INCIVO®
PRODUCT INFORMATION
Page 1 of 39INCIVO (120523) API
Attachment 1: Product information for AusPAR Incivo Janssen-Cilag Pty Ltd PM-2010-03576-3-2 Final 26 October 2012. This Product Information was approved at the time this AusPAR was published.name of the MEDICINE
Telaprevir
The chemical name is(1S, 3aR, 6aS)2((S)2{(S)2Cyclohexyl2 [(pyrazine2carbonyl)amino]acetylamino}3,3dimethylbutyryl)octahydrocyclopenta[c]pyrrole1carboxylic acid ((S)1cyclopropylaminooxalylbutyl)amide.
Molecular Formula: C36H53N7O6CAS: 402957-28-2MW: 679.9
DESCRIPTION
The active ingredient telaprevir is an inhibitor of the Hepatitis C Virus (HCV) NS3 4A protease, an enzyme that is essential for HCV replication.Telaprevir drug substance is a white to off-white powder with a solubility in water of 0.0047mg/mL. The apparent log (P1-octanol/aqueous solution) values of telaprevir at room temperature (24±3°C) are 3.96 (pH1), 3.87 (pH5), and 4.00 (pH7). The high apparent partition coefficient is consistent with the low aqueous solubility of the drug substance, and, hence, the hydrophobic nature of telaprevir.
INCIVO is available as yellow, caplet-shaped, filmcoated tablets of approximately 20 mm in length,marked with “T375” on one side. The inactive ingredients are hypromellose acetate succinate, sodium lauryl sulfate, calcium hydrogen phosphate anhydrous, croscarmellose sodium, cellulose - microcrystalline, silicon dioxide, sodium stearyl fumarate, polyvinyl alcohol, macrogol 3350, talc - purified, titanium dioxide and iron oxide yellow.
Pharmacology
Pharmacotherapeutic group: Directacting antiviral.
Pharmacodynamics
Mechanism of Action
Telaprevir is an inhibitor of the HCVNS34A serine protease, which is essential for viral replication.
Antiviral activity in cell culture
In an HCVsubtype1b replicon assay, the telaprevir IC50 value against wildtype HCV was 354 nM, similar to a subtype1a infectious virus assay IC50value of280 nM.In biochemical enzymatic assays, telaprevir showed similar inhibition against HCV genotypes 1a/b (21nM) and 2a/b (16nM), and reduced activity against genotype 3a (57nM) and 4a (130nM) NS34A proteases. 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 additive or moderate synergy in reducing HCV-RNA levels in HCV replicon cells.
In vitro Resistance
HCVvariants associated with ontreatment virologic failure or relapse were evaluated by sitedirected mutagenesis in the replicon assay (see PHARMACOLOGY - Pharmacodynamics: Clinical Experience). Variants V36A/M, T54A/S, R155K/T, and A156S conferred lower levels of in vitro resistance to telaprevir (3- to 25fold increase in telaprevir IC50), and the A156V/T and V36M+R155K variants conferred higher levels of in vitro resistance to telaprevir (>25fold increase in telaprevir IC50). Replicon variants generated from patientderived sequences showed similar results.
In vitro Crossresistance
Telaprevirresistant variants were tested for crossresistance against representative protease inhibitors in the HCVreplicon system. Replicons with single substitutions at position155 or156 and double variants with substitutions at residues36 and155 showed crossresistance to all protease inhibitors tested (e.g. boceprevir) with a wide range of sensitivities. All telaprevirresistant variants studied remained fully sensitive to interferonalfa, ribavirin, and representative HCVnucleoside and nonnucleoside polymerase inhibitors in the replicon system. There are currently no clinical data on retreating subjects who have failed an HCVNS34A protease inhibitorbased therapy, such as telaprevir, nor are there data on repeated courses of telaprevir treatment.
Clinical virology studies
In Phase2 and3 clinical trials of telaprevir, treatmentnaïve and prior treatmentfailure subjects with predominant telaprevirresistant variants at baseline (pretreatment) were rare (V36M, T54A and R155K1% and T54S2.7%). Predominant baseline resistance to telaprevir does not preclude successful treatment with telaprevir, peginterferon alfa, and ribavirin.
A total of 215of 1,169subjects treated with a T12/PR regimen in Phase3 clinical trials had ontreatment virologic failure (n=125) or relapse (n=90). Based on population sequencing analyses of HCV in these 215subjects, the emergence of telaprevirresistant HCVvariants was detected in 105(84%) virologic failures and in 55(61%) relapsers, and wildtype virus was detected in 15(12%) virologic failures and in 24(27%) relapsers. HCVsequencing data were not available for 16(7%) subjects. Sequence analyses of the telaprevirresistant variants identified substitutions predominantlyat 4positions in the NS34A protease region, consistent with the mechanism of action for telaprevir (V36, T54, R155,and A156). Ontreatment virologic failure during telaprevir treatment was predominantly associated with higherlevel resistant variants, and relapse was predominantly associated with lowerlevel resistant variants or wildtype virus.
In an additional 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 INCIVO treatment (Table1). 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 INCIVO-treated subjects who did not achieve SVR.
Subjects with HCVgenotype1a predominately had V36M and R155K single and combination variants, while subjects with HCVgenotype1b predominately had V36A, T54A/S, and A156S/T variants. This difference is likely due to the higher genetic barrier for the V36M and R155K substitutions for genotype1b than genotype1a. Among subjects treated with telaprevir, ontreatment virologic failure was more frequent in subjects with genotype1a than with genotype 1b and more frequent in prior null responders than in other populations (treatmentnaïve, prior relapsers, prior partial responders; see PHARMACOLOGY - Pharmacodynamics: Clinical Experience, Efficacy in Previously Treated Adults).
Table1: Treatment Emergent Substitutions in Pooled Phase 3 Studies:Subjects who did not achieve SVR24 in INCIVO 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 Variants
Followup analysis of INCIVOtreated subjects who did not achieve an SVR showed that the population of wildtype virus increased and the population of telaprevirresistant variants became undetectable over time after the end of telaprevir treatment. Of a combined 255treatmentnaïve and previously treated subjects from Phase3 studies 108, 111, and C216 in whom telaprevirresistant variants had emerged during treatment, 152(60%) subjects no longer had resistant variants detected by population sequencing (median followup of 10months). Of the 393resistant variants detected in the 255subjects, 68% of NS336, 84% of NS354, 59% of NS3155, 86% of NS3156, and 52% of NS336M+NS3155K variants were no longer detected.
In a followup study of 98treatmentnaïve and prior treatmentfailure subjects who were treated with a INCIVO regimen in a Phase2 or Phase3 study and did not achieve SVR, telaprevirresistant variants were no longer detected in 85% (83/98) of subjects (median followup of 27.5months). Clonal sequencing analysis of a subset of subjects who had wildtype HCV by population sequencing (n=20), comparing the frequency of resistant variants before the start of telaprevir treatment and at followup, showed that the HCV variant population in all subjects had returned to pretreatment levels.
Pharmacokinetics
The pharmacokinetic properties of telaprevir have been evaluated in healthy adult volunteers and in subjects with chronic HCVinfection. Telaprevir is to be administered orally with food as 750mg(two film coated 375 mg tablets) every 8hours for 12weeks, in combination with peginterferon alfaand ribavirin. Exposure to telaprevir is higher during coadministration of peginterferon alfa and ribavirin than after administration of telaprevir alone.
Telaprevir exposure is comparable during coadministration with either peginterferon alfa2a and ribavirin or peginterferon alfa2b and ribavirin.
Absorption:
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 4–5hours. In vitro studies performed with human Caco2 cells indicated that telaprevir is a substrate of Pglycoprotein (Pgp).
The exposure to telaprevir was increased by 20% when taken following a highfat caloric meal (56g fat, 928kcal) compared to an intake following a standard normal caloric meal (21g fat, 533kcal). When compared to administration following a standard normal caloric meal, exposure (AUC) decreased by 73% when telaprevir was taken on an empty stomach, by 26% following a lowcalorie highprotein meal (9g fat, 260kcal), and by 39% following a lowcalorie lowfat meal (3.6g fat, 249kcal). Therefore, telaprevir should be taken with food.
Distribution:
Telaprevir is approximately 59% to 76% bound to plasma proteins. Telaprevir binds primarily to alpha 1acid glycoprotein and albumin.
After oral administration, the typical apparent volume of distribution (Vd) was estimated to be 252l, with an interindividual variability of 72.2%.
Biotransformation:
Telaprevir is extensively metabolised in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in faeces, plasma, and urine. After repeated oral administration, Rdiastereomer of telaprevir (30fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the αketoamide 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 CYP isoform responsible for telaprevir metabolism. Studies using recombinant human CYP supersomes showed that telaprevir was a CYP3A4 inhibitor, and a time- and concentrationdependent inhibition of CYP3A4 by telaprevir was observed in human liver microsomes. No inhibition by telaprevir of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 isozymes was observed in vitro. In vitro studies also suggest that telaprevir has a low potential to induce CYP2C, CYP3A, or CYP1A and is therefore considered unlikely to demonstrate inductionbased drugdrug interactions when coadministered with corresponding substrates.
Elimination:
Following administration of a single oral dose of 750 mg 14Ctelaprevir in healthy subjects, 90% of total radioactivitiy was recovered in faeces, urine and expired air within 96hours postdose. The median recovery of the administered radioactive dose was approximately 82% in the faeces, 9% in exhaled air and 1% in urine. The contribution of unchanged 14C–telaprevir and VRT127394 towards total radioactivity recovered in faeces was 31.8% and 18.7%, respectively.
After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4l/h with an interindividual variability of 27.2%. The mean elimination halflife after singledose oral administration of telaprevir 750mg typically ranged from about 4.0to 4.7hours.
Linearity/nonlinearity:
The exposure (AUC) to telaprevir increased slightly greater than proportionally to the dose after singledose administration of 375up to 1,875mg with food, possibly due to saturation of metabolic pathways or efflux transporters.
An increase in dose from 750mgevery 8hours to 1,875mgevery 8hours in a multipledose study resulted in a less than proportional increase (i.e., about 40%) in telaprevir exposure.
Special populations:
Paediatric population:
Data in the paediatric population are currently not available.
Renal impairment:
The pharmacokinetics of telaprevir were assessed after administration of a single dose of 750mg to HCVnegative subjects with severe renal impairment (CrCl <30ml/min). The mean telaprevir Cmax and AUC were 10% and 21% greater, respectively, compared to healthy subjects (see DOSAGE AND ADMINISTRATION).
Hepatic impairment:
Telaprevir is primarily metabolised in the liver. Steadystate exposure to telaprevir was 15% lower in subjects with mild hepatic impairment (ChildPugh Class A, score56) compared to healthy subjects. Steadystate exposure to telaprevir was 46% lower in subjects with moderate hepatic impairment (ChildPugh Class B, score79) compared to healthy subjects (see DOSAGE AND ADMINISTRATION).
Gender:
The effect of subject gender on telaprevir pharmacokinetics was evaluated using population pharmacokinetics of data from Phase2 and3 studies of INCIVO. No dose adjustments are deemed necessary based on gender.
Race:
Population pharmacokinetic analysis of INCIVO in HCVinfected subjects indicated that race had no apparent effect on the exposure to telaprevir. There are limited efficacy and safety data in the clinical development program in Asian patients.
Elderly:
There is limited clinical data on the use of INCIVO in HCVpatients aged ≥65years.
Clinical trials
Clinical experience
The efficacy and safety of INCIVO in subjects with genotype 1 chronic hepatitis C were evaluated in three Phase3 studies: 2in treatmentnaïve subjects and 1in previously treated subjects. The study in previously treated subjects enrolled prior relapsers (subjects with HCVRNA undetectable at end of treatment with a pegylated interferonbased regimen, but HCVRNA detectable within 24weeks of treatment followup) and prior nonresponders (subjects who did not have undetectable HCVRNA levels during or at the end of a prior course of at least 12weeks of treatment). The nonresponderpopulation was comprised of twosubgroups: prior partial responders (greater than or equal to 2log10 reduction in HCVRNA at week12, but not achieving HCVRNA undetectable at end of treatment with a peginterferon and ribavirin) and prior null responders (less than 2log10 reduction in HCVRNA at week12 of prior treatment with peginterferon and ribavirin). Subjects in these studies had compensated liver disease, detectable HCVRNA, and liver histopathology consistent with chronic hepatitis C. Unless otherwise indicated, INCIVO was administered at a dosage of 750mg every 8hours; the peginterferon alfa2a dose was 180µg/week, and the ribavirin dose was 1,000mg/day (subjects weighing <75kg) or 1,200mg/day (subjects weighing ≥75kg). Plasma HCVRNA values were measured using the COBAS® TaqMan® HCVtest (version2.0), for use with the High Pure System. The assay had a lower limit of quantification of 25IU/ml. In the description of Phase3 study outcomes below, SVR,considered virologic cure, was defined based on the HCV RNA assessment in the study week72 visit window, using the last measurement in the window.In the case of missing data within the week72 window, the last HCV RNA data point from week12 of follow-up onwards was used. In addition, the limit of quantification of 25IU/ml was used to determine SVR.
Efficacy in treatmentnaïve adults
Study108 (ADVANCE)
Study108 was a randomised, doubleblind, parallelgroup, placebocontrolled, Phase3 study conducted in treatmentnaïve subjects. INCIVO was given for the first 8weeks of treatment (T8/PR regimen) or the first 12weeks of treatment (T12/PR regimen) in combination with peginterferon alfa2a and ribavirin for either 24or 48weeks. Subjects who had undetectable HCVRNA at weeks4 and12 (extended rapid viral response; eRVR)received 24weeks of peginterferon alfa2a and ribavirin treatment, and subjects who did not have undetectable HCVRNA at week4 and week12 (no eRVR) received 48weeks of peginterferon alfa2a and ribavirin treatment. The control regimen (Pbo/PR) had a fixed treatment duration of 48weeks, with telaprevirmatching placebo for the first 12weeks and peginterferon alfa2a and ribavirin for 48weeks.
The 1,088enrolled subjects had a median age of 49years (range: 18to69); 58%of the subjects were male; 23% had a body mass index ≥30kg/m2;9% were Black; 11% were Hispanic or Latino; 2% were Asian; 77% had baseline HCVRNA levels ≥800,000IU/ml; 15% had bridging fibrosis; 6% had cirrhosis; 59% had HCVgenotype1a; and 40%had HCVgenotype1b.
The SVR rate for the T8/PR group was 72% (261/364) (P0.0001 compared to Pbo/PR48 group). Table2 shows the response rates for the recommended T12/PR and the Pbo/PR48 groups.
Table2:Response rates: Study 108Treatment outcome / T12/PR
N=363
n/N (%) / Pbo/PR48
N=361
n/N (%)
SVRa / 79% (285/363)
(74%, 83%)b / 46% (166/361)
(41%, 51%)b
Undetectable HCVRNA at weeks 4 and 12 (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)
Undetectable HCVRNA at End of Treatment / 82% (299/363) / 62% (225/361)
Relapse / 4% (13/299) / 26% (58/225)
T12/PR: INCIVO for 12weeks with peginterferon alfa2a and ribavirin for 24or 48weeks;
Pbo/PR: placebo for 12weeks with peginterferon alfa2a and ribavirin for 48weeks
aP0.0001; T12/PR compared to Pbo/PR48. The difference in SVR rates (95% confidence interval) between the T12/PR and Pbo/PR groups was 33(26, 39).
b95% confidence interval
SVR rates were higher (absolute difference of at least 28%) for the T12/PR group than for the Pbo/PR48 group across subgroups by sex, age, race, ethnicity, body mass index, HCVgenotype subtype, baseline HCVRNA (<800,000, ≥800,000IU/ml), and extent of liver fibrosis. Table3 shows SVR rates for subject subgroups.
Table3:SVR rates for patient subgroups: Study108 (ADVANCE)Subgroup / T12/PR / Pbo/PR
Men / 78% (166/214) / 46% (97/211)
45 to ≤65years of age / 73%(157/214) / 39% (85/216)
Black / 62% (16/26) / 29% (8/28)
Hispanic Latino / 77% (27/35) / 39% (15/38)
BMI≥30kg/m2 / 73%(56/77) / 44% (38/87)
Baseline HCVRNA ≥800,000IU/ml / 77%(215/281) / 39%(109/279)
HCVgenotype1a / 75% (162/217) / 43% (90/210)
HCVgenotype1b / 84% (119/142) / 51% (76/149)
Baseline liver fibrosis
No fibrosis, minimal fibrosis, or portal fibrosis / 82% (237/290) / 49% (140/288)
Bridging fibrosis / 63% (33/52) / 35% (18/52)
Cirrhosis / 71% (15/21) / 38% (8/21)
T12/PR: INCIVO for 12weeks with peginterferon alfa2a and ribavirin for 24or 48weeks;
Pbo/PR: placebo for 12weeks with peginterferon alfa2a and ribavirin for 48weeks
Study111 (ILLUMINATE)
Study 111 was a Phase3, randomised, open label study conducted in treatmentnaïve subjects. The study was designed to compare SVR rates in subjects with undetectable HCVRNA at weeks4 and12 (extended rapid viral response; eRVR) who were treated with INCIVO for 12weeks in combination with peginterferon alfa2a and ribavirin for either 24weeks (T12/PR24 regimen) or 48weeks (T12/PR48 regimen). Subjects with undetectable HCVRNA at weeks4 and12 (eRVR) were randomised at week20 to receive either 24weeks or 48weeks of peginterferon alfa2a and ribavirin treatment. The primary assessment was an evaluation of noninferiority, using a margin of 10.5% of the 24week regimen compared to the 48week regimen in subjects with undetectable HCVRNA at weeks4 and12.
The 540enrolled subjects had a median age of 51years (range: 19to70); 60% of the subjects were male; 32% had a body mass index ≥30kg/m2; 14% were Black; 10% were Hispanic or Latino; 2% were Asian; 82% had baseline HCVRNA levels >800,000IU/ml; 16% had bridging fibrosis; 11% had cirrhosis; 72% had HCVgenotype1a; and 27% had HCVgenotype1b.
A total of 352 (65%) subjects had undetectable HCVRNA at weeks4 and12 (eRVR). Table4 shows response rates. In subjects who had undetectable HCVRNA at weeks4 and12 (eRVR), there was no additional benefit to extending peginterferon alfa2a and ribavirin treatment to 48weeks (difference in SVR rates of 2%; 95% confidence interval: 4%, 8%).
Table4:Response rates: Study 111 (ILLUMINATE)Subjects with undetectable HCVRNA at weeks 4 and 12 (eRVR) / T12/PR
All Subjectsa
N=540
Treatment outcome / T12/PR24
N=162 / T12/PR48
N=160
SVR / 92% (149/162)
(87%, 96%)b / 90% (144/160)
(84%, 94%)b / 74% (398/540)
(70%, 77%)b
Undetectable HCVRNA at End of Treatment / 98% (159/162) / 93% (149/160) / 79% (424/540)
Relapse / 6% (10/159) / 1% (2/149) / 4% (19/424)
T12/PR24: INCIVO for 12weeks with peginterferon alfa2a and ribavirin for 24weeks;
T12/PR48: INCIVO for 12weeks with peginterferon alfa2a and ribavirin for 48weeks
aAll subjects includes the 322subjects with undetectable HCVRNA at weeks4 and12 and the 218other subjects treated in the study (118who did not have undetectable HCVRNA at week4 and12 and 100who discontinued the study before week20, when randomisation occurred).
b95% confidence interval
The SVR rate for Black subjects was 62% (45/73).
Table5 shows SVR rates by extent of liver fibrosis at baseline.
Table5:SVR rates by extent of liver fibrosis at baseline: Study111 (ILLUMINATE)Subgroup / Subjects with undetectable HCVRNA at weeks 4 and 12(eRVR) / T12/PR
All Subjectsa
T12/PR24 / T12/PR48
No fibrosis, minimal fibrosis, or portal fibrosis / 96% (119/124) / 91% (115/127) / 77% (302/391)
Bridging fibrosis / 95% (19/20) / 86% (18/21) / 74% (65/88)
Cirrhosis / 61% (11/18) / 92% (11/12) / 51% (31/61)
T12/PR24: INCIVO for 12weeks with peginterferon alfa2a and ribavirin for 24weeks;
T12/PR48: INCIVO for 12weeks with peginterferon alfa2a and ribavirin for 48weeks
aAll subjects includes the 322subjects with undetectable HCVRNA at weeks4 and12 and the 218other subjects treated in the study (118who did not have undetectable HCVRNA at weeks4 and12 and 100who discontinued the study before week20, when randomisation occurred)
Efficacy in previously treated adults
StudyC216 (REALIZE)
Study C216 was a randomised, doubleblind, placebocontrolled, Phase3 study conducted in subjects (relapsers, partial responders, and null responders) who did not achieve SVR with prior treatment with peginterferon alfa2a and ribavirin or peginterferon alfa2b and ribavirin.
Subjects were randomised in a 2:2:1 ratio to one of three treatment groups: simultaneous start (T12/PR48): INCIVO from day1 through week12; delayed start (T12(DS)/PR48): INCIVO from week5 through week16; Pbo/PR48: placebo through week16. All treatment regimens had a 48week duration of peginterferon alfa2a and ribavirin treatment.
The 662enrolled subjects had a median age of 51years (range: 21to70); 70%of the subjects were male; 26% had a body mass index ≥30kg/m2; 5% were Black; 11% were Hispanic or Latino; 2% were Asian; 89% had baseline HCVRNA levels >800,000IU/ml; 22% had bridging fibrosis; 26% had cirrhosis; 54% had HCVgenotype1a; and 46% had HCVgenotype1b.
SVR rates for the T12(DS)/PR group were 88%(124/141) for prior relapsers, 56%(27/48) for prior partial responders, and 33%(25/75) for prior null responders. Table6 shows the response rates for the recommended simultaneous start (T12/PR48) and the Pbo/PR48 arms.