- Category: Experimental HCV Drugs
- Published on Tuesday, 04 March 2014 16:11
- Written by Keith Alcorn
A 12-week triple combination of direct-acting antivirals developed by AbbVie cured at least 99% of previously untreated people with genotype 1 hepatitis C infection, Rajendar Reddy of the University of Pennsylvania Hospital told the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) in Boston on Tuesday. This is expected to be the first approved interferon- and ribavirin-free combination for genotype 1b, available by the end of 2014.
Only one virological failure occurred during treatment, no patients relapsed immediately after completing therapy, and the only other "treatment failures" were 2 patients counted as virological failures after they did not turn up for their 12-week post-treatment monitoring visits.
The results came from the PEARL-III study, one of the largest of 6 Phase 3 studies of AbbVie’s direct-acting antiviral regimen. AbbVie is one of several companies racing to develop interferon-free combinations of oral drugs that can cure hepatitis C within 12 or 24 weeks.
These are the first results from AbbVie’s Phase III development program to be presented at a scientific conference. AbbVie plans to submit data from these studies to the Food and Drug Administration early in the second quarter of 2014 for U.S. marketing approval, and hopes to gain approval before the end of this year. European Union approval is likely to follow soon afterwards. If approved, the combination will the first to provide treatment for HCV genotype 1b without the need for interferon or ribavirin -- a significant step forward, as many of the side effects of in hepatitis C treatment are associated with interferon and ribavirin.
Genotype 1b is the most common genotype of hepatitis C globally, and comprises the largest proportion of infections in the European region, Latin America, Russia, Turkey, China, and Japan.
The AbbVie Phase III studies compared various durations of treatment with a combination of the HCV protease inhibitor ABT-450 boosted with ritonavir in a coformulation with the HCV NS5A inhibitor ABT-267, plus the HCV non-nucleoside polymerase inhibitor ABT-333, with or without ribavirin. The studies were done in untreated and previously treated patients, including those with cirrhosis. However, the completed studies did not include patients with HIV/HCV coinfection.
PEARL-III recruited 419 previously untreated patients with HCV genotype 1b infection. All participants received the triple combination of direct-acting antivirals (called 3D) and were randomized in a 1:1 ratio to receive ribavirin (n=210) or placebo (n=209). Treatment in PEARL III lasted for 12 weeks.
Approximately half of study participants in the ribavirin arm were women, and a majority of participants in the placebo arm were women (59%), an unusually high representation for a study of hepatitis C treatment. 95% of participants were Caucasian and 77% were recruited in the European region. The mean age of the study population was around 49 years. The majority of study participants had little or no evidence of liver disease: 68% in the ribavirin-sparing arm and 71% in the ribavirin arm had F0 or F1 fibrosis. Only 21% of the study population had a favorable IL28B CC genotype, which confers better response to interferon-based treatment.
Cure rates were extremely high in both study arms. 99.0% of patients in the ribavirin-sparing arm and 99.5% of patients in the ribavirin arm achieved a sustained virologic response 12 weeks after the completion of treatment (SVR12). One case of virologic rebound occurred at week 10 of treatment, while 2 patients who achieved a virological response at the end of treatment were subsequently lost to follow up. Other than these cases, there were no treatment failures. There were no significant differences in response by baseline characteristics, including IL28B genotype.
Treatment was well tolerated. There were no treatment discontinuations due to adverse events and the most common adverse events reported during the study were headache and fatigue, which each occurred in just over 1 in 5 patients. Pruritis and nausea were the only adverse events that occurred more frequently in the ribavirin arm. Hemoglobin levels fell below the lower limit of normal in 51% of patients in the ribavirin arm compared with 3% in the ribavirin-sparing arm, and 9% of the ribavirin arm developed anemia compared to none in the ribavirin-sparing arm. The ribavirin dose was reduced in 9% of patients in the ribavirin arm. All of these patients achieved SVR12.
The study investigators concluded that in patients with hepatitis C genotype 1b, a 12-week course of ABT-450/ritonavir, ABT-333, and ABT-267 -- the so-called 3D combination -- is a highly effective and well-tolerated treatment that can be administered without ribavirin.
P Ferenci, A Nyberg, D Bernstein, et al. PEARL III: SVR >99% after 12 Wks of ABT-450/r/267 + ABT-333 ± RBV in Treatment Naive HCV GT1b Infection. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 29LB.
AbbVie. AbbVie to Present Late-breaker PEARL-III Study in Patients with Chronic Hepatitis C at the 21st Conference on Retroviruses and Opportunistic Infections. Press release. March 3, 2014.