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AASLD 2012: Abbott Interferon-free Combination 'Promising' in Harder-to-treat People with Hep C

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Over 79% of previously untreated and null-responder patients with genotype 1a hepatitis C achieved a sustained virological response 12 weeks after completing treatment with an interferon-free combination of 2 or 3 direct-acting antiviral agents developed by Abbott (ABT-450, ABT-267, and/or ABT-333), investigators reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this week in Boston.

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In the group receiving all 3 drugs plus ribavirin, 96% of patients achieved a sustained virological response 12 weeks after the end of treatment (known as SVR12), while only 2 out of 148 patients with HCV genotype 1b receiving any of the drug combinations tested in the study failed to achieve SVR12.

Investigators previously reported data on the use of Abbott drugs in interferon-free regimens for untreated patients at the European Association for the Study of the Liver International Liver Congress (EASL 2012) in Barcelona in April. Those analyses looked at combinations of 2 drugs.

New data were presented at the AASLD meeting from Phase 2 studies that recruited non-cirrhotic untreated patients and previous null responders to pegylated interferon plus ribavirin, testing a combination of 2 or 3 directly-acting antivirals with or without ribavirin in patients with genotype 1 HCV infection.

Kris Kowdley, director of the Liver Center of Excellence at Virginia Mason Medical Center in Seattle, presented results from the Aviator study, a Phase 2b study designed to identify optimal drug combinations for further study in Phase 3 licensing trials.

Treatment-naive participants received the HCV protease inhibitor ABT-450 at 1 of 2 doses (100 mg or 200 mg), boosted by 100 mg ritonavir -- an inhibitor of the CYP 3A4 enzyme -- in order to raise plasma levels. This was combined with the HCV NS5A inhibitor ABT-267 (25 mg once-daily) and/or the non-nucleoside polymerase inhibitor ABT-333 (400 mg twice-daily) with or without ribavirin for 8 or 12 weeks.

Previous null responders were randomized to 1 of 2 arms, a combination of ABT-450/r and ABT-267 with ribavirin, or all 3 DAAs in combination with weight-based ribavirin.

SVR12 results were reported for 448 patients. The data were presented by intent-to treat, meaning that all participants who received at least 1 dose were assessed at each time point in the study and counted as treatment failures if they dropped out due to side effects or missed study visits. This method of analysis is intended to better approximate the real-world effectiveness of a treatment regimen compared with an on-treatment analysis, which only captures those people who stayed on treatment -- by definition, those who did best.

Most participants (n=358) were taking hepatitis C therapy for the first time. The remaining 90 people had previously been treated with pegylated interferon and ribavirin. All patients had HCV genotype 1 infection and none had liver cirrhosis. A majority of patients (56%) were men, their mean age was 50 years, and two-thirds had subtype 1a infection, which is harder to treat. (HCV genotype 1a is the predominant subtype in the U.S.; 1b predominates in Europe).

Among genotype 1a patients, the best response rates were seen in individuals treated with the 4-drug combination of ritonavir-boosted ABT-450 with ABT-267, ABT-333, and ribavirin. 97.5% of treatment-naive patients taking this combination responded to treatment, as did 93% of previously treated patients.

SVR 12 Rates

Treatment-naive, 8 weeks:

ABT-450/r + ABT-267 + ABT-333 + ribavirin:

·      HCV 1a: 84%;

·      HCV 1b: 96%

Treatment-naive, 12 weeks:

ABT-450/r + ABT-333 + ribavirin:

·      HCV 1a: 79%;

·      HCV 1b: 100%.

ABT-450/r + ABT-267 + ribavirin:

·      HCV 1a: 85%;

·      HCV 1b: 100%.

ABT-450/r + ABT-267 + ABT-333:

·      HCV 1a: 83%;

·      HCV 1b: 96%.

ABT-450/r + ABT-267 + ABT-333 + ribavirin:

·      HCV 1a: 96%;

·      HCV 1b: 100%.

Null responders, 12 weeks:

ABT-450/r + ABT-267 + ribavirin:

·      HCV 1a: 81%;

·      HCV 1b: 100%.

ABT-450/r + ABT-267 + ABT-333 + ribavirin:

·      HCV 1a: 89%;

·      HCV 1b: 100%.

Larger studies will be required to determine whether these rates of response can be reproduced in more diverse populations. Some interferon-free combination studies have seen differences in response according to IL28b CC gene status, a predictor of response to interferon, but Kowdley said that no substantial difference in outcomes had been seen in the Aviator study population.

The consistently high response rates in patients with HCV 1b suggest that people with this subtype will be candidates for ribavirin-sparing regimens in the future, said Kowdley. More research will be needed to determine the characteristics of patients with HCV subtype 1a who are most likely to achieve a sustained virological response with a 3-drug direct-acting antiviral regimen without ribavirin.

Therapy was well tolerated overall. Only 2 patients (1%) stopped taking their treatment because of side effects, and in both cases they subsequently resumed treatment and achieved a sustained virological response. There were 5 serious adverse events, but only 1 -- joint pain -- was possibly treatment-related.

The most common side effects were fatigue and headache. Side effect incidence was similar between the treatment-naive and treatment-experienced patients, ranging between 27% and 31%.

The investigators were encouraged by these findings, concluding that the 4-drug combination was effective and safe, regardless of prior treatment history.

11/13/12

Reference

KV Kowdley, E Lawitz, F Poordad, et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR rates (observed data) of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract LB-1.

Other Source

Abbott. Abbott Presents Promising Phase 2b Interferon-free Hepatitis C Results at 2012 Liver Meeting. Press release. November 10, 2012.