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Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin
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Journal of Hepatology July 2012
Dominique Larrey1,
Ansgar W. Lohse2, Victor de Ledinghen3, Christian Trepo4,
Tilman Gerlach5, Jean-Pierre Zarski6, Albert Tran7, Philippe Mathurin8, Robert Thimme9, Keikawus Arasteh10, Christian Trautwein11, Andreas Cerny12, Nektarios Dikopoulos13, Marcus Schuchmann14, Markus H. Heim15, Guido Gerken16, Jerry O. Stern17, Katherine Wu17, Nasri Abdallah18, Birgit Girlich19, Joseph Scherer17, Frank Berger20, Martin Marquis21, George Kukolj21, Wulf Bocher22, Jurgen Steffgen22,
ABSTRACT
Background & Aims
BI 207127 is a potent non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor in vitro.
Methods
In this double-blind, placebo-controlled study, 57 HCV genotype (GT)-1 patients (n=27 treatment-naive [TN]; n=30 treatment-experienced [TE]) with compensated liver disease were randomised for 28-day treatment with 400, 600, or 800mg BI 207127 three times daily (TID) or placebo (only TN) in combination with peginterferon alfa 2a and ribavirin (PegIFN/RBV). Plasma HCV RNA was measured by Roche COBAS TaqMan assay.
Results
HCV RNA decreased in a dose-dependent manner with little difference between 600mg (TN 5.6log10, TE 4.2log10) and 800mg (TN 5.4log10, TE 4.5log10). Rapid virological response (RVR; HCV RNA <15IU/ml) at day 28 occurred in 11/19 TN and 4/30 TE patients treated with BI 207127. GT-1b patients had stronger reductions in HCV RNA than GT-1a (RVR: TN 64% vs. 43%; TE 33% vs. 5%). There were no breakthroughs (HCV RNA rebound >1log10 from nadir) in the TN groups, whereas 3/30 TE patients experienced breakthrough due to P495-mutations. Gastrointestinal adverse events (AEs) and rash were the major AEs and most frequent at higher doses. One and four patients discontinued due to AEs in the 600 and 800mg groups, respectively. Overall, tolerability was good and better at 600mg than 800mg.
Conclusions
BI 207127 in combination with PegIFN/RBV demonstrated strong antiviral activity with a favourable safety and tolerability profile. The best benefit/risk ratio was observed at 600mg.
Introduction
Increased understanding of the hepatitis C virus (HCV) life cycle has resulted in the discovery of several viral targets for antiviral therapy, including the NS3/4A protease, the NS5B polymerase and NS5A. Numerous direct-acting antivirals (DAAs) are currently under development, the most advanced of which are the NS3/4A protease inhibitors (PIs) boceprevir and telaprevir, targeting the most prevalent and difficult-to-cure HCV genotype (GT)-1. Both compounds have recently been approved by the FDA as part of a combination treatment with peginterferon alfa and ribavirin (PegIFN/RBV) for use in treatment-naive (TN) and treatment-experienced (TE) patients [1], [2]. Combination with PegIFN/RBV is required to prevent the rapid selection of resistance mutations that occurs in PI monotherapy and results in viral breakthrough [3], [4].
DAAs active against other HCV GTs are currently being developed [5]. PIs represent an important advancement in the treatment of chronic HCV GT-1 by increasing sustained viral response rates from around 45% with PegIFN/RBV to 65-75% with triple therapy. Second generation PIs such as BI 201335 and TMC435 with improved pharmacokinetics (PK) are in phase III development and may enhance efficacy and tolerability with more convenient dosing (once-daily treatment, low pill burden) [6], [7], [8].
Most patients that fail treatment with telaprevir or boceprevir, in combination with PegIFN/RBV, have resistance mutants at the time of failure that may persist and prevent retreatment with another PI [9], [10]. Such patients may be addressed in the future by treatment with DAAs of different modes of action and non-overlapping resistance profiles, such as NS5B polymerase inhibitors or NS5A inhibitors. BI 207127 is a specific and reversible thumb pocket 1, non-nucleoside HCV NS5B polymerase inhibitor (NNI) with high antiviral activity in vitro (EC50 in cell-based-HCV subgenomic replicon 23 and 11nM for GT-1a and GT-1b, [data on file]). Based on the in vitro EC50 and the PK profile from a single rising dose study in healthy volunteers, a three times daily (TID) dosing schedule was predicted to maintain optimal plasma concentrations.
In a clinical phase I multiple rising dose study, BI 207127 given as monotherapy at doses up to 1200mg every 8h (Q8H) for 5days exhibited very strong and dose-dependent antiviral activities, along with a rather low frequency of resistance mutations, in HCV patients with GT-1 infection [11], [12]. Here, we report the results of a phase Ib randomised, double-blind, placebo-controlled trial (1241.7) investigating safety, antiviral activity and PK of BI 207127 in combination with PegIFN/RBV for 4weeks in TN and TE HCV GT-1 patients.
Materials and methods
Patients
Patients were enrolled in France, Germany and Switzerland. Eligible patients were male or female (with documented hysterectomy or postmenopausal), 18-70years of age, had chronic hepatitis C infection of GT-1, with a HCV viral load (VL) 100,000IU/ml at screening. Patients were either TN or TE; TE patients were defined as failures to treatment with PegIFN/RBV who had received at least 12weeks of therapy and were further classified as either null responders (<1log10 maximum reduction in HCV RNA from baseline at any time during treatment), or partial responders (maximal reduction in HCV RNA >1log10 at any time, but never achieved HCV RNA below the level of detection with a sensitive assay [required minimum limit of detection 50IU/ml]). Relapsers were excluded from the trial to keep the study population more homogenous, particularly as a similar response to that observed in treatment naive patients would have been expected in a study limited to 4-week duration. Cirrhosis was ruled out by biopsy or elastometry (FibroScan®; cut-off used by investigators ranged from 12.5 to 16.0kPa) performed within 24months prior to study enrolment. Patients with hepatitis B virus or human immunodeficiency virus co-infection, concurrent liver disease other than HCV, past treatment with any experimental polymerase inhibitor, or hyperbilirubinaemia (>1.5xupper limit of normal not due to Gilbert's polymorphism) were excluded. The study was conducted according to the ethical principles of the Declaration of Helsinki and in compliance with all Good Clinical Practice guidelines. It was approved by the health authorities and the ethics committees in the involved countries. All patients provided written informed consent prior to trial participation. ClinicalTrials.gov number: NCT00905632.
Study design
This was a phase Ib, multi-centre, randomised, double-blind trial, which was placebo-controlled for TN patients only. Target enrolment was 54 HCV infected patients. Given that this trial was a phase Ib exploratory study, no formal decision-based reasoning was included in the calculation of the sample size. The number of patients chosen was representative of other typical phase Ib trials to compare the safety of each arm with placebo. TN patients were randomised 2:2:2:3 to 400, 600, 800mg TID BI 207127 or matching placebo, plus PegIFN/RBV for 28days. TE patients were randomised 1:1:1 to 400, 600, or 800mg BI 207127 TID plus PegIFN/RBV for 28days. Within both subpopulations, randomisation was stratified by GT-1a or GT-1b. BI 207127 was taken TID with an interval no greater than 12h between doses. Patients were advised to take BI 207127 after a snack, as BI 207127 absorption is improved after food intake. PegIFN alfa 2a was administered subcutaneously at a dose of 180μg per week, and RBV was given orally at a dose of 1000mg per day (body weight <75kg) or 1200mg per day (body weight 75kg) in two divided doses. Patients were advised to use sun protection. After 4weeks, patients were given the opportunity to continue PegIFN alfa 2a or 2b and RBV up to week 48 at the investigators discretion.
Efficacy assessments
Plasma samples were collected from patients at screening and days 1, 2, 4, 8, 15, 22, 27, 28, 29, and 30. HCV RNA was determined by Roche COBAS® TaqMan® HCV/HPS v2.0 assay with a lower limit of quantification (LLOQ) of 25IU/ml and a lower limit of detection (LLOD) of 15IU/ml. HCV GT was determined using the Trugene HCV assay (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA) and confirmed by NS5B-region sequencing [13].
Drug resistance monitoring
Genotypic analysis was performed by population sequencing for the complete NS5B polymerase gene [12] on all baseline samples, and samples above 1000IU/ml at the end of BI 20727 dosing (4weeks). Sequences from all time points were compared to their respective baseline sequences and amino acid changes known to confer resistance to this class of NS5B inhibitor were identified [14].
Safety assessments
All adverse events (AEs) occurring during the course of the trial were documented and reported by the investigator. Electrocardiogram (ECG), vital signs and routine laboratory parameters were also evaluated. A rash management plan was provided where the intensity of rash was graded as mild (localised), moderate (diffuse, 30% to 70% body surface area), or severe (diffuse generalised, mucous membrane involvement, organ dysfunction, signs of anaphylaxis, or life threatening). Treatment of rash was at the investigator's discretion and was dependent on individual patient symptoms, but in cases of severe rash, treatment with BI 207127 as well as PegIFN/RBV had to be stopped.
PK assessments
Trough plasma samples were collected from patients at day 1, 2, 4, 8, 12, 17, 22, 27, 28, 29, and 30; intensive PK sampling was conducted at day 1 and 28. The concentration of BI 207127 in plasma samples was determined by a validated high performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS) assay.
Statistical analysis
The primary end point for this trial was viral response at day 28, defined as at least a 3log10 drop in VL from baseline with no evidence of virologic rebound, defined as 1log10 increase in VL from nadir. In a comparable 4-week study with the nucleoside HCV NS5B polymerase inhibitor (NI) R1626 [15], placebo plus PegIFN/RBV showed a mean VL decrease of 2.4log10 in a TN population. In TE patients, the mean response to placebo plus PegIFN/RBV after 4weeks is generally lower, e.g. <1.5log10, in a population with non-response or partial response [16]. Therefore, a 3log10 drop in VL from baseline to day 28 was considered sufficient to allow a clear differentiation from placebo as a minimally acceptable virologic response threshold for future longer term treatment trials. Secondary end points included rapid virological response (RVR), defined as HCV RNA < LLOD at day 28 of treatment, as well as the rate of patients with HCV RNA < LLOQ at day 28. Safety end points included occurrence of adverse events, vital signs, physical examination, discontinuation due to AEs and laboratory abnormalities. Safety was monitored by a Data Safety Monitoring Board. Descriptive statistics for efficacy, safety and PK end points were calculated.
Results
Patient disposition and baseline characteristics
A total of 75 (34 TN and 41 TE) patients were screened (Supplementary Fig. 1). Of these, 57 were randomised; all randomised patients were treated. Five patients discontinued; all were TE patients and all discontinuations related to AEs (refer to safety section). Table 1 shows a summary of baseline characteristics. Most patients were male and Caucasian, with a mean age of 48.9years. Baseline HCV RNA was comparable for all TN and TE groups ranging from 6.4log10IU/ml to 6.8log10IU/ml. There were no relevant differences for any of the baseline characteristics between treatment groups.
Efficacy
Fig. 1 shows the mean change from baseline in HCV RNA during BI 207127 treatment over time. The initial decrease in HCV RNA was very strong and dose-dependent; however, at the end of 4-week treatment, there was little difference between 600 and 800mg for both TN (mean change 5.5log10 and 5.4log10 vs. 1.6log10 for placebo) and TE patients (4.1log10 and 4.4log10 vs. 3.0log10 with 400mg). The initial decrease in VL (day 1) was faster in the 600 and 800mg dose groups, than in the 400mg group.
TN patients showed a steep and rapid decline of HCV RNA at all tested doses of BI 207127 in combination with PegIFN/RBV, as compared with placebo plus PegIFN/RBV (Fig. 1A). The primary end point of a 3log10 reduction in HCV RNA from baseline at day 28 without virologic rebound was achieved by 18/19 (94.7%) TN patients treated with BI 207127, compared with only 1/8 (12.5%) of patients treated with placebo plus PegIFN/RBV (Table 2A). The only TN patient who did not reach the primary end point was GT-1a and was treated with the lowest dose of 400mg. RVR rates of TN patients were 50%, 57%, and 50% for the 400, 600, and 800mg dose groups, respectively, as compared with 0% with placebo (Table 2B). Furthermore, 67%, 86%, and 100% of TN patients treated with 400, 600, and 800mg of BI 207127 achieved HCV RNA <
LLOQ, as compared with 0 patients treated with placebo. Thus, while the 400mg dose showed slightly lower response rates, antiviral activity was similar between the 600 and 800mg dose groups of BI 207127 in TN patients. With the limitation of small subgroups, there seemed to be only a small difference between TN patients infected with GT-1a or GT-1b (RVR: 43% vs. 64%) (Table 2B).
TE patients showed a rapid, but overall slower decline in HCV RNA at all tested doses, with the lowest decline at 400mg TID, and stronger declines at 600 and 800mg TID of BI 207127 (Fig. 1B). As expected, for patients with previous non-response to PegIFN/RBV, response rates to BI 207127 plus PegIFN/RBV were lower than for TN patients: 40%, 56%, and 55% of patients treated with 400, 600, and 800mg TID BI 207127 met the primary end point of a 3log10 reduction in HCV RNA from baseline to day 29. Breakthrough (HCV rebound >1log from nadir) was observed in 2 (20%) and 1 (11%) TE patients treated with 400 and 600mg BI 207127, respectively; breakthrough was not observed in TN patients (Table 2A). No patient developed a rise in HCV RNA <1log10 from nadir. Corresponding RVR rates in TE patients were 0%, 22%, and 18% at 400, 600, and 800mg TID of BI 207127, with two additional patients achieving HCV RNA < LLOQ in the 400 and 600mg TID dose groups (Table 2B). In all TE dose groups, GT-1a responses were lower than for GT-1b (RVR: 5% vs. 33%). As in TN patients, the 400mg dose showed lower response rates, while antiviral activity was very similar between the 600 and 800mg dose groups (Table 2C). In all dose groups, the antiviral response was slightly lower in null responders compared with partial responders (Table 2D).
Viral resistance
All three TE patients that experienced viral breakthrough during BI 207127 treatment encoded for a NS5B amino acid substitution at P495 that was not present at baseline. The predominant mutations encoded for changes to a leucine, a serine or a glutamine (P495P/L; P495Q/P/S/L; P495Q). These modifications were consistent with previous observations in the BI 207127 5-day monotherapy study [11], [12], and were detectable as early as day 8 of treatment, and persisted up to day 85. By the end of follow-up, the viruses in all three patients had reverted to the wild type amino acid at position 495.
Safety
All patients treated with BI 207127 plus PegIFN/RBV and 7/8 patients with placebo had at least one AE (Table 3). All were rated as either mild or moderate, with the exception of one AE (syncope, see below). Gastrointestinal (GI) AEs (mainly nausea, diarrhoea and vomiting) and rash/photosensitivity skin reactions appeared to be more frequent and dose-dependent in the BI 207127 dose groups compared with placebo. The characteristic appearance of the observed rash was either maculo-papular or papular. Photosensitivity reactions represented nearly half of the reported rash cases.
There were no deaths during the 4-week combination treatment. Two serious AEs were observed; one rash, leading to discontinuation of treatment at 800mg, and one syncope, with orthostatic dysregulation as a pre-existing condition, who continued treatment with 400mg BI 207127. In addition, 1/17 patients treated with 600mg BI 207127 discontinued due to nausea and diarrhoea. A further three patients treated with 800mg BI 207127 discontinued due to different AEs (1 rash/photosensitivity reaction, 1 gastrointestinal intolerance with loss of weight, 1 cholestatic jaundice).
A summary of safety laboratory analyses is shown in Table 4. In comparison with placebo, there were no clinically relevant changes in laboratory parameters. However, in comparison with placebo, a slight, dose-dependent decrease in white blood cells (WBCs), mainly neutrophils, was observed together with BI 207127 treatment. There were no clinically significant changes in vital signs or ECGs.
PK
The PK parameters of BI 207127 are provided in Supplementary Table 1. Consistent with previous observations [11], the t1/2 of BI 207127 was short (~4h); therefore there was no accumulation of BI 207127 during the trial. In contrast, in all dose groups high initial exposures were followed by a continuous decline towards the end of treatment. Only the highest dose of 800mg TID did not apparently achieve steady state after 4weeks. The mechanisms are under investigation. The geometric mean of total exposure (AUC, Cmax, or Cpre) showed no noticeable difference between TN and TE patients, but supra dose-proportionality in the tested dose range. Previous PegIFN/RBV treatment did not influence the PK of BI 207127. PK parameters varied within and between subjects; the coefficient of variation ranged between 20% and 110% and increased with dose. Drug exposure and VL response showed a noticeable correlation despite the variability observed in both of them.
Discussion
This is the first report of antiviral activity of a thumb pocket 1 NNI in combination with PegIFN/RBV. BI 207127 plus PegIFN/RBV induced strong and rapid antiviral responses against HCV GT-1 with good safety and tolerability. The primary end point of a 3log10 reduction in HCV RNA from baseline to day 28 without virologic rebound was achieved in 18/19 (94.7%) TN patients treated with BI 207127, compared with only 1/8 (12.5%) TN patients treated with placebo and 15/30 (50%) TE patients.
For TN patients, the median change in HCV RNA from baseline was greater than 5log10IU/ml at all dose groups compared with 1.4log10 for patients receiving PegIFN/RBV. At the higher dose groups of 600 and 800mg, all TN patients except one achieved a decrease in VL below LLOQ (HCV RNA <25IU/ml), with most patients exhibiting RVR, regardless of their GT (GT-1a vs. GT-1b). There was no rebound for TN patients receiving BI 207127 in combination with PegIFN/RBV. In contrast, none of the placebo patients achieved VL below LLOQ during the first 28days of treatment.
The NS5B polymerase provides different target structures to inhibit viral replication: nucleoside or nucleotide analogues (NIs) bind to the active site and inhibit RNA replication as chain terminators, while NNIs bind to one of four allosteric sites. It has been demonstrated that the BI 207127 class of compounds inhibit an initiation event of the NS5B polymerase by binding to the thumb pocket 1 [14]. This NS5B pocket interacts with an N-terminal loop that bridges the finger and thumb domains and is relatively well conserved among HCV genotypes; the major P495 drug resistant mutants that have been selected in vitro [14] were also selected at a low frequency in this study and were shown to revert to wild type without drug selective pressure.
Several reports demonstrate the activity of NNIs combined with PegIFN/RBV. The activity of the palm pocket 1 NS5B polymerase inhibitor ABT-333 has been tested in TN HCV GT-1 patients (n=30) at doses of 300, 600, or 1200mg twice daily (BID) for 2-day monotherapy followed by combination with PegIFN/RBV for 26days [17], [18]. Combination treatment with ABT-333 resulted in a 2.3log10 greater decrease in VL compared with PegIFN/RBV and placebo. In comparison, the decrease in VL for TN patients treated with BI 207127 plus PegIFN/RBV in the current study was stronger, ranging between 3.6 and 4.2log10 greater than PegIFN/RBV and placebo.
A larger study of the palm pocket 2 NS5B polymerase inhibitor HCV-796 in combination with PegIFN/RBV (n=244) in both TN and TE HCV GT-1 patients demonstrated an RVR rate of 52.1% (n=82), compared with 6.9% for PegIFN/RBV alone [19]. It should be noted that in this trial RVR was defined as <50IU/ml rather than the more usual <15IU/ml. Despite the promising virologic response, unexpected elevations in liver enzymes were observed and development of HCV-796 has been halted [19].
The palm pocket 1 NS5B polymerase inhibitor ANA598 was dosed at either 200mg (n=29) or 400mg (n=34) BID in combination with PegIFN/RBV in GT-1 TN patients [20], [21]. In total 56% and 42% of patients in the 200 and 400mg arms, respectively, demonstrated RVR, compared with 13% of patients receiving PegIFN/RBV plus placebo.
Given as monotherapy, the highest tested dose (2x700mg/day) of the thumb pocket 2, NS5B inhibitor, filibuvir, resulted in a mean 2.3log10 decrease in HCV RNA in TN patients [22], whereas 5-day monotherapy with BI 207127 resulted in a 3.8log10 reduction in HCV RNA [11]. In TN HCV GT-1 patients (n=35), the addition of filibuvir (200, 300, or 500mg [n=8] BID) to PegIFN/RBV for 4weeks significantly increased the proportion of patients achieving RVR compared with PegIFN/RBV plus placebo (p<0.05), ranging from 60% to 75% for filibuvir plus PegIFN/RBV vs. 0% for PegIFN/RBV plus placebo [23], [24], [25]. The RVR rates from these latter two studies are similar to those achieved in the current study with BI 207127.
NIs have been shown to provide a high resistance barrier to selection of resistance mutants in vitro and in vivo, but are dose limited in clinical trials by hematological side effects. High doses of the NI R1626 (2x4500mg) administered for 4weeks in combination with PegIFN/RBV in TN HCV GT-1 patients (n=84) resulted in RVR in 74% of patients, compared with 5% of patients who received PegIFN/RBV alone [15]. However, several cases of common toxicity criteria (CTC) grade 3/4 lymphopenia and neutropenia were observed, which led to termination of the development of R1626. The follow-up compound, mericitabine (R7128), in combination with PegIFN/RBV, achieved RVR in 5/11 TN patients (45%) and a median decrease in HCV RNA from baseline of 4log10 [26].
In summary, the rates of RVR and median decrease in HCV RNA levels demonstrated with BI 207127 plus PegIFN/RBV in TN patients appear to be at least equivalent to the levels of antiviral activity demonstrated by other NS5B polymerase inhibitors when administered with PegIFN/RBV, and comparable to those of a PI with PegIFN/RBV in such patients [27], [28].
In contrast to other polymerase inhibitors, the activity of BI 207127 combined with PegIFN/RBV was also tested in TE patients. As expected, TE patients with non-response to previous PegIFN/RBV had lower median changes in HCV RNA from baseline ranging from 2.9log10 (400mg TID), to 4.2log10 (600mg TID), and 4.5log10 (800mg TID). This difference in efficacy between TE and TN patients indicates the need of inherent interferon responsiveness, even with triple therapy. However, the change in HCV RNA in these most difficult-to-treat patients was still more than 1.5log10 (400mg TID), 2.8log10 (600mg TID), and 3.1log10 (800mg TID) higher than seen in the TN placebo group, with only three rebounds occurring at 400 and 600mg BI 207127. At the higher dose groups, 22.2% and 18.2% of patients achieved RVR at day 28, although they were null or partial responders to previous PegIFN/RBV treatment. This confirms the strong antiviral activity of BI 207127 in combination with PegIFN/RBV, even though the antiviral activity in TE patients is lower compared with PIs [29].
A multiple rising dose monotherapy study [11], [12] demonstrated the emergence of viral variants conferring resistance to BI 207127 in only 5/46 non-cirrhotic patients treated for 5days with increasing doses of BI 207127 monotherapy. In support of this finding, the rate of viral rebounds (in total 3/57 patients) in this PegIFN/RBV combination study is very low, indicating that this thumb pocket 1 inhibitor might have a higher barrier to resistance compared with NNIs targeting other sites of the NS5B polymerase [30]. BI 207127 belongs to the thumb pocket 1 class of NNIs that displace the NS5B amino-terminal 1 finger loop from the upper thumb domain and interfere with a conformational change required to initiate RNA synthesis. In contrast to other sites that are exposed on the surface of the NS5B polymerase, the thumb pocket 1 binding site comprises an interface between functional domains that restricts sequence polymorphism and may provide a higher resistance barrier compared to other NNIs [14].
The PK characteristics of BI 207127 after combination therapy with PegIFN/RBV were similar to monotherapy at steady state. Of note, the total exposure of TID dosing was comparable to dosing Q8H [11]. Co-administration of PegIFN/RBV did not alter the pharmacokinetics of BI 207127.
In terms of safety and tolerability, there was an increased incidence of mild-to-moderate rash, photosensitivity and GI side effects associated with higher doses (600 and 800mg) of BI 207127 in combination with PegIFN/RBV. An increase in side effects related to the GI tract has also been reported for other HCV NS5B polymerase inhibitors, e.g. R7128 [26] and PIs, e.g. BI 201335 [31] and telaprevir [32]. Rash is also observed with treatment with several HCV PIs e.g. BI 201335 [32] and even more pronounced with telaprevir treatment [32]. These side effects of BI 207127 could be monitored and managed successfully with appropriate clinical monitoring and treatment. Slight reductions in neutrophils were observed that were not clinically relevant. In contrast, treatment with the NI R1626 resulted in a high incidence of CTC grade 4 neutropenia [15] which finally led to the termination of development of this agent. Less pronounced neutropenia was observed with the NI R7128 but there were still a few CTC grade 4 cases at doses of 2x1500mg R7128 BID [26].
Decrease in WBC is a typical side effect of PegIFN/RBV. There is no evidence for a hematotoxic effect of BI 207127 since there were no findings in preclinical studies (data on file), a 5-day monotherapy study [11] or an IFN-free combination with the PI BI 201335 [33].
Overall, the tolerability of 600mg TID was better than that of 800mg TID as evidenced by four of the five premature discontinuations in the 800mg group.
In summary, BI 207127 in combination with PegIFN/RBV induced a strong and rapid antiviral response with few rebounds after 4weeks of treatment in TE and especially TN GT-1 HCV infected patients, and was well tolerated. Since overall cure rates in combination with PegIFN/RBV seem to be generally lower than for PI-based treatments, the major value of NS5B polymerase inhibitors in the future treatment of HCV is likely to be oral combination with other potent DAAs. On the basis of these results, BI 207127 is currently being further assessed in an all-oral combination treatment study for chronic HCV GT-1 infection.
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