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EASL 2014: Sofosbuvir + Simeprevir Shows High Cure Rates for Hep C Patients with or without Cirrhosis

A 12-week oral regimen of sofosbuvir (Sovaldi) plus simeprevir (Olysio) without pegylated interferon or ribavirin led to sustained virological response in 93% of genotype 1 hepatitis C patients with either absent to moderate liver fibrosis or with advanced fibrosis or cirrhosis, according to data from the COSMOS trial presented last week at the 49th EASL International Liver Congress in London.

Researchers are still learning about predictors of response to direct-acting antivirals for hepatitis C, but some of the traditional factors that predicted good response to interferon-based therapy no longer play a major role and some may become unimportant.

The Phase 2 COSMOS trial enrolled 2 cohorts of genotype 1 chronic hepatitis C patients traditionally considered hard to treat. Cohort 1 included 80 prior null responders -- people who saw little or no drop in HCV RNA with previous interferon-based therapy -- who had absent to moderate fibrosis. Cohort 2 included 87 previously untreated patients and prior null responders with advanced fibrosis or compensated cirrhosis.

In this open-label study participants were randomly assigned to receive sofosbuvir (150 mg once-daily) plus simeprevir (400 mg once-daily), taken either with or without weight-based ribavirin, for either 12 or 24 weeks.

Gilead Sciences' nucleotide HCV polymerase inhibitor sofosbuvir was approved in the U.S. in December 2013 and in the European Union in January 2014. Janssen's HCV protease inhibitor simeprevir, also approved in the U.S. late last year, is expected to receive European approval next month.

Although the drugs' official indications do not include use together in interferon-free regimens, recent guidelines issued by both U.S. (AASLD/IDSA/IAS-USA) and European (EASL) liver disease experts recommend this combination for people with HCV genotypes 1 or 4 who are unable or unwilling to take interferon.

Cohort 1

Mark Sulkowski from Johns Hopkins presented findings from a sub-analysis of Cohort 1, looking at the effect of predictive factors including HCV subtype 1a vs 1b, presence of viral resistance mutations, patients' IL28B status, and fibrosis stage.

About 60% of Cohort 1 participants were men, 71% were white, 29% were black, and the median age was 56 years. Approximately three-quarters had harder-to-treat subtype 1a, and 39% of these had the Q80K resistance variant at baseline. As is typical of null responders, most (94%) had unfavorable IL28B non-CC patterns associated with poor interferon responsiveness. About 40% had absent (Metavir stage F0) or mild (stage F1) fibrosis and 60% had moderate fibrosis (stage F2).

As previously reported at least year's AASLD Liver Meeting, 93% of participants taking simeprevir/sofosbuvir alone and 96% taking simeprevir/sofosbuvir plus ribavirin for 12 weeks achieved sustained virological response at 12 weeks after finishing treatment (SVR12). Among those treated for 24 weeks, SVR12 rates were 93% and 79%, respectively.

Sulkowski presented stratified data excluding a small number of participants with "non-virological failure" such as loss to follow-up.

Results

• There was 1 relapser in each of the 12-week arms and 1 in the 24-week triple therapy arm.
• HCV subtype: all participants with genotype 1b achieved SVR12 in all treatment arms, as did 100% of those with genotype 1a lacking the Q80K resistance variant at baseline; among genotype 1a patients with pre-existing Q180K, however, SVR12 rates were 83%-89%.
• IL28B status: everyone in all treatment arms with either the most favorable CC variant or the intermediate CT variant achieved SVR12; among those with the least favorable TT variant, the overall cure rate was 83%, falling to 67% among those assigned to 12-week dual therapy.
• Fibrosis stage: cure rates were high across the board, with 97% of people with stage F0-F1 and 96% of those with stage F2 achieving SVR12; there were no notable differences according to dual vs triple therapy or 12 vs 24 weeks duration.

Rapid virological response (RVR), or reaching undetectable viral load by week 4 of treatment, was a strong predictor of sustained response when using interferon-based therapy. Here, 76% of participants overall experienced RVR, of whom 95% went on to achieve SVR12 -- but so did 100% of patients without RVR. However, people taking dual therapy did appear to have a slower initial response than those who added ribavirin, with RVR rates of 57%-69% vs 80%-85% with triple therapy.

"SVR12 rates were high regardless of baseline characteristics," the researchers concluded. "On-treatment virological response, including RVR, was not predictive of SVR."

Cohort 2

Eric Lawitz from the University of Texas Health Science Center presented late-breaking findings from COSMOS Cohort 2. Because people with advanced fibrosis or cirrhosis are at greater risk for treatment failure, this cohort was started later after investigators saw high response rates in Cohort 1.

About two-thirds of Cohort 2 participants were men, 91% were white, 9% were black, and the median age was 58 years. (People over age 70 were excluded, but Lawitz said he would not do this again in the future.) Again, 78% had subtype 1a, 40% with the Q80K mutation. About half were prior null responders and 79% had unfavorable non-CC IL28B variants. Just over half had advanced fibrosis (stage F3) and 47% had compensated cirrhosis (stage F4).

Results

• Sustained response rates in Cohort 2 were similar to those of people with less advanced liver disease in Cohort 1.
• 93% of participants assigned to simeprevir/sofosbuvir either alone or with ribavirin for 12 weeks achieved SVR12; among those treated for 24 weeks, SVR12 rates were 93% and 100%, respectively.
• Everyone treated for 24 weeks was cured regardless of HCV subtype; in the 12-week treatment arms, 2 genotype 1a patients without the Q80K baseline mutation and 1 with the mutation relapsed.
• 2 people (both in the 24-week triple therapy arm) had non-virological failure.
• People with all IL28B variants had SVR12 rates greater than 90%, with no clear pattern.
• Overall SVR12 rates were 98% for people with advanced fibrosis and 95% for those with cirrhosis.
• There were 3 relapsers, all treated for 12 weeks (2 with and 1 without ribavirin); 2 of the relapsers had cirrhosis (1 a prior null responder, the other treatment-naive).
• Treatment was generally safe and well-tolerated even for patients with advanced liver disease.
• There were 4 serious adverse events and 1 discontinuation for this reason.
• The most common side effects were fatigue, headache, and nausea.
• 13% of participants developed anemia, all but 1 in the ribavirin-containing arms.

Again, the researchers concluded that SVR12 rates were high, regardless of baseline characteristics, and that extent of liver fibrosis/cirrhosis and prior treatment history did not play a role.

The current package insert for simeprevir states that pre-treatment testing for the Q80K variant is "strongly recommended," but this may be unnecessary when using it with other direct-acting antivirals. "As we enter the world of multiple DAAs, additional DAAs should cover Q180K, so don’t need to test for it," Lawitz said.

Given that ribavirin adds side effects but did not appear to improve efficacy, a pair of Phase 3 trials testing sofosbuvir/simeprevir alone -- OPTIMIST-1 for non-cirrhotics and OPIMIST-2 for people with cirrhosis -- are now recruiting. Since 12 weeks of treatment was highly effective in COSMOS, the new studies will compare 8 vs 12 weeks to see if treatment can safely be shortened to just 2 months.

4/13/14

References

M Sulkowski, IM Jacobson, R Ghalib, et al. Mangia A et al. Once-daily simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 prior null responders with Metavir F0-2: COSMOS study subgroup analysis. 49th Annual Meeting of the European Association for the Study of the Liver (EASL 2014). London, April 9-13, 2014. Abstract 07.

E Lawitz, R Ghalib, M Rodriguez-Torres, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCVgenotype 1 prior null-responder/treatment-naive patients (COSMOS study): primary endpoint (SVR12) results in patients with Metavir F3-4 (Cohort 2). 49th Annual Meeting of the European Association for the Study of the Liver (EASL 2014). London, April 9-13, 2014. Abstract O165.

Other Sources

Janssen. Final Data from the Phase 2 COSMOS Study of Janssen’s Once-Daily Simeprevir in Combination with Sofosbuvir Presented at The International Liver Congress 2014 of the European Association for the Study of the Liver (EASL). Press release. April 12, 2014.

Janssen Initiates Phase 3 OPTIMIST Trials of Once-Daily Simeprevir in Combination with Once-Daily Sofosbuvir for the Treatment of Genotype 1 Chronic Hepatitis C.Press release. April 2, 2014.