Back HCV Treatment EASL 2012: Abbott Interferon-Free HCV Combinations Show Early Promise for Untreated Patients

EASL 2012: Abbott Interferon-Free HCV Combinations Show Early Promise for Untreated Patients

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Two interferon-free antiviral regimens being developed by Abbott showed high hepatitis C cure rates in small studies of treatment-naive patients presented last week at the 47th International Liver Congress (EASL 2012) in Barcelona.

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Abbott is pursuing the development of several interferon-free regimens in which the investigational protease inhibitor ABT-450, boosted with the CYP3A inhibitor ritonavir in order to allow once-daily dosing, is combined with a non-nucleoside polymerase inhibitor.

The first study to be presented combined ABT-450 with the non-nucleoside HCV NS5B inhibitor ABT-072, also dosed once daily, both with ribavirin.

The combination was evaluated in 11 treatment-naive patients with HCV genotype 1. None had cirrhosis and all had the favorable IL28B CC genotype in order to maximize the possibility of successful second-line treatment with pegylated interferon and ribavirin in the event of treatment failure.

They received treatment lasting 12 weeks. This consisted of the investigational protease inhibitor ABT-450, at a dose of 150 mg once daily with a 100 mg ritonavir booster. This was combined with 400 mg once-daily dose of ABT-072 and weight-based ribavirin (1000-1200 mg), dosed twice daily. The aim of the study was to assess the safety, tolerability, pharmacokinetics, and antiviral activity of the two investigational drugs.

Viral load was monitored throughout treatment, on its completion at week 12, and again 24 weeks after therapy was finished. An undetectable viral load (<LLOQ) at this final time point was considered to be a sustained virological response, or cure.

Approximately three-quarters of patients (73%) were men and 82% were white. Median baseline viral load was 6.9 log IU/ml and in all patients was above 800,000 copies IU/ml.

The investigational regimen was shown to have a rapid and sustained anti-hepatitis C effect.

All the patients had a viral load below 25 IU/ml by week 3 and this remained suppressed until the end of therapy at week 12.

Viral load rebounded in 1 patient 8 weeks after the completion of treatment, but in the others it remained suppressed below the lower limit of quantification at week 24 (SVR24). A second patient experienced viral breakthrough by 36 weeks post-treatment, leading to a SVR36 rate of 81%.

There were no deaths or serious side effects. The most commonly reported adverse events, all of which were mild, included headache (36%), fatigue (27%), nausea (27%), and dry skin (27%). Two patients developed indirect bilirubin elevations (2 x ULN) within the first week of treatment, but these resolved with further dosing and were not associated with transaminase elevations.

ABT-450/r and ABT-333

The second study to be presented was the combination of ABT-450/ritonavir and the twice-daily non-nucleoside NS5B polymerase inhibitor ABT-333, again combined with weight-based ribavirin.

This regimen was evaluated both in treatment-naive patients with HCV genotype 1 and in previous non-responders to pegylated interferon and ribavirin. IL28B genotype was not a requirement for entry to this study. More than half of treatment-naive patients, and all non-responders, had the IL28B CT or TT gene patterns associated with poorer response to interferon-based therapy.

The study compared 2 doses of ABT-450/r (250 mg or 150 mg, each boosted with 100 mg ritonavir) in treatment-naive patients. All prior non-responders received a dose of 150 mg. All participants also received a 400 mg dose of ABT-333.

 

Treatment-naive

ABT-450/r 250 mg + ABT-333 400 mg

 

 

N=19

Treatment-naive

ABT-450/r 150 mg + ABT-333 400 mg

 

 

N=1

Previous non-responders

ABT-450/r 150 mg + ABT-333 400 mg

 

N=17

RVR: HCV RNA < 25 IU/ml at week 4

90%

79%

88%

eRVR: HCV RNA < 25 IU/ml weeks 4-12

90%

79%

65%

Discontinuations

1, due to ALT/AST elevation

1 due to non-medical reason at week 1

6 viral breakthroughs on treatment

3 viral relapse 2 weeks post-therapy

SVR4: HCV RNA < 25 IU/ml at week 4

95%

93%

47%

SVR12: HCV RNA < 25 IU/ml at week 12

95%

93%

47%

No patients discontinued treatment due to adverse events, but 4 experienced severe adverse events (fatigue, pain, vomiting, and hyperbilirubinaemia). The most common mild or moderate adverse events were fatigue (42%), nausea, and headache. Six patients experienced elevations of indirect bilirubin, caused by ABT-450, which has an effect on the bilirubin transporter OATP.

4/27/12

References

E Lawitz, F Poordad, KV Kowdley, et al. A 12-week interferon-free regimen of ABT-450r, ABT-072 and ribavirin was well tolerated and achieved sustained virological response in 91% of treatment-naive HCV IL28B-CC genotype-1 infected patients. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 13.

F Poordad, E Lawitz, KV Kowdley, et al. 12-week interferon-free regimen of ABT-450/r + ABT-333 + ribavirin achieved SVR12 in more than 90% of treatment-naive HCV genotype-1-infected subjects and 47% of previous non-responders. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 1399.