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.
Glossary
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
- transaminase
An
enzyme that can be measured in a blood sample that indicates the health of the
liver.
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.