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Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: A phase 1b multiple ascending dose study
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Journal of Hepatology June 2011 vol. 54 j 1130-1136
Danoprevir is now in development with low-dose ritonavir boosting which makes it a once-daily dose, and may have the affect it has in HIV increasing potency & reducing risk for development resistance:
1. Activity of danoprevir plus low-dose ritonavir in combination with peginterferon alfa-2a (40KD) plus ribavirin in previous null responders h ... Apr 3, 2011
www.natap.org/2011/EASL/EASL_21.htm - Cached
2. Low prevalence of danoprevir resistance identified in genotype 1b ...
Apr 3, 2011 ... EASL: Activity of danoprevir plus low-dose ritonavir in combination with peginterferon alfa-2a (40KD) plus ribavirin in previous null ...
www.natap.org/2011/EASL/EASL_70.htm - Cached
3. IMPACT OF LOW-DOSE RITONAVIR BOOSTING ON THE PHARMACOKINETICS OF ...
Low-dose RTV significantly enhances danoprevir C12h (representative of Cmin ... The co-administration of danoprevir single dose and low-dose RTV was safe ...
www.natap.org/2010/EASL/EASL_52.htm - Cached
4. Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients: Antiviral activity, safety, and pharmacokinetics of danoprevir ...
"In conclusion, this study confirms that the use of low dose danoprevir plus low dose ritonavir to reduce the overall danoprevir exposure is a feasible ...
www.natap.org/2011/HCV/040411_01.htm - Cached
5. InterMune Reports Virologic Response of Ritonavir-Boosted Danoprevir
Apr 14, 2010 ... Dan Welch, Chairman and CEO of InterMune commented, "Importantly, 18 of 25 patients (72%) treated with ritonavir-boosted danoprevir had HCV ...
www.natap.org/2010/EASL/EASL_10.htm - Cached
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Nicole Forestier1,, Dominique Larrey2, Dominique Guyader3, Patrick Marcellin4, RŽgine Rouzier5, Alain Patat6, Patrick Smith7, Williamson Bradford8, Steven Porter8, Lawrence Blatt8, Scott D. Seiwert8, Stefan Zeuzem1
1J.W. Goethe Universitat, Frankfurt, Germany; 2CHU Montpellier, France; 3Pontchaillou Hospital, Rennes, France; 4H™pital Beaujon, Clichy, France; 5Centre CAP, Montpellier, France; 6Biotrial, Rennes, France; 7Genentech, Inc., South San Francisco, CA, USA; 8InterMune, Inc., Brisbane, CA, USAReceived 27 May 2010; received in revised form 2 November 2010; accepted 4 November 2010
Background & Aims: Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection.
Methods: Four cohorts of treatment-naïve (TN) patients (100mgq12h, 100mgq8h, 200mgq12h, 200mgq8h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300mgq12h) were investigated.
Results: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9log10IU/ml and -3.2log10IU/ml in TN receiving 200mg q8h and 200mg q12h, respectively. End of treatment viral decline in these two cohorts was within 0.1log10IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype.
Conclusions: Danoprevir was safe and well tolerated when administered for 14days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log10IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.
Introduction
Hepatitis C virus (HCV) is a single-stranded ribonucleic acid (RNA) virus that infects approximately 170 million people worldwide [1]. HCV infection is a major cause of chronic liver disease, cirrhosis, and primary hepatocellular carcinoma, and is currently among the leading indications for liver transplantation in both the United States and Europe [2], [3].
The current standard of care for patients with chronic HCV infection consists of the combined administration of pegylated interferon-alfa (PEG-IFN-alfa) and ribavirin (RBV) for 24-48weeks. While this approach is largely effective in patients with HCV genotypes 2 and 3, approximately 50% of patients infected with HCV genotype 1 fail to achieve a sustained virologic response (SVR), defined as undetectable HCV RNA 24weeks after the completion of therapy [4]. Moreover, the well-described toxicities associated with both PEG-IFN-alfa and RBV frequently lead to dose reductions or premature discontinuation of therapy, further limiting the likelihood of achieving a sustained virologic response. Indeed, in a clinical trial, evaluating treatment with pegylated interferon-alfa and ribavirin, dose modifications were necessary in approximately one-third of patients [4] and 10-14% of patients in this and similar trials discontinued therapy due to a treatment emergent adverse event or laboratory abnormality [4], [5], [6]. In light of these limitations, there is a clear need for novel therapeutic agents that offer enhanced antiviral activity with improved tolerability for patients with chronic HCV infection.
Activity of the NS3/4A protease plays an essential role in viral replication and potentially in the suppression of host immune responses to HCV infection [7].
HCV NS3/4A serine protease inhibitors (PIs) can be divided into two chemical classes, macrocyclic inhibitors and linear tetrapeptide derivatives. Several PIs, both macrocyclic and non-macrocyclic, are currently in clinical development. The most advanced compounds, telaprevir and boceprevir, are linear tetrapeptides currently under phase 3 evaluation and are expected to be approved in 2011/2012. Whereas linear tetrapeptide and macrocyclic inhibitors do not differ in general with respect to their antiviral activity in HCV patients, their resistance profiles differ significantly. However, substitution at position R155 in NS3 has been found to confer resistance to both macrocyclic and non-macrocyclic PIs.
Danoprevir is an orally bioavailable macrocyclic PI that was developed through a structure informed, rational drug design campaign. The biochemical potency of danoprevir is<65pM, its potency against a genotype 1b subgenomic replicon is 1.8nM, and it displays a high degree of specificity judged by its lack of inhibition of a broad panel of human serine proteases and other cellular proteins (specificity index of>45,000-fold) [8], [9]. Preclinical pharmacokinetic analysis indicates that danoprevir has relatively low plasma exposure but liver exposure predictive of a robust antiviral effect [9]. In a phase I single ascending dose study, danoprevir was found to be safe and generally well tolerated in healthy adult subjects at doses ranging from 2 to 1600mg [10]. Food consumption in this study increased both AUC and CT, while slightly lowering Cmax. The study reported here assessed the safety, pharmacokinetics, and antiviral activity of multiple ascending oral doses of danoprevir as a monotherapy for 14days in patients with chronic HCV genotype 1 infection.
Materials and methods
Study design
Eligible patients were randomized to receive monotherapy with oral danoprevir or matched placebo for 14days in a randomized, double-blind, placebo-controlled study composed of two parts. Part A was a dose ranging study of multiple ascending doses of danoprevir in treatment-naïve (TN) HCV genotype 1 patients. Four cohorts of 10 patients each were randomized (8:2) to treatment with danoprevir or placebo equivalent. Danoprevir was administered orally in soft gelatin capsule form in total daily doses ranging from 200 to 600mg. In Part B, a single dose level was explored in a cohort of non-responders (NR) to prior PEG-IFN-alfa/RBV, defined as patients who had failed to achieve a >2log10 reduction in HCV RNA at week 12 or undetectable HCV RNA at week 24 or beyond during a standard course of therapy with PEG-IFN-alfa/RBV. In Part A, TN (Cohorts 1-5) were permitted but not required to begin standard of care (SOC) treatment with PEG-IFN-alfa/RBV anytime after 24h following the last dose of the study drug. Since there is no standard of care (SOC) for NR, patients in Part B were not eligible to receive any additional HCV therapy before Day 44.
Patients were observed in a phase I research facility from the night before the first dose until 48h following the last dose of study drug (Day 16). Standard clinical and laboratory evaluations were performed at baseline and at regular intervals throughout the study period. The study drug was administered approximately 20-30min after a standardized meal.
Patients were randomized using an interactive voice response system (IVRS) that assigned a patient identification number that corresponded to treatment assignment (danoprevir or placebo) according to the randomization code.
The study was conducted in full accordance with the 1996 Declaration of Helsinki. The study protocol was reviewed and approved by the independent ethics committee at each participating research facility, and written informed consent was obtained from each patient or legal guardian prior to study screening.
Patients
Eligible patients were men and women between 18 and 65years of age with a history of chronic HCV genotype 1 infection and detectable plasma HCV RNA (>1x104IU/ml) at the study screening visit. Additional enrollment criteria included a body mass index (BMI) between 18 and 30, minimum body weight of 45kg, and a liver biopsy or non-invasive procedure (liver scan) within the previous 2years showing no evidence of cirrhosis. In addition, patients in Part A were required to have no history of prior therapy with interferon-based regimens; patients in Part B were required to have failed previous interferon-alfa and ribavirin-based therapy as defined above.
Patients were excluded from the study if they met any of the following criteria: decompensated liver disease; impaired liver function; clinical or histopathologic evidence of cirrhosis; history of non-hepatitis C chronic liver disease; positive screening for hepatitis B surface antigen or human immunodeficiency virus infection; history of active malignancy within the preceding 5years; history of clinically significant cardiovascular or cerebrovascular disease; treatment with pegylated interferon-alfa and ribavirin (Part A) or treatment with pegylated interferon-alfa and ribavirin within 3months before screening (Part B); treatment with growth factors within 3months before screening; history of drug abuse within the previous year; regular consumption of more than one glass of alcohol per day for women or two glasses of alcohol per day for men; participation in an investigational drug study within 3months of screening or any prior participation in a study of an experimental HCV therapy; and selected laboratory abnormalities, including serum ALT >5 times the upper limit of the reference range, creatinine clearance <30ml/min, or total bilirubin >26μmol/L. Pregnant or lactating women, women of childbearing potential, and male partners of pregnant or lactating women were excluded from enrollment. Additionally, any patient who, in the opinion of the investigator, was not a suitable candidate for enrollment or was unlikely to comply with the requirements of the study was also excluded from enrollment.
Safety assessments
Safety was continuously monitored by qualified medical personnel at each participating research facility. Safety assessments included physical examination, vital signs, standard clinical laboratory tests, 12-lead electrocardiogram (ECG), cardiac laboratory tests (troponin and creatinine kinase), and daily patient interviews. A single treatment-naïve patient (TN) in the placebo group was lost to follow-up prior to the Day 44 follow-up visit.
Pharmacokinetics
Blood and urine samples for danoprevir pharmacokinetic (PK) analyses were collected at regular intervals throughout the study period. Blood samples were obtained on Day 1 prior to the first morning dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12h after the first dose. Pre-dose blood samples were also collected on days 2, 3, 5, 7, 9, and 13 to determine danoprevir trough concentrations. On Day 14, blood samples were collected prior to the first morning dose and at the same schedule as on Day 1. Danoprevir plasma concentration was determined by API 4000 tandem mass spectrometer (Applied Biosystems, Foster City, CA) coupled with ACQUITY UPLC system (Waters Co., Milford, MA). The plasma samples were prepared by a solid-phase extraction (SPE) procedure prior to LC-MS/MS analysis. The linear dynamic range of the LC-MS/MS assay was 0.01-100ng/ml with a 50μl plasma sample. Pharmacokinetic exposure estimates (AUC0-24, Cmax, and CT) were obtained using non-compartmental methods using SAS¨ Version 9.1.3 (SAS Institute Inc., Cary, NC). CT was defined as the 8h post dose concentration in q8h cohorts and the 12h post dose concentration in q12h cohorts.
Viral kinetics
The antiviral activity of danoprevir was assessed by measuring plasma HCV RNA levels at scheduled intervals from baseline to Day 14. Specifically, blood samples for HCV RNA analysis were obtained on Days 1, 2, 3, 7, 9, and 14. Plasma HCV RNA levels were quantified using the COBAS Ampliprep/COBAS Taqman HCV assay (Roche Molecular Diagnostics, Pleasanton, CA). The linear dynamic range of the assay was 43IU/ml to 6.9x107IU/ml. The lower limit of quantification (LLOQ) was 43IU/ml and the limit of detection (LOD) was 15IU/ml.
NS3 sequence characterization and virologic fate
Rebound, plateau, and continuous decline viral response patterns were defined by end of treatment (EOT) viral load relative to nadir viral load in a manner similar to that previously described [11]. An EOT viral load >1.0log10IU/ml above nadir viral load was considered as a virologic rebound and an EOT viral load <1.0 log10IU/ml above nadir viral load was considered to reach plateau. Virologic profiles not meeting these definitions were classified as continuous decline. For viral resistance testing, viral RNA was extracted from patient samples taken prior to the first dose on days 1, 3, 7, 14, 21, and 90 using the QIAamp Virus BioRobot 9604 kit (Qiagen, Valencia, CA). The NS3 protease sequence was amplified by standard procedures. Sequencing of purified DNA was performed with an Applied Biosystems 3730 DNA analyzer (Applied Biosystems, Foster City, CA). Each sequence was examined by two independent investigators. Samples were classified as HCV subtypes 1a or 1b by NS3 sequence composition.
Statistical analysis
No formal prospective calculations of statistical power were made. The sample size was determined based on clinical judgment and historical experience from studies of a similar type and duration. Viral kinetic and safety data were summarized using descriptive statistics for each cohort and the pooled placebo group. All patients who received at least one dose of study drug were included in the safety analysis. Three treatment naïve patients in the 200mg q12h cohort who were mis-dosed at a single study site were excluded from the efficacy analysis. All analyses and tabulations were performed using SAS¨ Version 9.1.3 (SAS Institute Inc., Cary, NC).
Results
Baseline characteristics
A total of 50 patients met all eligibility criteria and consented to participate in the study. All randomized patients completed both the 14-day study drug dosing period and the Day 21 follow-up visit. Demographic and baseline characteristics, including median HCV RNA levels, were similar across treatment groups and dosing cohorts (Table 1).
Safety
Danoprevir was safe and generally well tolerated. There were no clinically significant laboratory or ECG abnormalities, and no patient discontinued treatment due to an adverse event. Adverse events occurred in three out of 10 (30%) patients in the placebo groups and 21 out of 40 (53%) patients in the danoprevir groups. Events that occurred in two or more of the 40 danoprevir-treated patients included headache (n=5), flatulence (n=3), myalgia (n=3), diarrhea (n=2), back pain (n=2), and dysuria (n=2) (Table 2). Of these, headache and diarrhea were also observed in the 10 placebo-treated patients (n=2 and n=1, respectively) (Table 2).
Adverse events were generally mild and transient and were not associated with the treatment group or dose level. A single serious adverse event of benign paroxysmal vertigo was reported in a danoprevir-treated patient with a history of similar symptoms. The event was assessed by the investigator as unrelated to the study treatment and resolved rapidly without discontinuation of study drug.
Adverse events of moderate severity (Grade 2) were reported by two patients each in the placebo and danoprevir groups during study drug dosing. In the placebo group, Grade 2 events included headache and tooth abscess (one patient each). In the danoprevir group, Grade 2 neutropenia was observed in a single patient in whom Grade 1 neutropenia had been reported at baseline. Grade 1 hypertension was observed in one danoprevir treated patient and in one placebo treated patient. Additionally, one patient in the danoprevir group reported a toothache of moderate severity. As noted previously, none of these events resulted in premature discontinuation of the study drug and all events resolved spontaneously without sequelae. No patient in either treatment group reported a rash or other treatment-emergent dermatologic adverse events.
Pharmacokinetics
Danoprevir exposure in plasma was determined on Day 14 (Table 3). Median plasma AUC0-24 increased with total daily dose in a fashion that was slightly more than dose proportional. Median plasma Cmax similarly increased with administered dose. Median plasma AUC0-24 in NR at a total daily dose of 600mg at Day 14 (422ngh/ml) was similar to the median Day 14 plasma AUC0-24 in treatment naïve patients (TN) at the same total daily dose (368ngh/ml, 200mgq8h). Median Day 14 plasma CT in NR (0.43ng/ml) was intermediate to that observed in TN receiving 200mg at q8h and 200mg q12h (1.01 and 0.20ng/ml, respectively). Danoprevir was rapidly cleared from the plasma compartment, the median terminal half-life (T1/2) ranged from 1.5 to 2.1h across all cohorts. Plasma exposure parameters on Day 1 were similar to those observed at Day 14 (data not shown).
Viral kinetics
Treatment with danoprevir resulted in rapid and dose-dependent reductions in plasma HCV RNA (Table 4 and Fig. 1). Median virologic effect was greatest in TN patients receiving total daily doses of 600mg (200mg q8h) and second largest in TN patients receiving a total daily dose of 400mg (200mg q12h). The median maximal HCV RNA reduction from baseline was -3.9log10IU/ml (range, -5.0 to -3.0) in the 200mg q8h dosing cohort and -3.2log10IU/ml (range, -4.4 to -2.4) in the 200mg q12h dosing cohort. Median reduction in HCV RNA at the end of treatment (EOT, Day 14) was within 0.1log10IU/ml of the maximal reduction in these two cohorts (Table 4), indicating sustained viral suppression over the entire dosing period. All TN patients in the 200mg q12h and 200mg q8h dosing cohorts achieved a >2-log10 reduction in plasma HCV RNA during study treatment. Lower total daily doses of danoprevir (100mg q8h or q12h) provided more modest median maximal declines in HCV RNA and antiviral effects were not as persistent at EOT as compared to those displayed by the upper dose TN cohorts. In the single NR cohort (300mg q12h), the median maximal HCV RNA reduction from baseline was -2.9log10IU/ml (range, -4.2 to -2.2) and median EOT reduction was -2.5log10IU/ml (range, -4.2 to -0.8) (Table 4).
Interestingly, both the maximal and EOT viral responses in NR were lower than those observed in upper dose TN cohorts (Table 4). Median maximal decline was 0.3log10IU/ml lower than that observed in TN patients receiving 200mg q12h and 1.0log10IU/ml lower than that observed in TN patients receiving 200mg q8h. At EOT, the median HCV RNA reduction in NR was 0.6 and 1.3log10IU/ml lower than that observed in these two respective cohorts. Inferior exposure in NR does not account for this difference, since Day 14 AUC0-24 was highest in NR, and Day 14 CT in NR was intermediate compared to that observed in TN patients receiving 200mg q8h and 200mg q12h (Table 3).
In all danoprevir-treated patients, a rapid initial decline in plasma HCV RNA was observed (Fig. 1A-E). In general, the initial decline was more pronounced in TN receiving 200mg q12h or 200mg q8h and NR receiving 300mg q12 compared to TN receiving 100mg q12h or 100mg q8h.
In Part A, TN were eligible to begin treatment with PEG-IFN-alfa/RBV 24h following the last dose of the study drug (~11-times to 16-times the plasma half-life of danoprevir). Thirty-one out of 37 TN elected the PEG-IFN-alfa/RBV therapy. Off treatment responses of these patients varied, indicating a variable responsiveness to PEG-IFN-alfa/RBV (Fig. 1A-D and F). NR were not eligible to receive any additional HCV therapy before Day 44. Five out of eight NR elected the PEG-IFN-alfa/RBV therapy and all showed minimal responsiveness, confirming their suboptimal response to PEG-IFN-alfa/RBV (Fig. 1E and F).
Alanine aminotransferase (ALT)
Median serum ALT levels decreased appreciably in all danoprevir-treated dose groups but increased slightly from baseline to Day 14 in placebo treated patients. Among TN, the median change in serum ALT was -19.0U/L in the 100mg q12h cohort, -36.0U/L in the 100mg q8h cohort, -21.0U/L in the 200mg q12h cohort, and -37.5U/L in the 200mg q8h cohort. In contrast, the median serum ALT increased +7.0U/L in placebo-treated TN. In NR, the median change in serum ALT was -34.5U/L in the danoprevir-treated group, compared with +5.0U/L in the placebo-treated group. Among TN patients with elevated serum ALT at baseline, levels normalized by Day 14, in 14 out of 19 (74%) patients in the danoprevir-treated group and 0 out of 6 (0%) patients in the placebo-treated group. In the NR cohort, ALT levels normalized by Day 14 in 4 out of 6 (67%) danoprevir-treated patients who had elevated levels at baseline; in contrast, ALT levels remained elevated at Day 14 in each of the 2 placebo patients. Day 14 serum ALT remained normal in all 10 danoprevir-treated patients (TN and NR) who had a normal baseline ALT. In contrast, both placebo-treated TN patients with normal baseline ALT had elevated levels at Day 14.
NS3 sequence characterization and virologic fate
Virologic response in individual patients was classified as continuous decline, plateau, or rebound based on viral load at EOT relative to nadir viral load (Fig. 2). Of the evaluable TN patients receiving danoprevir, 8/29, 10/29, and 11/29 displayed a rebound, plateau, and continual decline of HCV RNA, respectively. In the single NR cohort 2/8, 3/8, and 3/8 patients displayed a virologic rebound plateau and continual decline, respectively. Thus, the overall incidence of virologic rebound, plateau, and continual decline in parts A and B was 10/37 (27%), 13/37 (35%), and 14/37 (38%), respectively. In general, patients displaying a continuous decline profile were in the upper dose cohorts.
Plots of median antiviral effects in TN and NR using this classification indicate that the first rapid phase of viral decline and a second slower phase of viral decline remained similar in rebound and continuous decline groups until Day 7 and diverged thereafter (Fig. 2). Median antiviral effect in plateau patients showed a more modest initial reduction of approximately 2log10IU/ml that was maintained from Day 3 to EOT.
Patients infected with HCV subtype 1a were more likely to experience virologic rebound compared to subtype 1b (Table 5). The majority of danoprevir-treated patients harbored subtype 1b HCV (23/37 or 62%). However, subtype 1b patients represented the minority of patients experiencing virologic rebound (2/10 or 20%). Subtype 1b patients were more likely to experience either a plateau or a continuous decline in HCV RNA compared to subtype 1a patients.
Population-based and clonal sequence analysis of NS3 protease at EOT indicated that every patient who experienced virologic rebound carried a treatment-emergent substitution at position 155 in NS3 in which arginine was at least partially substituted for lysine (R155K). Two rebound patients also carried a distinct viral variant with a D168E substitution in NS3. Both R155K and D168E persisted following cessation of danoprevir treatment and conferred reduced susceptibility to danoprevir in vitro, albeit at differing levels [8], [12]. Of the 13 patients experiencing virologic plateau, two subtype 1a patients carried R155K and one subtype 1b patients each carried D168V/E, D168T, and R155Q.
Discussion
Danoprevir is a potent inhibitor of the NS3/4A protease that displays a high degree of specificity in vitro [9] and is currently in phase 2b clinical development for the treatment of chronic HCV, in combination with peginterferon alfa-2a and ribavirin. Danoprevir is also currently under study in combination with the nucleoside-based polymerase inhibitor RG7128 with and without pegylated interferon and ribavirin [13], [14]. The present study assessed the safety, pharmacokinetics, and antiviral activity of multiple ascending oral doses of danoprevir as a 14-day monotherapy in patients with chronic HCV infection.
Danoprevir reduced HCV RNA in a robust, dose dependent manner when administered in both q8 and q12h schedules. Similar to data reported for other NS3/4A PIs [15], [16], HCV RNA reductions occurred rapidly and were typically sustained through Day 14 in upper dose cohorts. Median maximal HCV RNA reductions in the 200mg q8h dosing cohort approached 4log10IU/ml and were over 3log10IU/ml in the 200mg q12h dosing cohort (Table 4). A dose administered every 12h resulted in lower antiviral effects compared to the same dose administered every 8h, suggesting a higher total daily dose of danoprevir in a q12 schedule would be required to achieve antiviral effects equivalent to those provided by lower dose in a q8h schedule.
To initially gauge whether the antiviral effect of danoprevir would be similar in TN and NR, a single cohort of NR was included in this study. A slightly lower median antiviral effect was observed in the NR cohort compared to the 200mg q12 and q8 TN cohorts despite the higher plasma exposure provided by 300mg q12h in NR (Table 3). Because of the small sample size, future studies are required to establish whether protease inhibitor therapy in these difficult-to-treat patients affords viral kinetic responses that are distinct from those observed in treatment naïve patients.
The overall incidence of virologic rebound with danoprevir monotherapy was 27%, comparable to that reported for another NS3/4A PI [17]. As expected, patients experiencing continuous decline in viral load were typically in upper dose cohorts. Population sequence analysis indicated that, regardless of HCV subtype, patients experiencing virologic rebound carried NS3 in which arginine at position 155 was replaced with lysine (R155K). The persistence of this substitution following the cessation of danoprevir therapy suggests a high level of fitness, as it has been previously observed [17], [18]. The lower incidence of viral rebound in subtype 1b compared to subtype 1a may reflect the requirement for two nucleotide substitutions to generate R155K in subtype 1b compared to the single nucleotide substitution required in subtype 1a. The relative absence of drug resistance mutations in patients experiencing virologic plateau may reflect a lack of significant selective pressure by danoprevir in the lower dose cohorts, as it has been reported for another NS3 PI [19]. Thus, it appears that R155K represents the dominant NS3 substitution associated with viral rebound in genotype 1 during danoprevir monotherapy.
Due to the relatively high virologic rebound rate during protease inhibitor monotherapy, it is now recognized that this class of inhibitors will need to be used in combination with other antiviral agents. Recent studies with other agents have shown that drug resistant viral variants selected during monotherapy are replaced by wild type virus over time [20]. Future long term studies with danoprevir are likewise required to determine the longevity of drug resistant viral variants subsequent to therapy, as this will be an important issue regarding possible retreatment options for the patients.
In conclusion, danoprevir was safe and well tolerated when administered as monotherapy for 14days to patients with chronic HCV genotype 1 infection. The treatment resulted in rapid and substantial reductions in viral load that were generally sustained throughout the duration of therapy in both q8 and q12 schedules at the higher doses tested. The barrier to virologic rebound in subtype 1b HCV appears to be higher than that in subtype 1a HCV owing to a reliance on the R155K substitution for viral escape in both subtypes. These data support the continued clinical development of danoprevir in chronic HCV infection.
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