- Category: Experimental HCV Drugs
- Published on Thursday, 10 April 2014 00:00
- Written by Keith Alcorn
A 12-week course of 3 direct-acting antivirals developed by AbbVie, plus ribavirin, cured 96.3% of treatment-experienced patients with hepatitis C genotype 1, Stefan Zeuzem of the J.W. Goethe University Hospital in Frankfurt reported on Thursday at the 49th EASL International Liver Congress in London.
The AbbVie combination consists of 3 drugs that each target a different stage in the viral lifecycle of hepatitis C, used without interferon. New interferon-free combinations are being developed by several pharmaceutical companies and represent a major advance over the previous standard of care. Interferon-free treatment appears better tolerated and can cure a much higher proportion of patients in a shorter time.
The data presented by Zeuzem come from the SAPPHIRE II study, a Phase 3 trial which recruited 394 genotype 1 patients (58% subtype 1a, 41% subtype 1b) who did not respond to a previous course of dual therapy with pegylated interferon/ribavirin. Patients were eligible for inclusion if they had relapsed, had a partial response, or had a null response; 49% were previous null responders.
The study was designed to evaluate a 12-week course of interferon-free treatment in a patient population that has been hard to treat with interferon-based therapy. The median age of study participants was 55 years. The study population had less advanced liver disease. None of the patients had cirrhosis, and 68% had stage F0 or F1 (absent to mild) fibrosis.
Participants were randomized on a 3:1 basis to receive the oral interferon-free combination or placebo. The investigational therapy consisted of the protease inhibitor ABT-450 with a ritonavir booster (150/100 mg once-daily), the NS5A inhibitor ombitasvir (ABT-267) (250 mg once-daily), the non-nucleoside NS5B polymerase inhibitor dasabuvir (ABT-333) (250 mg twice-daily), and ribavirin. Therapy lasted for 12 weeks and the primary outcome was the sustained virological response rate 12 weeks after completion of treatment (SVR12).
Overall, 96.3% of patients receiving the investigational therapy had SVR at week 12 post-treatment. SVR12 rates were similar regardless of previous treatment outcome (95.3% for individuals who relapsed, 100% for patients with a partial response, and 95.2% for those with a prior null response).
SVR12 rates among patients receiving the study medication were comparable for genotype 1a and 1b (96.0% vs 96.7%). All cases of virological failure in the study occurred after the completion of treatment: 7 patients experienced a viral breakthrough between 2 and 8 weeks after completing treatment; 6 of these viral breakthroughs occurred in patients who had been null responders to previous treatment.
The only adverse event that occurred more frequently in the investigational therapy arm was pruritus (itching), which was reported by 13.8% of patients in the treatment arm and 5.2% of those receiving the placebo. Only 1% of patients receiving the investigational combination discontinued therapy early. These 3 discontinuations were due to elevated liver enzymes (ALT/AST), severe diarrhea, and kidney failure that occurred on the first day of treatment (this case was considered unconnected to the investigational therapy).
There was no significant difference in the development of laboratory abnormalities. Less than 5% of patients developed anemia as a consequence of ribavirin treatment, and no patient developed anemia that was severe enough to require erythropoietin treatment in order to restore hemoglobin to normal levels.
Questioned about the extent to which patients were excluded from the study due to potentially hazardous drug-drug interactions related to ritonavir (an inhibitor of CYP3A4, a liver enzyme involved in the metabolism of numerous medicines), Zeuzem said that the incidence was likely to have been "a very low 1-digit percentage." He argued that the main issue regarding ritonavir-related drug interactions was the need for medical education to ensure that physicians, especially hepatologists unfamiliar with ritonavir, understand the potential interactions. Zeuzem pointed out that some of the drugs that interact with ritonavir, such as statins, could be safely interrupted for 12 weeks, or patients could be switched to alternative drugs that do not have problematic interactions with ritonavir.
AbbVie's 3-drug combination is due to be submitted for marketing approval in the U.S. and European Union imminently, and the company hopes to achieve U.S. Food and Drug Administration marketing approval before the end of 2014.
S Zeuzem, I Jacobson, T Baykal et al. SAPPHIRE II: phase 3 placebo-controlled study of interferon-free, 12-week regimen of ABT-450/ABT-267, ABT-333, and ritonavir in treatment-experienced adults with hepatitis C genotype 1. 49th Annual Meeting of the European Association for the Study of the Liver (EASL 2014). London, April 9-13, 2014. Abstract 01.