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Daclatasvir + Asunaprevir + BMS-791325 Cures Most Genotype 1 Hepatitis C

An interferon-free oral combination of 3 direct-acting antiviral agents developed by Bristol-Myers Squibb led to sustained virological response in more than 90% of treatment-naive chronic hepatitis C patients with HCV genotype 1a or 1b, according to a report in the February 2014 issue of Gastroenterology.

The advent of direct-acting drugs that interfere with different steps of the HCV lifecycle has revolutionized treatment for chronic hepatitis C, but many patients and providers are waiting for all-oral regimens that avoid the side effects of interferon and, ideally, ribavirin.

Gregory Everson from the University of Colorado at Denver and colleagues conducted a Phase 2a trial to evaluate the safety and efficacy of an all-oral triple combination of the HCV NS5A inhibitor daclatasvir (formerly BMS-790052), the HCV protease inhibitor asunaprevir (formerly BMS-650032), and the non-nucleoside polymerase inhibitor BMS-791325.

This open-label study (AI443-014) included 66 previously untreated chronic hepatitis C patients. About 60% were men, most were white, and the median age was 50 years. Three-quarters had harder-to-treat HCV subtype 1a, the rest 1b. About one-third had the favorable IL28B CC gene pattern associated with good interferon responsiveness. Patients with liver cirrhosis -- a harder-to-treat group -- were excluded.

Participants were randomly assigned to receive 60 mg once-daily daclatasvir, 200 mg twice-daily asunaprevir, and 75 mg or 150 mg twice-daily BMS-791325 for either 12 or 24 weeks. The primary endpoint was sustained virological response, or HCV RNA >25 IU/mL, at 12 weeks after completing treatment (SVR12).

Results were previously reported in part at the AASLD Liver Meeting this past November and the EASL International Liver Congress last April.

Results

• HCV viral load declined rapidly after starting therapy, with all but 2 participants reaching levels >25 IU/mL by treatment week 4.
• 92% of participant achieved SVR12 in a modified intention-to-treat analysis. Virological response was similar in patients treated for 12 or 24 weeks.
• SVR12 rates were similar for people with HCV subtypes 1a and 1b, as well as for people with IL28B CC and non-CC status.
• 2 patients experienced viral breakthrough while on therapy and 1 person had a post-treatment relapse.
• The 3-drug combination was generally safe and well-tolerated.
• Serious adverse events were rare, and no participants discontinued therapy due to serious adverse events or adverse events related to the treatment regimen. The most common side effects were headache, asthenia (weakness), and gastrointestinal symptoms.

Based on these findings the study authors concluded, "In a Phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection."

Other all-oral hepatitis C regimens, including Gilead Sciences sofosbuvir (Sovaldi) plus ledipasvir and AbbVie's "3D" combination are further along in the development pipeline. However, there is still room for additional interferon-free therapies -- especially treatments that work well for people with HCV subtype 1a and drugs that could potentially cost less than sofosbuvir's $1000 per pill price tag.

Bristol-Myers Squibb has submitted daclatasvir plus asunaprevir -- which works well as a dual regimen against HCV subtype 1b -- for approval in Japan, where this is the predominant genotype. The company has also requested European approval of daclatasvir as a single agent, which will position it to be paired with sofosbuvir.

1/28/14

Reference

GT Everson, KD Sims, M Rodriguez-Torres, et al. Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection. Gastroenterology 146(2):420-429. February 2014.