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EASL 2013: Daclatasvir + Asunaprevir + BMS-791352 Looks Promising as Interferon-free Combo

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An all-oral regimen containing 3 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 a late-breaking poster presentation at the EASL 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-790052), the NS3 protease inhibitor asunaprevir (formerly BMS-650032), and Bristol-Myers Squibb's non-nucleoside NS5B polymerase inhibitor BMS-791325.

This open-label study (AI443-014) 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 3-drug combination containing 60 mg once-daily daclatasvir, 200 mg twice-daily asunaprevir, and BMS-791325. Initially, 32 participants were randomly assigned to receive BMS-791325 at a dose of 75 mg twice-daily for either 24 or 12 weeks. After favorable safety assessment, another 34 patients were randomized to receive 150 mg 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), or continued undetectable HCV RNA after finishing therapy. Everson presented earlier findings at the AASLD Liver Meeting.

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.

Results

  • 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.
  • At 4 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, and an SVR36 rate 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 1 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 1 participant who experienced viral breakthrough at week 8 of therapy and also intensified treatment (follow-up ongoing) plus 1 other patient who 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 75 mg or 150 mg 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 3-drug regimen was generally safe and well-tolerated regardless of BMS-791325 dose or treatment duration.
  • There were 2 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, diarrhea, 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 75 mg 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 75 mg or 150 mg 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 by the end of the year a Phase 3 study of daclatasvir, asunaprevir, and BMS-791325 in a fixed-dose coformulation. 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.

5/1/13

Reference

GT Everson, KD Sims, M Rodriguez-Torres, et al. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1423.

Other Source

Bristol-Myers Squibb. High Rates of SVR Demonstrated in Phase II Study with Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and BMS-791325 in Treatment-Naive Patients with Genotype 1 Chronic Hepatitis C Infection. Press release. April 23, 2013.