By Chris Berrie
BARCELONA, Spain -- April 25, 2012 -- Combining ABT-450 with ritonavir
(ABT-450/r) plus ABT-333 plus ribavirin (RBV) is well tolerated, provides high
sustained virological response (SVR) in treatment-naïve patients infected with
hepatitis C virus (HCV) genotype 1, and shows relatively high SVR in previous
interferon-based nonresponders, researchers said here at the 47th Annual
Meeting of the European Association for the Study of the Liver (EASL).
At present, there are no treatment options for HCV-infected patients who are
ineligible or intolerant to the interferons.
“This is the first study combining ABT-450 with ABT-333 with ribavirin without
interferon in genotype 1 patients who were either treatment-naïve or previous
treatment failures,” stated Fred Poordad, MD, Chief of Hepatology and Liver
Transplantation at the Comprehensive Transplant Center of Cedars-Sinai Medical
Center, Los Angeles, California, presenting this open-label study here on April
21.
The study design included 3 arms, the first 2 of which treated naïve patients
with chronic HCV genotype 1 infection using ABT-333 400 mg twice daily plus RBV
1,000-1,200 mg once daily plus ABT-450/r either 250/100 mg once daily (arm 1; n
= 19) or 150/100 mg once daily (arm 2; n = 14). The third treatment arm was
similar to arm 2, but treated prior partial or null responders to previous
pegylated interferon plus RBV treatments (arm 3; n = 17).
The treatments were for 12 weeks, with 48 weeks follow-up.
These patients were mainly male, with a mean age of just over 50 years, and
were largely HCV genotype 1a. For IL28B genotype, 52.6% were CC in arm A and
35.7% in arm B, with no IL28B CC in arm 3.
The primary endpoint was extended rapid virological response (eRVR) based on
HCV RNA lower than the limit of detection from treatment weeks 4 to 12. As the
intent-to-treat analysis, these reached 90%, 79% and 59% in arms 1, 2, and 3,
respectively.
Similarly, for SVRs at weeks 4 (SVR4) and 12 (SVR12), high levels of response
were achieved for arms 1 (95%, 93%, respectively) and 2 (95%, 93%). These SVR4
and SVR12 responses were also relatively high for the previous nonresponding
patients in arm 3 (47%, 47%).
Comparisons across IL28B CT versus TT showed no differences in SVR12 either for
treatment-naïve patients, as arms 1 plus 2 (100% vs 100%) or for previous
nonresponders (50% vs 40%).
Based on clonal sequencing, Dr. Poordad highlighted the resistant variants at
baseline and at virologic failure in the previous nonresponders of arm 3. “It
is important to note that patients who had virologic failure developed
resistance variants to both the protease inhibitor as well as the polymerase
inhibitor,” he noted.
In the safety analysis, there were no deaths or serious adverse events
throughout, with only 1 adverse event leading to premature discontinuation, in
arm 1. Four patients showed adverse events assessed as severe, without
requiring study-drug interruption or discontinuation: hyperbilirubinaemia,
fatigue, pain, and vomiting.
The treatment-emergent adverse events and the laboratory abnormalities noted
were largely the same type and levels across the 3 treatment arms. Dr. Poordad
also noted that the transient asymptomatic elevation of indirect bilirubin that
was seen is consistent with the known effect of ABT-450 on the bilirubin
transporter OATO1B1.
“It does appear that ABT-450 with ritonavir, ABT-333 plus ribavirin for 12
weeks has the potential to achieve very high SVR in a high proportion of
patients without interferon,” he concluded.
Funding for this study was provided by Abbott.
[Presentation title: A 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. Abstract 1399]
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