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AASLD 2011: Daclatasvir plus Asunaprevir Rapidly Suppresses HCV in Prior Null Responders

A dual antiviral regimen containing the novel hepatitis C virus (HCV) NS5A inhibitor daclatasvir (BMS-790052) plus the NS3 protease inhibitor asunaprevir (BMS-650032) -- without interferon -- produced rapid and sustained viral suppression in Japanese prior null responders with HCV genotype 1b, researchers reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) this week in San Francisco.

The approval of the first direct-acting antiviral agents (DAAs), the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek), have begun to usher in a new era of hepatitis C treatment. Until recently, most clinical trials have combined investigational DAAs with pegylated interferon/ribavirin standard therapy -- which has suboptimal effectiveness for hard-to-treat patients and causes side effects that lead many people to delay or refuse therapy -- but several teams are now reporting data from studies of all-oral, interferon-free regimens.

Kazuaki Chayama from Hiroshima University in Japan and colleagues conducted an open-label study to test Bristol-Meyers Squibb's daclatasvir plus asunaprevir for 24 weeks in people with null response to prior therapy with pegylated interferon/ribavirin with or without boceprevir or telaprevir (< 2 log reduction in HCV RNA). This lack of response is thought to be related to poor natural interferon responsiveness, which has been linked to IL28B gene pattern and black race/ethnicity. Null responders are particularly difficult-to-treat and urgently needs better therapeutic options.

Daclatasvir and asunaprevir have both shown good overall safety and antiviral potency in laboratory and early human studies, but higher doses of asunaprevir were discontinued to ALT elevation suggesting liver toxicity.

This ongoing study (AI447-017) began with a sentinel cohort of 10 prior null responder chronic hepatitis C patients. In contrast with most hepatitis C studies in the U.S. and Europe, a majority of the Japanese participants (60%) were women and the median age was higher, at 62 years. All had HCV genotype 1b, reflecting the distribution in the Japanese patient population; 20% had the favorable IL28B CC pattern and 80% had the intermediate CT pattern (none had TT).

Results

• At week 4, 90% of participants had HCV RNA below the lower limit of quantification (LLOQ), though just 40% were undetectable.
• By week 8, however, 90% were both below LLOQ and undetectable.
• 90% of patients demonstrated sustained virological response, with undetectable viral load at weeks 12, 24, 36 (12 weeks post-treatment, or SVR12), and 48 (24 weeks post-treatment, or SVR24).
• No cases of viral breakthrough were observed.
• Several participants had baseline viral mutations associated with resistance to daclatasvir (L28M, R30Q, L31M, Y93H) and some NS3 protease inhibitors (T54S, Q80L), but this did not appear to affect virological response.
• Daclatasvir plus asunaprevirwas generally well-tolerated.
• The most common adverse events were diarrhea (7 patients) and headache (4 patients).
• 2 patients experienced serious adverse events (1 with grade 3 fever, 1 with grade 4 hyperbilirubinemia).
• There were no changes in electrocardiogram parameters.
• 2 people had mild and transient ALT elevation.
• 1 woman who discontinued treatment at week 4 due to hyperbilirubinemia had detectable HCV RNA when she stopped, but went on to become undetectable, with response sustained through 24 weeks.

Based on these findings, the researchers concluded, "Dual oral therapy with daclatasvir and asunaprevir provided rapid and persistent viral suppression in null responders with genotype 1b infection."

The study demonstrates that "high cure rates are possible with dual oral DAA therapy" in this difficult-to-treat patient population, Chayama said.

Investigator affiliations: Hiroshima University, Hiroshima, Japan; Toranomon Hospital, Tokyo, Japan; Sapporo Kosei General Hospital, Sapporo, Japan; Bristol-Myers KK, Tokyo, Japan; Bristol-Myers Squibb, Research and Development, Wallingford, CT; Bristol-Myers Squibb, Research and Development, Princeton, NJ.

11/8/11

Reference

K Chayama, S Takahashi, Y Kawakami, et al. Dual Oral Combination Therapy with the NS5A Inhibitor BMS-790052 and the NS3 Protease Inhibitor BMS-650032 Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 1b-Infected Null Responders. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract LB-4.

Other Source

Bristol-Myers Squibb. All-Oral Treatment Regimen of Bristol-Myers Squibb’s Investigational NS5A and NS3 Inhibitors Achieved 90% Sustained Virologic Response (SVR12) in Phase II Study Sentinel Cohort of Genotype 1b Null Responders. Press release. November 7, 2011.