A two-drug combination of direct-acting
antivirals developed by AbbVie achieved sustained virologic response in 95% of
previously untreated patients with genotype 1b hepatitis C infection after 12
weeks of treatment, without the need for use of pegylated interferon or
ribavirin, Eric Lawitz of Texas Liver Institute reported on Sunday at the 64th
meeting of the American Association for the Study of Liver Diseases in
In people with genotype 1b infection who
had failed to respond to a previous course of pegylated interferon and ribavirin,
the same combination achieved sustained virologic response in 90% of trial
AbbVie is already testing ABT-450, an HCV
protease inhibitor boosted by ritonavir, and ABT-267, an Ns5A inhibitor, in
several phase III studies in combination with a third drug, the non-nucleoside
polymerase inhibitor ABT-333. These trials will begin to report results by the
end of 2013, and it is likely that AbbVie will submit a licensing application
in early 2014 for this three-drug, interferon-free combination in order to
achieve marketing approval in the second half of 2014.
The results presented on Sunday came from a
phase II study designed to determine whether a two-drug combination of a
protease inhibitor and an NS5A inhibitor would be sufficiently potent to
achieve a high cure rate in patients with genotype 1b hepatitis C infection.
Genotype 1b HCV has a higher barrier to the development of drug resistance than
genotype 1a. This raises the possibility that patients with genotype 1b
infection may be able to use two highly potent direct-acting antivirals instead
of three to achieve a cure with 12 weeks of treatment, potentially reducing the
risk of side-effects and drug-drug interactions with other medications.
The PEARL-1 study was a phase II trial that
enrolled 42 previously untreated patients with hepatitis C infection and 40
previous null responders. Previously untreated patients were 59% male and 26%
African American; prior null responders were 37% male and 2.5% African
All participants received 12 weeks of
treatment with ABT-450 (150mg once daily boosted with 100mg of ritonavir in
order to maintain high drug levels of ABT-450), and ABT-267 (25mg once daily).
The primary endpoint of the study was the proportion of patients with a sustained virologic response
12 weeks after completion of a 12-week course of treatment (SVR-12).
In the previously untreated group, 95.2% of
patients (40 of 42) achieved a sustained virologic response 12 weeks after the
completion of treatment. Two patients were lost to follow up but there were no
recorded virological failures in the previously untreated group.
In the previous null responder group, 90% of
patients (36 of 40) achieved a sustained virologic response 12 weeks after the
completion of treatment. Four virological failures occurred in this group: one
viral breakthrough during treatment after an initial treatment response, and
three post-treatment virological relapses.
The study drugs were fairly well tolerated.
The most commonly reported adverse effects reported during the study were
headache (33% of previously untreated patients and 25% of prior null
responders) and nausea (19% of previously untreated patients but no prior null
responders). Two serious adverse events occurred that were not considered to be
related to the study drug, and one patient temporarily interrupted treatment
after a grade 3 liver enzyme (ALT) elevation.
This combination will now go forward into
Questioned regarding the potential for drug
interactions between the ritonavir booster used in this combination and other
classes of medication, presenter Eric Lawitz said that in his view, the
interaction between ritonavir and other drugs metabolised by the CYP 3A4 liver
enzyme was “manageable”.
Use of ritonavir 100mg alongside at least 18
drugs from 10 different classes is contraindicated; these include commonly
prescribed medications such as antiarrhthymics, ergot alkaloids used in
migraine treatment, and the statins simvastatin and lovastatin.