Two interferon-free antiviral regimens being developed by Abbott showed high hepatitis C cure rates in small studies of treatment-naïve patients presented last week at the International Liver Congress in Barcelona.
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 dosed with ribavirin.
The combination was evaluated in eleven treatment-naïve patients with HCV genotype 1. None had cirrhosis and all had the IL28B CC gene variant in order to maximize the possibility of successful second-line treatment with pegylated interferon and ribivirin in the event of treatment failure.
They received treatment lasting twelve weeks. This consisted of the investigational protease inhibitor ABT-450, at a dose of 150 mg once daily with a 100mg ritonavir booster. This was combined with 400 mg once-daily dose of ABT-072 and weight-based ribavirin (1000 – 1200mg), 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 twelve 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 log10 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 three and this remained suppressed until the end of therapy at week twelve.
Viral load rebounded in one patient eight 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 SVR 36 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 (2xULN) 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-naïve 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 two doses of ABT-450/r (250mg or 150mg, each boosted with 100mg of ritonavir) in treatment-naïve patients. All prior non-responders received a dose of 150mg. All participants received a 400mg dose of ABT-333.
|
Treatment-naïve ABT-450/r 250mg + ABT-333 400mg
N=19 |
Treatment-naïve ABT-450/r 150mg + ABT-333 400mg
N=14 |
Previous non-responders ABT-450/r 150mg + ABT-333 400mg
N=17 |
|
|
RVR: HCV RNA < 25 IU/ml at w4 |
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 w1 |
6 viral breakthroughs on treatment 3 viral relapse 2 weeks post-therapy |
|
SVR4: HCV RNA < 25 IU/ml at w4 |
95% |
93% |
47% |
|
SVR12: HCV RNA < 25 IU/ml at w12 |
95% |
93% |
47% |
No patients discontinued treatment due to adverse events, but four patients 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.
Lawitz E 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-naïve HCV IL28B-CC genotype-1 infected patients. International Liver Congress, 2012.
Poordad F et al. 12-week interferon-free regimen of ABT-450/r + ABT-333 + ribavirin achieved SVR12 in more than 90% of treatment-naïve HCV genotype-1-infected subjects and 47% of previous non-responders. International Liver Congress, 2012.