Simeprevir & sofosbuvir demonstrates good early cure rate with or without ribavirin

An all-oral combination of simeprevir plus sofosbuvir, with or without ribavirin, led to an early cure for most hard-to-treat prior null responders with genotype 1 hepatitis C studied in the phase 2a COSMOS trial, according to a presentation last week at the 20^th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.

The advent of direct-acting antiviral agents has brought about a new era of treatment for chronic hepatitis C virus (HCV) infection. Several new drug candidates have been shown to increase effectiveness when added to pegylated interferon and ribavirin, but many people with hepatitis C and their clinicians are awaiting regimens that omit interferon and its difficult side-effects.

Eric Lawitz from Alamo Medical Research in Texas presented interim findings from an open-label, exploratory phase 2a study looking at all-oral regimens containing simeprevir (formerly TMC435), a NS3/4A protease inhibitor being jointly developed by Janssen and Medivir, plus Gilead Sciences' NS5B polymerase inhibitor sofosbuvir (formerly GS-7977), with or without ribavirin.

With a large field of direct-acting agents speeding through the development pipeline, several have been shown work very well for easier-to-treat hepatitis C patients. The challenge now is to find regimens that are effective and tolerable for more difficult-to-treat groups, including prior null responders who saw little or no HCV RNA reduction with prior interferon-based therapy, and people with advanced liver disease.

COSMOS was designed to include two cohorts of prior null responders with genotype 1 HCV. Cohort 1 enrolled 80 people with absent-to-moderate fibrosis (Metavir stage F0 to F2) to evaluate initial safety, whilst the subsequent Cohort 2 enrolled people with severe fibrosis (stage F3) or cirrhosis (stage F4). The study excluded people with HIV or hepatitis B co-infection.

Just under two-thirds of participants in Cohort 1 were men, 71% were white, 29% were African American and the median age was 56 years. All had baseline viral load of at least 10,000 IU/ml and previously showed less than a 2-log₁₀ decline in HCV RNA with prior interferon therapy. As is typical for null responders, almost all had unfavourable IL28B gene patterns associated with poor interferon response (70% CT and 24% TT), and 78% had the more difficult HCV sub-type 1a. Liver biopsies within the past three years revealed that 41% had absent-to-mild (F0-F1) and 59% had moderate (F2) fibrosis.

Participants were randomly assigned to receive 150mg once-daily simeprevir plus 400mg once-daily sofosbuvir, either in a dual combination or with 1000 to 1200mg/day weight-adjusted ribavirin taken twice daily. Further, they were randomised to receive the dual or triple regimen for either 12 or 24 weeks.

Lawitz presented data from an interim analysis done when all Cohort 1 participants in the 12-week arms had been followed for a month after finishing therapy, allowing researchers to report rates of sustained virological response, or continued undetectable HCV RNA, at 4 weeks post-treatment (SVR4); 8-week post-treatment (SVR8) data were also presented. In addition, about half of participants in the 24-week treatment arms had reached the end of treatment and about one-third had SVR4/SVR8 results.

SVR4 is too soon to determine whether people are actually cured, as relapse may still occur after this point. European and US regulatory authorities now consider sustained response at twelve weeks post-treatment (SVR12) to be a valid measure of treatment success.

The researchers saw that HCV viral load fell sharply after starting therapy, with 85% in the ribavirin-containing 12-week arm and 57% in the ribavirin-sparing 12-week arm achieving rapid virological response (RVR) at week 4. Corresponding rates in the 24-week arms were 82 and 67%, respectively.

All participants (100%) in both 12-week arms had undetectable HCV RNA at the end of treatment, as did 83% in the ribavirin-containing and 90% in the ribavirin-sparing 24-week arms. No viral breakthroughs occurred during treatment.

Two people in the 12-week treatment arms – one on the ribavirin-containing regimen and one on the ribavirin-sparing regimen – relapsed after finishing therapy, producing SVR4 rates of 96 and 93%, respectively; SVR8 rates remained the same. All 24 participants who reached the 12-week post-treatment milestone achieved SVR12, and all eight who reached the 24-week point still had undetectable HCV (SVR24). Amongst the eleven people with sufficient follow-up in the 24-week treatment arms, no relapses had occurred to date.

Lawitz explained that the two relapsers both reported excellent adherence and took all drug doses, yet viral load rose rapidly soon after stopping treatment. Both were obese men (one white and one black) with HCV sub-type 1a and the IL28B TT pattern, and both had the Q80K simeprevir resistance mutation at baseline. One man also gained the D168E and I170T simeprevir resistance mutations during treatment, but there were no new sofosbuvir resistance mutations. Further analysis showed SVR8 rates of 100% for people with sub-type 1b and for sub-type 1a patients without the pre-existing Q80K mutation.

Treatment was generally safe and well tolerated across treatment arms. There were no serious adverse events reported, but two participants discontinued early due to adverse events (one in the 24-week ribavirin-containing arm and one in the 24-week ribavirin-sparing arm).

The most common side-effects were fatigue (22%), headache (20%), insomnia (18%) and nausea (14%). About 5% overall experienced grade 3-4 bilirubin elevations – only in the ribavirin-containing arms – while about 8% had grade 3-4 asymptomatic pancreatic amylase or lipase elevations.

Interestingly, within the 12-week treatment group side-effects appeared less frequent with the three-drug regimen overall. But rates of anaemia clearly favoured the ribavirin-sparing regimen: 11% and 25% of people taking the triple regimen for 12 and 24 weeks developed anaemia (including 10% who reduced their ribavirin dose), compared with none in the ribavirin-sparing arms.

"Simeprevir + sofosbuvir with or without ribavirin for 12 week yielded high SVR rates in prior null responders with mild-to-moderate fibrosis," the researchers concluded.

In this study SVR4 and SVR8 rates were high and nearly equal with or without ribavirin – which is known to help prevent relapse – despite higher early response rates in the triple-therapy arms. It is too soon to say ribavirin is not needed to achieve a cure, but SVR12 and SVR24 data so far are promising. Lawitz suggested that RVR may not necessarily be a predictive factor for sustained response with interferon-free treatment, as it is for interferon-based therapy.

Based on these interim findings, the second cohort of people with advanced fibrosis or cirrhosis was started and is now fully enrolled.