Daclatasvir + asunaprevir + BMS-791352 looks promising as interferon-free combination

An all-oral regimen containing three next-generation antivirals taken for either 12 or 24 weeks produced sustained virological response in more than 90% of previously untreated genotype 1 chronic hepatitis C patients in a phase 2a study, according to interim findings presented last week at the 48^th International Liver Congress (EASL 2013) in Amsterdam.

The advent of direct-acting antivirals (DAAs) has changed the treatment paradigm for chronic hepatitis C. Although several DAAs have been shown to improve treatment response when added to pegylated interferon and ribavirin, many patients and clinicians are awaiting all-oral regimens that avoid interferon and its difficult side-effects.

Gregory Everson from the University of Colorado and colleagues conducted an open-label trial comparing interferon- and ribavirin-sparing regimens containing the HCV NS5A replication complex inhibitor daclatasvir (formerly BMS-790062), the NS3 protease inhibitor asunaprevir (formerly BMS-650032) and Bristol-Myers Squibb's non-nucleoside NS5B polymerase inhibitor BMS-791325.

This open-label study enrolled 66 treatment-naive chronic hepatitis C patients without liver cirrhosis. Overall about 60% were men (ranging from 44 to 72% in the different treatment arms), about 80% were white, about 20% were black and the median age was 50 years. Three-quarters had harder-to-treat HCV subtype 1a, the rest 1b. About one-third had the favourable IL28B CC gene pattern which predicts good interferon responsiveness.

All participants received a three-drug combination containing 60mg once-daily daclatasvir, 200mg twice-daily asunaprevir and BMS-791325. Initially, 32 participants were randomly assigned to receive BMS-791325 at a dose of 75mg twice daily for either 24 or 12 weeks.

After favourable safety assessment, another 34 patients were randomised to receive 150mg BMS-791325 twice daily for 24 or 12 weeks. Because patients started treatment at different times, researchers reported varying durations of sustained virological response (SVR, considered a cure), or continued undetectable HCV RNA after finishing therapy:

• Group 1 (n=16): Daclatasvir + asunaprevir + 75mg BMS-791325 for 24 weeks: SVR24.

• Group 2 (n=16): Daclatasvir + asunaprevir + 75mg BMS-791325 for 12 weeks: SVR36.

• Group 3 (n=16): Daclatasvir + asunaprevir + 150mg BMS-791325 for 24 weeks: SVR4.

• Group 4 (n=18): Daclatasvir + asunaprevir + 150mg BMS-791325 for 12 weeks: SVR12.

Viral decline was rapid using both dosing regimens. By week 4 of treatment 100% of participants in Groups 1, 2 and 3, and 89% in Group 4 had rapid virological response, and most still had undetectable viral load at the end of treatment.

Four weeks post-treatment, SVR rates were 94, 94, 94 and 89% in Groups 1, 2, 3 and 4, respectively, in a modified intention-to-treat analysis. Sustained response rates remained the same at post-treatment week 12 for Groups 1, 2 and 4, with Group 3 not having reached this endpoint. SVR24 rates for Group 1 and 2 were 88 and 94%, respectively. Finally, an SVR36 of 88% was reported for Group 2.

All treatment 'failures' in Groups 1 and 2 were due to missing data from participants who had previously reached undetectable viral load but did not return for further testing. Group 3 included one participant who experienced viral breakthrough at week 6 of therapy. Treatment was intensified by adding pegylated interferon/ribavirin, but the patient discontinued due to an adverse event.

Group 4 included one person who experienced viral breakthrough at week 8 of therapy and also intensified treatment (follow-up ongoing). In addition, one other patient experienced early relapse between the end of treatment and post-treatment week 4. Drug resistance mutations were detected in both Group 4 patients with treatment failure. No relapses have been observed so far after SVR4 in any group.

Treatment was equally effective regardless of whether the 75mg or 150mg dose of BMS-791325 was used or whether the duration of therapy was 12 or 24 weeks. The researchers did not report a breakdown of results by HCV subtype or IL28B status in this interim analysis.

The three-drug regimen was generally safe and well tolerated, again regardless of BMS-791325 dose or treatment duration. There were two serious adverse events, both considered unrelated to the DAAs under study, and no participants stopped treatment for this reason (except for the interferon intensification case described above).

The most frequently reported side-effects were headache, weakness, diarrhoea and nausea, with abdominal pain being more common at the higher dose. No serious changes in liver enzymes (ALT or AST), bilirubin or blood cell counts were observed.

"The all-oral, interferon-free, ribavirin-free, ritonavir-free combination [of daclatasvir, asunaprevir, and BMS-791325 at 75mg or 150 mg twice daily] achieved > 90% SVR4 (61/66) and SVR12 (30/32) by modified intent-to-treat analysis in predominantly genotype 1a patients, IL-28Bnon-CC patients," the researchers concluded.

High rates of SVR appear to be similar with either 12 or 24 weeks of treatment and with either the 75mg or 150mg dose of BMS-791325, and treatment was "highly tolerable at either dose level," with similar adverse event rates regardless of dose or treatment duration, they added.

Bristol-Myers Squibb indicated in a press release that it plans to start a phase 3 study of daclatasvir, asunaprevir and BMS-791325 in a fixed-dose coformulation by the end of the year. The poster noted that daclatasvir is also being studied in other all-oral, ribavirin-free regimens in combination with simeprevir (formerly TMC435), sofosbuvir (formerly GS-7977) or VX-135.