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HIV and Coverage of the
46th Annual Meeting of the European
Association for the Study of the Liver

March 30 - April 3, 2011, Berlin, Germany

Boosted ABT-450 Improves Early Response to Interferon for Hepatitis C

Addition of the experimental HCV protease inhibitor ABT-450, boosted with ritonavir, to standard therapy increased the likelihood of complete early virological response at 12 weeks in previously untreated genotype 1 chronic hepatitis C patients.

By Liz Highleyman

Direct-acting antiviral drugs targeting various steps of the hepatitis C virus (HCV) lifecycle are expected to bring about a new treatment paradigm, especially for people with hard-to-treat HCV genotype 1. These agents will initially be added to standard therapy consisting of pegylated interferon plus ribavirin, but some are already being tested in all-oral regimens.

As described at the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this month in Berlin, Eric Lawitz and colleagues conducted a Phase 2a clinical trial of ABT-450, an HCV protease inhibitor jointly developed by Abbott and Enanta.

Prior studies showed that boosting with ritonavir (Norvir, developed as an HIV protease inhibitor) increased ABT-450 plasma concentrations and enabled once-daily dosing.

The present analysis included 35 treatment-naive chronic hepatitis C patients randomly assigned to receive ABT-450/ritonavir or placebo. About 70% were men, about 80% were white, and the average age was 50 years; 80% had HCV genotype 1a. (Other participants in the larger study received 2 other experimental agents, the non-nucleoside HCV polymerase inhibitors ABT-072 or ABT-333.)

Participants received ABT-450/ritonavir at doses of 50/100 mg, 100/100 mg, or 200/100 mg once-daily, or placebo, as monotherapy for 3 days, followed by 12 weeks of ABT-450/ritonavir or placebo at the same dose in combination with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin. After week 12, they continued on pegylated interferon/ribavirin through week 48. Interim results from a planned analysis at week 12 were presented at EASL.


During the 3 days of monotherapy, response was similar in all 3 ABT-450/ritonavir dose arms, with a mean maximum HCV RNA decrease of around 4 log IU/mL, compared with 0.36 log IU/mL in the placebo group.
In an intent-to-treat analysis at 4 weeks, 88% of patients receiving ABT-450/ritonavir plus pegylated interferon/ribavirin achieved rapid virological response (RVR; HCV RNA < 25 IU/mL) compared with only 9% in the placebo arm.
At 12 weeks, 92% receiving ABT-450/ritonavir vs 18% receiving placebo achieved complete early virological response (cEVR, again HCV RNA < 25 IU/mL).
No participants receiving ABT-450/ritonavir plus pegylated interferon/ribavirin experienced virological rebound during 12 weeks of therapy.
HCV sub-genotype (1a or 1b), baseline HCV RNA, and IL28B gene pattern were not associated with differences in virological response.
Boosted ABT-450 was generally well-tolerated and no novel adverse events were observed.
Adverse events and laboratory abnormalities were generally similar in the ABT-450/ritonavir and placebo groups, and were consistent with those of standard therapy.
No drug-related serious adverse events were reported.
A larger proportion of ABT-450/ritonavir recipient experienced decreased neutrophil counts, but the average magnitude of decrease was greater in the placebo arm; no patients discontinued therapy due to neutropenia.

"At week 12, a statistically significantly greater proportion of subjects taking ABT-450/ritonavir + [pegylated interferon/ribavirin] (92%) achieved complete early virologic response compared with those subjects taking placebo + [pegylated interferon/ribavirin] (18%)," the investigators concluded.

"When combined with [pegylated interferon/ribavirin], ABT-450/ritonavir was safe and well tolerated during 12 weeks of treatment, with an adverse event and laboratory abnormality profile comparable to that of [pegylated interferon/ribavirin] alone," they added.

In a separate analysis of 3-day resistance data, ABT-450/ritonavir dosed at 200/100 mg "appeared to more consistently suppress the emergence of ABT-450-associated resistant variants" than the 2 lower doses, according to a press release issued by Abbott.

"We will continue to explore the use of ABT-450/ritonavir and our other investigational HCV treatments in a variety of patient populations and combinations, with and without pegylated interferon alfa," said Scott Brun, MD, Abbott's divisional vice president for infectious disease development.

Investigator affiliations: Alamo Medical Research, San Antonio, TX; Abbott, Abbott Park, IL; Cedars-Sinai Medical Center, Los Angeles, CA.


E Lawitz, I Gaultier, F Poordad, et al. ABT-450/Ritonavir (ABT-450/r) Combined with Pegylated Interferon Alpha-2a and Ribavirin After 3-Day Monotherapy in Genotype 1 HCV-Infected Treatment-naive Subjects: 12-Week Interim Efficacy and Safety Results. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 252.

Other Source
Abbott. Abbott and Enanta Present Positive 12-Week Results and 3-Day Resistance Data From Phase 2 Study of ABT-450/r for Treatment of Hepatitis C. Press release. April 4, 2011.

























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