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Incivek

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CLINICAL PHARMACOLOGY

Mechanism of Action

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

Pharmacodynamics

ECG Evaluation

The effect of telaprevir 750 and 1875 mg on QTc interval was evaluated in a double-blind, double-dummy, randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 44 subjects. In the trial with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the threshold for regulatory concern. The dose of 1875 mg is adequate to represent the high exposure clinical scenario.

Pharmacokinetics

The pharmacokinetic properties of telaprevir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following multiple doses of telaprevir (750 mg every 8 hours) in combination with peginterferon alfa and ribavirin in treatment-na´ve subjects with genotype 1 chronic hepatitis C, mean (SD) Cmax was 3510 (1280) ng/mL, Cmin was 2030 (930) ng/mL, and AUC8h was 22,300 (8650) ng•hr/mL.

Telaprevir total exposure (AUC24h,ss) was similar regardless of whether the total daily dose of 2250 mg was administered as 750 mg every 8 hours or 1125 mg twice daily.

Absorption and Bioavailability

Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours. In vitro studies performed with human Caco-2 cells indicated that telaprevir is a substrate of P-glycoprotein (P-gp). Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telaprevir alone.

Effects of Food on Oral Absorption

The systemic exposure (AUC) to telaprevir was increased by 237% when telaprevir was administered with a standard fat meal (containing 533 kcal and 21 g fat) compared to when telaprevir was administered under fasting conditions. In addition, the type of meal significantly affects exposure to telaprevir. Relative to fasting, when telaprevir was administered with a low-fat meal (249 kcal, 3.6 g fat) and a high-fat meal (928 kcal, 56 g fat), the systemic exposure (AUC) to telaprevir was increased by approximately 117% and 330%, respectively. Doses of INCIVEK were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat in the Phase 3 trials. Therefore, INCIVEK should always be taken with food (not low fat).

Distribution

In vitro, within a concentration range of 0.1 μM (68 ng per mL) to 20 μM (13600 ng per mL), telaprevir is approximately 59% to 76% bound to plasma proteins. Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding is concentration dependent, decreasing with increasing concentrations of telaprevir. After oral administration, the typical apparent volume of distribution (Vd/F) was estimated to be 252 L, with an inter-individual variability of 72%.

Metabolism

Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated-oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the α-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir. In vitro studies using recombinant human cytochrome P450 (CYP) isoforms indicated that CYP3A4 was the major isoform responsible for CYP-mediated telaprevir metabolism. In vitro studies using recombinant aldo-ketoreductases indicated that these and potentially other reductases are also responsible for the reduction of telaprevir. Other proteolytic enzymes are also involved in the hydrolysis of telaprevir. These non-CYP mediated pathways of metabolism likely play a major role after multiple dosing of telaprevir.

Elimination

Following administration of a single oral dose of 750 mg 14C-telaprevir in healthy subjects, 90% of total radioactivity was recovered in feces, urine and expired air within 96 hours post-dose. The median recovery of the administered radioactive dose was approximately 82% in the feces, 9% in exhaled air and 1% in urine. The contribution of unchanged 14C-telaprevir and the R-diastereomer of telaprevir towards total radioactivity recovered in feces was 31.9% and 18.8%, respectively. After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4 L per hour with an inter-individual variability of 27.2%. The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours.

Specific Populations

Hepatic Impairment

Steady-state exposure to telaprevir was reduced by 46% in HCV-negative subjects with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. The appropriate dose of INCIVEK in HCV-infected subjects with moderate or severe hepatic impairment has not been determined and therefore INCIVEK is not recommended in these populations.

Steady-state exposure to telaprevir was reduced by 15% in HCV-negative subjects with mild hepatic impairment (Child-Pugh Class A) compared to healthy subjects. Dose modification of INCIVEK is not required when administered to subjects with mild hepatic impairment. In previously treated subjects who had compensated liver disease and were treated with INCIVEK in combination with peginterferon alfa and ribavirin, subjects with cirrhosis had similar PK parameters compared to those without cirrhosis.

Renal Impairment

After administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl less than 30 mL per min), the LS means of telaprevir Cmax and AUCinf were increased by 3% and 21%, respectively, compared to healthy subjects.

Gender

The effect of subject gender on telaprevir pharmacokinetics was evaluated using population pharmacokinetics of data from clinical trials of telaprevir. No dose adjustments are deemed necessary based on gender.

Race

Population pharmacokinetic analysis of telaprevir in HCV-infected subjects indicated that race had no apparent effect on the exposure to telaprevir.

Geriatric Use

Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19-70 years) investigated (35 subjects 65 years of age and older), subject age did not have a clinically relevant effect on the exposure to telaprevir.

Pediatric Use

The pharmacokinetics of INCIVEK in pediatric patients have not been evaluated.

Drug Interactions

In vitro studies indicated that telaprevir is a substrate and a strong inhibitor of CYP3A and P-gp. In vitro studies indicated that telaprevir is also an inhibitor of OATP1B1 and OATP2B1. No inhibition by telaprevir of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 isozymes was observed in vitro. In vitro studies also suggest that telaprevir does not induce CYP1A, CYP3A, CYP2B6, or CYP2C. Furthermore, in vitro studies suggest that telaprevir is neither a substrate for BCRP, OATP1B1, OATP2B1, or MRP2, nor an inhibitor of BCRP, MRP2, OCT2, and OAT1 transporters. Clinical trials were conducted to evaluate the effect of drugs that can affect or be affected by telaprevir during co-administration (Tables 6 and 7).

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

Drug Dose and Schedule N Effect on Telaprevir PKa LS Mean Ratio (90% CI) of Telaprevir PK With/Without Co-administered Drug
Drug Telaprevir Cmax AUC or Cavg,ss b Cmin
Carbamazepine 200 mg q12h for 17 days 750 mg q8h for 10 days 11 0.79
(0.70; 0.90)
0.68
(0.58; 0.79)
0.53
(0.44; 0.65)
Escitalopram 10 mg qd for 7 days 750 mg q8h for 14 days 13 1.00
(0.95; 1.05)
0.93
(0.89; 0.97)
0.91
(0.86; 0.97)
Esomeprazole 40 mg qd for 6 days 750 mg single dose 24 0.95
(0.86; 1.06)
0.98
(0.91; 1.05)
NA
Ketoconazole Ketoconazole 400 mg single dose 750 mg single dose 17 1.24
(1.10; 1.41)
1.62
(1.45; 1.81)
NA
Oral Contraceptive Norethindrone/ ethinyl estradiol 0.5 mg/0.035 mg qd for 21 days 750 mg q8h for 21 days 23 1.00
(0.93; 1.07)
0.99
(0.93; 1.05)
1.00
(0.93; 1.08)
Phenytoin 200 mg q12h for 17 days 750 mg q8h for 10 days 7 0.68
(0.60; 0.77)
0.53
(0.47; 0.60)
0.32
(0.25; 0.42)
Rifampin 600 mg qd for 8 days 750 mg single dose 16 0.14
(0.11; 0.18)
0.08
(0.07; 0.11)
NA
Anti-HIV Drugs
Atazanavir
(ATV)/ritonavir
(rtv)
300 mg ATV/ 100 mg rtv qd for 20 days 750 mg q8h for 10 days 14 0.79
(0.74; 0.84)
0.80
(0.76; 0.85)
0.85
(0.75; 0.98)
Darunavir
(DRV)/ritonavir
(rtv)
600 mg DRV/ 100 mg rtv bid for 20 days 750 mg q8h for 10 days 11
(N=14 for Cmax)
0.64
(0.61; 0.67)
0.65
(0.61; 0.69)
0.68
(0.63; 0.74)
Efavirenz 600 mg qd for 20 days 750 mg q8h for 10 days 21 0.91
(0.82; 1.02)
0.74
(0.65; 0.84)
0.53
(0.44; 0.65)
Fosamprenavir
(fAPV)/ ritonavir (rtv)
700 mg fAPV/ 100 mg rtv bid for 20 days 750 mg q8h for 10 days 18 0.67
(0.63; 0.71)
0.68
(0.63; 0.72)
0.70
(0.64; 0.77)
Lopinavir (LPV)/ritonavir
(rtv)
400 mg LPV/ 100 mg rtv bid for 20 days 750 mg q8h for 10 days 12 0.47
(0.41; 0.52)
0.46
(0.41; 0.52)
0.48
(0.40; 0.56)
Raltegravir 400 mg bid for 11 days 750 mg q8h for 7 days 20 1.07
(0.98; 1.16)
1.07
(1.00; 1.15)
1.14
(1.04; 1.26)
Ritonavir 100 mg single dose 750 mg single dose 14 1.30
(1.15; 1.47)
2.00
(1.72; 2.33)
NA
Ritonavir 100 mg q12h for 14 days 750 mg q12h for 14 days 5 0.85
(0.63; 1.13)
0.76b,c
(0.60; 0.97)
0.68
(0.57; 0.82)
Tenofovir disoproxil fumarate (TDF) 300 mg qd TDF for 7 days 750 mg q8h for 7 days 16 1.01
(0.96; 1.05)
1.00
(0.94; 1.07)
1.03
(0.93; 1.14)
Tenofovir disoproxil fumarate (TDF) and efavirenz (EFV) 600 mg EFV /300 mg TDF qd for 7 days 1125 mg q8h for 7 days 15 0.86c
(0.76; 0.97)
0.82c (0.73; 0.92) 0.75c (0.66; 0.86)
600 mg EFV /300 mg TDF qd for 7 days 1500 mg q12h for 7 days 16 0.97c
(0.88; 1.06)
0.80b,c (0.73; 0.88) 0.52c
(0.42; 0.64)
NA: not available/ not applicable; N = Number of subjects with data; qd = once daily; bid = twice daily; q8h = every 8 hours; q12h = every 12 hours
a The direction of the arrow
(↑ = increase, ↓ = decrease, ⇔ = no change) indicates the direction of the change in PK
b Cavg,ss = Average concentrations at steady state
(AUCτ/τ).
c Value with co-administered drug and telaprevir / value with telaprevir 750 mg q8h alone
*Data provided are under fed conditions unless otherwise noted.

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

Drug Dose and Schedule N Effect on Drug PKa LS Mean Ratio (90% CI) of Drug PK With/Without Telaprevir
Drug Telaprevir Cmax AUC Cmin
Alprazolam 0.5 mg single dose 750 mg q8h for 11 days 17 0.97
(0.92; 1.03)
1.35
(1.23; 1.49)
NA
Amlodipine 5 mg single dose 750 mg q8h for 7 days 19 1.27
(1.21; 1.33)
2.79
(2.58; 3.01)
NA
Atorvastatin 20 mg single dose 750 mg q8h for 7 days 19 10.60
(8.74; 12.85)
7.88
(6.84; 9.07)
NA
Buprenorphine Buprenorphine maintenance therapy
(4 to 24 mg/daily in combination with naloxone)
750 mg q8h for 7 days 14 0.80
(0.69; 0.93)
0.96
(0.84; 1.10)
1.06
(0.87; 1.30)
Carbamazepine 200 mg q12h for 17 days 750 mg q8h for 10 days 11 1.09
(0.98; 1.21)
1.10
(0.99; 1.23)
1.10
(0.97; 1.24)
Cyclosporine A
(CsA)
100 mg single dose when administered alone; 10 mg single dose when coadministered with telaprevir
(D8)
750 mg q8h for 11 days 9 0.13
(0.11; 0.16) Dose norm.: 1.32
(1.08; 1.60)
0.46
(0.39; 0.55) Dose norm.: 4.64
(3.90; 5.51)
NA
Digoxin 0.5 mg single dose 750 mg q8h for 11 days 20 1.50
(1.36; 1.65)
1.85
(1.70; 2.00)
NA
Escitalopram 10 mg qd, for 7 days 750 mg q8h for 14 days 13 0.70
(0.65; 0.76)
0.65
(0.60; 0.70)
0.58
(0.52; 0.64)
Ethinyl estradiol (EE), coadministered with norethindrone (NE) 0.035 mg qd EE/ 0.5 mg qd NE for 21 days 750 mg q8h for 21 days 24 0.74
(0.68; 0.80)
0.72
(0.69; 0.75)
0.67
(0.63; 0.71)
Ketoconazole 400 mg single dose 1250 mg q8h for 4 doses 81 1.23
(1.14; 1.33)
1.46
(1.35; 1.58)
NA
  200 mg single dose 1250 mg q8h for 4 doses 28 1.75
(1.51; 2.03)
2.25
(1.93; 2.61)
NA
R-Methadone Methadone maintenance therapy
(40 to 120 mg/daily)
750 mg q8h for 7 days 15 0.71
(0.66; 0.76)
0.71
(0.66; 0.76)
0.69
(0.64; 0.75)
S-Methadone Methadone maintenance therapy
(40 to 120 mg/daily)
750 mg q8h for 7 days 15 0.65
(0.60; 0.71)
0.64
(0.58; 0.70)
0.60
(0.54; 0.67)
Midazolam (iv) 0.5 mg iv single dose 750 mg q8h for 9 days 22 1.02
(0.8; 1.31)
3.40
(3.04; 3.79)
NA
Midazolam (oral) 2 mg oral single dose 750 mg q8h for 11 days 21 2.86
(2.52; 3.25)
8.96
(7.75; 10.35)
NA
Norethindrone (NE), coadministered with EE 0.035 mg qd EE/ 0.5 mg qd NE for 21 days 750 mg q8h for 21 days 24 0.85
(0.81; 0.89)
0.89
(0.86; 0.93)
0.94
(0.87; 1.0)
Phenytoin 200 mg q12h for 17 days 750 mg q8h for 10 days 7 1.27
(1.09; 1.47)
1.31
(1.15; 1.49)
1.36
(1.21; 1.53)
Tacrolimus 2 mg single dose when administered alone; 0.5 mg single dose when coadministered with telaprevir (D8) 750 mg q8h for 13 days 9 2.34
(1.68; 3.25) Dose norm.: 9.35
(6.73; 13.0)
17.6
(13.2; 23.3) Dose norm.: 70.3
(52.9; 93.4)
NA
Zolpidem 5 mg single dose 750 mg q8h for 11 days 19 0.58
(0.52; 0.66)
0.53
(0.45; 0.64)
NA
Anti-HIV Drugs
Atazanavir (ATV), boosted with ritonavir (rtv) 300 mg ATV/ 100 mg rtv qd for 20 days 750 mg q8h for 10 days 7 0.85
(0.73; 0.98)
1.17
(0.97; 1.43)
1.85
(1.40; 2.44)
Darunavir
(DRV), boosted with ritonavir (rtv)
600 mg DRV/ 100 mg rtv bid for 20 days 750 mg q8h for 10 days 11
(N=14 for Cmax)
0.60
(0.56; 0.64)
0.60
(0.57; 0.63)
0.58
(0.52; 0.64)
600 mg DRV/ 100 mg rtv bid for 24 days 1125 mg q12h for 4 days 15 0.53
(0.47; 0.59)
0.49
(0.43; 0.55)
0.42
(0.35; 0.51)
Efavirenz 600 mg qd for 20 days 750 mg q8h for 10 days 21 0.84
(0.76; 0.93)
0.93
(0.87; 0.98)
0.98
(0.94; 1.02)
Efavirenz (EFV), coadministered with tenofovir disoproxil fumarate (TDF) 600 mg EFV /300 mg TDF qd for 7 days 1125 mg q8h for 7 days 15 0.76
(0.68; 0.85)
0.82
(0.74; 0.90)
0.90
(0.81; 1.01)
600 mg EFV /300 mg TDF qd for 7 days 1500 mg q12h for 7 days 16 0.80
(0.74; 0.86)
0.85
(0.79; 0.91)
0.89
(0.82; 0.96)
Fosamprenavir (fAPV), boosted with ritonavir
(rtv)
700 mg fAPV/ 100 mg bid rtv for 20 days 750 mg q8h for 10 days 18 0.65
(0.59; 0.70)
0.53
(0.49; 0.58)
0.44
(0.40; 0.50)
700 mg fAPV/ 100 mg bid rtv for 24 days 1125 mg q12h for 4 days 17
(N=18 for Cmin)
0.60
(0.55; 0.67)
0.51
(0.47; 0.55)
0.42
(0.37; 0.47)
Lopinavir
(LPV), boosted with ritonavir
(rtv)
400 mg LPV/ 100 mg rtv bid for 20 days 750 mg q8h for 10 days 12 0.96
(0.87; 1.05)
1.06
(0.96; 1.17)
1.14
(0.96; 1.36)
Raltegravir 400 mg bid for 11 days 750 mg q8h for 7 days 20 1.26
(0.97; 1.62)
1.31
(1.03; 1.67)
1.78
(1.26; 2.53)
Tenofovir disoproxil fumarate 300 mg qd for 7 days 750 mg q8h for 7 days 16 1.30
(1.16; 1.45)
1.30
(1.22; 1.39)
1.41
(1.29; 1.54)
Tenofovir, on coadministration of tenofovir disoproxil fumarate (TDF) and efavirenz (EFV) 600 mg EFV /300 mg TDF qd for 7 days 1125 mg q8h for 7 days 15 1.22
(1.12; 1.33)
1.10
(1.03; 1.18)
1.17
(1.06; 1.28)
600 mg EFV /300 mg TDF qd for 7 days 1500 mg q12h for 7 days 16 1.24
(1.13; 1.37)
1.10
(1.03; 1.17)
1.06
(0.98; 1.15)
aThe direction of the arrow
(↑ = increase, ↓ = decrease, ⇔ = no change) indicates the direction of the change in PK.

Microbiology

Mechanism of Action

Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.

Antiviral Activity in Cell Culture

In an HCV subtype 1b replicon assay, the telaprevir EC50 value against wild-type HCV was 354 nM in a 2-day cell culture assay, and in a subtype 1a infectious virus assay, the EC50 value was 280 nM in a 5-day cell culture assay. In biochemical enzymatic assays, the median IC50 values of telaprevir against genotype 2, 3a, and 4a were 16 nM (range 6-32 nM; n=5), 40 nM (range 39-88 nM; n=5), and 130 nM (n=1), respectively, compared to a median IC50 value of 20 nM (range 16-23; n=2) for genotype 1a and 20 nM for genotype 1b (range 13-33; n=4). The presence of 40% human serum reduced the anti-HCV activity of telaprevir by approximately 10-fold. Evaluation of telaprevir in combination with interferon alfa or ribavirin showed no evidence of antagonism in reducing HCV RNA levels in HCV replicon cells.

Resistance

In Cell Culture

HCV genotype 1b replicons with reduced susceptibility to telaprevir have been selected in cell culture and characterized for telaprevir genotypic and phenotypic resistance. Additionally, resistance to telaprevir was evaluated in both biochemical and HCV genotype 1b replicon assays using site-directed mutants and recombinant NS3/4A from telaprevir Phase 2 clinical trials isolates. Variants V36A/M, T54A/S, R155K/T, A156S, R155T+D168N, and V36A+T54A conferred 3-to 25-fold reduced susceptibility to telaprevir; and A156V/T variants and the V36M/A+R155K/T and T54S/A+A156S/T double variants conferred greater than 62-fold reduced susceptibility to telaprevir. No amino acid substitutions were observed at the proteolytic cleavage sites.

In Clinical Trials

In a pooled analysis of subjects who did not achieve SVR (on-treatment virologic failure or relapse) from the controlled Phase 3 clinical trials, NS3 amino acid substitutions V36M/A/L, T54A/S, R155K/T, and A156S/T were determined to emerge frequently on INCIVEK treatment (Table 8). Nearly all of these substitutions have been shown to reduce telaprevir anti-HCV activity in cell culture or biochemical assays. No clear evidence of treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome was observed among subjects treated with INCIVEK who did not achieve SVR.

Telaprevir treatment-emergent resistance substitutions emerged in the majority of isolates from subjects who did not achieve SVR (Table 8): in almost 100% of subjects who failed during 12 weeks of T/PR and in the majority of subjects who failed on PR after Week 12 or who relapsed.

HCV genotype 1 subtype-associated patterns of INCIVEK treatment-emergent amino acid substitutions were observed. Subjects with HCV genotype 1a predominately had V36M and R155K or the combination of these variants, while subjects with HCV genotype 1b predominately had V36A, T54A/S, and A156S/T variants (Table 8). Among subjects treated with telaprevir, on-treatment virologic failure was more frequent in subjects with genotype 1a than with genotype 1b and more frequent in prior null responders [see Clinical Studies]. In the C211 Phase 3 clinical trial, there were no differences in the types of emerging variants between subjects receiving telaprevir 1125 mg twice daily and subjects receiving telaprevir 750 mg every 8 hours. Similar proportions of subjects in both treatment groups had telaprevir-resistant variants at the time of failure.

Table 8: Treatment-Emergent Substitutions in Pooled Phase 3 Trials: Subjects who did not achieve SVR24 in INCIVEK Combination Treatment Arms

Emerging Substitutions1 in NS3 Percent of No SVR Subjects (n)
N=525
Percent Subtype 1a No SVR Subjects (n)
N=356
Percent Subtype 1b No SVR Subjects (n)
N=169
Any substitution at V36, T54, R155, A156 or D168 62% (323) 69% (247) 45% (76)
R155K/T 38% (201) 56% (200) 0.6% (1)
V36M 33% (178) 49% (173) 3% (5)
V36M + R155K2 27% (142) 40% (142) 0% (0)
T54A/S 13% (68) 9% (31) 22% (37)
V36A/L 12% (65) 10% (37) 17% (28)
A156S/T 9% (48) 8% (28) 12% (20)
V36G/I, I132V, R155G/M, A156V/F/N or D168N Less than 2% Less than 2% Less than 2%
1Alone or in combination with other substitutions (includes mixtures)
2Subjects with this combination are also encompassed in two V36M and R155K rows above.

Persistence of Resistance-Associated Substitutions

Persistence of telaprevir-resistant NS3 amino acid substitutions has been observed following treatment failure. Of a combined 255 treatment-na´ve and previously treated subjects from Trials 108, 111, and C216 in whom telaprevir-resistant variants had emerged during treatment, 103 (40%) had detectable resistant variants by population sequencing at end of trial (follow-up range 2-70 weeks, median 45 weeks) and results for loss of variants were similar across the 3 trials. In the combined trials, 46% of the telaprevir-resistant substitutions in subtype 1a and 16% of the substitutions in subtype 1b were still detected by the end of trial: 29% of V36, 16% of T54, 38% of R155, 14% of A156, and 44% of V36M+R155K variants were detected at the end of trial.

In a 3-year follow-up trial of 56 treatment-na´ve and prior treatment-failure subjects who did not achieve SVR with a telaprevir regimen in a Phase 2 trial and had telaprevir-resistant variants after treatment failure, variants were detected by population sequencing in 11% (6/56) of subjects (median follow-up of 25 months). Telaprevir-resistant variants V36L/M, T54S, and R155K were detectable (present at greater than 25% of the viral population) in some subjects at 24 months. By 36 months, V36M, T54A/S, and A156N/S/T variants had fallen below the level of detection by population sequencing in all subjects. At 36 months, 3% of the subject isolates that had the R155K variant still had detectable R155K variants by population sequencing.

The lack of detection of a substitution based on a population-based assay does not necessarily indicate the substitution has declined to the pre-treatment level. The long-term clinical impact of the emergence or persistence of detectable INCIVEK resistance-associated substitutions is unknown. No data are available regarding INCIVEK efficacy among patients who were previously exposed to INCIVEK, or who previously failed treatment with a regimen containing INCIVEK.

Effect of Baseline HCV Substitutions/Polymorphisms on Treatment Response

A pooled analysis was conducted to explore the association between the detection (population-based assay) of baseline NS3/4A amino acid substitutions/polymorphisms and treatment outcome in Trials 108, 111, and C216. Baseline polymorphisms at NS3 position Q80 (Q80K, Q80L, Q80R), which are frequently observed in HCV genotype 1a-infected subjects and have been reported to reduce the activity of some HCV NS3/4A protease inhibitors, were not associated with reduced INCIVEK efficacy.

Telaprevir-associated resistance substitutions (substitutions at positions V36, T54, R155 or D168) were present at baseline in 5% (117/2217) of the available subject samples in the combined clinical trials. Given the small number of subjects with baseline telaprevir resistance substitutions, conclusions about their effect on response outcomes when these substitutions are present at baseline cannot be determined.

Cross-Resistance

Treatment-emergent NS3 amino acid substitutions detected in subjects treated with INCIVEK who did not achieve SVR in the clinical trials (substitutions at positions V36, T54, R155, A156 or D168) have been demonstrated to reduce the anti-HCV activity of boceprevir and other HCV NS3/4A protease inhibitors. The impact of prior INCIVEK exposure or treatment failure on the efficacy of boceprevir or other HCV NS3/4A protease inhibitors has not been studied. INCIVEK efficacy has not been established for patients with a history of exposure to NS3/4A protease inhibitors.

Cross-resistance is not expected between INCIVEK and interferons, or INCIVEK and ribavirin. HCV replicons expressing telaprevir-associated resistance substitutions remained fully sensitive to interferon-alfa and ribavirin, as well as other direct-acting antivirals with different mechanisms of action, such as NS5B polymerase inhibitors.

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). rs12979860 was genotyped in 454 of 1088 subjects in Trial 108 (treatment-na´ve) and 527 of 662 subjects in Trial C216 (previously treated) [see Clinical Studies) for trial descriptions]. SVR rates tended to be lower in subjects with the CT and TT genotypes compared to those with the CC genotype, particularly among treatment-na´ve subjects receiving PR48 (Table 9). Among both treatment-na´ve and previous treatment failures, subjects of all IL28B genotypes appeared to have higher SVR rates with regimens containing INCIVEK. The results of this retrospective subgroup analysis should be viewed with caution because of the small sample size and potential differences in demographic or clinical characteristics of the subtrial population relative to the overall trial population. In Trial C211, all subjects were prospectively tested for IL28B variants; there were no clinically relevant differences in SVR12 responses between q8h and twice-daily dosing within the genetic subgroups.

Table 9: SVR Rates by rs12979860 Genotype

Trial rs12979860 Genotype SVR, n/N (%)
T12/PR Pbo/PR48
108 (treatment-na´ve) C/C 45/50 (90%) 35/55 (64%)
  C/T 48/68 (71%) 20/80 (25%)
  T/T 16/22 (73%) 6/26 (23%)
    T12/PR48a Pbo/PR48
C216 (previously treated) C/C 60/76 (79%) 5/17 (29%)
  C/T 160/266 (60%) 9/58 (16%)
  T/T 49/80 (61%) 4/30 (13%)
C211 (treatment-na´ve) T12 Twice Daily/PR T12 q8h/PR
  C/C 97/105 (92%) 92/106 (87%)
  C/T 139/206 (67%) 141/208 (68%)
  T/T 38/58 (66%) 37/57 (65%)
aLead-in and immediate start T12/PR regimens pooled.

Clinical Studies

Description of Adult Clinical Trials

The efficacy and safety of INCIVEK in subjects with genotype 1 chronic hepatitis C were evaluated in 4 adequate and well-controlled clinical trials: 3 in treatment-na´ve subjects and one in previously treated subjects (relapsers, partial responders, and null responders). Subjects in these trials had compensated liver disease, detectable HCV RNA, and liver histopathology consistent with chronic hepatitis C. In the trials, INCIVEK was administered at a total daily dosage of 2250 mg as either 750 mg every 8 hours (Trials 108, 111, C211 and C216) or 1125 mg twice daily (Trial C211); the peginterferon alfa-2a (Peg-IFN-alfa-2a) dose was 180 micrograms per week, and the ribavirin (RBV) dose was 1000 mg per day (subjects weighing less than 75 kg) or 1200 mg per day (subjects weighing greater than or equal to 75 kg). Plasma HCV RNA values were measured during the clinical trials using the COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantitation of 25 IU per mL.

For Trials 108, 111, and C216, SVR was defined as HCV RNA less than 25 IU per mL at last observation within the SVR visit window (i.e., weeks 3278 for patients assigned to 24 weeks of treatment and weeks 56-78 for patients assigned to 48 weeks of treatment).

For Trial C211, SVR was defined as HCV RNA less than 25 IU/mL and assessed 12 weeks after the planned end of treatment, using the last measurement in the visit window.

Treatment-Na´ve Adults

Trial 108 (ADVANCE)

Trial 108 was a randomized, double-blind, parallel-group, placebo-controlled trial conducted in treatment-na´ve subjects (had received no prior therapy for HCV, including interferon or pegylated interferon monotherapy). INCIVEK was given for the first 8 weeks of treatment (T8/PR regimen) or the first 12 weeks of treatment (T12/PR regimen) in combination with Peg-IFN-alfa-2a/RBV for either 24 or 48 weeks. Subjects who had undetectable HCV RNA (Target Not Detected) at weeks 4 and 12 (extended Rapid Virologic Response [eRVR]) received 24 weeks of Peg-IFN-alfa-2a/RBV treatment, and subjects who did not have undetectable HCV RNA at weeks 4 and 12 (no eRVR) received 48 weeks of Peg-IFN-alfa-2a/RBV treatment. The control regimen (Pbo/PR48) had a fixed treatment duration, with telaprevir-matching placebo for the first 12 weeks and Peg-IFN-alfa-2a/RBV for 48 weeks.

The 1088 enrolled subjects had a median age of 49 years (range: 18 to 69); 59% of the subjects were male; 23% had a body mass index greater than or equal to 30 kg/m²; 9% were Black; 11% were Hispanic or Latino; 77% had baseline HCV RNA levels greater than 800,000 IU per mL; 15% had bridging fibrosis; 6% had cirrhosis; 59% had HCV genotype 1a; and 40% had HCV genotype 1b.

Table 10 shows the response rates for the T12/PR and Pbo/PR48 groups.

Table 10: Response Rates: Trial 108

Treatment Outcome T12/PR
N = 363
n/N (%)
Pbo/PR48
N = 361
n/N (%)
Overall SVR 79% (285/363) 46% (166/361)
eRVR 58% (212/363) 8% (29/361)
  SVR in eRVR subjects 92% (195/212) 93% (27/29)
No eRVR 42% (151/363) 92% (332/361)
  SVR in no eRVR subjects 60% (90/151) 42% (139/332)
Outcome for Subjects without SVR
On-treatment virologic failurea 7% (26/363) 29% (105/361)
Relapseb 4% (11/298) 24% (53/220)
Otherc 11% (41/363) 10% (37/361)
a On-treatment virologic failure was defined as meeting a protocol-defined stopping rule and/or having detectable HCV RNA at end of treatment with viral breakthrough.
b Relapse was defined as having less than 25 IU/mL at last observation within the planned end of treatment visit window followed by detectable HCV RNA during follow-up.
c Other includes subjects with detectable HCV RNA at the time of their last trial drug but who did not have viral breakthrough, and subjects with a missing SVR assessment.

In the T8/PR group, the overall SVR rate was 72%. The eRVR rate was 57% and the SVR rate for eRVR subjects was 86%. The SVR rate for no eRVR subjects was 52%. More subjects in the T8/PR group experienced virologic failure after Week 12 while receiving peginterferon alfa and ribavirin alone, 7% compared to 4% in T12/PR group.

SVR rates were higher (absolute difference of at least 22%) for the T12/PR group than for the Pbo/PR48 group across subgroups by sex, age, race, ethnicity, body mass index, HCV genotype subtype, baseline HCV RNA (less than 800,000, greater than or equal to 800,000 IU per mL), and extent of liver fibrosis. However, there were small numbers of subjects enrolled in some key subgroups. In the T12/PR group:

  • Twenty-one subjects had cirrhosis at baseline and the overall SVR in these subjects was 71% (15/21). Among subjects with cirrhosis, 43% (9/21) were assigned to 24 weeks of treatment and of those 78% (7/9) achieved SVR.
  • Twenty-six subjects were Black/African Americans. The overall SVR among Black/African American subjects was 62% (16/26). Among these subjects, 35% (9/26) were assigned to 24 weeks of treatment and of those 89% (8/9) achieved SVR.
Trial 111 (ILLUMINATE)

Trial 111 was a randomized, open-label trial conducted in treatment-na´ve subjects. The trial was designed to compare SVR rates in subjects achieving eRVR who were treated with INCIVEK for 12 weeks in combination with Peg-IFN-alfa-2a/RBV for either 24 weeks (T12/PR24 regimen) or 48 weeks (T12/PR48 regimen).

The 540 enrolled subjects had a median age of 51 years (range: 19 to 70); 60% were male; 32% had a body mass index greater than or equal to 30 kg/m²; 14% were Black; 10% were Hispanic or Latino; 82% had baseline HCV RNA levels greater than 800,000 IU per mL; 16% had bridging fibrosis; 11% had cirrhosis; 72% had HCV genotype 1a; and 27% had HCV genotype 1b.

The overall SVR rate for all subjects enrolled in the trial was 74%. A total of 352 (65%) subjects achieved eRVR and of those 322 (60%) were randomized to 24 weeks (T12/PR24, n=162) or 48 weeks (T12/PR48, n=160) of treatment. The SVR rates were similar at 92% (T12/PR24) and 90% (T12/PR48), respectively. Again, small numbers of subjects were enrolled in some key subgroups:

  • Sixty-one (11%) of subjects had cirrhosis at baseline. Among subjects with cirrhosis, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 61% (11/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group.
  • Blacks/African Americans comprised 14% (73/540) of trial subjects. Thirty-four (47%) Black/African American subjects achieved an eRVR and were randomized to T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 88% (15/17), compared to 92% (244/266) for Caucasians among randomized subjects.
Trial C211 (OPTIMIZE)

Trial C211 was a randomized, open-label, Phase 3 trial conducted in treatment-na´ve subjects. Enrolled subjects received 12 weeks of either INCIVEK 750 mg every 8 hours [T12 (q8h)/PR] or INCIVEK 1125 mg twice daily [T12 (twice daily)/PR] in combination with peginterferon alfa-2a and ribavirin. The trial was designed to compare twice-daily dosing [T12 (twice daily)/PR] versus q8h dosing [T12 (q8h)/PR] of INCIVEK. At week 12, INCIVEK dosing ended and subjects continued on peginterferon alfa-2a and ribavirin treatment. The total treatment duration was determined based on the subjects' individual on-treatment viral response. If a subject achieved undetectable HCV RNA < 25 IU/mL (target not detected) at week 4, the total treatment duration was 24 weeks. Otherwise, the total treatment duration was 48 weeks.

The 740 enrolled subjects had a median age of 51 years (range: 18 to 70); 60% of the subjects were male; 21% had a body mass index ≥ 30 kg/m²; 5% were Black; 2% were Asian; 85% had baseline HCV RNA levels ≥ 800,000 IU/ml; 15% had bridging fibrosis; 14% had cirrhosis; 57% had HCV genotype 1a; and 43% had HCV genotype 1b.

Table 11 shows the response rates for the T12 (twice daily)/PR group and the T12 (q8h)/PR groups by treatment outcomes. The overall SVR rates were similar at 74% [T12 (twice daily)/PR; 274/369] and 73% [T12 (q8h)/PR; 270/371], respectively.

Table 11: Response Rates: Trial C211

Treatment outcome T12 (twice daily)/PR
N = 369
% (n/N)
T12 (q8h)/PR
N = 371
% (n/N)
SVR 74% (274/369) 73% (270/371)
Undetectable HCV RNA (target not detected) at week 4a 69% (256/369) 67% (250/371)
SVR in subjects with undetectable HCV RNA (target not detected) at week 4 86% (221/256) 85% (213/250)
SVR in subjects who did not have undetectable HCV RNA at week 4 47% (53/113) 47% (57/121)
Outcome for Subjects without SVR 26% (95/369) 27% (101/371)
On-treatment virologic failureb 10% (38/369) 10% (36/371)
Relapsec 8% (23/300) 6% (19/293)
Otherd 9% (34/369) 12% (46/371)
T12 (twice daily)/PR: INCIVEK 1125 mg twice daily for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks; T12 (q8h)/PR: INCIVEK 750 mg every 8 hours for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks
aSubjects with planned total treatment duration of 24 weeks.
bOn-treatment-virologic failure includes subjects who met a protocol-defined virologic stopping rule and/or who had detectable HCV RNA at the time of their last dose of study drug and had viral breakthrough.
cRelapse was defined as having less than 25 IU/mL at the planned end of treatment followed by HCV RNA ≥ 25 IU/ml at the last observation within the SVR follow-up visit window.
dOther includes subjects with detectable HCV RNA at the planned end of treatment but who did not have viral breakthrough, and subjects with a missing SVR assessment during planned follow-up.

SVR rates were similar for the T12 (twice daily)/PR and T12 (q8h)/PR groups across subgroups determined by sex, age, race, ethnicity, body mass index, HCV genotype subtype, IL28B genotype, baseline HCV RNA (less than 800,000, greater than or equal to 800,000 IU per mL), and extent of liver fibrosis. However, there were small numbers of subjects enrolled in some key subgroups.

  • Fifty-four and 49 subjects in T12 (twice daily)/PR and T12 (q8h)/PR groups, respectively, had cirrhosis at baseline. The SVR rate in these subjects was 54% (29/54) in the T12 (twice daily)/PR group and 49% (24/49) in the T12 (q8h)/PR group. In the T12 (twice daily)/PR group, 52% (28/54) of subjects with cirrhosis achieved undetectable HCV RNA (target not detected) at week 4; their SVR rate was 68% (19/28). In the T12 (q8h)/PR group, 59% (29/49) achieved undetectable HCV RNA (target not detected) at week 4; their SVR was 59% (17/29). The SVR rate for subjects assigned 48 weeks of treatment was 38% (10/26) in the T12 (twice daily)/PR group and 35% (7/20) in the T12 (q8h)/PR.
  • Thirty-five subjects were Black/African Americans. The overall SVR among Black/African American subjects was 50% (10/20) in the T12 (twice daily)/PR group and 60% (9/15) in the T12 (q8h)/PR group. Among these subjects, 46% (16/35) were assigned to 24 weeks of treatment and of those 88% (14/16) achieved SVR.

Previously Treated Adults

Trial C216 (REALIZE)

Trial C216 was a randomized, double-blind, placebo-controlled trial conducted in subjects who did not achieve SVR with prior treatment with Peg-IFN-alfa-2a/RBV or Peg-IFN-alfa-2b/RBV. The trial enrolled prior relapsers (subjects with HCV RNA undetectable at end of treatment with a pegylated interferon-based regimen, but HCV RNA detectable within 24 weeks of treatment follow-up) and prior non-responders (subjects who did not have undetectable HCV RNA levels during or at the end of a prior course of at least 12 weeks of treatment). The nonresponder population included 2 subgroups: prior partial responders (greater than or equal to 2-log10 reduction in HCV RNA at week 12, but not achieving HCV RNA undetectable at end of treatment with peginterferon alfa and ribavirin) and prior null responders (less than 2-log10 reduction in HCV RNA at week 12 of prior treatment with peginterferon alfa and ribavirin).

Subjects were randomized in a 2:2:1 ratio to one of 2 INCIVEK combination treatment groups (with and without a Peg-IFN-alfa-2a/RBV lead-in) or a control group. The T12/PR48 group received INCIVEK and Peg-IFN-alfa-2a/RBV for 12 weeks (without a lead-in), followed by placebo and Peg-IFNalfa-2a/RBV for 4 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The T12 (DS)/PR48 group had a lead-in (delayed start of INCIVEK) with placebo and Peg-IFN-alfa-2a/RBV for 4 weeks, followed by INCIVEK and Peg-IFN-alfa-2a/RBV for 12 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The Pbo/PR48 group received placebo and Peg-IFN-alfa-2a/RBV for 16 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks.

The 662 enrolled subjects had a median age of 51 years (range: 21 to 70); 70% of the subjects were male; 26% had a body mass index greater than or equal to 30 kg/m²; 5% were Black; 11% were Hispanic or Latino; 89% had baseline HCV RNA levels greater than 800,000 IU per mL; 22% had bridging fibrosis; 26% had cirrhosis; 54% had HCV genotype 1a, and 46% had HCV genotype 1b. Null and partial responders had higher baseline HCV RNA levels and more advanced liver disease (cirrhosis) than relapsers; other characteristics were similar across these populations.

The lead-in and immediate start regimens produced comparable SVR and no SVR rates, so data from these 2 groups were pooled (Table 12).

Table 12: Response Rates: Trial C216

Treatment Outcome All T12/PR48a
% (n/N)
Pbo/PR48
% (n/N)
SVR rate
Prior relapsers 86% (246/286) 22% (15/68)
Prior partial responders 59% (57/97) 15% (4/27)
Prior null responders 32% (47/147) 5% (2/37)
Treatment Outcomes for Subjects Without SVR
On-treatment virologic failureb
Prior relapsers 1% (3/286) 26% (18/68)
Prior partial responders 18% (17/97) 70% (19/27)
Prior null responders 52% (76/147) 84% (31/37)
Relapsec
Prior relapsers 3% (8/254) 63% (27/43)
Prior partial responders 20% (14/71) 0% (0/4)
Prior null responders 24% (15/62) 50% (2/4)
aLead-in and immediate start T12/PR regimens pooled
bOn-treatment virologic failure includes subjects who met a protocol-defined virologic stopping rule or who had detectable HCV RNA at the time of their last dose of INCIVEK and subjects who had viral breakthrough on peginterferon alfa/ribavirin.
cRelapse rates are calculated with a denominator of subjects with undetectable HCV RNA (Target Not Detected) at the end of treatment.

Among prior relapsers, 76% (218/286) achieved an eRVR and of those 95% (208/218) achieved an SVR. In an earlier, dose-finding clinical trial, 78% (52/67) of prior relapsers achieved an eRVR and were treated with 24 weeks of peginterferon alfa and ribavirin (T12/PR24); of those 94% (49/52) achieved an SVR.

For all populations in the trial (prior relapsers, prior partial responders, and prior null responders), SVR rates were higher for the T12/PR group than for the Pbo/PR48 group across subgroups by sex, age, ethnicity, body mass index, HCV genotype subtype, baseline HCV RNA level, and extent of liver fibrosis.

Twenty-six percent (139/530) of subjects treated with INCIVEK had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 84% (48/57) compared to 7% (1/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders.

Four percent (19/530) of treatment experienced subjects who received INCIVEK combination treatment were Black/African Americans; the SVR rate for these subjects was 63% (12/19) compared to 66% (328/498) for Caucasians.

Last reviewed on RxList: 11/8/2013
This monograph has been modified to include the generic and brand name in many instances.

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