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Abbvie HCV - Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1
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Download the PDF here
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"In this article, we present the results of a phase 2b, open-label, multiple-group study that was designed to determine the safety and efficacy of various combinations of ABT-450/r, ABT-333, ABT-267, and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. The study design enabled multiple comparisons between treatment groups, allowing preliminary comparisons of treatment durations, antiviral-drug combinations, and ABT-450 doses in a single study."
-- the rate of sustained virologic response .......was 96% in the subgroup of patients who were never before treated that received 12 weeks of therapy with the full regimen - ABT-450/r+ABT-333+ABT-267+RBV, and 95% in the patients who were previously treated with Peg/Rbv.
"In this phase 2b study of interferon-free antiviral regimens for the treatment of chronic HCV genotype 1 infection without cirrhosis, the treatment regimens were associated with rates of sustained virologic response at 24 weeks after treatment that ranged from 83 to 100%.
The 12-week regimen was also associated with a 93% rate of sustained virologic response at 24 weeks after treatment among patients who had not had a response to prior therapy, with a similar rate among patients treated for 24 weeks, which suggests that 12 weeks may be the preferred duration in this population as well."
Recently released in the Abbvie press releases with updated new results from their ongoing phase 3 studies:
ABBVIE DEMONSTRATES 96 PERCENT SVR(12) IN ITS PHASE III STUDY OF TREATMENT-EXPERIENCED PATIENTS WITH GENOTYPE 1 HEPATITIS C - (12/18/13)
AbbVie Releases First of Six Phase III Results from Investigational All-Oral, Interferon-Free, 12-week Regimen, Showing 96 Percent SVR12 in Genotype 1 Hepatitis C Patients New to Therapy - (11/18/13)
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Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1
Kris V. Kowdley, M.D., Eric Lawitz, M.D., Fred Poordad, M.D., Daniel E. Cohen, M.D., David R. Nelson, M.D., Stefan Zeuzem, M.D., Gregory T. Everson, M.D., Paul Kwo, M.D., Graham R. Foster, F.C.R.P., Mark S. Sulkowski, M.D., Wangang Xie, Ph.D., Tami Pilot-Matias, Ph.D., George Liossis, B.A., Lois Larsen, Ph.D., Amit Khatri, Ph.D., Thomas Podsadecki, M.D., and Barry Bernstein, M.D.
N Engl J Med January 16, 2014
ABSTRACT
Background
An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.
Methods
In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.
Results
Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.
Conclusions
In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.)
Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, liver cancer, and end-stage liver disease.1 The current standard of care for chronic HCV genotype 1 infection is pegylated interferon (peginterferon) and ribavirin, with a protease inhibitor (boceprevir or telaprevir).2 Although the addition of a protease inhibitor has been associated with a significant increase in response rates, only approximately one third of patients who had not had a response to prior therapy with peginterferon and ribavirin had a sustained virologic response when re-treated with the addition of a protease inhibitor.3,4 Furthermore, these therapies are associated with adverse effects that can lead to early discontinuation of treatment.5-7 Patient characteristics, such as host genetic factors (e.g., IL28B rs12979860 CT or TT genotype), HCV subtype 1a, black race, and high baseline viral load, are also associated with poor response rates.6-8 New interferon-free therapies with greater activity in difficult-to-treat patients with HCV infection are needed.
ABT-450, a potent inhibitor of the HCV NS3/4A protease, is coadministered with 100 mg of ritonavir (ABT-450/r) to increase ABT-450 plasma levels and half-life, permitting once-daily dosing.9 ABT-333 is a nonnucleoside NS5B polymerase inhibitor. A recent pilot study involving patients with HCV genotype 1 infection who received 12 weeks of treatment with ABT-450/r, ABT-333, and ribavirin showed rates of sustained virologic response 12 weeks after treatment of 93 to 95% among previously untreated patients and 47% among patients who had not had a response or who had had only a partial response to prior therapy with peginterferon and ribavirin.10
The addition of a potent third direct-acting antiviral agent, the NS5A inhibitor ABT-267, may improve efficacy in patients for whom a poor response is predicted, including those who have not had a response to prior therapy. ABT-267 monotherapy for 3 days in previously untreated patients resulted in a mean decrease in the HCV RNA level of 3.10 log10 IU per milliliter.11 Because patients who have not had a response to prior therapy have historically had the lowest levels of response to retreatment, a favorable therapeutic outcome in this population would be likely to extend to other patient populations that have received therapy previously.
In this article, we present the results of a phase 2b, open-label, multiple-group study that was designed to determine the safety and efficacy of various combinations of ABT-450/r, ABT-333, ABT-267, and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. The study design enabled multiple comparisons between treatment groups, allowing preliminary comparisons of treatment durations, antiviral-drug combinations, and ABT-450 doses in a single study.
Methods
Study Population
Eligible patients were 18 to 70 years of age with a plasma HCV RNA level of more than 50,000 IU per milliliter at screening and no evidence of cirrhosis. Previously untreated patients and those who had not had a response to prior therapy (patients who had received peginterferon and ribavirin for at least 12 weeks and did not have a decline in the HCV RNA level of at least 2 log10 IU per milliliter) were eligible. Detailed eligibility criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.
Study Design
This study was designed as an open-label trial with respect to treatment durations, drug combinations, and doses for each of 14 treatment subgroups (Figure 1. Details of the randomization procedure are provided in the Supplementary Appendix.
ABT-450/r was administered in doses of 100 mg, 150 mg, or 200 mg of ABT-450 with 100 mg of ritonavir daily. The ABT-267 dose was 25 mg daily. The ABT-333 dose was 400 mg twice daily. The daily dose of ribavirin was 1000 mg (divided into doses of 400 mg and 600 mg) if the body weight was less than 75 kg or 1200 mg (600 mg twice daily) if the body weight was 75 kg or more. The treatment duration was 8, 12, or 24 weeks.
Study Oversight
All the patients provided written informed consent. The study was performed in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki, and the study protocol was approved by the relevant institutional review boards and regulatory agencies.
The study was designed jointly by the study investigators and the sponsor (AbbVie). The investigators gathered the data, and the sponsor conducted the data analyses. All the authors had full access to the data and signed confidentiality agreements with the sponsor regarding the data. The first draft of the manuscript was written by a medical writer employed by the sponsor and was edited and revised by the first author, with input from all the authors. All the authors reviewed and provided feedback on all subsequent versions of the manuscript. All the authors vouch for the completeness and accuracy of the data and analyses presented and confirm that the study was conducted and reported with fidelity to the protocol, which is available at NEJM.org.
Virologic and Safety Assessments
Details on the collection of plasma samples, HCV RNA measurement, resistance testing, and criteria for virologic failure are provided in the Supplementary Appendix. Assessments of adverse events and clinical laboratory testing were performed at each study visit. Events were classified as mild, moderate, or severe by the investigator.
Data on all adverse events were collected from the start of study-drug administration until 30 days after the last dose was administered. Data on serious adverse events were collected throughout the study.
Efficacy Analyses
The primary efficacy end point was sustained virologic response (HCV RNA level below the lower limit of quantitation [25 IU per milliliter]) at 24 weeks after the end of treatment. Analyses were performed on the modified intention-to-treat population, which included patients who had undergone randomization and received at least one dose of study drug. The primary analysis was a comparison of the rate of sustained virologic response at 24 weeks after treatment between previously untreated patients who received three direct-acting antiviral agents (including ABT-450/r administered in daily doses of 150 mg of ABT-450 and 100 mg of ritonavir) with ribavirin for 8 weeks (subgroup A) and those who received the same therapy for 12 weeks (subgroup G). Secondary analyses compared the rate of sustained virologic response at 24 weeks after treatment among other treatment groups and subgroups.
Virologic breakthrough during treatment was defined as two consecutive HCV RNA measurements of more than 1 log10 IU per milliliter above the nadir HCV RNA level or two consecutive HCV RNA measurements that were higher than the lower limit of quantitation at any time after the HCV RNA level had been less than the lower limit of quantitation. Virologic relapse was defined as a confirmed quantifiable HCV RNA level in a patient who had had an HCV RNA level that was less than the lower limit of quantitation at the end of treatment.
Statistical Analysis
SAS software, version 9.2, for the UNIX operating system (SAS Institute) was used for all analyses. Details of the sample-size determination and interim analysis are provided in the Supplementary Appendix. All statistical tests and confidence intervals were two-sided, with a significance level of 0.05. The stratum-adjusted Mantel-Haenszel method, with adjustment for the stratification variables at baseline (IL28B genotype [CC vs. non-CC] and HCV subgenotype [1a vs. non-1a]), was used to calculate between-group differences in the rates of sustained virologic response at 24 weeks after treatment and the two-sided 95% confidence intervals of the differences.
Results
Study Population
A total of 1013 patients with chronic HCV genotype 1 infection were screened at 97 sites in nine countries, including the United States. From October 2011 through April 2012, a total of 571 patients (438 previously untreated patients and 133 patients who had not had a response to prior therapy) underwent randomization and received at least one dose of study drug (Fig. S1 and Table S1 in the Supplementary Appendix). The final data collection for the analysis of the rate of sustained virologic response at 24 weeks after treatment occurred in August 2013. Demographic and clinical characteristics of the patients at baseline are shown in Table 1.
Efficacy
Primary Analysis
Across all treatment subgroups, the rates of sustained virologic response at 24 weeks after treatment ranged from 83 to 100% (Table S5 in the Supplementary Appendix). With respect to the primary analysis, among previously untreated patients who received treatment with three direct-acting agents plus ribavirin, with ABT-450/r administered as 150 mg of ABT-450 and 100 mg of ritonavir, the rate of sustained virologic response at 24 weeks after treatment was 88% in the subgroup that received 8 weeks of therapy and 95% in the subgroup that received 12 weeks of therapy (difference between 8-week and 12-week subgroups, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). Secondary analyses of the rates of sustained virologic response at 24 weeks after treatment are shown in Table S6 in the Supplementary Appendix.
Analysis According to ABT-450/r Dose
In a prespecified analysis comparing subgroups that received ABT-450/r administered as 100 mg of ABT-450 and 100 mg of ritonavir with those that received ABT-450/r administered as 150 mg of ABT-450 and 100 mg of ritonavir in otherwise identical regimens, the rates of sustained virologic response at 24 weeks were similar (93.6% and 94.3%, respectively; P=0.91). Therefore, the subgroups differing only in the dose of ABT-450 were combined, which resulted in nine groups for further analysis. With these groups combined, the rates of sustained virologic response at 24 weeks after treatment ranged from 83 to 96% among previously untreated patients and from 89 to 95% among patients who had not had a response to prior therapy (Figure 2).
Analysis According to Regimen
Across all treatment groups, the rates of sustained virologic response at 24 weeks after treatment were high regardless of host IL28B rs12979860 haplotype, HCV subtype, race, or HCV RNA level at baseline (Table S7 and S8 in the Supplementary Appendix). The rates of sustained virologic response were highest in the groups that received regimens that included three direct-acting agents plus ribavirin, but comparisons of the group that received three direct-acting agents plus ribavirin for 12 weeks with groups that received two direct-acting agents plus ribavirin did not show significant differences (Figure 3). Among patients administered three direct-acting antiviral agents with ribavirin for 12 weeks, the rates of sustained virologic response at 24 weeks after treatment were 96% among previously untreated patients and 93% among those who had not had a response to prior therapy.
Analysis According to Duration of Therapy
The rate of sustained virologic response at 24 weeks after treatment was higher among previously untreated patients who received three direct-acting agents plus ribavirin for 12 weeks than among those who received the same therapy for 8 weeks (96% and 88%, respectively) (Figure 3), but the difference was not significant. Among previously untreated patients who received three direct-acting agents with ribavirin, relapse after treatment occurred in 12%, 1%, and 2% of patients randomly assigned to 8 weeks, 12 weeks, and 24 weeks of therapy, respectively. None of these patients had virologic breakthrough. Among patients who had not had a response to prior therapy and who received this regimen, there were no relapses among patients treated for 12 weeks or for 24 weeks; 7% and 2% of the patients, respectively, had virologic breakthrough. A 24-week duration of therapy, as compared with a 12-week duration, was not associated with an increase in the rate of sustained virologic response, among either previously untreated patients or patients who had not had a response to prior therapy (P=0.24 and P=0.71, respectively). Information on virologic failure in each group is provided in Tables S9 and S10 in the Supplementary Appendix.
Among 166 patients with HCV genotype 1b infection who were previously untreated or who had not had a response to prior therapy and who received 12 or 24 weeks of any treatment regimen in this study, none had virologic failure. Relapse occurred in 1 patient with HCV genotype 1b infection who received 8 weeks of treatment.
No resistance-associated variants emerging during the treatment period were detected in 7 of the 10 samples from patients with relapse in the 8-week treatment group. In the 12-week and 24-week treatment groups, all but 1 of the samples obtained at breakthrough or relapse showed the emergence of variants known to confer resistance to ABT-450, ABT-267, or ABT-333. The most frequently detected variants that developed during the treatment period were at amino acid positions 168 in NS3, 28 and 30 in NS5A, and 556 in NS5B.
Safety
A total of eight patients (1%) discontinued study-drug therapy owing to adverse events, including six previously untreated patients and two who had not had a response to prior therapy (Table 2). The reasons for discontinuation included affective disorder, homicidal ideation, convulsion, jitteriness, and confusional state. Six of these patients had a sustained virologic response at 24 weeks after treatment, including both patients who had not had a response to prior therapy. Serious adverse events occurred in eight patients (1%) during the study treatment period or the following 30 days (Table 2). One event (arthralgia) was considered by the investigator to be possibly related to a study drug.
Adverse events that occurred during treatment in more than 20% of patients in any group are shown in Table 2. The most common adverse events were fatigue, headache, nausea, and insomnia. The nature and frequency of adverse events were similar across treatment groups. Adverse events that occurred during treatment in more than 5% of patients in any subgroup are listed in the Table S12 in the Supplementary Appendix.
Laboratory abnormalities of grade 3 or 4 that occurred in more than 1 patient in any group are shown in Table 2. A total of 11 patients (2%) had grade 3 elevations in the bilirubin concentration (predominantly indirect bilirubin), which normalized during or immediately after treatment. No patient had a grade 4 elevation. These elevations were not associated with elevations in aminotransferase levels. A total of 5 patients (1%) had a grade 3 elevation in the alanine aminotransferase level, with a maximum alanine aminotransferase level of 408 U per liter; there were no grade 4 elevations. Alanine aminotransferase levels normalized in each case without interruption of the study drug. Triglyceride values of grade 3 or 4 were observed in 7 patients (1%); in 4 patients, the samples were not obtained while the patient was fasting. Anemia developed during the treatment period in 5% of previously untreated patients, in 6% of patients who had not had a response to prior therapy, and in 1% of patients who did not receive ribavirin. No grade 3 or 4 decreases in the hemoglobin level were observed. Additional details regarding patients with laboratory abnormalities of grade 3 or 4 are provided in the Supplementary Appendix.
Discussion
In this phase 2b study of interferon-free antiviral regimens for the treatment of chronic HCV genotype 1 infection without cirrhosis, the treatment regimens were associated with rates of sustained virologic response at 24 weeks after treatment that ranged from 83 to 100%. Among previously untreated patients, the rate of treatment failure was lower among those receiving three direct-acting agents plus ribavirin for 12 weeks than among those who received the same regimen for only 8 weeks and among those who received fewer agents; extending the treatment to 24 weeks offered no further benefit. However, no differences in the rates of sustained virologic response reached statistical significance. The higher number of relapses among patients in the 8-week treatment group (in 10 of 80 patients, vs. in 1 of 79 patients in the 12-week treatment group) and the absence of resistance-associated variants in most patients who had a relapse in the 8-week treatment group suggest that 8 weeks of treatment might not be sufficient to eradicate the susceptible HCV population in these patients. Treatment durations longer than 8 weeks were not associated with a less favorable safety profile.
The 12-week regimen was also associated with a 93% rate of sustained virologic response at 24 weeks after treatment among patients who had not had a response to prior therapy, with a similar rate among patients treated for 24 weeks, which suggests that 12 weeks may be the preferred duration in this population as well. Previous studies have shown that patients who have not had a response to prior therapy with peginterferon and ribavirin have a poorer response to retreatment than do previously untreated patients, regardless of whether the treatments are interferon-based regimens or interferon-free combinations.10,14-16 In the current study, the rates of sustained virologic response at 24 weeks after treatment were similar among previously treated patients and patients who had not had a response to prior therapy. In addition, the rates in this study were consistently high, even in the presence of baseline characteristics that have been associated historically with poor rates of response to treatment, such as host IL28B non-CC genotype, HCV genotype 1a infection, black race, and high baseline HCV RNA levels.
Response rates to interferon-free, protease inhibitor-containing combination therapy have been reported to be higher among patients with HCV genotype 1b infection than among those with HCV genotype 1a infection.17,18 In this study, among 166 patients with HCV genotype 1b infection who received any 12-week or 24-week regimen and had not received treatment previously or had not had a response to prior therapy, there were no treatment failures, and only 1 of 24 patients who received an 8-week regimen had a relapse. These results suggest that a regimen containing fewer agents (e.g., without ribavirin) may be effective in treating this population, but this possibility would need to be explored in larger studies.
The results of other studies of interferon-free therapies currently in development have recently been published. Various regimens consisting of the investigational protease inhibitor faldaprevir and the nonnucleoside polymerase inhibitor deleobuvir with ribavirin, with treatment duration of 16 to 40 weeks, were associated with rates of sustained virologic response at 12 weeks after treatment of 52 to 69% among previously untreated patients with HCV genotype 1 infection, with low response rates among patients with HCV genotype 1a infection or an IL28B non-CC genotype.19 A 12-week regimen of the nucleotide polymerase inhibitor sofosbuvir with ribavirin was associated with rates of sustained virologic response at 24 weeks after treatment of 84% among 25 previously untreated patients with HCV genotype 1 infection and 10% among 10 patients who had not had a response to prior therapy.16
Preliminary data suggest that the addition of the NS5A inhibitor ledipasvir to sofosbuvir and ribavirin can improve the rates of sustained virologic response among patients who have not had a response to prior therapy.20 That finding is consistent with the similar rates we observed among previously untreated patients and those who had not had a response to prior therapy, suggesting that a regimen that is active against multiple viral targets may provide additional benefit in patients who have not had a response to prior therapy.
In this study, 1% of the patients had a serious adverse event during the study treatment period and the following 30 days; 1% of patients discontinued the study drug owing to an adverse event. Larger studies are needed, but this preliminary assessment of adverse events compares favorably with the findings in studies of treatment with telaprevir or boceprevir plus peginterferon and ribavirin, in which serious adverse events occurred in 9 to 14% of patients, and 10 to 16% of patients discontinued therapy owing to adverse events.5-7,15 The most common laboratory abnormality of grade 3 or 4 in this study, observed in 2% of patients, was a grade 3 elevation in the total bilirubin level. This finding appears to be related to the known inhibitory effect of protease inhibitors on the organic anion-transporting polypeptide 1B1.21,22
This study had several limitations. First, the open-label design could bias the assessment of adverse events. However, the use of objective, laboratory-based efficacy end points and laboratory assessments for safety mitigate this limitation. Second, the small number of patients in each study group limits the power to detect differences between groups. Third, patients with cirrhosis, who are less likely than those without cirrhosis to have a response to peginterferon and ribavirin,5,15 were excluded from this study. Finally, the fibrosis stage at baseline was assessed by means of serum biomarkers, transient elastography, or biopsy. The use of various methods limits the ability to assess the effect of the disease stage at baseline on treatment response.
In conclusion, in this phase 2b study, interferon-free combinations of ABT-450/r, ABT-267, ABT-333, and ribavirin were associated with high rates of sustained virologic response at 24 weeks after treatment among previously untreated patients with chronic HCV genotype 1 infection and among patients who had not had a response to prior therapy. These preliminary data suggest that a 12-week regimen of three direct-acting agents plus ribavirin is efficacious in patients without cirrhosis who either had not received treatment previously or had not had a response to prior therapy.
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