SILEN-C3, a Phase 2 Randomized Trial with Faldaprevir plus Pegylated Interferon α-2a and Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients

Abstract

Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143–2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).

Mechanisms Underlying Benign and Reversible Unconjugated Hyperbilirubinemia Observed with Faldaprevir Administration in Hepatitis C Virus Patients

“…A phase II study in treatment-naive patients with chronic HCV genotype (G) 1 infection reported significantly improved sustained virologic response rates with faldaprevir in combination with pegylated interferon (Peg-IFN) plus RBV (72-84%) versus Peg-IFN plus RBV alone (56%) (Sulkowski et al, 2013a). Substantial sustained virologic response rates were also observed in patients who were null responders (Sulkowski et al, 2013b) and in treatment-naive patients (Dieterich et al, 2014). Faldaprevir was generally well tolerated in clinical studies (Sulkowski et al, 2013a,b;Dieterich et al, 2014).…”

“…Substantial sustained virologic response rates were also observed in patients who were null responders (Sulkowski et al, 2013b) and in treatment-naive patients (Dieterich et al, 2014). Faldaprevir was generally well tolerated in clinical studies (Sulkowski et al, 2013a,b;Dieterich et al, 2014). At the highest dose (240 mg q.d.…”

“…Clinical findings regarding hyperbilirubinemia were assessed based on serum bilirubin data from one phase I (data on file) and three phase II (Sulkowski et al, 2013a,b;Dieterich et al, 2014) trials of faldaprevir. The clinical trials included in the current investigation were conducted in full compliance with the Guidelines of Good Clinical Practice and the Declaration of Helsinki, and were approved by all institutional review boards, ethical committees, and national authorities.…”

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

“…Four phase 2 studies evaluated the efficacy and safety of faldaprevir with PegIFN alfa-2a plus RBV [13][14][15][16]. In genotype-1 treatment-naïve patients, SVR rates of up to 84% were achieved compared with 56% for placebo plus PegIFN and RBV [13].…”

“…In addition, SVR rates were similar with faldaprevir 120 mg for 12 or 24 weeks [16]. The addition of faldaprevir to PegIFN and RBV was not associated with an increased incidence of anemia compared with PegIFN and RBV alone [13,16] and there have been no reports of potentially lifethreatening cutaneous adverse reactions in phase 2 studies [13,14,16]. Studies of faldaprevir and antiretrovirals have shown a lower potential for DDIs than first-wave PIs [17].…”