribavirin in non-cirrhotic HCV/HIV-1 co-infected treatment-naïve or prior relapser patients was response-guided using the same criteria. SVR (virologic cure) was defined as undetectable HCV RNA 24 weeks after planned end of treatment in the C206 study and was defined as HCV RNA < 25 IU/ml detectable or undetectable 12 weeks after the planned end of treatment in the HPC2002 study and phase 3 studies. Efficacy in treatment-naïve adults with HCV genotype 1 infection Study C208 (QUEST 1) and study C216 (QUEST 2) The efficacy of simeprevir in treatment-naïve patients with HCV genotype 1 infection was demonstrated in two randomised, double-blind, placebo-controlled, 2-arm, multicenter, phase 3 studies (study C208 and study C216). The design of both studies was similar. Patients received 12 weeks of once daily treatment with 150 mg simeprevir or placebo, plus peginterferon alfa-2a (studies C208 and C216) or peginterferon alfa-2b (study C216) and ribavirin, followed by 12 or 36 weeks of therapy with peginterferon alfa and ribavirin in accordance with the on-treatment protocol-defined RGT criteria. Patients in the control groups received 48 weeks of peginterferon alfa-2a or -2b and ribavirin. In the pooled analysis of studies C208 and C216, the 785 enrolled patients had a median age of 47 years (range: 18 to 73 years; with 2% above 65 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) ≥ 30 kg/m2; 78% had HCV RNA levels > 800,000 IU/ml; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 17% of the overall population and 34% of the patients with genotype 1a had Q80K polymorphism at baseline; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype. In study C208, all patients received peginterferon alfa-2a; in study C216, 69% of the patients received peginterferon alfa-2a and 31% received peginterferon alfa-2b. The proportion of patients who discontinued all treatment due to an adverse event was 2% in the simeprevir with peginterferon alfa and ribavirin treatment group compared to 1% in the placebo with peginterferon alfa and ribavirin treatment group. Discontinuation of simeprevir or placebo alone due to an adverse event was 1% in both treatments groups. Table 9 shows the response rates in treatment-naïve adult patients with HCV genotype 1 infection.
Seventy-eight percent (404/521) of simeprevir-treated patients had undetectable HCV RNA at week 4 (RVR); in these patients the SVR12 rate was 90%. The proportion of simeprevir-treated patients with HCV RNA < 25 IU/ml detectable at week 4 was 13% (70/521); 67% achieved SVR12. Seven percent (35/521) of simeprevir-treated patients had HCV RNA ≥ 25 IU/ml at week 4; in these patients the SVR12 rate was 20%. In both C208 and C216 studies, addition of simeprevir to peginterferon alfa and ribavirin did not increase severity of patient-reported fatigue, depressive symptoms or impairments in work and daily activities beyond what was observed in patients treated with peginterferon alfa and ribavirin alone. Additionally, simeprevir-treated patients had significantly reduced time (weeks) with fatigue and impairments in work and daily activity as compared to peginterferon alfa and ribavirin alone. SVR12 rates were statistically significantly higher for the simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype subtype, baseline HCV RNA (less than or equal to 800,000 IU/ml, greater than 800,000 IU/ml), METAVIR fibrosis score, and IL28B genotype. Table 10 shows the SVR rates by METAVIR fibrosis score and IL28B genotype.
Efficacy in adults with HCV genotype 1 infection who failed previous therapy Study HPC3007 (PROMISE) This was a randomised, double-blind, placebo-controlled, 2-arm, multicenter, phase 3 study in patients with HCV genotype 1 infection who relapsed after prior interferon-based therapy. Patients received 12 weeks of once daily treatment with 150 mg simeprevir or placebo, plus peginterferon alfa-2a and ribavirin, followed by 12 or 36 weeks of therapy with peginterferon alfa-2a and ribavirin in accordance with the protocol-defined RGT criteria. Patients in the control group received 48 weeks of peginterferon alfa-2a and ribavirin. The 393 enrolled patients in study HPC3007 had a median age of 52 years (range: 20 to 71 years; with 3% above 65 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI ≥ 30 kg/m2; 84% had HCV RNA levels > 800,000 IU/ml; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 13% of the overall population and 31% of the patients with genotype 1a had Q80K polymorphism at baseline; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype. The prior interferon-based HCV therapy was peginterferon alfa-2a/ribavirin (68%) or peginterferon alfa-2b/ribavirin (27%). The proportion of patients who discontinued all treatment due to an adverse event was 0.4% in the simeprevir with peginterferon alfa and ribavirin treatment group compared to none in the placebo with peginterferon alfa and ribavirin treatment group. None of the patients discontinued simeprevir alone due to an adverse event. Table 11 shows the response rates for the simeprevir and placebo treatment groups in adult patients with HCV genotype 1 infection who relapsed after prior interferon-based therapy.
Seventy-seven percent (200/260) of simeprevir-treated patients had undetectable HCV RNA at week 4 (RVR); in these patients the SVR12 rate was 87%. The proportion of simeprevir-treated patients with HCV RNA < 25 IU/ml detectable at week 4 was 18% (47/260); 60% achieved SVR12. Five percent (12/260) of simeprevir-treated patients had HCV RNA ≥ 25 IU/ml at week 4; in these patients the SVR12 rate was 42%. In study HPC3007, the increases in severity of patient-reported fatigue, depressive symptoms and impairments in work and daily activities were comparable in both treatment groups. The increases lasted longer in patients treated with peginterferon alfa and ribavirin alone. SVR12 rates were statistically significantly higher for the simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype subtype, baseline HCV RNA (less than or equal to 800,000 IU/ml, greater than 800,000 IU/ml), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 12 shows the SVR rates by METAVIR fibrosis score and IL28B genotype.
This was a randomised, double-blind, placebo-controlled, 7-arm, phase 2 study in patients with HCV genotype 1 infection, who failed prior therapy with peginterferon alfa and ribavirin (including prior relapsers, partial responders or null responders). Patients received 12, 24 or 48 weeks of 100 mg or 150 mg simeprevir in combination with 48 weeks of peginterferon alfa-2a and ribavirin, or 48 weeks of placebo in combination with 48 weeks of peginterferon alfa-2a and ribavirin. The 462 enrolled patients in study C206 had a median age of 50 years (range: 20 to 69 years; with 3% above 65 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI ≥ 30 kg/m2; 86% had HCV RNA levels > 800,000 IU/ml; 63% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 41% had HCV genotype 1a, and 58% HCV genotype 1b; 12% of the overall population and 27% of the patients with genotype 1a had Q80K polymorphism at baseline; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 patients). Forty percent of patients were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with peginterferon alfa and ribavirin. One hundred ninety-nine patients received simeprevir 150 mg once daily (pooled analysis) of which 66 patients received simeprevir for 12 weeks, and 66 patients received placebo in combination with peginterferon alfa and ribavirin. The proportion of patients who discontinued all treatment due to an adverse event was 5% in both the 150 mg simeprevir for 12 weeks and the placebo treatment groups; none of the patients discontinued simeprevir or placebo alone. Table 13 shows the response rates for the simeprevir and placebo treatment groups in prior partial responders and null responders.
In study C206, no treatment related differences in patient reported fatigue severity were observed. Fatigue increased to similar extent and returned to baseline levels after week 48 in all treatment arms. SVR24 rates were higher in the simeprevir-treated patients compared to patients receiving placebo in combination with peginterferon alfa and ribavirin, regardless of HCV geno/subtype, METAVIR fibrosis score and IL28B genotype. Table 14 shows the SVR rates by METAVIR fibrosis scores.
Study HPC3002 Interim data from an ongoing 3-year follow-up study (study HPC3002) in patients who achieved SVR with a simeprevir-based regimen in previous phase 2 studies showed that all patients (n=166) maintained undetectable HCV RNA during a median follow-up time of 16 months. Efficacy in adults with HCV genotype 1 and HIV-1 co-infection Study C212 This is an open label, single arm phase 3 study in HIV-1 patients co-infected with HCV genotype 1 who are treatment-naïve or failed prior HCV therapy with peginterferon alfa and ribavirin (including prior relapsers, partial responders or null responders). Non-cirrhotic treatment-naïve patients or prior relapsers received 12 weeks of once daily treatment with 150 mg simeprevir plus peginterferon alfa-2a and ribavirin, followed by 12 or 36 weeks of therapy with peginterferon alfa-2a and ribavirin in accordance with the protocol-defined RGT criteria. Prior non-responder patients (partial and null response) and all cirrhotic patients (METAVIR fibrosis score F4) received 36 weeks of peginterferon alfa-2a and ribavirin after the initial 12 weeks of simeprevir in combination with peginterferon alfa-2a and ribavirin. The 106 enrolled patients in study C212 had a median age of 48 years (range: 27 to 67 years; with 2% above 65 years); 85% were male; 82% were White, 14% Black or African American, 1% Asian, and 6% Hispanic; 12% had a BMI ≥ 30 kg/m2; 86% had HCV RNA levels > 800,000 IU/ml; 68% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 13% METAVIR fibrosis score F4; 82% had HCV genotype 1a, and 17% HCV genotype 1b; 28% of the overall population and 34% of the patients with genotype 1a had Q80K polymorphism at baseline; 27% had IL28B CC genotype, 56% IL28B CT genotype, and 17% IL28B TT genotype; 50% (n=53) were HCV treatment-naïve patients, 14% (n=15) prior relapsers, 9% (n=10) prior partial responders, and 26% (n=28) prior null responders. Eighty-eight percent (n=93) of the patients were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. The median baseline HIV-1 RNA levels and CD4+ cell count in patients not on HAART were 4.18 log10 copies/ml (range: 1.3-4.9 log10 copies/ml) and 677 x 106 cells/l (range: 489-1,076 x 106 cells/l), respectively. The median baseline CD4+ cell count in patients on HAART was 561 x 106 cells/ml (range: 275-1,407 x 106 cells/ml). The proportion of patients who discontinued all treatment due to an adverse event was 3%. The proportion of patients who discontinued simeprevir alone due to an adverse event was 1%. Table 15 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and null responders.
Seventy-one percent (37/52), 93% (14/15), 80% (8/10) and 36% (10/28) of simeprevir-treated treatment-naïve patients, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these patients the SVR12 rates were 89%, 93%, 75% and 90%, respectively. Six percent (3/52), 0% (0/15), 20% (2/10) and 25% (7/28) of simeprevir-treated treatment-naïve patients, prior relapsers, prior partial responders and prior null responders, respectively, had HCV RNA ≥ 25 IU/ml at week 4. The SVR12 rates were 0% in treatment-naïve patients, prior relapsers and prior null responders and 50% (1/2) in prior partial responders. Table 16 shows the SVR rates by METAVIR fibrosis scores and IL28B genotype.
Efficacy in adults with HCV genotype 4 infection Study HPC3011 (RESTORE) This is an ongoing open label, single arm phase 3 study in patients with HCV genotype 4 infection who are treatment-naïve or failed prior therapy with peginterferon alfa and ribavirin (including prior relapsers, partial responders or null responders). Treatment-naïve patients or prior relapsers received once daily treatment with 150 mg simeprevir plus peginterferon alfa-2a and ribavirin for 12 weeks, followed by 12 or 36 weeks of therapy with peginterferon alfa-2a and ribavirin in accordance with the protocol-defined RGT criteria. Prior non-responder patients (partial and null response) received once daily treatment with 150 mg simeprevir plus peginterferon alfa-2a and ribavirin for 12 weeks, followed by 36 weeks of peginterferon alfa-2a and ribavirin. The 107 enrolled patients in study HPC3011 with HCV genotype 4 had a median age of 49 years (range: 27 to 69 years; with 5% above 65 years); 79% were male; 72% were White, 28% Black or African American, and 7% Hispanic; 14% had a BMI ≥ 30 kg/m2; 60% had HCV RNA levels > 800,000 IU/ml; 57% had METAVIR fibrosis score F0, F1, or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; none of the patients had Q80K polymorphism at baseline; 33% (n=35) were treatment-naïve HCV patients, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders. The proportion of patients who discontinued simeprevir due to an adverse event was 1%. Table 17 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and prior null responders.
Eighty percent (28/35), 82% (18/22), 40% (4/10) and 48% (19/40) of simeprevir-treated treatment-naïve patients, prior relapsers, prior partial responders and prior null responders, respectively, had undetectable HCV RNA at week 4 (RVR). In these patients the SVR12 rates were 96%, 94%, 100% and 68%, respectively. Eleven percent (4/35), 5% (1/22), 10% (1/10) and 23% (9/40) of simeprevir-treated treatment-naïve patients, prior relapsers, prior partial responders and prior null responders, respectively, had HCV RNA ≥ 25 IU/ml at week 4; none achieved SVR12. Viral breakthrough rates were 24% (11/45), 20% (5/25) and 11% (4/36) in patients with genotype 4a, 4d and 4/other, respectively. The clinical relevance of this difference in viral breakthrough rates is unknown. Table 18 shows the SVR rates by METAVIR fibrosis scores and IL28B genotype
Study HPC2002 (COSMOS) This is an open-label, randomised phase 2a study to investigate the efficacy and safety of 12 or 24 weeks of simeprevir (150 mg once daily) in combination with sofosbuvir (400 mg once daily) with or without ribavirin in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0-F2 (Cohort 1), or treatment-naïve and prior null responder patients with METAVIR fibrosis score F3-F4 and compensated liver disease (Cohort 2). The 80 enrolled patients without advanced hepatic fibrosis in Cohort 1 had a median age of 56 years (range 27 to 70 years; with 8% above 65 years); 61% were male; 71% were White, 29% Black or African American; and 25% Hispanic, 30% had a BMI ≥ 30 kg/m2; 98% had HCV RNA levels > 800,000 IU/ml; 41% had METAVIR fibrosis score F0 or F1 and 59% had METAVIR fibrosis score F2; 78% had HCV genotype 1a, and the remaining patients had HCV genotype 1b; 39% of the overall population and 50% of the patients with genotype 1a had Q80K polymorphism at baseline; 6% had IL28B CC genotype, 70% IL28B CT genotype, and 24% IL28B TT genotype. All patients were prior null responders to peginterferon alfa and ribavirin. The 87 enrolled patients with advanced hepatic fibrosis in Cohort 2 had a median age of 58 years (range 28 to 70 years; with 3% above 65 years); 67% were male; 91% were White, 9% Black or African American; and 17% Hispanic 44% had a BMI ≥ 30 kg/m2; 84% had HCV RNA levels > 800,000 IU/ml; 53% had METAVIR fibrosis score F3 and 47% had METAVIR fibrosis score F4 (cirrhosis); 78% had HCV genotype 1a, and 22% HCV genotype 1b; 31% of the overall population and 40% of the patients with genotype 1a had Q80K polymorphism at baseline; 21% had IL28B CC genotype, 56% IL28B CT genotype, and 23% IL28B TT genotype. Fifty four percent of patients were prior null responders to peginterferon alfa and ribavirin and 46% were treatment-naïve. In both cohorts, none of the patients from the 12-week treatment groups discontinued treatment due to an adverse event. In the 24-week treatment groups, the proportion of patients who discontinued treatment due to an adverse event was 3% and 2% in Cohort 1 and 2, respectively. Table 19 shows the response rates for prior null responders in Cohort 1 and for treatment-naïve and prior null responder patients in Cohort 2.
The overall SVR12 rates in patients receiving 12 weeks of simeprevir in combination with sofosbuvir with or without ribavirin were 95% (39/41) and 93% (38/41) in Cohort 1 and Cohort 2, respectively, and 94% (77/82) across both cohorts. Ribavirin use and prior treatment status (treatment-naïve and prior null responders) did not impact treatment outcome. In Cohort 1, the SVR12 rates in the 24-week treatment groups were 79% (19/24) for the simeprevir with sofosbuvir with ribavirin treatment group and 93% (14/15) in the simeprevir with sofosbuvir without ribavirin treatment group. In Cohort 2, the SVR12 rates in the 24-week treatment groups were 93% (28/30) for the simeprevir with sofosbuvir with ribavirin treatment group and 100% (16/16) in the simeprevir with sofosbuvir without ribavirin treatment group. A total of 6 patients with viral relapse were reported (6/162, 4%): 4 occurred in HCV genotype 1a patients with baseline Q80K polymorphism (3 in Cohort 1 and 1 in Cohort 2) and 2 occurred in HCV genotype 1a patients without Q80K polymorphism. Table 20 shows the SVR12 rates by HCV geno/subtype and Q80K baseline polymorphism.
The effect of simeprevir 150 mg once daily and 350 mg once daily for 7 days on the QT interval was evaluated in a randomised, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg once daily), 4-way cross-over study in 60 healthy subjects. No meaningful changes in QTc interval were observed with either the recommended dose of 150 mg once daily or the supratherapeutic dose of 350 mg once daily. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with simeprevir in one or more subsets of the paediatric population from 3 years to less than 18 years of age in the treatment of chronic viral hepatitis C (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV infected patients. Plasma exposure of simeprevir (AUC) in HCV infected patients was about 2- to 3-fold higher compared to that observed in healthy subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with peginterferon alfa and ribavirin compared with administration of simeprevir alone. Absorption The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post dose. In vitro experiments with human Caco-2 cells indicated that simeprevir is a substrate of P-gp. Effect of food on absorption Compared to intake without food, administration of simeprevir with food to healthy subjects increased the AUC by 61% after a high-fat, high-caloric (928 kcal) and 69% after a normal caloric (533 kcal) breakfast, and delayed the absorption by 1 hour and 1.5 hours, respectively. Simeprevir must be taken with food (see section 4.2). The type of food does not affect exposure to simeprevir. Distribution Simeprevir is extensively bound to plasma proteins (> 99.9%), primarily to albumin and, to a lesser extent, alfa-1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. Biotransformation Simeprevir is metabolised in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A4 system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Moderate or strong inhibitors of CYP3A4 significantly increase the plasma exposure of simeprevir, and moderate or strong inducers of CYP3A4 significantly reduce plasma exposure of simeprevir. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity. In vitro experiments show that simeprevir is a substrate for the drug transporters P-glycoprotein (P-gp), MRP2, OATP1B1, OATP2B1 and OATP1B3. Simeprevir inhibits the uptake transporters OATP1B1 and NTCP and the efflux transporters P-gp/MDR1, MRP2 and BSEP. OATP1B1 and MRP2 are involved in the transport of bilirubin into and out of hepatocytes. The in vitro inhibitory profile of simeprevir for human BCRP, OATP1B3 and OCT2 has not been studied. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (up to 98%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in faeces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation. Elimination Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in faeces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in faeces accounted for on average 31% of the administered dose. The terminal elimination half-life of simeprevir was 10 to 13 hours in healthy subjects and 41 hours in HCV infected patients receiving 200 mg simeprevir. Linearity/non-linearity Plasma Cmax and the area under the plasma concentration time curve (AUC) increased more than dose proportional after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once daily dosing. Special populations Elderly (above 65 years of age) There is limited data on the use of simeprevir in patients older than 65 years. Age (18-73 years) had no clinically meaningful effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis (n=21, age above 65 years) of HCV infected patients treated with simeprevir. No dose adjustment of simeprevir is required in elderly patients (see section 4.2). Renal impairment Renal elimination of simeprevir is negligible. Therefore, it is not expected that renal impairment will have a clinically relevant effect on the exposure to simeprevir. Compared to healthy subjects with normal renal function (classified using the Modification of Diet in Renal Disease [MDRD] eGFR formula; eGFR ≥ 80 ml/min), the mean steady-state AUC of simeprevir was 62% higher with a 90% confidence interval of 27% lower to 3.6-fold higher in subjects with severe renal impairment (eGFR below 30 ml/min). As exposure may be increased in HCV infected patients with severe renal impairment, caution is recommended when prescribing simeprevir to these patients (see section 4.2). As simeprevir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with simeprevir regarding their use in patients with renal impairment. Hepatic impairment Simeprevir is primarily metabolised by the liver. Plasma exposure of simeprevir in HCV infected patients was about 2- to 3-fold higher compared to that observed in healthy subjects. Compared to healthy subjects with normal hepatic function, the mean steady-state AUC of simeprevir was 2.4-fold higher in non-HCV infected subjects with moderate hepatic impairment (Child-Pugh class B) and 5.2-fold higher in non-HCV infected subjects with severe hepatic impairment (Child-Pugh class C). No dose adjustment of simeprevir is necessary in patients with mild or moderate hepatic impairment; no dose recommendation can be given for patients with severe hepatic impairment (Child-Pugh class C). The safety and efficacy of simeprevir have not been studied in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C), therefore particular caution is recommended in these patients (see section 4.2). Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with simeprevir regarding their use in patients with hepatic impairment. Gender No dose adjustment is necessary based on gender. Gender had no clinically relevant effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin. Body weight No dose adjustment is necessary based on body weight or body mass index. These characteristics have no clinically relevant effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin. Race No dose adjustment is necessary based on race. Population pharmacokinetic estimates of exposure of simeprevir were comparable between Caucasian and Black/African American HCV infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin. In the phase 3 studies with HCV infected patients treated with 150 mg simeprevir once daily in combination with peginterferon alfa and ribavirin, the range of simeprevir plasma exposure in Asian patients was within the range observed in non-Asian patients. However, the mean simeprevir plasma exposure for these patients (n=14) was 3.4-fold higher than in the pooled phase 3 population. Given limited data, the potential risks and benefits of simeprevir should be carefully considered prior to use in East Asian patients. Patients co-infected with HIV-1 Pharmacokinetic parameters of simeprevir were comparable between patients with HCV genotype 1 infection with or without HIV-1 co-infection. Paediatric population The pharmacokinetics of simeprevir in children aged below 18 years have not been investigated. 5.3 Preclinical safety data In rodents, simeprevir elicited toxic effects in the liver, pancreas and gastrointestinal systems. Dosing of animals resulted in similar (dogs) or lower (rats) exposures than those observed in humans at the recommended dose of 150 mg once daily. In dogs, simeprevir was associated with a reversible multifocal hepatocellular necrosis with associated increases in ALT, AST, alkaline phosphatase and/or bilirubin. This effect was observed at higher systemic exposures (11-fold) than those in humans at the recommended dose of 150 mg once daily. Simeprevir in vitro was very mildly irritating to the eyes. In vitro, simeprevir induced a phototoxic response on BALB/c 3T3 fibroblasts after UVA exposure, in the absence and presence of protein supplements. Simeprevir was not irritating to rabbit skin, and is not likely to cause skin sensitisation. There were no adverse effects of simeprevir on vital functions (cardiac, respiratory and central nervous system) in animal studies. Carcinogenicity and mutagenicity Simeprevir was not genotoxic in a series of in vitro and in vivo tests. Carcinogenicity studies with simeprevir have not been conducted. Reproductive toxicology Studies carried out in rats did not reveal significant findings on fertility, embryo-fetal development or pre- and post-natal development at any of the tested doses (corresponding to a systemic exposure in rats similar or lower than that observed in humans at the recommended dose of 150 mg once daily). Supernumerary ribs and delayed ossification were reported in mice at 4-fold higher exposures than those observed in humans at the recommended dose of 150 mg once daily. In pregnant rats, simeprevir concentrations in placenta, fetal liver and foetus were lower compared to those observed in blood. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. Environmental Risk Assessment (ERA) Simeprevir is classified as a PBT (persistent, bioaccumulative and toxic) substance (see section 6.6). 6. Pharmaceutical particulars 6.1 List of excipients Capsule content Sodium lauryl sulfate Magnesium stearate Colloidal anhydrous silica Croscarmellose sodium Lactose monohydrate Capsule shell Gelatin Titanium dioxide (E171) Black printing ink Shellac (E904) Iron oxide black (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in the original package in order to protect from light. This medicinal product does not require any special temperature storage conditions. 6.5 Nature and contents of container Opaque polyvinylchloride/polyethylene/polyvinylidenechloride (PVC/PE/PVDC) aluminium push-through blister strips of 7 capsules. Pack sizes of 7 or 28 capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 8. Marketing authorisation number(s) EU/1/14/924/001 (7 capsules) EU/1/14/924/002 (28 capsules) 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 14 May 2014 10. Date of revision of the text 26th February 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 2013年11月25日,强生（JNJ）丙肝新药OLYSIO（simeprevir）已获FDA批准，联合聚乙二醇干扰素和利巴韦林（ribavirin），用于基因型1慢性丙型肝炎成人患者代偿性肝脏疾病（包括肝硬化）的治疗。 此前，FDA已于今年5月授予simeprevir新药申请（NDA）优先审查资格，同时该药于今年10月获得了FDA顾问委员会建议批准的积极意见。 Simeprevir监管文件的提交，部分由3个关键性III期临床试验数据支持：QUEST-1和QUEST-2在初治患者中开展，PROMISE则在基于干扰素疗法治疗后复发的患者中开展。 丙型肝炎（HCV）是一种血源性传染性肝脏疾病，若不及时治疗，可能对肝脏造成重大损害。在美国，约有320万丙型肝炎患者，每年约有1.5万人死于该病，大多死于丙型肝炎相关疾病，如肝硬化和肝癌。 关于OLYSIO（simeprevir）： Simeprevir是新一代NS3/4A蛋白酶抑制剂，为每日一次的口服药物，由Medivir公司和杨森（Janssen）联合开发，用于治疗慢性丙型肝炎成年患者的代偿性肝病，包括各个阶段的肝纤维化，其工作原理是通过阻断蛋白酶，来抑制HCV在肝脏细胞中的复制。 今年9月，simeprevir（在日本的商品名为Sovriad）获日本劳动卫生福利部（MHLW）批准，与聚乙二醇化干扰素和利巴韦林（ribavirin）联合用药，用于基因型-1慢性丙型肝炎病毒（HCV）感染者的治疗，这是simeprevir获得的全球首个监管批准。 simeprevir是一种新的直接作用抗病毒药物，也是第二代蛋白酶抑制剂，给药方式为：simeprevir+聚乙二醇干扰素+利巴韦林联合治疗12周，随后进行聚乙二醇干扰素+利巴韦林治疗12周或36周。 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Olysio（simeprevir hard capsules）简介：
新型丙型肝炎病毒药物Olysio（simeprevir hard capsules）获批上市近日，强生（JNJ）丙肝新药OLYSIO（simeprevir）获欧盟批准，联合其他药物，用于丙型肝炎病毒（HCV)基因型1和4慢性丙型肝炎（CHC）成人 ... 责任编辑：admin |
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