NEJM: Sofosbuvir, ABT-450, ABT-333 Look Good in Interferon-free Hepatitis C Regimens

Two 12-week, all-oral hepatitis C regimens -- Gilead's sofosbuvir, and Abbott's ABT-450 plus ABT-333, both with ribavirin -- produced promising cure rates in studies that have now been published in the January 3, 2013, New England Journal of Medicine.

 

The recent approval of the first direct-acting antiviral agents for hepatitis C virus (HCV) has brought about a new treatment paradigm, but many patients and providers continue to wait for all-oral therapy that avoids interferon and its difficult side effects.

Data on many experimental interferon-free combinations have been presented at conferences including the annual EASL International Liver Congress and the AASLD Liver Meeting. Study findings are also starting to make their way into medical journals. The latter reports do not include the most recent data, but they do have the benefit of peer-review.

Sofosbuvir

In this week's NEJM, Edward Gane from Auckland City Hospital in New Zealand and colleagues described early findings from the Phase 2 ELECTRON study, which is evaluating various combinations including sofosbuvir (formerly known as GS-7977 and before that PSI-7977), a once-daily nucleotide analog HCV polymerase inhibitor.

Gilead's ELECTRON trial has used an open-label evolving study design, adding additional arms to evaluate new regimens rather than starting separate trials.

Researchers initially looked at 40 easy-to-treat participants -- previously untreated people with HCV genotypes 2 or 3 -- who were assigned to receive 400 mg once-daily sofosbuvir plus 1000-1200 mg ribavirin for 12 weeks, with or without pegylated interferon alfa-2a (Pegasys) for 4, 8, or 12 weeks.

In this first stage of the study, all 10 people (100%) who received sofosbuvir plus ribavirin without interferon achieved sustained virological response at 24 weeks after completion of therapy (SVR24). All 30 people (100%) who received sofosbuvir plus ribavirin with any of the 3 doses of pegylated interferonalso achieved SVR24. Gane presented these findings at the 2011 Liver Meeting.

The study then added 2 new arms of treatment-naive genotype 2/3 patients: 10 who received sofosbuvir plus ribavirin plus pegylated interferon for 8 weeks, and 10 who took sofosbuvir monotherapy for 12 weeks.

The short triple regimen arm also achieved an SVR rate of 100%. This fell to 60%, however, for the monotherapy group, showing that sofosbuvir alone was not adequate even for the easiest-to-treat patients.

With these promising data in hand, ELECTRON next turned to people with difficult-to-treat HCV genotype 1. In 2 new arms, 25 treatment-naive patients and 10 null responders to prior interferon-based therapy were treated with sofosbuvir and ribavirin for 12 weeks.

All participants experienced a rapid decline in HCV RNA and had undetectable viral load at the end of the 12-week treatment period. 84% of the treatment-naive participants maintained undetectable viral load and achieved SVR24. Among the null responders, however, all but 1 relapsed after the end of treatment, yielding an SVR24 rate of just 10%. Gane reported these findings at the 2012 Conference on Retroviruses and Opportunistic Infections.

Across all study arms, sofosbuvir was generally safe and well-tolerated. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. Participants in the arms not receiving interferon experienced fewer side effects. No patients in any arm discontinued sofosbuvir or ribavirin due to adverse events.

"Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection," the researchers concluded.

"The uniform response during treatment is notable because the 8 treatment groups represented diverse patient populations -- patients who had an infection with HCV genotype 1, 2, or 3; those who had not received prior treatment for HCV infection; and those who had not had a response to prior treatment with interferon and ribavirin," they elaborated in their discussion. "A total of 63% of patients had a non-CC IL28B genotype (CT or TT), which correlates with a poor response to treatment. Of those patients with HCV genotype 1 infection, 89% were infected with HCV genotype 1a, which, when compared with HCV genotype 1b infection, is associated with lower rates of response to current telaprevir-based or boceprevir-based triple therapy."

"The absence of viral breakthrough in any patient during treatment in the study confirms that sofosbuvir has a high barrier to resistance," they continued. "Although in vitro resistance is observed in the replicon model after only 3 to 5 days of monotherapy with non-nucleoside NS5B, NS3-4A, and NS5A inhibitors, no in vitro resistance has been observed after 7 to 14 days of monotherapy with various nucleoside or nucleotide analogues."

"These early results potentially pave the way to address several unmet medical needs for [previously untreated] patients, who may benefit from a short-duration, all-oral regimen for HCV infection that does not include interferon," the authors wrote. "The pangenotypic antiviral efficacy of sofosbuvir supports the continued investigation of sofosbuvir with ribavirin alone or in combination with other direct-acting antiviral agents in various populations of patients with HCV infection."

Since the NEJM report was submitted for publication, further results have been presented at recent conferences.

An additional 2 arms of the ELECTRON trial were added to evaluate a 12-week triple regimen of sofosbuvir plus ribavirin plus Gilead's NS5A replication complex inhibitor GS-5885 in treatment-naive patients and prior null responders.

As Gane reported at the 2012 Liver Meeting, none of the 25 participants in the treatment-naive arm nor the 3 patients who reached this time point in the null responder arm relapsed by post-treatment week 4, giving an SVR4 rate of 100%.

Sofosbuvir has also shown excellent results in a 12-week dual combination with Bristol-Myers Squibb's NS5A inhibitor daclatasvir. However, Gilead indicated last spring that it would no longer pursue studies of this regimen, focusing instead on its own candidate. The company recently announced that it has started a Phase 3 trial (ION-I) to evaluate a fixed-dose coformulation of sofosbuvir plus GS-5885, with and without ribavirin, taken for 12 or 24 weeks.

ABT-450 and ABT-333

In the second NEJM report, Fred Poordad from the University of Texas Health Science Center in San Antonio and colleagues evaluated ABT-450, Abbott's HCV NS3 protease inhibitor, boosted with low-dose ritonavir (Norvir), plus the non-nucleoside NS5B polymerase inhibitor ABT-333 and ribavirin.

This Phase 2a open-label study included 33 treatment-naive participants and 17 prior partial or null responders with HCV genotype 1. Previously untreated patients were randomly assigned to receive 150 or 250 mg ABT-450 once-daily with 100 mg ritonavir, while the treatment-experienced people all got 150 mg. All participants also received 400 mg twice-daily ABT-333 and 1000-1200 mg/day ribavirin.

After 12 weeks of treatment, 93% of treatment-naive people taking 150 mg ABT-450 and 95% of those taking the 250 mg dose achieved SVR at 12 weeks after the end of treatment. The SVR12 rate fell to 47%, however, for prior non-responders; 6 patients experienced viral breakthrough and 3 relapsed.

Adverse events included abnormal liver function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus (itching), rash, and vomiting. 1 participant discontinued treatment due to elevated ALT. In previous studies of boosted ABT-450, 1 healthy volunteer had a grade 3 ALT elevation while receiving the 250 mg dose with other direct-acting agents. For this reason -- as well as the similar response rates observed in treatment-naive patients -- all treatment experienced patients received the 150 mg dose.

"This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection," the study authors concluded.

"The sustained-virologic-response rate of 47% among patients with a null or partial response to previous treatment with peginterferon and ribavirin, which is markedly lower than the rate among previously untreated patients, suggests that treatments including direct-acting antiviral agents are less effective in patients with a null or partial response to previous treatment than in previously untreated patients, even in the absence of interferon therapy," they elaborated. Their discussion also included an overview of other interferon-free regimens under study.

"More-potent regimens will be needed to achieve similar rates of sustained virologic response in this population, possibly with the addition of a third direct-acting antiviral agent that has a complementary mechanism of action," the researchers continued. "Although longer durations of therapy could be considered, we found that most of the virologic failures in the patients with a null or partial response to previous therapy occurred during treatment. Extending the treatment duration beyond 12 weeks would not have prevented the virologic failures in these patients."

Poordad presented these findings at the 2012 EASL meeting. Further data from the AVIATOR trial, looking at all-oral combinations of boosted ABT-450, ABT-333, and the NS5A inhibitor ABT-267, with or without ribavirin, for 8 or 12 weeks were presented at the 2012 Liver Meeting.

1/3/13

References

E Gane, CA Stedman, RH Hyland, et al. Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. New England Journal of Medicine 368(1):34-44. January 3, 2013.

F Poordad, E Lawitz, KV Kowdley, et al. Exploratory Study of Oral Combination Antiviral Therapy for Hepatitis C. New England Journal of Medicine 368(1):45-53. January 3, 2013.