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Olysio

CLINICAL PHARMACOLOGY

Mechanism Of Action

Simeprevir is a direct-acting antiviral (DAA) agent against the hepatitis C virus [see Microbiology].

Pharmacodynamics

Evaluation of Effects on Electrocardiogram

The effect of simeprevir 150 mg once daily and 350 mg once daily for 7 days on the QT interval was evaluated in a randomized, 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.

Pharmacokinetics

The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and the area under the plasma concentration time curve (AUC) increased more than dose-proportionally 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. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2-to 3-fold higher compared to that observed in HCV-uninfected 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. In HCV-infected subjects, the mean steady-state predose plasma concentration was 1936 ng/mL (standard deviation: 2640) and the mean steady-state AUC24 was 57469 ng.h/mL (standard deviation: 63571).

Absorption

Simeprevir is orally bioavailable. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post dose.

In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp.

Effects of Food on Oral Absorption

Administration of simeprevir with food to healthy subjects increased the relative bioavailability (AUC) by 61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively.

Distribution

Simeprevir is extensively bound to plasma proteins (greater than 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.

In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3.

Metabolism

Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir [see DRUG INTERACTIONS].

Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) 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 feces 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 feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose.

The terminal elimination half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects receiving 200 mg simeprevir.

Specific Populations

Geriatric Use

There is limited data on the use of OLYSIO in patients aged 65 years and older. Age (18-73 years) had no clinically meaningful effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV-infected subjects treated with OLYSIO. No dose adjustment of OLYSIO is required in geriatric patients [see Use In Specific Populations].

Renal Impairment

Renal elimination of simeprevir is negligible. Compared to HCV-uninfected subjects with normal renal function (classified using the Modification of Diet in Renal Disease [MDRD] eGFR formula; eGFR greater than or equal to 80 mL/min) the mean steady-state AUC of simeprevir was 62% higher in HCV-uninfected subjects with severe renal impairment (eGFR below 30 mL/min). Based on the observed and expected changes in simeprevir exposure, no dose adjustment of OLYSIO is needed in patients with mild, moderate or severe renal impairment. The safety and efficacy of OLYSIO have not been studied in HCV-infected patients with severe renal impairment or end-stage renal disease, including patients requiring dialysis [see Use In Specific Populations].

In a population pharmacokinetic analysis of mild or moderate renally impaired HCV-infected subjects treated with OLYSIO 150 mg once daily, creatinine clearance was not found to influence the pharmacokinetic parameters of simeprevir. It is therefore not expected that renal impairment will have a clinically relevant effect on the exposure to simeprevir.

As simeprevir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Refer to the respective prescribing information for peginterferon alfa and ribavirin regarding use in patients with renal impairment.

Hepatic Impairment

Simeprevir is primarily metabolized by the liver. Compared to HCV-uninfected subjects with normal hepatic function, the mean steady-state AUC of simeprevir was 2.4-fold higher in HCV-uninfected subjects with moderate hepatic impairment (Child-Pugh Class B) and 5.2-fold higher in HCV-uninfected subjects with severe hepatic impairment (Child-Pugh Class C). No dose adjustment of OLYSIO is necessary in patients with mild hepatic impairment (Child-Pugh Class A). 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). In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. No dose recommendation can be given for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients with moderate or severe hepatic impairment [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Based on a population pharmacokinetic analysis of HCV-infected subjects treated with OLYSIO, liver fibrosis stage did not have a clinically relevant effect on the pharmacokinetics of simeprevir.

Refer to the respective prescribing information for peginterferon alfa and ribavirin regarding use in patients with hepatic impairment.

Gender, Body Weight, Body Mass Index

No dose adjustment is necessary based on gender, body weight or body mass index. These characteristics have no clinically meaningful relevant effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV-infected subjects treated with OLYSIO.

Race

Based on results from studies in HCV-uninfected subjects and HCV-infected subjects, simeprevir exposures are higher in Asians compared to Caucasians. In the Phase 3 trials, the mean simeprevir plasma exposure in Asian subjects (n=14) was 3.4-fold higher than in the pooled Phase 3 population. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients of East Asian ancestry [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Population pharmacokinetic estimates of exposure of simeprevir were comparable between Caucasian and Black/African American HCV-infected subjects.

Drug Interactions

[See also WARNING AND PRECAUTIONS and DRUG INTERACTIONS]

In vitro studies indicated that simeprevir is a substrate and mild inhibitor of CYP3A and a substrate and inhibitor of P-gp and OATP1B1/3. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. In vivo, simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity.

Simeprevir is transported into the liver by OATP1B1/3 where it undergoes metabolism by CYP3A. Based on results from in vivo studies, co-administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir, which may lead to loss of efficacy.

Drug interaction studies were performed in healthy adults with simeprevir (at the recommended dose of 150 mg once daily unless otherwise noted) and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and Cmin values of simeprevir are summarized in Table 6 (effect of other drugs on OLYSIO). The effect of co-administration of OLYSIO on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 7 (effect of OLYSIO on other drugs). For information regarding clinical recommendations, see DRUG INTERACTIONS.

Table 6: Drug Interactions: Pharmacokinetic Parameters for Simeprevir in the Presence of Co-administered Drugs

Drug Dose and Schedule N Effect on PK * LS Mean Ratio (90% CI) of Simeprevir PK Parameters with/without Drug
Drug Simeprevir Cmax AUC Cmin
Erythromycin 500 mg t.i.d. for 7 days 150 mg q.d. for 7 days 24 4.53
(3.91-5.25)
7.47
(6.41-8.70)
12.74
(10.19-15.93)
Escitalopram 10 mg q.d. for 7 days 150 mg q.d. for 7 days 18 0.80
(0.71-0.89)
0.75
(0.68-0.83)
0.68
(0.59-0.79)
Rifampin 600 mg q.d. for 7 days 200 mg q.d. for 7 days 18 1.31
(1.03-1.66)
0.52
(0.41-0.67)
0.08
(0.06-0.11)
Anti-HIV Drugs
Darunavir/Ritonavir† 800/100 mg q.d. for 7 days 50 mg and 150 mg q.d. for 7 days 25 1.79
(1.55-2.06)
2.59
(2.15-3.11)
4.58
(3.54-5.92)
Efavirenz 600 mg q.d. for 14 days 150 mg q.d. for 14 days 23 0.49
(0.44-0.54)
0.29
(0.26-0.33)
0.09
(0.08-0.12)
Raltegravir 400 mg b.i.d. for 7 days 150 mg q.d. for 7 days 24 0.93
(0.85-1.02)
0.89
(0.81-0.98)
0.86
(0.75-0.98)
Rilpivirine 25 mg q.d. for 11 days 150 mg q.d. for 11 days 21 1.10
(0.97-1.26)
1.06
(0.94-1.19)
0.96
(0.83-1.11)
Ritonavir 100 mg b.i.d. for 15 days 200 mg q.d. for 7 days 12 4.70
(3.84-5.76)
7.18
(5.63-9.15)
14.35
(10.29-20.01)
Tenofovir disoproxil fumarate 300 mg q.d. for 7 days 150 mg q.d. for 7 days 24 0.85
(0.73-0.99)
0.86
(0.76-0.98)
0.93
(0.78-1.11)
CI = Confidence Interval; N = number of subjects with data; NA = not available; PK = pharmacokinetics; LS = least square; q.d. = once daily; b.i.d. = twice daily; t.i.d. = three times a day
* The direction of the arrow (↑ = increase, ↓ = decrease, ↔= no change) indicates the direction of the change in PK (i.e., AUC).
† The dose of OLYSIO in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir compared to 150 mg once daily in the OLYSIO alone treatment group.

Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of OLYSIO

Drug Dose and Schedule N Effect on PK * LS Mean Ratio (90% CI) of Co-Administered Drug PK Parameters with/without OLYSIO
Drug Simeprevir Cmax AUC Cmin
Atorvastatin 2-hydroxy-atorvastatin 40 mg single dose 150 mg q.d. for 10 days 18 1.70
(1.42-2.04)
2.12
(1.72-2.62)
NA
1.98
(1.70-2.31)
2.29
(2.08-2.52)
NA
Caffeine 150 mg 150 mg q.d. for 11 days 16 1.12
(1.06-1.19)
1.26
(1.21-1.32)
NA
Cyclosporine 100 mg single dose 150 mg q.d. for 7 days 14 1.16
(1.07-1.26)
1.19
(1.13-1.26)
NA
Dextromethorphan Dextrorphan 30 mg 150 mg q.d. for 11 days 16 1.21
(0.93-1.57)
1.08
(0.87-1.35)
1.03
(0.93-1.15)
1.09
(1.03-1.15)
NA NA
Digoxin 0.25 mg single dose 150 mg q.d. for 7 days 16 1.31
(1.14-1.51)
1.39
(1.16-1.67)
NA
Erythromycin 500 mg t.i.d. for 7 days 150 mg q.d. for 7 days 24 1.59
(1.23-2.05)
1.90
(1.53-2.36)
3.08
(2.54-3.73)
Escitalopram 10 mg q.d. for 7 days 150 mg q.d. for 7 days 17 1.03
(0.99-1.07)
1.00
(0.97-1.03)
1.00
(0.95-1.05)
Ethinyl estradiol (EE), co-administered with norethindrone (NE) 0.035 mg q.d. EE + 1 mg q.d. NE for 21 days 150 mg q.d. for 10 days 18 1.18
(1.09-1.27)
1.12
(1.05-1.20)
1.00
(0.89-1.13)
Midazolam (oral) 0.075 mg/kg 150 mg q.d. for 10 days 16 1.31
(1.19-1.45)
1.45
(1.35-1.57)
NA
Midazolam (i.v.) 0.025 mg/kg 150 mg q.d. for 11 days 16 0.78
(0.52-1.17)
1.10
(0.95-1.26)
NA
R(-) methadone† 30-150 mg q.d., individualised dose 150 mg q.d. for 7 days 12 1.03
(0.97-1.09)
0.99
(0.91-1.09)
1.02
(0.93-1.12)
Norethindrone NE), co-administered with EE 0.035 mg q.d. EE + 1 mg q.d. NE for 21 days 150 mg q.d. for 10 days 18 1.06
(0.99-1.14)
1.15
(1.08-1.22)
1.24
(1.13-1.35)
Omeprazole 40 mg single dose 150 mg q.d. for 11 days 16 1.14
(0.93-1.39)
1.21
(1.00-1.46)
NA
Rifampin 25-desacetyl-rifampin 600 mg q.d. for 7 days 200 mg q.d. for 7 days 18 0.92
(0.80-1.07)
1.00
(0.93-1.08)
17 1.08
(0.98-1.19)
1.24
(1.13-1.36)
NA NA
Rosuvastatin 10 mg single dose 150 mg q.d. for 7 days 16 3.17
(2.57-3.91)
2.81
(2.34-3.37)
NA
Simvastatin Simvastatin acid 40 mg single dose 150 mg q.d. for 10 days 18 1.46
(1.17-1.82)
1.51
(1.32-1.73)
NA
3.03
(2.49-3.69)
1.88
(1.63-2.17)
NA
Tacrolimus 2 mg single dose 150 mg q.d. for 7 days 14 0.76
(0.65-0.90)
0.83
(0.59-1.16)
NA
S-Warfarin 10 mg single dose 150 mg q.d. for 11 days 16 1.00
(0.94-1.06)
1.04
(1.00-1.07)
NA

Anti-HIV Drugs

Darunavir‡ Ritonavir‡ 800mg q.d. for 7 days 50 mg q.d. for 7 days 25 1.04
(0.99-1.10)
1.18
(1.11-1.25)
1.31
(1.13-1.52)
100 mg q.d. for 7 days 1.23
(1.44-1.32)
1.32
(1.25-1.40)
1.44
(1.30-1.61)
Efavirenz 600 mg q.d. for 14 days 150 mg q.d. for 14 days 23 0.97
(0.89-1.06)
0.90
(0.85-0.95)
0.87
(0.81-0.93)
Raltegravir 400 mg b.i.d. for 7 days 150 mg q.d. for 7 days 24 1.03
(0.78-1.36)
1.08
(0.85-1.38)
1.14
(0.97-1.36)
Rilpivirine 25 mg q.d. for 11 days 150 mg q.d. for 11 days 23 1.04
(0.95-1.13)
1.12
(1.05-1.19)
1.25
(1.16-1.35)
Tenofovir disoproxil fumarate 300 mg q.d. for 7 days 150 mg q.d. for 7 days 24 1.19
(1.10-1.30)
1.18
(1.13-1.24)
1.24
(1.15-1.33)
CI = Confidence Interval; i.v.= intravenous; N = number of subjects with data; NA = not available; PK = pharmacokinetics; LS = least square; q.d. = once daily; b.i.d. = twice daily; t.i.d. = three times a day
* The direction of the arrow
(↑ = increase, ↓ = decrease, ↔= no change) indicates the direction of the change in PK (i.e., AUC).
† The interaction between OLYSIO and the drug was evaluated in a pharmacokinetic study in opioid-dependent adults on stable methadone maintenance therapy.
‡ The dose of OLYSIO in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir which is lower than the recommended 150 mg dose.

Microbiology

Mechanism of Action

Simeprevir is an inhibitor of the HCV NS3/4A 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

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. Activity of simeprevir against a selection of genotype 1a (N=78) and genotype 1b (N=59) chimeric replicons carrying NS3 sequences derived from HCV NS3/4A protease-inhibitor-na´ve subjects resulted in median fold change (FC) in EC50 values of 1.4 (interquartile range, IQR: 0.8 to 11) and 0.4 (IQR: 0.3 to 0.7) compared to reference genotype 1b replicon, respectively. Genotype 1a (N=33) and 1b (N=2) isolates with a baseline Q80K polymorphism resulted in median FC in simeprevir EC50 value of 11 (IQR: 7.4 to 13) and 8.4, respectively. The presence of 50% human serum reduced simeprevir replicon activity by 2.4-fold. Combination of simeprevir with interferon, ribavirin, NS5A inhibitors, NS5B nucleoside analog polymerase inhibitors or NS5B non-nucleoside analog polymerase inhibitors, including NS5B thumb 1-, thumb 2-, and palm-domain targeting drugs, was not antagonistic.

Resistance in Cell Culture

Resistance to simeprevir was characterized in HCV genotype 1a and 1b replicon-containing cells. Ninety-six percent (96%) of simeprevir-selected genotype 1 replicons carried one or multiple amino acid substitutions at NS3 protease positions F43, Q80, R155, A156, and/or D168, 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 F43, Q80, S122, R155, A156, and D168 reduced susceptibility to simeprevir. Replicons with D168V or A, and R155K substitutions displayed large reductions in susceptibility to simeprevir (FC in EC50 value greater than 50), whereas other substitutions such as Q80K or R, S122R, and D168E displayed lower reductions in susceptibility (FC in EC50 value between 2 and 50). Other substitutions such as Q80G or L, S122G, N or T did not reduce susceptibility to simeprevir in the replicon assay (FC in EC50 value lower than 2). Amino acid substitutions at NS3 positions Q80, S122, R155, and/or D168 that were associated with lower reductions in susceptibility to simeprevir when occurring alone, reduced susceptibility to simeprevir by more than 50-fold when present in combination.

Resistance in Clinical Studies

In a pooled analysis of subjects treated with 150 mg OLYSIO in combination with peginterferon alfa and ribavirin who did not achieve SVR in the controlled Phase 2b and Phase 3 clinical trials, emerging amino acid substitutions at NS3 positions Q80, S122, R155 and/or D168 were observed in 180 out of 197 (91%) subjects. Substitutions D168V and R155K alone or in combination with other substitutions at these positions emerged most frequently (Table 8). Most of these emerging substitutions have been shown to reduce susceptibility to simeprevir in cell culture replicon assays.

HCV genotype 1 subtype-specific patterns of simeprevir treatment-emergent amino acid substitutions were observed in subjects not achieving SVR. Subjects with HCV genotype 1a predominately had emerging R155K alone or in combination with amino acid substitutions at NS3 positions Q80, S122 and/or D168, while subjects with HCV genotype 1b had most often an emerging D168V substitution (Table 8). In subjects with HCV genotype 1a with a baseline Q80K amino acid substitution an emerging R155K substitution was observed most frequently at failure.

Table 8: Treatment-Emergent Amino Acid Substitutions in Pooled Phase 2b and Phase 3 Trials: Subjects who did not Achieve SVR with 150 mg OLYSIO in Combination with Peginterferon alfa and Ribavirin

Emerging Amino Acid Substitutions in NS3 Genotype 1a *
N=116
% (n)
Genotype 1b
N=81
% (n)
Any substitution at NS3 position F43, Q80, S122, R155, A156, or D168† 95 (110) 86 (70)
D168E 15 (17) 17 (14)
D168V 10 (12) 61 (49)
Q80R‡ 4 (5) 12 (10)
R155K 77 (89) 0 (0)
Q80X+D168X# 4 (5) 14 (11)
R155X+D168X# 13 (15) 4 (3)
Q80K‡, S122A/G/I/T‡, S122R, R155Q, D168A, D168F‡, D168H, D168T, I170T Less than 10% Less than 10%
*May include few subjects infected with HCV genotype 1 viruses of non-1a/1b subtypes.
† Alone or in combination with other substitutions (includes mixtures).
‡ Substitutions only observed in combinations with other emerging substitutions at one or more of the NS3 positions Q80, S122, R155 and/or D168.
# Subjects with these combinations are also included in other rows describing the individual substitutions. X represents multiple amino acids. Other double or triple substitutions were observed with lower frequencies.
Note: substitutions at NS3 position F43 and A156 were selected in cell culture and associated with reduced simeprevir activity in the replicon assay but were not observed at time of failure.

Persistence of Resistance–Associated Substitutions

The persistence of simeprevir-resistant NS3 amino acid substitutions was assessed following treatment failure in the pooled analysis of subjects receiving 150 mg OLYSIO in combination with peginterferon alfa and ribavirin in the Phase 2b and Phase 3 trials. The proportion of subjects with detectable levels of treatment-emergent, resistance-associated variants was followed post treatment for a median time of 28 weeks (range 0 to 70 weeks). Resistant variants remained at detectable levels in 32 out of 66 subjects (48%) with single emerging R155K and in 16 out of 48 subjects (33%) with single emerging D168V.

The lack of detection of virus containing a resistance-associated substitution does not necessarily indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing OLYSIO-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. In the pooled analysis of the Phase 3 trials QUEST 1 and QUEST 2, and in the PROMISE trial, the efficacy of OLYSIO in combination with peginterferon alfa and ribavirin was substantially reduced in subjects infected with HCV genotype 1a virus with the NS3 Q80K polymorphism at baseline [see CLINICAL PHARMACOLOGY and Clinical Studies].

The observed prevalence of NS3 Q80K polymorphic variants at baseline in the overall population of the Phase 2b and Phase 3 trials was 14%; while the observed prevalence of the Q80K polymorphism was 30% in subjects infected with HCV genotype 1a and 0.5% in subjects infected with HCV genotype 1b. The observed prevalence of Q80K polymorphic variants at baseline in the U.S. population of the Phase 2b and Phase 3 trials was 35% overall, 48% in subjects infected with HCV genotype 1a and 0% in subjects infected with HCV genotype 1b. With the exception of the NS3 Q80K substitution, baseline polymorphic variants at NS3 positions F43, Q80, S122, R155, A156, and/or D168, which were associated with reduced simeprevir activity in replicon assays, were generally uncommon (1.3%) in subjects with HCV genotype 1 infection in the Phase 2b and Phase 3 trials (n=2007).

Cross-Resistance

Cross-resistance is expected among NS3/4A protease inhibitors. Some of the treatment-emergent NS3 amino acid substitutions detected in OLYSIO-treated subjects who did not achieve SVR in clinical trials, including R155K, which emerged frequently, and I170T, which emerged infrequently, have been shown to reduce the anti-HCV activity of the NS3/4A protease inhibitors, boceprevir and/or telaprevir.

The most frequently occurring boceprevir or telaprevir treatment-emergent NS3 amino acid substitutions that are expected to impact subsequent treatment with OLYSIO include R155K and A156T or V. The NS3 amino substitutions V36A or G and I170A or T, which displayed slight shifts in susceptibility to simeprevir in replicon cultures, may emerge in patients who do not achieve SVR with boceprevir or telaprevir, and may therefore also impact subsequent treatment with OLYSIO.

Pharmacogenomics

A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to peginterferon alfa and ribavirin (PR). In the Phase 3 trials, IL28B genotype was a stratification factor.

Overall, SVR rates were lower in subjects with the CT and TT genotypes compared to those with the CC genotype. Among both treatment-na´ve subjects and those who experienced previous treatment failures, subjects of all IL28B genotypes had the highest SVR rates with OLYSIO-containing regimens (Table 9).

Table 9: SVR12 Rates by IL28B rs12979860 Genotype

Trial (Population) IL28B rs12979860 Genotype OLYSIO + PR % (n/N) Placebo + PR % (n/N)
QUEST 1 and QUEST 2 (treatment-na´ve) C/C 95 (144/152) 80 (63/79)
C/T 78 (228/292) 41 (61/147)
T/T 61 (47/77) 21 (8/38)
PROMISE (prior relapser) C/C 89 (55/62) 53 (18/34)
C/T 78 (131/167) 34 (28/83)
T/T 65 (20/31) 19 (3/16)

SVR12: sustained virologic response 12 weeks after planned end of treatment (EOT).

Animal Toxicology And/Or Pharmacology

Cardiovascular toxicity consisting of acute endocardial and myocardial necrosis restricted to the left ventricular subendocardial area was seen in 2 out of 6 animals in a 2-week oral dog toxicity study at an exposure approximately 28 times the mean AUC in humans at the recommended daily dose of 150 mg. No cardiac findings were observed in a 6-month and a 9-month oral toxicity study at exposures, respectively, of 11 and 4 times the mean AUC in humans at the recommended daily dose of 150 mg.

Clinical Studies

The efficacy of OLYSIO in patients with HCV genotype 1 infection was evaluated in two Phase 3 trials in treatment-na´ve subjects (trials QUEST 1 and QUEST 2), one Phase 3 trial in subjects who relapsed after prior interferon-based therapy (PROMISE) and one Phase 2b trial in subjects who failed prior therapy with peginterferon (Peg-IFN) and ribavirin (RBV) (including prior relapsers, partial and null responders) (ASPIRE). Prior relapsers were subjects who had undetectable HCV RNA at the end of prior IFN-based therapy and detectable HCV RNA during follow-up; prior partial responders were subjects with prior on-treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and detectable HCV RNA at the end of prior therapy with Peg-IFN and RBV; and null responders were subjects with prior on-treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg-IFN and RBV. Subjects in these trials had compensated liver disease (including cirrhosis), HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with CHC.

In subjects who were treatment-na´ve and prior relapsers, the overall duration of treatment with Peg-IFN-alfa and RBV in the Phase 3 trials was response-guided. In these subjects, 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 lower than 25 IU/mL (detectable or undetectable) at Week 4 AND undetectable HCV RNA at Week 12. Plasma HCV RNA levels were measured using the Roche 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 subjects with inadequate on-treatment virologic response discontinued treatment in a timely manner.

SVR (virologic cure) was defined as undetectable HCV RNA 24 weeks after planned end of treatment (SVR24) in the Phase 2b trial and was defined as HCV RNA lower than 25 IU/mL detectable or undetectable 12 weeks after the planned end of treatment (SVR12) in the Phase 3 trials.

Treatment-Na´ve Adult Subjects With HCV Genotype 1 Infection

The efficacy of OLYSIO in treatment-na´ve patients with HCV genotype 1 infection was demonstrated in two randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The design of both trials was similar. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, plus Peg-IFN-alfa-2a (QUEST 1 and QUEST 2) or Peg-IFN-alfa-2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa and RBV in accordance with the on-treatment protocol-defined RGT criteria. Subjects in the control groups received 48 weeks of Peg-IFN-alfa-2a or -2b and RBV.

In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the OLYSIO and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m²; 78% had HCV RNA levels greater than 800000 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; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg-IFN-alfa-2a; in QUEST 2, 69% of the subjects received Peg-IFN-alfa-2a and 31% received Peg-IFN-alfa-2b.

Table 10 shows the response rates in treatment-na´ve adult subjects with HCV genotype 1 infection. In the OLYSIO treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 10: Treatment Outcome in Treatment-Na´ve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2; Intent-to-Treat Analysis)

Treatment Outcome OLYSIO + PR
N=521
% (n/N)
Placebo + PR
N=264
% (n/N)
Overall SVR12 (genotype 1a and 1b) 80 (419/521) 50 (132/264)
  Genotype 1a 75 (191/254) 47 (62/131)
    Without Q80K 84 (138/165) 43 (36/83)
    With Q80K 58 (49/84) 52 (23/44)
  Genotype 1b 85 (228/267) 53 (70/133)
Outcome for all subjects without SVR12
On-treatment failure* 8 (42/521) 33 (87/264)
Viral relapse† 11 (51/470) 23 (39/172)
OLYSIO: 150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT. Includes 4 OLYSIO-treated subjects who experienced relapse after SVR12.

In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of OLYSIO-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 88% (405/459).

Seventy-eight percent (78%; 404/521) of OLYSIO-treated subjects had undetectable HCV RNA at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404), while 8% (32/392) with undetectable HCV RNA at end of treatment had viral relapse.

SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 11 shows the SVR rates by METAVIR fibrosis score.

Table 11: SVR12 Rates by METAVIR Fibrosis Score in Treatment-Na´ve Adult Patients with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2)

Subgroup OLYSIO + PR
% (n/N)
Placebo + PR
% (n/N)
F0-2 84 (317/378) 55 (106/192)
F3-4 68 (89/130) 36 (26/72)

OLYSIO: 150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

SVR12 rates were higher for subjects receiving OLYSIO with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (62% and 42%, respectively) (QUEST 2).

Adult Subjects With HCV Genotype 1 Infection Who Failed Prior Therapy

The PROMISE trial was a randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN-based therapy. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Subjects in the control group received 48 weeks of Peg-IFN-alfa-2a and RBV.

Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m²; 84% had HCV RNA levels greater than 800000 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; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN-based HCV therapy was Peg-IFN-alfa-2a /RBV (68%) or Peg-IFN-alfa-2b/RBV (27%).

Table 12 shows the response rates for the OLYSIO and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon-based therapy. In the OLYSIO treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 12: Treatment Outcome in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE; Intent-to-Treat Analysis)

Treatment Outcome OLYSIO + PR
N=260
% (n/N)
Placebo + PR
N=133
% (n/N)
Overall SVR12 (genotype 1a and 1b) 79 (206/260) 37 (49/133)
  Genotype 1a 70 (78/111) 28 (15/54)
    Without Q80K 78 (62/79) 26 (9/34)
    With Q80K 47 (14/30) 30 (6/20)
  Genotype 1b 86 (128/149) 43 (34/79)
Outcome for all subjects without SVR12
On-treatment failure* 3 (8/260) 27 (36/133)
Viral relapse† 18 (46/249) 48 (45/93)
OLYSIO: 150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow-up HCV RNA assessment. Includes 5 OLYSIO-treated subjects who experienced relapse after SVR12.

In PROMISE, 93% (241/260) of OLYSIO-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241).

Seventy-seven percent (77%; 200/260) of OLYSIO-treated subjects had undetectable HCV RNA at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200), while 13% (25/196) with undetectable HCV RNA at end of treatment had viral relapse.

SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 13 shows the SVR rates by METAVIR fibrosis score.

Table 13: SVR12 Rates by METAVIR Fibrosis Score in Adult Patients with HCV Genotype 1 Infection who Relapsed after Prior Interferon-Based Therapy (PROMISE)

Subgroup OLYSIO + PR
% (n/N)
Placebo + PR
% (n/N)
F0-2 82 (137/167) 41 (40/98)
F3-4 73 (61/83) 24 (8/34)
OLYSIO: 150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

The ASPIRE trial was a randomized, double-blind, placebo-controlled, 7-arm, Phase 2b trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Subjects received 12, 24 or 48 weeks of 100 mg or 150 mg OLYSIO in combination with 48 weeks of Peg-IFN-alfa-2a and RBV, or 48 weeks of placebo in combination with 48 weeks of Peg-IFN-alfa-2a and RBV.

Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 462 subjects enrolled in the ASPIRE trial had a median age of 50 years (range: 20 to 69 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI greater than or equal to 30 kg/m²; 86% had HCV RNA levels greater than 800000 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; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 subjects); 12% of the overall population and 27% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg-INF-alfa and RBV. One hundred ninety-nine subjects received OLYSIO 150 mg once daily (pooled analysis) of which 66 subjects received OLYSIO for 12 weeks and 66 subjects received placebo in combination with Peg-IFN-alfa and RBV.

Table 14 shows the response rates for the OLYSIO and placebo treatment groups in prior relapsers, prior partial responders and prior null responders.

Table 14: Treatment Outcome in Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy (ASPIRE Trial, Prior Partial and Null Responders)

Treatment Outcome 150 mg OLYSIO 12 Weeks + PR
N=66
% (n/N)
Pooled 100 mg and 150 mg OLYSIO 12 Weeks + PR
N=132
% (n/N)
Placebo + PR
N=66
% (n/N)
SVR24
  Prior relapser 77 (20/26) 83 (44/53) 37 (10/27)
  Prior partial responders 65 (15/23) 67 (31/46) 9 (2/23)
  Prior null responders 53 (9/17) 45 (15/33) 19 (3/16)
Outcome for all subjects without SVR24
On-treatment virologic failure *  
  Prior relapser 8 (2/26) 6 (3/53) 22 (6/27)
  Prior partial responders 22 (5/23) 20 (9/46) 78 (18/23)
  Prior null responders 35 (6/17) 36 (12/33) 75 (12/16)
Viral Relapse†
  Prior relapser 13 (3/23) 8 (4/49) 47 (9/19)
  Prior partial responders 6 (1/17) 8 (3/36) 50 (2/4)
  Prior null responders 18 (2/11) 20 (4/20) 25 (1/4)
150 mg OLYSIO: 150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks; Placebo: placebo with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR24: sustained virologic response 24 weeks after planned EOT.
* On-treatment virologic failure was defined as the proportion of subjects who met the protocol-specified treatment stopping rules (including stopping rule due to viral breakthrough) or who had detectable HCV RNA at EOT (for subjects who completed therapy).
† Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at EOT and with at least one follow-up HCV RNA assessment.

In prior partial responders, SVR24 rates in subjects receiving OLYSIO with Peg-IFN-alfa and RBV were 47% and 77% in subjects with HCV genotype 1a and 1b, respectively, compared to 13% and 7%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV. In prior null responders, SVR24 rates in subjects receiving OLYSIO with Peg-IFN-alfa and RBV were 41% and 47% in subjects with HCV genotype 1a and 1b, respectively, compared to 0% and 33%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV.

SVR24 rates were higher in the OLYSIO-treated subjects compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype.

Last reviewed on RxList: 1/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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