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Daclatasvir + Asunaprevir Is Highly Effective Against Hepatitis C Genotype 1b

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An all-oral combination of daclatasvir plus asunaprevir, without pegylated interferon or ribavirin, cured 87% of genotype 1b patients who were ineligible for or could not tolerate interferon and 81% of prior non-responders in a Japanese study published in the June 2014 edition of Hepatology.

The former standard of care for chronic hepatitis C virus (HCV) included pegylated interferon plus ribavirin, which can cause difficult side effects including flu-like symptoms, depression, and anemia. For this reason, many patients either decline interferon-based therapy or stop early, and many are awaiting interferon-free regimens.

Hiromitsu Kumada from Toranomon Hospital in Tokyo and colleagues conducted a Phase 3 study to evaluate Bristol-Meyers Squibb's HCV NS5A replication complex inhibitor daclatasvir (formerly BMS-790052) plus the NS3 protease inhibitor asunaprevir (formerly BMS-650032) in an all-oral regimen. Findings werepreviously presented in part at the 2013 AASLD Liver Meeting.

This open-label trial enrolled more than 250 chronic hepatitis C patients with HCV subtype 1b, the predominant type in Japan. Among the participants included in the analysis, 100 were treatment-naive but considered interferon ineligible (due to contraindications such as advanced age, comorbidities such as depression, or other factors) and 35 were interferon-intolerant (stopped prior therapy early due to toxicities), while 87 previously did not respond well to interferon (including 36 prior partial responders and 48 null responders).

In contrast with most U.S. and European studies, two-thirds of participants were women and the average age was older at 63 years, with 40% being over age 65. Half had the favorable IL28B CC gene variant associated with interferon responsiveness and 10% had liver cirrhosis. People with liver cancer or with HIV or hepatitis B coinfection were excluded, as were those who had been treated with other HCV protease or NS5A inhibitors.

All participants received 60 mg once-daily daclatasvir plus 100 mg twice-daily asunaprevir for 24 weeks. They were followed for an additional 24 weeks post-treatment to determine sustained virological response (SVR24), or continued undetectable HCV RNA after finishing therapy.

Results

  • 87% of interferon-ineligible or intolerant participants achieved SVR24.
  • 81% of prior non-responders achieved SVR24 (78% for partial responders and 81% for null responders).
  • Sustained response rates were statistically similar among patients with and without liver cirrhosis (91% vs 84%, respectively).
  • Participants younger than 65 years and older patients also had similar cure rates (81% vs 90%, respectively).
  • SVR24 rates were also the same for patients with IL28B CC and non-CC gene patterns (85% for both).
  • Overall, 15% of patients experienced virological failure: 14 with viral breakthrough during treatment, 3 still had detectable viral load at the end of treatment, and 17 relapsed after finishing treatment.
  • Patients with L31M/V or Y93H viral variants at baseline were less likely to achieve sustained response.
  • People who experienced virological failure were more likely to have daclatasvir and asunaprevir trough concentrations below the median, but still within the expected range.
  • 13% of participants -- 14 in each treatment group -- discontinued therapy early, mainly due to adverse events or lack of efficacy.
  • 6% of participants experienced serious adverse events and 5% discontinued due to adverse events.
  • The most common adverse events were nasopharyngitis (upper respiratory inflammation), increased ALT and AST liver enzymes, headache, diarrhea, and fever.

"Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well-tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy," the study authors concluded.

"These high rates of SVR obtained with daclatasvir and asunaprevir represent a significant improvement of cure rates in patient populations typically associated with poor responses to other therapies or with limited therapeutic options," they elaborated. "Other factors typically associated with a poor response to therapy, including male gender, high baseline HCV RNA, advanced age, non-CC IL28B genotype, and cirrhosis, did not appear to impact response rates, although the number of patients in these subgroups was small."

In April Bristol-Myers Squibb submitted a New Drug Application requesting U.S. Food and Drug Administration (FDA) approval for daclatasvir plus asunaprevir, which has been designated a "breakthrough therapy." Approval is also pending in Japan. Studies have shown that daclatasvir plus asunaprevir dual therapy is not very effective against HCV subtype 1a, but adding the non-nucleoside polymerase inhibitor BMS-791325 as third agent cured most people with either HCV 1a or 1b.

6/11/14

Reference

H Kumada, Y Suzuki, K Ikeda, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 59(6):2083-2091. June 2014.