O65 High Rate of Sustained Virologic Response in Patients With HCV Genotype-1a Infection: A Phase 2 Trial of Faldaprevir, Deleobuvir and Ppi-668, With and Without Ribavirin

Lalezari, J.; Holland, L. J.; Glutzer, E.; Elgadi, Mabrouk; Stern, Jerry O.; Colonno, Richard J.; Halfon, Siman-Tov; Ruby, Eric; Huang, Naya; Nash, E.F.; Brown, Nathaniel

doi:10.1016/s0168-8278(14)60067-2

Cited by 3 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Faldaprevir (120 mg QD) plus PR was well tolerated, with a safety profile similar to that of PR alone and a low rate of adverse events (AEs) leading to discontinuations. High SVRs have also been achieved with faldaprevir in phase II interferon-free combinations with deleobuvir (a nonnucleoside NS5B inhibitor) and ribavirin (SOUND-C3) and with PPI-668 (an NS5A inhibitor), deleobuvir, and RBV in patients infected with GT-1a or 18).The pharmacokinetic profile of faldaprevir supports QD administration (19). Phase Ib pharmacokinetic data showed that following administration of faldaprevir (20 to 240 mg QD), concentrations of the drug in plasma peaked at 2 to 6 h and increased supraproportionally with dose (19).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Huang

Moschetti

Lang

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

e Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC 0 -ؕ ) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.) C hronic hepatitis C virus (HCV) infection is a cause of renal dysfunction and associated with a number of comorbidities that can affect renal function (1, 2).As impaired renal function may influence drug metabolism and pharmacokinetics (PK) (3, 4), dose adjustments might be required in this patient population to avoid excess drug accumulation, which can impact drug efficacy and safety. While the introduction of the NS3/4A protease inhibitors telaprevir and boceprevir represented a significant advance in the management of patients with chronic HCV genotype 1 (GT-1) infection, their use is associated with some disadvantages (5). In addition to being associated with a number of significant serious side effects (including rash, anemia, and gastrointestinal symptoms), these protease inhibitors require three times daily dosing due to short halflives, have a complex drug-drug interaction profile (limiting coadministration with other agents), and are associated with a marked decline in renal function (6-8).In order to improve the safety, efficacy, and convenience of HCV treatments, a number of second-generation direct-acting antivirals (DAAs) for the treatment of patients infected with HCV GT-1 are in clinical development or have recently been approved (9-11). Faldaprevir is a potent HCV NS3/4A protease inhibitor (12), which, in combination with pegylated alpha-2a interferon and ribavirin (RBV) (PR), has been shown to be highly effective for the treatment of chronic HCV GT-1 infection (13-16). In the phase III STARTVerso1 trial, once-daily (QD) faldaprevir (120 mg) plus PR achieved sustained virologic response rates 12 weeks after completion of treatment (SVR12) of ...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Huang

Moschetti

Lang

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Inhibitors of NS5A have high anti-viral potency in the picomolar range and have been studied in multiple DAA combinations. Regimens consisting of an NS5B thumb-pocket 1 NNI (deleobuvir with RBV, beclabuvir, or TMC-647055) with an NS3 PI and an NS5A inhibitor resulted in higher SVR12 rates in both GT-1a and GT-1b (≥92% SVR12 [ 24 , 27 , 32 ]), compared with studies reported here with two DAAs plus RBV [ 24 , 32 ]. IFN-free combinations that include the NI sofosbuvir with an NS5A inhibitor (ledipasvir), with or without RBV, can achieve high SVR rates (up to 97% [ 33 ]), further highlighting the importance of including an NI and/or NS5A inhibitor in DAA regimens.…”

Section: Discussionmentioning

confidence: 75%

Resistance Analyses of HCV NS3/4A Protease and NS5B Polymerase from Clinical Studies of Deleobuvir and Faldaprevir

et al. 2016

View full text Add to dashboard Cite

Background & AimThe resistance profile of anti-hepatitis C virus (HCV) agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B amino-acid variants among HCV genotype (GT)-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor), deleobuvir (HCV polymerase non-nucleoside inhibitor), and ribavirin in multiple clinical studies.MethodsHCV NS3/4A and NS5B population sequencing (Sanger method) was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B) and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b). Persistence and time to loss of resistance-associated variants (RAVs) was estimated using Kaplan–Meier analysis.ResultsFaldaprevir RAVs (NS3 R155 and D168) and deleobuvir RAVs (NS5B 495 and 496) were rare (<1%) at baseline. Virologic response to faldaprevir/deleobuvir/ribavirin was not compromised by common baseline NS3 polymorphisms (e.g. Q80K in 17.5% of GT-1a) or by NS5B A421V, present in 20% of GT-1a. In GT-1b, alanine at NS5B codon 499 (present in 15% of baseline sequences) was associated with reduced response. Treatment-emergent RAVs consolidated previous findings: NS3 R155 and D168 were key faldaprevir RAVs; NS5B A421 and P495 were key deleobuvir RAVs. Among on-treatment virologic breakthroughs, RAVs emerged in both NS3 and NS5B (>90%). Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b); some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b). Median time to loss of GT-1b NS5B P495 RAVs post-treatment (5 months) was less than that of GT-1b NS3 D168 (8.5 months) and GT-1a R155 RAVs (11.5 months).ConclusionFaldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b) may reduce response to this deleobuvir-based regimen.

show abstract

Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis C genotype-4

Esmat

Elbaz

Raziky

et al. 2018

Journal of Hepatology

View full text Add to dashboard Cite

O65 High Rate of Sustained Virologic Response in Patients With HCV Genotype-1a Infection: A Phase 2 Trial of Faldaprevir, Deleobuvir and Ppi-668, With and Without Ribavirin

Cited by 3 publications

References 0 publications

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Resistance Analyses of HCV NS3/4A Protease and NS5B Polymerase from Clinical Studies of Deleobuvir and Faldaprevir

Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis C genotype-4

Contact Info

Product

Resources

About