Interferon‐free treatment of chronic hepatitis C with faldaprevir, deleobuvir and ribavirin: <scp>SOUND</scp>‐C3, a Phase 2b study

Zeuzem, Stefan; Dufour, Jean–François; Buti, Marı́a; Soriano, Vincent; Buynak, Robert; Mantry, Parvez S.; Taunk, Jawahar; Stern, Jerry O.; Vinisko, Richard; Gallivan, John-Paul; Böcher, Wulf O.; Mensa, Federico

doi:10.1111/liv.12693

Cited by 19 publications

(28 citation statements)

References 15 publications

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“…Overall, the safety profile observed in this study was consistent with that reported in the faldaprevir clinical trial program in subjects without renal impairment (13)(14)(15)(16)(17). Increased levels of indirect bilirubin were not accompanied by elevations of other markers of liver toxicity, and these clinically irrelevant, transient indirect bilirubin increases are a well-known effect of treatment with faldaprevir, which is an inhibitor of UGT1A1 and hepatic uptake transporters (35).…”

Section: Discussionsupporting

confidence: 74%

“…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 GT-1b (17,18).…”

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confidence: 99%

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

Huang

Moschetti

Lang

et al. 2015

Antimicrob Agents Chemother

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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 ...

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

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

Huang

Moschetti

Lang

et al. 2015

Antimicrob Agents Chemother

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“…This is consistent with results in the more recent SOUND-C3 study (28) and may be due to the lower potency of deleobuvir against GT-1a than GT-1b (29,30). Higher response rates were observed among GT1b-infected patients with less advanced liver disease than among those with more advanced liver disease in the BID28W arm (86% without cirrhosis versus 80% with cirrhosis; 91% for F0 to F2 versus 75% for F3 to F4), although this was not a pattern consistently observed across arms.…”

Section: Discussionsupporting

confidence: 81%

“…Higher response rates were observed among GT1b-infected patients with less advanced liver disease than among those with more advanced liver disease in the BID28W arm (86% without cirrhosis versus 80% with cirrhosis; 91% for F0 to F2 versus 75% for F3 to F4), although this was not a pattern consistently observed across arms. In the SOUND-C3 study, 19/20 (95%) patients with GT-1b infection achieved SVR12, including all four patients with cirrhosis (28).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Faldaprevir, Deleobuvir, and Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C Virus Infection and Advanced Liver Fibrosis or Cirrhosis

Zeuzem

Soriano

Asselah

et al. 2015

Antimicrob Agents Chemother

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Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n ‫؍‬ 362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-timesdaily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.)

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“…BI207127 developed by Boehringer-Ingelheim was tested in combination with faldaprevir and Ribavirin. Data from an SOUND-C3 study showed that the triple combination gave 95% survival rate in genotype 1b patients [87]. Currently, phase III trials are being completed for BI207127 in combination with faldaprevir and Ribavirin in chronically infected HCV GT1b treatment-naive patients [NCT01728324].…”

Section: Coumestan Derivativesmentioning

confidence: 99%

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Polamreddy

Vishwakarma

Gundla

2016

Int J Pharm Pharm Sci

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Hepatitis C, a chronic disease affecting the global population significantly is caused majorly by Hepatitis C virus [HCV]. Among the several druggable targets explored for Hepatitis C, the viral protein, non-structural protein 5B [NS5B] is the target of choice for researchers as it is the key enzyme in the HCV replication and its active site is conserved among all genotypes. In the recent years the landscape of Hepatitis C therapies, have evolved from Peg-Interferon [PEG-INF]/Ribavirin, to directly acting anti-virus along with PEG-INF and finally, INF free regimens with greater than 90% sustained virological response [SVR]. The launch of Sofosbuvir, a nucleotide inhibitor of NS5B marks the major paradigm in hepatitis C research. Sofosbuvir exhibits, pan-genotypic activity, low barrier to resistance, highly effective and safe. However, the high prices of these medications limit their universal access. This review will focus on progress towards the discovery and development of NS5B inhibitors targeting allosteric sites and active site, covering the chemical class and structure-activity relationships.

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Interferon‐free treatment of chronic hepatitis C with faldaprevir, deleobuvir and ribavirin: SOUND‐C3, a Phase 2b study

Abstract: The interferon-free regimen of faldaprevir, deleobuvir and ribavirin was efficacious in patients infected with genotype-1b and generally well tolerated.

Cited by 19 publications

References 15 publications

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

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

Efficacy and Safety of Faldaprevir, Deleobuvir, and Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C Virus Infection and Advanced Liver Fibrosis or Cirrhosis

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

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