Nov 28, 2013
According to information presented at AASLD 2013 in Washington, D.C. this month, results of the Phase 2 trial called Cosmos Study shows high rates of SVR in G1 patients with mild - moderate fibrosis as well as null responders. Patients included both mild - moderate fibrosis and advanced fibrosis, treatment naive, and prior null responders. The trial included 12 weeks of treatment with simeprevir and sofosbuvir with or without ribavirin. Link is the bottom.
AASLD 2013: Simeprevir + Sofosbuvir Produces High Sustained Response Rates for Hard-to-treat Patients
Published on Sunday, 03 November 2013 00:00
Written by Liz Highleyman
A 12-week all-oral combination of simeprevir plus sofosbuvir led to sustained virological response in 93% of genotype 1 prior null responders with mild-to-moderate liver fibrosis, working as well as a longer course of treatment or triple therapy including ribavirin, according to late-breaking findings from the COSMOS trial presented this week at the 64thAASLD Liver Meeting in Washington, DC. The study also showed that 100% of treatment-naive patients and null responders with advanced fibrosis or cirrhosis achieved early sustained response at 4 weeks post-treatment using the same dual regimen.
The advent of next-generation direct-acting antivirals (DAAs) has been described as a revolution in the treatment of chronic hepatitis C virus (HCV) infection. While the first of these new agents will initially be approved as add-ons to interferon-based therapy, people with hepatitis C and their clinicians are eagerly awaiting interferon-free regimens.
Multiple DAAs developed by several major drug companies have performed well in all-oral regimens in trials to date, but their effectiveness varies based on a bewildering array of factors including HCV subtype (1b vs 1a), host IL28B gene pattern (CC vs non-CC), prior treatment status (untreated, relapser, prior partial or null responder). and extent of liver damage (absent, mild, or moderate fibrosis vs advanced fibrosis or cirrhosis).
Ira Jacobson from Weill Cornell Medical College presented findings from the Phase 2a COSMOS trial, evaluating oral regimens containing Janssen/Medivir's HCV protease inhibitor simeprevir (formerly TMC435) and Gilead Science’s nucleotide polymerase inhibitor sofosbuvir (formerly GS-7977), taken with or without ribavirin.
This open-label study enrolled 2 cohorts of genotype 1 chronic hepatitis C patients:
• Cohort 1: 80 prior interferon null responders with absent-to-moderate fibrosis (Metavir stage F0-F2);
• Cohort 2: 87 treatment-naive individuals and prior null responders with advanced fibrosis or compensated cirrhosis (F3-F4).
About 60% of participants in Cohort 1 were men, 29% were black, and the median age was 56 years. Just over three-quarters had harder-to-treat HCV subtype 1a, and half of these had the Q80K resistance mutation at baseline. Only 6% had the favorable IL28B CC gene variant associated with good interferon responsiveness -- typical of null responders. About 40% had stage F0-F1 fibrosis while 60% had F2.
In Cohort 2, two-thirds were men, 9% were black, and the median age was 58 years. Again, 78% had subtype 1a, 40% with the Q80K mutation. Participants were about evenly divided between treatment-naives and null responders, and 21% had the favorable CC variant. Just over half had advanced fibrosis, the rest cirrhosis.
Participants were randomly assigned to receive a dual regimen of 150 mg once-daily simeprevir plus 400 mg once-daily sofosbuvir, or else a triple regimen of these 2 drugs plus 1000-1200 mg weight-based ribavirin taken twice-daily. In addition, they were randomized to receive these regimens for either 12 or 24 weeks.
Jacobson presented results from a planned interim analysis. Cohort 1 started earlier and had long enough follow-up to determine sustained virological response at 12 weeks after completing treatment (SVR12), which is considered a cure. Cohort 2 started later and had 4-week post-treatment follow-up results (SVR4), which is too soon to declare them cured as relapses could still occur.
All participants treated for 12 week completed therapy in both cohorts. In Cohort 1, about 87% treated for 24 weeks finished therapy; 2 people in the dual therapy arm and 3 in the triple therapy arm stopped early, 1 in each arm due to adverse events. More than 90% of Cohort 2 participants treated for 24 weeks were still in treatment or follow-up; again 1 in each arm discontinued due to adverse events.
• In Cohort 1, all participants who completed therapy had undetectable HCV RNA at the end of treatment and no viral breakthroughs occurred.
• Among those treated for 12 weeks, 93% taking simeprevir/sofosbuvir and 96% taking simeprevir/sofosbuvir/ribavirin achieved SVR12; there was 1 relapser in each regimen arm.
• Among those treated for 24 weeks, SVR12 rates were 93% and 79%, respectively; there was 1 relapser and 4 people with "non-virological failure" in the ribavirin arm.
• In Cohort 2, all 14 participants who completed therapy had undetectable end-of-treatment viral load with no breakthroughs.
• 100% of both treatment-naive patients and null responders taking simeprevir/sofosbuvir who had adequate follow-up (7 of each) achieved SVR4, as did 100% of naive participants and 93% of null responders treated with simeprevir/sofosbuvir/ribavirin.
• In both cohorts, 100% of people with HCV subtype 1b or with subtype 1a but lacking the Q80K mutation achieved SVR12 or SVR4; 3 relapsers in Cohort 1 and 1 in Cohort 2 had subtype 1a with the mutation (SVR12 of 89% and SVR4 of 91%, respectively).
• Looking at the effect of adding ribavirin to the 12-week course of therapy for difficult-to-treat subgroups in both cohorts combined:
o Among people with unfavorable IL28B status, 96% taking either the ribavirin-sparing or ribavirin-containing regimen achieved SVR4;
o Among prior null responders, the SVR4 rate was 95% using either regimen;
o Among people with cirrhosis, SVR4 rates were 100% without and 91% with ribavirin.
• Treatment was generally safe and well tolerated.
• Among people treated for 12 weeks in both cohorts combined, there were no serious adverse events, grade 3-4 laboratory abnormalities, or discontinuations due to adverse events with either regimen.
• Among people treated for 24 weeks, serious adverse events were rare (3%-4%) and there were 2 discontinuations due to adverse events in both regimen arms.
• The most common side effects were fatigue, headache, nausea, and insomnia, which occurred with similar frequency in both the ribavirin-sparing and ribavirin-containing arms.
• Anemia and elevated bilirubin, however, were more common among ribavirin recipients.
Based on these findings, the researchers concluded that treatment with simeprevir plus sofosbuvir, with or without ribavirin, resulted in high SVR12 rates (79%-96%) in HCV genotype 1 null responders with stage F0-F2 fibrosis, as well as high SVR4 rates (96%-100%) in naive and null responder patients with stage F3 fibrosis or F4 cirrhosis.
Addition of ribavirin to simeprevir and sofosbuvir "may not be needed to achieve high rates of SVR in this patient population," they added. "12 weeks of treatment may confer similar SVR rates compared with 24 weeks of treatment."
A press release issued by Medivir went further, stating that the interim results "show no benefit from adding ribavirin to simeprevir and sofosbuvir."
Given last month's recommendation for approval of both simeprevir and sofosbuvir by a U.S. Food and Drug Administration advisory committee, Jacobson was asked about the prospect of using these drugs together off-label as an interferon-free regimen, especially for patients with advanced disease who need treatment now but cannot tolerate ribavirin.
"It's difficult to provide definitive guidance," Jacobson replied. "But all of us want to help our patients, and it's not difficult to imagine extrapolating from these data."
IM Jacobson, RM Ghalib, M Rodriguez-Torres, et al.SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. AbstractLB-3.
Medivir. Results from the COSMOS study with Simeprevir and Sofosbuvir in cirrhotic and non-cirrhotic HCV genotype 1 patients presented at AASLD. Press release. November 4, 2013.