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CROI 2013: Simeprevir + Sofosbuvir Demonstrates Good Early Cure Rate With or Without Ribavirin

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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 at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) last week 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 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 AB, plus Gilead Sciences' NS5B nucleotide analog polymerase inhibitor sofosbuvir (formerly GS-7977), with or without ribavirin.

With a large field of direct-acting agents racing through the development pipeline, several have been shown to 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 2 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, while Cohort 2 subsequently enrolled people with severe fibrosis (stage F3) or cirrhosis (stage F4).

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-logdecline in HCV RNA with prior interferon therapy. As is typical for null responders, almost all had unfavorable IL28B gene patterns associated with poor interferon response (70% CT and 24% TT), and 78% had the more difficult HCV subtype 1a. Liver biopsies within past 3 years revealed that 41% had absent-to-mild (F0-F1) and 59% had moderate (F2) fibrosis. People with hepatitis B or HIV coinfection were excluded.

Participants were randomly assigned to receive 150 mg once-daily simeprevir plus 400 mg once-daily sofosbuvir either in a dual combination or with 1000-1200mg/day weight-adjusted ribavirin taken twice daily. Further, they were randomized 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 patients are actually cured, as relapse may still occur after this point. U.S. and European regulatory authorities now consider sustained response at 12 weeks post-treatment (SVR12) to be a valid measure of treatment success.

Results

  • HCV viral load fell sharply after starting therapy in all treatment arms.
  • 85% of participants in the ribavirin-containing 12-week arm and 57% in the ribavirin-sparing 12-week arm achieved rapid virological response (RVR) at week 4.
  • Corresponding RVR 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.
  • 2 people in the 12-week treatment arms -- 1 on the ribavirin-containing regimen and 1 on the ribavirin-sparing regimen -- relapsed after finishing therapy.
  • SVR4 rates were 96% and 93%, respectively, and SVR8 rates remained the same.
  • All 24 participants who reached the 12-week post-treatment milestone achieved SVR12, and all 8 who reached the 24-week post-treatment point still had undetectable HCV (SVR24).
  • Among 11 people with sufficient follow-up data in the 24-week treatment arms, no relapses had occurred to date.
  • Treatment was generally safe and well-tolerated across treatment arms.
  • No serious adverse events were reported, but 2 participants discontinued early due to adverse events (1 in the 24-week ribavirin-containing arm and 1 in the 24-week ribavirin-sparing arm).
  • The most common side effects were fatigue (22%), headache (20%), insomnia (18%), and nausea (14%).
  • About 5% of participants 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 3-drug regimen overall.
  • Rates of anemia, however, clearly favored 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 plus sofosbuvir with or without ribavirin for 12 week yielded high SVR rates in prior null responders with mild-to-moderate fibrosis," the researchers concluded.

Lawitz explained that the 2 relapsers both had good adherence and took all drug doses, yet viral load rose steeply soon after stopping treatment. Both were obese men (1 white and 1 black) with HCV subtype 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, but there were no emergent sofosbuvir resistance mutations. Further analysis showed SVR8 rates of 100% for people with subtype 1b and for subtype 1a patients without the pre-existing Q80K mutation.

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.

3/11/13

Reference

E Lawitz, R Ghalib, M Rodriguez-Torres, et al. Suppression of Viral Load through 4 Weeks Post-Treatment Results of a Once-daily Regimen of Simeprevir + Sofosbuvir with or without Ribavirin in Hepatitis C Virus GT 1 Null Responders. 20th Conferenceon Retroviruses and Opportunistic Infections. Atlanta, abstract 155LB, 2013. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 155LB.

Other Source

Medivir. Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. Press release. March 6, 2013.