June 30, 2016
Recommended Topic Related To:

Olysio

"The U.S. Food and Drug Administration today approved Sovaldi (sofosbuvir) to treat chronic hepatitis C virus (HCV) infection. Sovaldi is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the "...

A A A

Olysio

CLINICAL PHARMACOLOGY

Mechanism Of Action

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

Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc study in 60 healthy subjects, simeprevir 150 mg (recommended dose) and 350 mg (2.3 times the recommended dose) did not affect the QT/QTc interval.

Pharmacokinetics

The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and 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 Peg-IFN-alfa and RBV compared with administration of simeprevir alone. In Phase 3 trials with Peg-IFN-alfa and RBV in HCV-infected subjects, the geometric mean steady-state pre-dose plasma concentration was 1009 ng/mL (geometric coefficient of variation [gCV] = 162%) and the geometric mean steady-state AUC24 was 39140 ng.h/mL (gCV = 98%).

Absorption

The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of OLYSIO in fed conditions is 62%. 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

Compared to intake without food, administration of simeprevir with food to healthy subjects increased the AUC by 61% after a high-fat, high-caloric breakfast (928 kcal) and by 69% after a normal-caloric breakfast (533 kcal), 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 (1.3 times the recommended dosage) 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 (1.3 times the recommended dosage) of 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 [see Use in Specific Populations].

Renal Impairment

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).

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 [see Use in Specific Populations].

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

Hepatic Impairment

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) [see Use in Specific Populations].

Based on a population pharmacokinetic analysis of HCV-infected subjects with mild hepatic impairment (Child-Pugh Class A) treated with OLYSIO, liver fibrosis stage did not have a clinically relevant effect on the pharmacokinetics of simeprevir.

Gender, Body Weight, Body Mass Index

Gender, body weight or body mass index 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

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

In a Phase 3 trial conducted in China and South Korea, the mean plasma exposure of simeprevir in East Asian HCV-infected subjects was 2.1-fold higher compared to non-Asian HCV-infected subjects in a pooled Phase 3 population from global trials [see Use in Specific Populations].

Patients Co-infected with HIV-1

Simeprevir exposures were slightly lower in subjects with HCV genotype 1 infection with HIV-1 co-infection compared to subjects with HCV genotype 1 mono-infection. This difference is not considered to be clinically meaningful.

Drug Interactions

[See also WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]

In vitro studies indicated that simeprevir is a substrate and mild inhibitor of CYP3A. 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 not a clinically relevant inhibitor of cathepsin A enzyme activity.

In vitro, simeprevir is a substrate for P-gp, MRP2, BCRP, OATP1B1/3 and OATP2B1; simeprevir inhibits the uptake transporters OATP1B1/3 and NTCP and the efflux transporters P-gp/MDR1, MRP2, BCRP and BSEP and does not inhibit OCT2. The inhibitory effects of simeprevir on the bilirubin transporters OATP1B1/3 and MRP2 likely contribute to clinical observations of elevated bilirubin [see ADVERSE REACTIONS].

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 9 (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 10 (effect of OLYSIO on other drugs). For information regarding clinical recommendations, see DRUG INTERACTIONS.

Table 9: Drug Interactions: Pharmacokinetic Parameters for Simeprevir in the Presence of Co-administered Drugs

Co-administered Drug Dose (mg) and Schedule N Effect on * PK LS Mean Ratio (90% CI) of Simeprevir PK Parameters with/without Drug
Drug Simeprevir Cmax AUC Cmin
Cyclosporine† individualized dose* 150 mg q.d. for 14 days 9 4.74
(3.12-7.18)
5.81
(3.56-9.48)
NA
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)
Tacrolimus† individualized dose‡ 150 mg q.d. for 14 days 11 1.79
(1.22-2.62)
1.85
(1.18-2.91)
NA
Anti-HCV Drug
Sofosbuvir# 400 mg q.d. 150 mg q.d. 21 0.96
(0.71-1.30)
0.94
(0.67-1.33)
NA
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).
† Comparison based on historic controls. Interim data from a Phase 2 trial in combination with an investigational drug and RBV in HCV-infected post-liver transplant patients.
‡ Individualized dose at the discretion of the physician, according to local clinical practice.
# Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial.
§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 10: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of OLYSIO

Co-administered Drug Dose (mg) 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 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
2-hydroxy-atorvastatin 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) 1.03
(0.93-1.15)
1.08
(0.87-1.35) 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., individualized 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)
NA
17 1.08
(0.98-1.19)
1.24
(1.13-1.36)
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-HCV Drug
Sofosbuvir‡ 400 mg q.d. 150 mg q.d. 22 1.91
(1.26-2.90)
3.16
(2.25-4.44)
NA
GS-331007# 0.69
(0.52-0.93)
1.09
(0.87-1.37)
NA
Anti-HIV Drugs
Darunavir§ 800 mg 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)
Ritonavir§ 100 mg q.d. for 7 days 1.23
(1.14-1.32)
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.
‡ Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial.
# Primary circulating metabolite of sofosbuvir.
§ 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. Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment-nave genotype 1a-or genotype 1b-infected patients displayed median fold change (FC) in EC50 values of 1.4 (interquartile range, IQR: 0.8 to 11; N=78) and 0.4 (IQR: 0.3 to 0.7; N=59) 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. Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment-nave genotype 4a-, 4d-, or 4r-infected patients displayed median FC in EC50 values of 0.5 (IQR: 0.4 to 0.6; N=38), 0.4 (IQR: 0.2 to 0.5; N=24), and 1.6 (IQR: 0.7 to 4.5; N=8), compared to reference genotype 1b replicon, respectively. A pooled analysis of chimeric replicons carrying the NS3 sequences from HCV protease inhibitor-nave patients infected with other HCV genotype 4 subtypes, including 4c (N=1), 4e (N=2), 4f (N=3), 4h (N=3), 4k (N=1), 4o (N=2), 4q (N=2), or unidentified subtype (N=7) displayed a median FC in EC50 value of 0.7 (IQR: 0.5 to 1.1; N=21) compared to reference genotype 1b replicon. The presence of 50% human serum reduced simeprevir replicon activity by 2.4-fold. Combination of simeprevir with IFN, RBV, NS5A inhibitors, nucleoside analog NS5B polymerase inhibitors or non-nucleoside analog NS5B 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 Peg-IFN-alfa and RBV who did not achieve SVR in the controlled Phase 2 and Phase 3 clinical trials (PILLAR, ASPIRE, QUEST 1 and QUEST 2, PROMISE), emerging virus with 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 11). 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. HCV genotype 1a predominately had emerging R155K alone or in combination with amino acid substitutions at NS3 positions Q80, S122 and/or D168, while HCV genotype 1b had most often an emerging D168V substitution (Table 11). In HCV genotype 1a with a baseline Q80K amino acid polymorphism, an emerging R155K substitution was observed most frequently at failure.

Table 11: Emergent Amino Acid Substitutions in Controlled Phase 2 and Phase 3 Trials: Subjects who did not Achieve SVR with 150 mg OLYSIO in Combination with Peg-IFN-alfa and RBV

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) 60 (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 virus carrying 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.
§ Emerged alone (n=2) or in combination with R155K (n=3).
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.

The majority of HCV genotype 1-infected subjects treated with OLYSIO in combination with sofosbuvir (with or without RBV) for 12 or 24 weeks who did not achieve SVR due to virologic reasons and with sequencing data available had emerging NS3 amino acid substitutions at position 168 and/or R155K: 5 out of 6 subjects in COSMOS and 1 out of 3 subjects in OPTIMIST-1. The emerging NS3 amino acid substitutions were similar to those observed in subjects who did not achieve SVR following treatment with OLYSIO in combination with Peg-IFN-alfa and RBV. No emerging NS5B amino acid substitutions associated with sofosbuvir resistance were observed in subjects who did not achieve SVR following treatment of OLYSIO in combination with sofosbuvir (with or without RBV) for 12 or 24 weeks.

In the RESTORE trial in genotype 4-infected subjects, 30 out of 34 (88%) subjects who did not achieve SVR had emerging amino acid substitutions at NS3 positions Q80, T122, R155, A156 and/or D168 (mainly substitutions at position D168; 26 out of 34 [76%] subjects), similar to the emerging amino acid substitutions observed in genotype 1-infected subjects.

Persistence Of Resistance–Associated Substitutions

The persistence of simeprevir-resistant virus was assessed following treatment failure in the pooled analysis of subjects receiving 150 mg OLYSIO in combination with Peg-IFN-alfa and RBV in the controlled Phase 2 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 Peg-IFN-alfa and RBV was substantially reduced in subjects infected with HCV genotype 1a virus with the NS3 Q80K polymorphism at baseline [see Clinical Studies].

The observed prevalence of NS3 Q80K polymorphic variants at baseline in the overall population of the Phase 2 and Phase 3 trials (PILLAR, ASPIRE, PROMISE, QUEST 1 and QUEST 2) 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 these Phase 2 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 polymorphism, baseline HCV variants with polymorphisms at NS3 positions F43, Q80, S122, R155, A156, and/or D168 that were associated with reduced simeprevir activity in replicon assays were generally uncommon (1.3%) in subjects with HCV genotype 1 infection in these Phase 2 and Phase 3 trials (n=2007).

The Q80K polymorphic variant was not observed in subjects infected with HCV genotype 4.

Cross-Resistance

Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance between OLYSIO and other NS3/4A protease inhibitors is expected. No cross-resistance is expected between direct-acting antiviral agents with different mechanisms of action. OLYSIO remained fully active against substitutions associated with resistance to NS5A inhibitors, NS5B nucleoside and non-nucleoside polymerase inhibitors.

Pharmacogenomics

A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C [cytosine] to T [thymine] substitution) is a strong predictor of response to Peg-IFN-alfa and RBV (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 (Tables 12 and 13). Among both treatment-nave subjects and those who experienced previous treatment failures, subjects of all IL28B genotypes had the highest SVR rates with OLYSIO-containing regimens (Table 12).

Table 12: SVR12 Rates by IL28B rs12979860 Genotype in Adult Subjects with HCV Genotype 1 Infection Receiving OLYSIO 150 mg Once Daily with Peg-IFN-alfa and RBV Compared to Subjects Receiving Placebo with Peg-IFN-alfa and RBV (QUEST 1, QUEST 2, PROMISE)

Trial (Population) IL28B rs12979860 Genotype OLYSIO + PR
% (n/N)
Placebo + PR
% (n/N)
QUEST 1 and QUEST 2 (treatment-naive subjects) 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 relapsers) 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).

Table 13: SVR12 Rates by IL28B rs12979860 Genotype in Adult Patients Receiving OLYSIO 150 mg Once Daily in Combination with Peg-IFN-alfa and RBV (C212 and RESTORE)

Trial (Population) IL28B rs12979860 Genotype Treatment-Naive Subjects % (n/N) Prior Relapsers % (n/N) Prior Partial Responders % (n/N) Prior Null Responders % (n/N)
C212 (HIV-1 co-infection) C/C 100 (15/15) 100 (7/7) 100 (1/1) 80 (4/5)
C/T 70 (19/27) 100 (6/6) 71 (5/7) 53 (10/19)
T/T 80 (8/10) 0 (0/2) 50 (1/2) 50 (2/4)
RESTORE (HCV genotype 4) C/C 100 (7/7) 100 (1/1) - -
C/T 82 (14/17) 82 (14/17) 60 (3/5) 41 (9/22)
T/T 80 (8/10) 100 (4/4) 60 (3/5) 39 (7/18)
SVR12: sustained virologic response 12 weeks after planned 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.

If OLYSIO is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on animal toxicology.

Clinical Studies

Overview Of Clinical Trials

The efficacy of OLYSIO in combination with sofosbuvir in subjects with HCV genotype 1 infection was evaluated in one Phase 2 trial (COSMOS) in prior null responders and treatment-nave subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis, and in two Phase 3 trials in subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis (OPTIMIST-2 and OPTIMIST-1, respectively) who were HCV treatment-nave or treatment-experienced (following prior treatment with IFN [pegylated or non-pegylated], with or without RBV) (see Table 14). Efficacy data from OPTIMIST-2, which evaluated OLYSIO in combination with sofosbuvir in subjects with compensated cirrhosis, are not shown because subjects in this trial received a shorter than recommended duration of therapy.

Table 14: Trials Conducted with OLYSIO in Combination with Sofosbuvir

Trial Population Relevant Study Arms (Number of Subjects Treated)
COSMOS (open-label) GT 1, TN or TE*, with compensated cirrhosis or without cirrhosis
  • OLYSIO + sofosbuvir (12 weeks) (28)
  • OLYSIO + sofosbuvir (24 weeks) (31)
OPTIMIST-1 (open-label) GT 1, TN or TE†, without cirrhosis
  • OLYSIO + sofosbuvir (12 weeks) (155)
OPTIMIST-2 (open-label) GT 1, TN or TE†, with compensated cirrhosis
  • OLYSIO + sofosbuvir (12 weeks) (103)
GT: genotype; TN: treatment-nave; TE: treatment-experienced.
* Includes only null responders to prior Peg-IFN/RBV therapy.
† Includes relapsers and non-responders to prior Peg-IFN-based therapy (with or without RBV), and IFN-intolerant subjects.

The efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection was evaluated in three Phase 3 trials in treatment-nave subjects (QUEST 1, QUEST 2 and TIGER), one Phase 3 trial in subjects who relapsed after prior interferon-based therapy (PROMISE), one Phase 2 trial in subjects who failed prior therapy with Peg-IFN and RBV (including prior relapsers, partial and null responders) (ASPIRE), and one Phase 3 trial in subjects with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-nave or failed previous HCV therapy with Peg-IFN and RBV (C212), as summarized in Table 15.

The efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 4 infection was evaluated in one Phase 3 trial in treatment-nave subjects or subjects who failed previous therapy with Peg-IFN and RBV (RESTORE) (see Table 15).

Table 15: Trials Conducted with OLYSIO in Combination with Peg-IFN-alfa and RBV

Trial Population Relevant Study Arms (Number of Subjects Treated)
QUEST-1 (double-blind) GT 1, TN, with compensated cirrhosis or without cirrhosis
  • OLYSIO + Peg-IFN-alfa + RBV (264)
  • Placebo (130)
QUEST-2 (double-blind) GT 1, TN, with compensated cirrhosis or without cirrhosis
  • OLYSIO + Peg-IFN-alfa + RBV (257)
  • Placebo (134)
TIGER (double-blind) GT 1, TN, with compensated cirrhosis or without cirrhosis
  • OLYSIO + Peg-IFN-alfa + RBV (152)
  • Placebo (152)
PROMISE (double-blind) * GT 1, TE , with compensated cirrhosis or without cirrhosis
  • OLYSIO + Peg-IFN-alfa + RBV (260)
  • Placebo (133)
ASPIRE (double-blind) GT 1, TE, with compensated cirrhosis or without cirrhosis
  • OLYSIO + Peg-IFN-alfa + RBV (66)
  • Placebo (66)
C212 (open-label) GT 1, TN or TE, with compensated cirrhosis or without cirrhosis, HCV/HIV-1 co-infected
  • OLYSIO + Peg-IFN-alfa + RBV (106)
RESTORE (open-label) GT 4, TN or TE, with compensated cirrhosis or without cirrhosis
  • OLYSIO + Peg-IFN-alfa + RBV (107)
GT: genotype; TN: treatment-nave; TE: treatment-experienced, includes prior relapsers, partial responders and null responders following prior treatment with Peg-IFN and RBV.
* Includes only relapsers after prior IFN-based therapy.

Prior relapsers were subjects who had HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected 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 HCV RNA detected 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. These trials included subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis, HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with chronic HCV infection. In subjects who were treatment-nave 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 (detected or not detected) at Week 4 AND HCV RNA not detected 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 lower limit of quantification 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. In the Phase 3 trial C212 in HCV/HIV-1 co-infected subjects, the total duration of treatment with Peg-IFN-alfa and RBV in treatment-nave and prior relapser subjects with compensated cirrhosis was not response-guided; these subjects received a fixed total duration of HCV treatment of 48 weeks. The total duration of treatment with Peg-IFN-alfa and RBV in non-cirrhotic HCV/HIV-1 co-infected treatment-nave or prior relapser subjects was response-guided using the same criteria.

OLYSIO In Combination With Sofosbuvir

Adult Subjects With HCV Genotype 1 Infection

The efficacy of OLYSIO (150 mg once daily) in combination with sofosbuvir (400 mg once daily) in HCV genotype 1-infected treatment-nave or treatment-experienced subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis was demonstrated in one Phase 2 trial (COSMOS) and one Phase 3 trial (OPTIMIST-1).

The COSMOS trial was an open-label, randomized Phase 2 trial to investigate the efficacy and safety of 12 or 24 weeks of OLYSIO (150 mg once daily) in combination with sofosbuvir (400 mg once daily) without or with RBV in HCV genotype 1-infected prior null responders with METAVIR fibrosis score F0-F2, or treatment-nave subjects and prior null responders with METAVIR fibrosis score F3-F4 and compensated liver disease. Results from treatment arms containing RBV in addition to OLYSIO and sofosbuvir in the COSMOS trial are not shown because efficacy was similar with or without RBV, and thus addition of RBV to OLYSIO and sofosbuvir is not recommended. In this trial, 28 subjects received 12 weeks of OLYSIO in combination with sofosbuvir and 31 subjects received 24 weeks of OLYSIO in combination with sofosbuvir. These 59 subjects had a median age of 57 years (range 27 to 68 years; with 2% above 65 years); 53% were male; 76% were White, and 24% Black or African American; 46% had a BMI greater than or equal to 30 kg/m² ; the median baseline HCV RNA level was 6.75 log10 IU/mL; 19%, 31% and 22% had METAVIR fibrosis scores F0-F1, F2 and F3, respectively, and 29% had METAVIR fibrosis score F4 (cirrhosis); 75% had HCV genotype 1a of which 41% carried Q80K at baseline, and 25% had HCV genotype 1b; 14% had IL28B CC genotype, 64% IL28B CT genotype, and 22% IL28B TT genotype; 75% were prior null responders to Peg-IFN-alfa and RBV, and 25% were treatment-nave.

OPTIMIST-1 was an open-label, randomized Phase 3 trial in HCV genotype 1-infected subjects without cirrhosis who were treatment-nave or treatment-experienced (including prior relapsers, non-responders and IFN-intolerant subjects). Subjects were randomized to treatment arms of different durations. One hundred fifty-five subjects received 12 weeks of OLYSIO with sofosbuvir. The 155 subjects without cirrhosis receiving 12 weeks of OLYSIO with sofosbuvir had a median age of 56 years (range 19 to 70 years; with 7% above 65 years); 53% were male; 78% were White, 20% Black or African American, and 16% Hispanic; 37% had a BMI ≥ 30 kg/m² ; the median baseline HCV RNA level was 6.83 log10 IU/mL; 75% had HCV genotype 1a of which 40% had Q80K polymorphism at baseline, and 25% had HCV genotype 1b; 28% had IL28B CC genotype, 55% IL28B CT genotype, and 17% IL28B TT genotype; 74% were treatment-nave and 26% were treatment-experienced.

In the COSMOS and OPTIMIST-1 trials, SVR12 was achieved in 170/176 (97%) subjects without cirrhosis treated with 12 weeks OLYSIO in combination with sofosbuvir, as shown in Table 16. In the COSMOS trial, 10/10 (100%) subjects with compensated cirrhosis (Child-Pugh A) who received 24 weeks of OLYSIO with sofosbuvir achieved SVR12.

Table 16: Virologic Outcomes in Adults without Cirrhosis Receiving 12 Weeks of OLYSIO with Sofosbuvir (Pooled data from OPTIMIST-1 and COSMOS Trials)

Response Rates OLYSIO+ sofosbuvir*12 weeks
N=176% (n/N)
Overall SVR12 97 (170/176)
Outcome for subjects without SVR12
  Viral relapse† 3 (5/175)
SVR12: sustained virologic response 12 weeks after actual (OPTIMIST-1) or planned (COSMOS) EOT.
* 150 mg once daily OLYSIO for 12 weeks with 400 mg once daily sofosbuvir.
† Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at EOT. In addition to five subjects with viral relapse, one subject failed to achieve SVR12 due to missing SVR12 data. No subjects experienced on-treatment virologic failure.

Among subjects without cirrhosis in OPTIMIST-1 who received 12 weeks of OLYSIO in combination with sofosbuvir, similar SVR12 rates were observed among subgroups, including: treatment-nave and treatment-experienced subjects (112/115 [97%] and 38/40 [95%] respectively), subjects with HCV genotype 1a with and without NS3 Q80K polymorphism (44/46 [96%] and 68/70 [97%], respectively), genotype 1b (38/39 [97%]), and subjects with IL28B CC and non-CC genotypes (43/43 [100%] and 107/112 [96%], respectively).

OLYSIO In Combination With Peg-IFN-alfa And RBV

Treatment-Nave Adult Subjects With HCV Genotype 1 Infection

The efficacy of OLYSIO in treatment-nave 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 designs of both trials were 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; 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) greater than or equal to 30 kg/m² ; 78% had baseline 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 17 shows the response rates in treatment-nave 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 17: Virologic Outcomes in Treatment-Nave Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2 Trials)

Response Rate 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 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 HCV RNA detected 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 HCV RNA not detected 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-nine percent (79%; 404/509) of OLYSIO-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404).

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 18 shows the SVR rates by METAVIR fibrosis score.

Table 18: SVR12 Rates by METAVIR Fibrosis Score in Treatment-Nave Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2 Trials)

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).

Treatment-Nave East Asian Subjects With HCV Genotype 1 Infection

TIGER was a Phase 3, randomized, double-blind, placebo-controlled trial in HCV genotype 1-infected treatment-nave adult subjects from China and South Korea.

In this trial, 152 subjects received 12 weeks of once-daily treatment with 150 mg OLYSIO 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 protocol-defined RGT criteria; and 152 subjects received 12 weeks of placebo plus Peg-IFN-alfa-2a and RBV, followed by 36 weeks therapy with Peg-IFN-alfa-2a and RBV. These 304 subjects had a median age of 45 years (range: 18 to 68 years; with 2% above 65 years); 49% were male; all were East Asians (81% were enrolled in China, and 19% in South Korea); 3% had a body mass index (BMI) greater or equal to 30 kg/m² ; 84% had baseline HCV RNA levels greater than 800000 IU/mL; 82% had METAVIR fibrosis score F0, F1 or F2, 12% METAVIR fibrosis score F3, and 6% METAVIR fibrosis score F4 (cirrhosis); 1% had HCV genotype 1a, and 99% HCV genotype 1b; less than 1% of the overall population had Q80K polymorphism at baseline; 79% had IL28B CC genotype, 20% IL28B CT genotype, and 1% IL28B TT genotype. Demographics and baseline characteristics were balanced across the OLYSIO 150 mg and placebo treatment groups.

SVR12 rates were 91% (138/152) in the OLYSIO 150 mg treatment group and 76% (115/152) in the placebo treatment group [see ADVERSE REACTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY].

Adult Subjects With HCV Genotype 1 Infection Who Failed Prior Peg-IFN-alfa And RBV 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; 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 greater than or equal to 30 kg/m² ; 84% had baseline 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 19 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 19: Virologic Outcomes in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)

Response Rates 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 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 HCV RNA detected 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 HCV RNA not detected 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%; 200/259) of OLYSIO-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200).

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 20 shows the SVR rates by METAVIR fibrosis score.

Table 20: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)

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, Phase 2 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).

In this trial, 66 subjects received 12 weeks of 150 mg OLYSIO in combination with Peg-IFN-alfa-2a and RBV for 48 weeks, and 66 subjects received placebo in combination with Peg-IFN-alfa-2a and RBV for 48 weeks. These 132 subjects had a median age of 49 years (range: 20 to 66 years; with 1% above 65 years); 66% were male; 93% were White, 3% Black or African American, and 2% Asian; 27% had a BMI greater than or equal to 30 kg/m² ; 85% had baseline HCV RNA levels greater than 800000 IU/mL; 64% had METAVIR fibrosis score F0, F1, or F2, 18% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 43% had HCV genotype 1a, and 57% HCV genotype 1b; 17% had IL28B CC genotype, 67% IL28B CT genotype, and 16% IL28B TT genotype (information available for 93 subjects); 27% of the overall population and 23% 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-IFN-alfa and RBV. Demographics and baseline characteristics were balanced between the 12 weeks 150 mg OLYSIO and placebo treatment groups.

Table 21 shows the response rates for the 12 weeks of 150 mg OLYSIO and placebo treatment groups in prior relapsers, prior partial responders and prior null responders.

Table 21: Virologic Outcomes in Prior Partial and Null Responders with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy (ASPIRE Trial)

Response Rates OLYSIO + PR
N=66 % (n/N)
Placebo + PR
N=66 % (n/N)
SVR24
  Prior relapsers 77 (20/26) 37 (10/27)
  Prior partial responders 65 (15/23) 9 (2/23)
  Prior null responders 53 (9/17) 19 (3/16)
Outcome for subjects without SVR24
  On-treatment virologic failure*
  Prior relapsers 8 (2/26) 22 (6/27)
  Prior partial responders 22 (5/23) 78 (18/23)
  Prior null responders 35 (6/17) 75 (12/16)
Viral relapse†
  Prior relapsers 13 (3/23) 47 (9/19)
  Prior partial responders 6 (1/17) 50 (2/4)
  Prior null responders 18 (2/11) 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 defined as undetectable HCV RNA 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 HCV RNA detected at EOT (for subjects who completed therapy).
† Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at EOT and with at least one follow-up HCV RNA assessment.

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.

Subjects With HCV/HIV-1 Co-Infection

C212 was an open-label, single-arm Phase 3 trial in HIV-1 subjects co-infected with HCV genotype 1 who were treatment-nave or failed prior HCV therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Non-cirrhotic treatment-nave subjects or prior relapsers received 12 weeks of once-daily treatment with 150 mg OLYSIO 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. Prior non-responder subjects (partial and null response) and all cirrhotic subjects (METAVIR fibrosis score F4) received 36 weeks of Peg-IFN-alfa-2a and RBV after the initial 12 weeks of OLYSIO in combination with Peg-IFN-alfa-2a and RBV.

The 106 enrolled subjects in the C212 trial 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 greater than or equal to 30 kg/m² ; 86% had baseline HCV RNA levels greater than 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 subjects 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-nave subjects, 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 subjects were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (except rilpivirine) were prohibited from use in this study.

The median baseline HIV-1 RNA levels and CD4+ cell count in subjects not on HAART were 4.18 log10 copies/mL (range: 1.3-4.9 log10 copies/mL) and 677 106 cells/L (range: 489-1076 106 cells/L), respectively. The median baseline CD4+ cell count in subjects on HAART was 561 106 cells/mL (range: 275-1407 106 cells/mL).

Table 22 shows the response rates in treatment-nave, prior relapsers, prior partial responders and null responders.

Table 22: Virologic Outcomes in Adult Subjects with HCV Genotype 1 Infection and HIV-1 Co-Infection (C212 Trial)

Response Rates Treatment-N aive Subjects
N=53 % (n/N)
Prior Relapsers
N=15 % (n/N)
Prior Partial Responders
N=10 % (n/N)
Prior Null Responders
N=28 % (n/N)
Overall SVR12 (genotype 1a and 1b) 79 (42/53) 87 (13/15) 70 (7/10) 57 (16/28)
Genotype 1a 77 (33/43) 83 (10/12) 67 (6/9) 54 (13/24)
Genotype 1b 90 (9/10) 100 (3/3) 100 (1/1) 75 (3/4)
Outcome for subjects without SVR12
On-treatment failure* 9 (5/53) 0 (0/15) 20 (2/10) 39 (11/28)
Viral relapse† 10 (5/48) 13 (2/15) 0 (0/7) 12 (2/17)
150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 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 one prior null responder who experienced relapse after SVR12.

Eighty-nine percent (n=54/61) of the OLYSIO-treated treatment-nave subjects and prior relapsers without cirrhosis were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 87%.

Seventy-one percent (n=37/52), 93% (n=14/15), 80% (n=8/10) and 36% (n=10/28) of OLYSIO-treated treatment-nave subjects, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these subjects the SVR12 rates were 89%, 93%, 75% and 90%, respectively.

Table 23 shows the SVR rates by METAVIR fibrosis scores.

Table 23: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection and HIV-1 co-Infection (C212 Trial)

Subgroup Treatment-Naive Subjects % (n/N) Prior Relapsers % (n/N) Prior Partial Responders % (n/N) Prior Null Responders % (n/N)
F0-2 89 (24/27) 78 (7/9) 50 (1/2) 57 (4/7)
F3-4 57 (4/7) 100 (2/2) 67 (2/3) 60 (6/10)
150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks.
SVR12: sustained virologic response 12 weeks after planned EOT.

Two subjects had HIV virologic failure defined as confirmed HIV-1 RNA at least 200 copies/mL after previous less than 50 copies/mL; these failures occurred 36 and 48 weeks after end of OLYSIO treatment.

Adult Subjects With HCV Genotype 4 Infection

RESTORE was an open-label, single-arm Phase 3 trial in subjects with HCV genotype 4 infection who were treatment-nave or failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Treatment-nave subjects or prior relapsers received once-daily treatment with 150 mg OLYSIO plus Peg-IFN-alfa-2a and RBV for 12 weeks, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Prior non-responder subjects (partial and null response) received once-daily treatment with 150 mg OLYSIO plus Peg-IFN-alfa-2a and RBV for 12 weeks, followed by 36 weeks of Peg-IFN-alfa-2a and RBV.

The 107 enrolled subjects in the RESTORE trial 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 greater than or equal to 30 kg/m² ; 60% had baseline HCV RNA levels greater than 800,000 IU/mL; 57% had METAVIR fibrosis score F0, F1 or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 33% (n=35) were treatment-nave HCV subjects, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders.

Table 24 shows the response rates in treatment-nave, prior relapsers, prior partial responders and null responders. Table 25 shows the SVR rates by METAVIR fibrosis scores.

Table 24: Virologic Outcomes in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)

Response Rates Treatment-N aive Subjects
N=35 % (n/N)
Prior Relapsers
N=22 % (n/N)
Prior Partial Responders
N=10 % (n/N)
Prior Null Responders
N=40 % (n/N)
Overall SVR12 83 (29/35) 86 (19/22) 60 (6/10) 40 (16/40)
Outcome for subjects without SVR12
On-treatment failure* 9 (3/35) 9 (2/22) 20 (2/10) 45 (18/40)
Viral relapse† 9 (3/35) 5 (1/22) 20 (2/10) 15 (6/40)
150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 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 (or unconfirmed detectable) HCV RNA at actual EOT.

Table 25: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)

Subgroup Treatment-Naive Subjects
% (n/N)
Prior Relapsers
% (n/N)
Prior Partial Responders
% (n/N)
Prior Null Responders
% (n/N)
F0-2 85 (22/26) 91 (10/11) 100 (5/5) 47 (8/17)
F3-4 78 (7/9) 82 (9/11) 20 (1/5) 35 (7/20)
150 mg OLYSIO for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks.
SVR12: sustained virologic response 12 weeks after planned EOT.

Last reviewed on RxList: 6/6/2016
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.