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Antiviral activity of telaprevir (VX-950) and
peginterferon alfa-2a in patients with hepatitis C
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Hepatology Sept 2007
Nicole Forestier 1 2 *, Hendrik W. Reesink 3, Christine J. Weegink 3, Lindsay McNair 4, Tara L. Kieffer 4, Hui-May Chu 4, Susan Purdy 4, Peter L.M. Jansen 3, Stefan Zeuzem 1 2
1Saarland University Hospital, Homburg, Germany
2J.W. Goethe University Hospital, Frankfurt, Germany
3Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
4Vertex Pharmaceuticals Incorporated, Cambridge, MA
Abstract
Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa-2a for 14 days. Previously untreated patients with genotype 1 hepatitis C were randomized to receive placebo and peginterferon alfa-2a (n = 4); telaprevir (n = 8); or telaprevir and peginterferon alfa-2a (n = 8).
Telaprevir was given as 750 mg oral doses every 8 hours; peginterferon alfa-2a was given as weekly 180 ug subcutaneous injections. The median change in HCV RNA from baseline to day 15 was -1.09 log10 (range, -2.08 to -0.46) in the placebo and peginterferon alfa-2a group; -3.99 log10 (range, -5.28 to -1.26) in the telaprevir group, and -5.49 log10 (range, -6.54 to -4.30) in the telaprevir and peginterferon alfa-2a group.
Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa-2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa-2a.
The majority of adverse events were mild. There were no serious adverse events or premature discontinuations. Twelve weeks after starting off-study standard therapy, HCV RNA was undetectable in all 8 patients in the telaprevir and peginterferon alfa-2a group, 5 patients in the telaprevir group, and 1 patient in the placebo and peginterferon alfa-2a group.
Conclusion: This study confirmed the substantial antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir combined with peginterferon alfa-2a.
Article Text
Infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease. HCV infection is often asymptomatic and can increase the risk of cirrhosis and its sequelae. Approximately 50% of patients infected with genotype 1 hepatitis C do not achieve a sustained viral response with the current standard therapy (peginterferon and ribavirin), and the standard therapy is associated with several side effects, including influenza-like symptoms, depression, neutropenia, and anemia.[1][2]
Telaprevir (VX-950), a member of a new class of specifically targeted antiviral therapies for hepatitis C (STAT-C), is a reversible, selective, orally bioavailable inhibitor of the HCV NS3/4A protease, an enzyme required for viral replication.[3] In a 14-day clinical trial in patients with genotype 1 chronic hepatitis C, telaprevir was well tolerated and showed substantial antiviral effects.[4] HCV RNA levels decreased by at least 2 log10 in all 28 patients treated with telaprevir. In the 750-mg dose group, which had the highest trough plasma concentrations of telaprevir, the median reduction in HCV RNA was 4.4 log10, and 2 patients had undetectable HCV RNA levels. Some patients treated with telaprevir had viral breakthrough during the 14-day dosing period.[4] Analysis of the NS3 protease sequence suggested that the breakthrough was related to selection of viral variants with decreased sensitivity to telaprevir.[4]
Unlike the specifically targeted antiviral activity of telaprevir, the activity of interferon against HCV is due to the stimulation of hundreds of genes that result in nonspecific antiviral and immunomodulatory effects (reviewed in Feld and Hoofnagle[5]). When given as monotherapy, peginterferon alfa has limited efficacy against chronic hepatitis C.[6][7] In HCV replicon studies, interferon and telaprevir had synergistic effects in reducing HCV RNA,[8] and viral variants with decreased sensitivity to telaprevir remained sensitive to interferon.[9] Based on these data and the different antiviral mechanisms of action of telaprevir and interferon, it was hypothesized that the combination of telaprevir and peginterferon alfa would result in greater antiviral activity than either telaprevir or peginterferon alfa alone and would reduce the incidence of viral breakthrough.
Therefore, in this phase 1 trial of telaprevir in patients with genotype 1 chronic hepatitis C, our primary objective was to evaluate the effect of telaprevir in combination with peginterferon alfa-2a on HCV kinetics. We also assessed the safety and tolerability of the combination of telaprevir and peginterferon alfa-2a and the effect on the selection of HCV variants.
Materials and Methods
Study Design and Organization
This randomized study was conducted at 2 collaborative sites in the Netherlands (Pharma BioResearch BV and Academic Medical Center) and 1 site in Germany (Saarland University Hospital) from October 2005 through March 2006. The study was conducted in full compliance with the guidelines of Good Clinical Practice and of the World Medical Assembly Declaration of Helsinki. Before the study started, the institutional review boards at each site reviewed and approved the protocol and informed consent form. All patients provided written informed consent before participating in any study-related activity.
The study was placebo-controlled for telaprevir; peginterferon alfa-2a treatment was open-label. A total of 20 patients were enrolled and randomized into 1 of 3 treatment regimens: placebo every 8 hours (q8h) orally for 14 days and peginterferon alfa-2a via subcutaneous injection once weekly for 2 weeks (4 patients); telaprevir q8h orally for 14 days (8 patients); or telaprevir q8h orally for 14 days and peginterferon alfa-2a once weekly for 2 weeks (8 patients) (Fig. 1). Placebo and VX-950 were administered in the fed state (30 minutes following the intake of food) beginning on day 2 and ending on day 15.
The first telaprevir dose was a 1250-mg loading dose, and subsequent doses were 750 mg q8h. We gave peginterferon alfa-2a by subcutaneous injection at a dose of 180 ug on days 1 and 8. All study drug dosing occurred in an inpatient clinical setting. After completing study drug dosing, we offered patients the opportunity to begin standard therapy for chronic hepatitis C (180 ug/week peginterferon alfa-2a and 1000 or 1200 mg/day ribavirin, depending on body weight). As specified in the protocol, patients returned for follow-up visits 1 week and 12 weeks after the end of the study drug dosing period. We also conducted additional follow-up visits, at the discretion of the investigators.
The randomization list was created using a computerized random-number generator. We randomized patients using an interactive voice-response system that assigned the patient number and randomized the patient to 1 of the 3 treatment groups and to a bottle number containing either telaprevir or placebo, as appropriate.
Telaprevir was supplied as 250-mg tablets for oral administration. Placebo was identically supplied and formulated except that it contained no telaprevir. Peginterferon alfa-2a was manufactured by Roche Pharmaceuticals (Hoffmann-La Roche Inc., Basel, Switzerland).
Participants
Patients were men and women of nonchildbearing potential aged between 18 and 60 years. Patients satisfied the following criteria for inclusion in the study: genotype 1 chronic hepatitis C; had not received any prior therapy for hepatitis C, including approved treatments or participation in studies of investigational treatments; HCV RNA level >1 X 105 IU/ml, confirmed by repeat measurement of 2 separate samples taken during the screening period; alanine aminotransferase (ALT) concentration
Exclusion criteria prohibited individuals who met any of the following criteria from enrolling in the study: contraindications to peginterferon alfa-2a or ribavirin; decompensated liver disease; alcohol-related cirrhosis or primary biliary cirrhosis; positive screening for hepatitis B surface antigen or human immunodeficiency virus coinfection; donation of blood (500 ml) within 60 days before the first dose of study drug; concurrent antiviral therapy (except for antiviral agents approved for treatment of herpes viruses) within 3 months preceding study entry; regular treatment with nontopical medications or with topical medications with known systemic absorption within 4 weeks before study drug administration (with the exception of estrogen replacement therapy for women); regular consumption of more than 24 units of alcoholic drinks per week or more than 8 cups of coffee per day; history of drug abuse within 6 months of study entry; history of methadone use within 3 months of study entry; positive urine screen for drugs of abuse; participation in an investigational drug study within 90 days before study drug administration or participation in more than 2 drug studies in the last 12 months (excluding the present study); or participation in a prior clinical study of telaprevir unless it was documented that the patient had been randomized to placebo treatment. Patients were also excluded if they had a history of any illness that, in the opinion of the investigator or the patient's general practitioner, may have confounded the results of the study or posed an additional risk in administering study drug to the patient. This included but was not limited to a history of relevant drug or food allergies; cardiovascular or central nervous system disease; clinically significant illness; or mental illness that may have affected compliance with study requirements.
Pharmacokinetics
We collected serum samples on day 1 (first day of peginterferon alfa-2a dosing) and days 2, 4, 6, 8, 9, and 12 for analysis of peginterferon alfa pharmacokinetics. We collected plasma samples on day 2 (first day of telaprevir dosing) and days 4, 8, 11, 13, and 15 for analysis of telaprevir pharmacokinetics. We calculated pharmacokinetic parameters using noncompartmental analysis. We performed 2-sample t tests to compare telaprevir maximum plasma concentration (Cmax) values between the treatment groups.
HCV RNA Measurements
We determined HCV genotype and subtype by sequence analysis of the 5' noncoding region of HCV (TRUGENE 5NC HCV Genotyping Kit; Bayer HealthCare, Diagnostics Division, Tarrytown, NY). We determined plasma HCV RNA levels using the Roche COBAS TaqMan HCV/HPS assay (Roche Molecular Systems Inc., Branchburg, NJ). The linear dynamic range of the assay was 30 IU/ml to 2.0 X 108 IU/ml. The lower limit of quantitation of the assay was 30 IU/ml, and the limit of detection (LOD) was 10 IU/ml. We measured HCV RNA levels on days 1 through 4 and on days 8, 11, 13, and 15 of the study drug dosing period and 3 days, 1 week, and 12 weeks after the end of study drug dosing. Investigators and patients were blinded to HCV RNA results during the study drug dosing period.
HCV NS3 Sequence Analysis
For HCV NS3 sequence analysis, we isolated HCV RNA from plasma samples collected on day 1 before the first dose of study drug, on days 4, 8, 12, and 15 of the study drug dosing period, and 1 week after the end of study drug dosing. We amplified the full 534-basepair NS3 protease domain from plasma HCV RNA by seminested RT-PCR, then we cloned and sequenced it. The LOD for the sequencing assay was about 100 IU/ml. We analyzed changes in the sequence from baseline, and then we correlated the mutation patterns with clinical viral suppression or viral rebound during and after the end of dosing. We performed phenotypic studies of all single mutants and double mutants to determine whether the mutations decreased the sensitivity of the virus to telaprevir. For phenotypic analysis, we cloned, purified, and expressed viral variants, and we determined the enzymatic median inhibitory concentration (IC50) against telaprevir.
Safety Assessments
We conducted safety assessments during the dosing period and at the 1-week follow-up visit, including physical examinations (days 1, 15, and follow-up); clinical laboratory tests (days 1, 3, 6, 9, 12, 15, and follow-up); vital sign measurements (days 2, 15, and follow-up), electrocardiograms (day 1 and follow-up); and questioning of patients about adverse events (throughout the study drug dosing period and at follow-up).
Statistical Methods
We made no prospective calculations of statistical power. We selected the sample size to provide information on the effects of telaprevir and peginterferon alfa on HCV kinetics during 14 days of dosing.
For HCV RNA levels and clinical laboratory assessments, we defined the baseline as the median of all predose values. We summarized log10 HCV RNA values using descriptive statistics for each treatment group and scheduled time point. We reported descriptive statistics for clinical laboratory and vital sign data. We used categorical presentation for adverse events.
Results
Baseline Characteristics
We enrolled and randomized 20 patients into the study (Fig. 1). All completed the study drug dosing period and the 1-week and 12-week follow-up visits and were included in the analyses. Of the 20 patients in the study, 12 (60%) were men, and all were Caucasian (Table 1). The median baseline HCV RNA levels were similar in the 3 treatment groups. All patients were 100% compliant with study drug dosing.
Pharmacokinetics
Telaprevir exposure (Cmax) on the first day of telaprevir dosing was not significantly different between the telaprevir and telaprevir and peginterferon alfa-2a groups (P = 0.81). The median Cmax values were 3695 ng/ml for the telaprevir group and 3391 ng/ml for the telaprevir and peginterferon alfa-2a group. There was a trend toward higher telaprevir median exposure values at steady-state (day 14) in the telaprevir and peginterferon alfa-2a group compared with the telaprevir group, but the difference was not statistically significant (P = 0.07 for Cmax). Peginterferon alfa-2a concentrations in both dose groups were within the range given in the Pegasys package insert.[10] Because of small sample sizes and the nature of study design (parallel dose group), we can draw no definitive conclusions about the effect of telaprevir on peginterferon alfa-2a concentrations.
HCV RNA Levels
Figure 2 shows median HCV RNA levels from baseline to day 15. The median change in HCV RNA from baseline to day 15 was -1.09 log10 (range, -2.08 to -0.46) in the placebo and peginterferon alfa-2a group; -3.99 log10 (range, -5.28 to -1.26) in the telaprevir group, and -5.49 log10(range, -6.54 to -4.30) in the telaprevir and peginterferon alfa-2a group. On day 15, HCV RNA levels were below the lower limit of quantitation (<30 IU/ml) in 6 patients in the telaprevir and peginterferon alfa-2a group, and 4 patients had undetectable HCV RNA levels (Table 2). In the telaprevir group, 1 patient had undetectable HCV RNA levels at day 15.
All patients had a biphasic viral decline (Fig. 3A-C). The rapid first phase was similar in the telaprevir group and the telaprevir and peginterferon alfa-2a group. The second phase of decline was more sustained in the telaprevir and peginterferon alfa-2a group than in the telaprevir group. All patients in the telaprevir and peginterferon alfa-2a group had continued decline during the study drug dosing period. One patient in the telaprevir and peginterferon alfa-2a group had a less steep decline in HCV RNA than the other patients in that treatment group. In the telaprevir group, 4 patients had continued decline, 2 patients had viral plateau, and 2 had viral rebound.
A total of 19 patients started standard therapy within 1 week after completing the study drug dosing period. One patient in the telaprevir group declined standard therapy because she was 'not ready for heavy treatment'. This patient had viral rebound during the study drug dosing period and had the highest HCV RNA levels in the telaprevir group from days 11 through 15 of the dosing period (see Fig. 3B; patient's data are represented with closed circles). At the week 12 follow-up visit, HCV RNA was undetectable in 5 patients in the telaprevir group and in all 8 patients in the telaprevir and peginterferon alfa-2a group (Table 3).
HCV NS3 Sequence Analysis
Because of the rapid HCV RNA response in patients treated with telaprevir, HCV RNA levels declined below the LOD of the sequencing assay for at least 1 time point in all patients who received telaprevir and peginterferon alfa-2a and in some patients who received telaprevir alone. Thus, sequencing data are not available for many time points in patients who received telaprevir.
A detailed kinetic study of viral variants will be presented elsewhere. Briefly, in the 4 patients who received telaprevir alone and who had HCV RNA levels that plateaued or rebounded, we found viral variants with single mutations or double mutations conferring decreased sensitivity to telaprevir (low-level resistance: V36A/M and R155K/T; high-level resistance: A156V/T, V36A/M+R155K/T, or V36A/M+A156V/T). The patient in the telaprevir group who had the highest HCV RNA levels between days 11 and 15 of the dosing period had high-level resistant variants, starting on day 8 of the dosing period. Of the 4 patients who received telaprevir alone and whose HCV RNA levels showed continued decline, 3 had virus that predominantly harbored the A156V/T mutation by the end of dosing (day 15). However, HCV RNA levels in these three patients continued to decline after the end of study drug dosing, while patients were receiving peginterferon alfa-2a in combination with ribavirin.
Of the 8 patients who received telaprevir and peginterferon, sequencing data are available for 7 patients at day 4, 6 patients at day 8, 1 patient at days 12 and 15, and 1 patient at the 1-week follow-up visit. Only wild-type virus was detected in 5 patients. Viral variants were detected in 2 patients. One patient had the A156T variant at day 8, and another patient had the V36A variant at the 1-week follow-up visit. All 8 patients had undetectable HCV RNA levels at the 12-week follow-up visit (Table 3).
ALT and AST Levels
In all treatment groups, median serum ALT and AST values decreased between baseline and day 15. Median changes from baseline in ALT and AST were, respectively, -15 U/l (range, -53 to 6) and -6 U/l (range, -11 to 6) for the placebo and peginterferon alfa-2a group, -61 U/l (range, -125 to -16) and -28 U/l (range, -88 to -13) for the telaprevir group, and -16 U/l (range, -30 to 49) and -7 U/l (range, -27 to 67) for the telaprevir and peginterferon alfa-2a group. In the placebo and peginterferon alfa-2a group, 2 patients had elevated ALT at baseline and at day 15. In the telaprevir group, 7 patients had elevated ALT at baseline, and 5 of these patients had normal ALT levels (normal range, 6 to 34 IU/ml) at day 15. In the telaprevir and peginterferon alfa-2a group, 3 patients had elevated ALT at baseline, and 2 of these patients had normal ALT levels at day 15.
Safety
There were no serious adverse events or premature discontinuations. Adverse events occurred in 4 (100%) patients in the placebo and peginterferon alfa-2a group, 6 (75%) patients in the telaprevir group, and 8 (100%) patients in the telaprevir and peginterferon alfa-2a group. The most common adverse events were headache, muscle aches, dry skin, diarrhea, and nausea; each event was more frequent in the peginterferon alfa-2a group and the telaprevir and peginterferon alfa-2a groups than in the telaprevir group (Table 4). Mild rash occurred in 1 patient in the telaprevir group and 2 patients in the telaprevir and peginterferon alfa-2a group; the rashes resolved without treatment. One patient in the telaprevir and peginterferon alfa-2a group had moderate rash that began on day 2 of the treatment period and resolved on day 8 following treatment with topical nonsteroidal powder.
Adverse events that were of moderate severity and considered related to the study drug were reported by 2 patients in the telaprevir and peginterferon alfa-2a group (headache; rash, described above; and insomnia) and 1 patient in the telaprevir group (pruritus). All other adverse events in the study were of mild intensity.
Results for some other clinical laboratory parameters were outside the appropriate reference ranges; these findings occurred at isolated time points only and were not reported to be clinically significant, with the exception of neutropenia in 1 patient in the placebo and peginterferon alfa-2a group. There were no clinically significant findings in vital sign or electrocardiogram assessments.
Discussion
The present study was the second clinical trial of telaprevir in patients with genotype 1 chronic hepatitis C and the first to evaluate telaprevir combination therapy. The study was designed to explore the effect of telaprevir in combination with peginterferon on HCV kinetics, and the safety and pharmacokinetics of this combination. The median change in HCV RNA from baseline to day 15 in patients who received placebo and peginterferon alfa-2a was -1.09 log10; this result is consistent with other studies of interferon monotherapy in patients with genotype 1 hepatitis C.[6][7][11]
As in the prior phase 1b study,[4] telaprevir demonstrated substantial antiviral activity: in the 8 patients who received telaprevir alone, the median change from baseline to day 15 was -3.99 log10, and 1 patient achieved undetectable HCV RNA levels. The median change from baseline in HCV RNA of -5.5 log10 in the telaprevir and peginterferon alfa-2a group and the undetectable HCV RNA levels in 4 patients in this group confirmed the hypothesis that telaprevir in combination with peginterferon would result in a greater antiviral effect than telaprevir alone. As in the prior study, plasma HCV RNA levels declined in 2 phases: an initial rapid decline followed by a more gradual decline. Peginterferon appeared to affect the second phase of viral decline, which was greater and more sustained in patients who received telaprevir and peginterferon alfa-2a than in patients who received telaprevir alone. Consistent with this finding, all patients who received telaprevir and peginterferon alfa-2a had continual viral decline during the second phase, whereas viral rebound or plateau occurred after day 8 in 4 patients who received telaprevir alone. Viral dynamic modeling analysis[12] showed that the emax values (maximum antiviral effectiveness) for the first slope of viral decline were similar in the telaprevir (emax = 0.9996) and telaprevir and peginterferon alfa-2a groups (emax = 0.9994 for telaprevir). The baseline characteristics of the groups revealed some imbalances in the characteristics of the patients in each of the 3 study arms. However, we did not consider these substantial enough to affect the conclusions of this study. A prior study has shown no relationship between normal or elevated ALT levels at baseline and the response to standard therapy with peginterferon and ribavirin.[13]
Analysis of the HCV NS3 protease domain sequence from patients in a previous clinical study of telaprevir monotherapy showed that viral rebound during the 14-day treatment period was associated with the presence of viral variants with reduced sensitivity to telaprevir.[4] Consistent with these findings, the viral rebound observed in patients who received telaprevir alone in the present study was associated with the selection of similar variants. In HCV replicon studies, these viral variants remained sensitive to interferon.[9] In patients receiving telaprevir and peginterferon alfa-2a, the only evidence of viral selection was detection of the A156T variant in 1 patient at day 8 and the V36A variant in another patient at the 1-week follow-up visit. Despite the presence of these variants, the patients' HCV RNA levels continued to decline and remained undetectable at 12 weeks after the end of dosing, suggesting that peginterferon alfa and ribavirin or the immune response were able to suppress the remaining virus.
One patient in the telaprevir and peginterferon alfa-2a group had less of a decrease in HCV RNA levels than the other patients in that treatment group. The reason for this is unknown. A review of the baseline characteristics and pharmacokinetic data for this patient did not suggest any explanation for the lesser decline, and there were no viral variants detected in this patient.
Median ALT and AST levels, which were elevated at baseline, decreased in all treatment groups. The decrease was larger in the telaprevir group than in the telaprevir and peginterferon alfa-2a group. This difference between the groups may have been due to the higher median baseline values in the telaprevir group than in the telaprevir and peginterferon alfa-2a group or to a discordance between antiviral and biochemical response, which has been observed during treatment with peginterferon monotherapy.[6] Decreases in ALT and AST were also observed in patients treated with telaprevir in a prior phase 1b study.[4]
Typical adverse events associated with interferon treatment, such as nausea, myalgia, headache, and dizziness, had a higher incidence in patients who received placebo and peginterferon alfa-2a or telaprevir and peginterferon alfa-2a than in patients who received telaprevir alone. Although the small sample size and short treatment duration limit the conclusions that can be drawn about the safety results, the data do not suggest an increased risk in patients dosed with telaprevir in combination with peginterferon alfa-2a beyond that anticipated from the safety profile of these 2 compounds when they are dosed individually. Further studies with larger sample sizes and longer treatment periods are required to further evaluate the safety profile of telaprevir and telaprevir in combination with peginterferon.
In conclusion, the viral kinetic data confirmed the substantial antiviral effects of telaprevir monotherapy and demonstrated increased antiviral effects of the combination of telaprevir with pegylated interferon. There was no viral breakthrough in the telaprevir and peginterferon alfa-2a combination group, suggesting that combination therapy represents a better clinical development path than telaprevir alone. The majority of adverse events were mild, and there were no premature discontinuations. Future studies will evaluate whether telaprevir, in combination with pegylated interferon, will improve sustained viral response rates and possibly allow for shorter treatment durations.
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