Daclatasvir + sofosbuvir shows high hep C cure rate, new studies underway

A dual oral regimen of daclatasvir plus sofosbuvir cured more than 90% of chronic hepatitis C patients without interferon or ribavirin, according to a report in the January 16, 2014, New England Journal of Medicine. A series of new studies of this combination in difficult-to-treat groups including people with HIV/HCV coinfection and liver transplant recipients is underway.

The advent of direct-acting antiviral agents has started a revolution in hepatitis C treatment, but many people with hepatitis C and their care providers are awaiting all-oral regimens that avoid the notorious side-effects of interferon.

Mark Sulkowski from Johns Hopkins and fellow investigators with the AI444040 Study Group evaluated interferon-free therapy consisting of Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir (formerly BMS-790052) and Gilead Science's recently approved HCV polymerase inhibitor sofosbuvir (formerly GS-7977 and PSI-7977), with or without ribavirin.

This combination was initially studied before Gilead purchased Pharmasset – the company that discovered daclatasvir – and discontinued the research in favour of focusing on its own NS5A inhibitor, ledipasvir (GS-5885). Data from this study were previously presented in part at the 2012 AASLD Liver Meeting and the 2013 EASL International Liver Congress.

This open-label Phase 2 trial included a total of 211 participants at 18 centres in the US between June 2011 and November 2012. The study initially enrolled 44 previously untreated participants with HCV genotype 1 and 44 patients with HCV genotypes 2 or 3. It was then expanded to include an additional 82 treatment-naive genotype 1 patients and 41 who were prior non-responders to triple therapy with pegylated interferon, ribavirin, and either boceprevir (Victrelis) or telaprevir (Incivek).

Overall, just over half of participants (52%) were men, most (about 80%) were white, and the mean age was 52 years. A majority (63%) had harder-to-treat HCV subtype 1a, 17% had 1b, 12% had genotype 2, and 9% had genotype 3. The proportion with the favorable IL28B CC gene variant ranged from about 20% to nearly 60% in the various treatment arms, being lower for prior non-responders. About two-thirds had moderate-to-advanced liver fibrosis or cirrhosis (stage F2-F4).

In the first stage of the study, participants received 60mg daclatasvir once-daily plus 400mg sofosbuvir once-daily, with or without ribavirin, for 24 weeks (some received a 7-day sofosbuvir lead-in before adding daclatasvir). In the second stage, patients were randomly assigned to receive the same doses of daclatasvir and sofosbuvir, with or without ribavirin, for 12 weeks (if treatment naive) or 24 weeks (if treatment experienced). The primary endpoint was sustained virological response (SVR), or continued undetectable HCV RNA (<25 IU/mL), at 12 weeks post-treatment (SVR12).

• 207 of 211 participants (98%) completed their assigned 12 or 24 weeks of therapy.
• 98% of the 126 treatment-naive genotype 1 patients achieved sustained virological response.
• The SVR12 rate was also 98% for the 41 genotype 1 prior non-responders.
• SVR12 rates were similar for HCV subtypes 1a and 1b (98 and 100%, respectively).
• 92% of the 26 genotype 2 patients achieved SVR12.
• 89% of the 18 genotype 3 patients achieved sustained response.
• 1 patient (genotype 3) experienced viral breakthrough while on therapy and 2 experienced post-treatment viral rebound (which in 1 case was suspected to be due to reinfection rather than relapse).
• Response rates were similar in participants who received ribavirin and those who did not (94 and 98%, respectively).
• Response rates also did not differ significantly according to IL28B CC versus non-CC status (93 and 98%, respectively).
• There did not appear to be a relationship between baseline NS5A resistance mutations and virological response.
• Daclatasvir and sofosbuvir were generally safe and well-tolerated.
• 7% of participants experienced serious adverse events and <1% discontinued treatment early (2 people, due to stroke and worsening fibromyalgia).
• The most common side-effects were fatigue (37%), headache (29%), and nausea (19%), which occurred with similar frequency regardless of ribavirin use or treatment duration.
• Anaemia was more common among participants who received ribavirin.

Based on these findings, the study authors concluded, "Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir."

"Our study shows that the combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients, including patients who had persistent HCV variants conferring resistance to protease inhibitors after unsuccessful treatment with telaprevir or boceprevir," they elaborated in their discussion. "Daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients with characteristics that were previously associated with a poor response to treatment – HCV genotypes 1a and 3, the non-CC IL28B genotype, and black race."

"In our study, response rates were similar among patients treated with ribavirin and those treated without it; however, ribavirin recipients had a greater decrease in the hemoglobin level," they added. "Our findings may reflect the antiviral potency and high resistance barrier of the daclatasvir-sofosbuvir combination and suggest that ribavirin is not required with every oral direct-acting antiviral regimen."

Now that sofosbuvir has been approved by the Food and Drug Administration, Bristol-Myers Squibb is able to once again use it in combination studies with daclatasvir. Three such Phase 3 trials are now underway, though not yet recruiting participants.

The ALLY 1 trial will look at daclatasvir and sofosbuvir for people with HCV genotypes 1-6 who have cirrhosis that may require future transplantation or who have received liver transplants. Participants will initially be treated with daclatasvir plus sofosbuvir for 12 weeks, and those who relapse, require retreatment, or undergo transplantation while on treatment may have ribavirin added or therapy extended.

The ALLY 2 trial will test daclatasvir plus sofosbuvir without ribavirin for treatment-naive and treatment-experienced people with HIV/HCV coinfection, while ALLY 3 will evaluate the dual combination in a larger population of treatment-naive and treatment-experienced patients with HCV genotype 3 – the group with the lowest response rate in the previous trial.