Terms used in these reports:
- RVR (Rapid virological response)= No virus detected at week 4
- eRVR(Extended rapid virological response) = No virus detected at week 4 and week 12
- EVR (Early Virological Response) — 2 log drop of HCV RNA after 12 weeks.
- cEVR = Complete Early Virological Response — No virus detected after 12 Weeks.
- SVR12 (Sustained virological response) = No virus detected at 12 weeks after completion of treatment.
- SVR24 = No virus detected at 24 weeks after completion of treatment.
BMS (Bristol-Myers Squibb) are developing 2 new drugs for the treatment of hepatitis C. The two drugs are:
• Asunaprevir (BMS-650032) a protease inhibitor
• Daclatasvir (BMS-790052) an NS5A inhibitor
A copy of the latest press release that was unveiled at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) is below.
BMS Daclatasvir plus Asunaprevir
The study found a very high rate of 12-week sustained virological response (SVR12) in people with HCV genotype 1a amongst patients who received new direct-acting antiviral agents with pegylated interferon and ribavirin.
The findings came from a Phase 2a study of asunaprevir, an HCV protease inhibitor, combined with daclatasvir, an inhibitor of the HCV NS5A protein. The drugs are being developed by BMS, potentially for use in combination. The study was designed to evaluate once- and twice-daily dosing of asunaprevir in combination with daclatasvir, with or without pegylated interferon and ribavirin.
Like a number of other studies presented at this meeting, the trial was designed to give a preliminary picture of the potential for these agents to cure hepatitis C when used without interferon or ribavirin. The side effects of interferon, and the fact that some people fail to respond to interferon due to genetic characteristics or due to resistance induced by prior treatment, make the identification of interferon-free regimens essential for people who have failed to respond to a previous interferon-containing regimen.
Interferon-free treatment will also be highly attractive for anyone needing treatment for the first time, because it is likely to come with fewer side effects, and treatment may be completed in 6 or even 3 months.
However, research studies are also evaluating the use of new regimens with and without ribavirin, because this drug causes anemia, causing treatment regimens to be terminated prematurely owing to poor tolerance.
This randomized study was open-label and involved people with genotype 1 HCV infection. It excluded patients with cirrhosis. All had previously received standard therapy with pegylated interferon and ribavirin, but were classified as null responders, having failed to achieve a sustained virological response (SVR).
A total of 101 people were recruited to the study. There was a high prevalence of factors associated with a poorer response to treatment in the study population. Over 95% of participants lacked the IL28B CC gene variant, which predicts a favorable response to interferon-based treatment, and 89% had an HCV viral load above 10 million IU/mL.
Participants with HCV genotype 1b were randomized to 1 of 4 treatment arms, consisting of 24 weeks of the HCV protease inhibitor daclatasvir (60 mg once daily) plus:
- asunaprevir (200 mg twice daily) (n=18, restricted to participants with genotype 1b);
- asunaprevir (200 mg once daily) (n=20, restricted to participants with genotype 1b);
- asunaprevir (200 mg twice daily) plus pegylated interferon and ribavirin (n=20);
- asunaprevir (200 mg once daily) plus pegylated interferon and ribavirin (n=21).
Participants with HCV genotype 1a were randomized to receive 1 of the 2 pegylated interferon-containing regimens, due to the higher risk of viral breakthrough and consequent null response in this group of patients.
The vast majority of participants (36 of 41) receiving interferon-containing regimens had HCV genotype 1a infection.
A fifth treatment group -- receiving daclatasvir 60 mg once daily plus asunaprevir 200 mg twice daily plus ribavirin (n=22) -- was recruited separately and consisted of participants with either genotype 1a or 1b infection.
Overall, 95% of participants who received the 4-drug, interferon-containing regimens achieved HCV viral load below the lower limit of quantification (LLOQ, 25 IU/mL) at week 4 of treatment, and all participants had HCV RNA < LLOQ at week 12.
Further, 95% of participants (39 of 41) had sustained virological response 12 weeks after the completion of treatment, suggesting that these interferon-containing regimens are highly effective and comparable in efficacy to other regimens that contain combinations of new antiviral drugs with pegylated interferon and ribavirin.
Only 2 cases of post-treatment virological relapse were observed, 1 at week 4 and 1 at week 12 after completion of treatment.
In the dual-treatment group (genotype 1b only), 78% of participants receiving asunaprevir twice daily and 65% receiving asunaprevir once daily achieved SVR12. There were 8 cases of viral breakthrough; HCV RNA was re-suppressed with the addition of pegylated interferon and ribavirin in all cases. In 5 cases, naturally existing HCV variants with resistance to daclatasvir were found to have been present prior to treatment.
The study found that, in the triple-therapy arm, 56% of participants with genotype 1a experienced viral breakthrough in the absence of interferon, compared with none of the genotype 1b patients. This result confirmed the findings of a previous study, which also found a higher rate of viral breakthrough in participants with genotype 1a who received daclatasvir and asunaprevir without ribavirin.
These findings led the investigators to conclude that the interferon-free combination of daclatasvir and asunaprevir with ribavirin should not be pursued in harder-to-treat genotype 1a null responders.
"These data suggest that interferon-free treatment regimens for genotype 1 patients may need to be tailored according to sub-genotype," presenter Anna Lok from the University of Michigan at Ann Arbor told the meeting.
No participant stopped taking either daclatasvir or asunaprevir because of side effects.
The most common side effects among people taking the dual combination of daclatasvir and asunaprevir were headache, diarrhea, weakness, and nausea. These side effects were also observed in participants taking the 4-drug regimen, among whom hair loss and irritability were also common.
The authors concluded that the 4-drug combination of daclatasvir and asunaprevir with pegylated interferon and ribavirin is highly effective for patients with either genotype 1a or genotype 1b who did not respond to earlier treatment with pegylated interferon and ribavirin. Preliminary data also suggested that treatment with daclatasvir/asunaprevir alone was effective, but only for people with genotype 1b infection.
AS Lok, DF Gardiner, C Hezode,et al. Sustained virologicresponse in chronic HCV genotype (GT) 1-infected null responders with combination of daclatasvir (DCV; NS5A inhibitor and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 79.
Bristol-Myers Squibb. Investigational Hepatitis C Quad Therapy Regimen of Daclatasvir and Asunaprevir Plus Interferon Alfa and Ribavirin Achieved SVR24 in 93% of Difficult-to-Treat Genotype 1a/b Prior Null Responders in Expanded Phase II Study. Press release. November 11, 2012.
Bristol-Myers Squibb. Investigational Hepatitis C Dual DAA Regimen of Daclatasvir and Asunaprevir Achieved SVR12 in 78% of Difficult-to-Treat Genotype 1b Prior Null Responders
In Expanded Phase II Study. Press release. November 11, 2012.