www.hivandhepatitis.com

HCV Polymerase Inhibitor Mericitabine Boosts Interferon/Ribavirin Cure Rate

A 24-week response-guided triple regimen consisting of Roche's NS5B polymerase inhibitor mericitabine plus pegylated interferon and ribavirin produced a greater likelihood of sustained viral suppression than a 48-week course of pegylated interferon/ribavirin alone, according to a report in the January 28, 2013, online advance edition of Hepatology.

Direct-acting antiviral agents (DAAs) that interfere with specific steps of the hepatitis C virus (HCV) lifecycle have ushered in a new era of treatment. While many patients and clinicians await all-oral regimens, some people with progressive liver disease do not have time to wait and may benefit from using DAAs with interferon.

Paul Pockros from the Scripps Clinic and fellow JUMP-C investigators conducted a Phase 2b trial comparing mericitabine (formerly RG7128) plus pegylated interferon/ribavirin versus standard therapy. Mericitabine is a selective nucleoside analog polymerase inhibitor that disables the enzyme that copies HCV's genetic material during viral replication.

This multicenterstudy included 166 treatment-naive chronic hepatitis C patients with hard-to-treat HCV genotypes 1 or 4. About 60% were men, three-quarters were white, 12% were black, and the average age was 50 years. About 60% had HCV subtype 1a (more difficult to treat) and 30% had subtype 1b. About one-quarter had advanced liver fibrosis or cirrhosis.

Participants were randomly assigned to receive 1000 mg mericitabine or placebo twice-daily in combination with pegylated interferon alfa-2a (Pegasys) and weight-adjusted ribavirin for 24 weeks. Within the mericitabine arm, those who experienced extended rapid virological response (RVR), or HCV RNA < 15 IU/mL from week 4 through 22, stopped all treatment at week 24. The rest continued on pegylated interferon/ribavirin alone through week 48.

The primary efficacy endpoint was sustained virological response (SVR), or continued undetectable HCV viral load 24 weeks after completing treatment. Results were previously presented in part at the 2011 EASL International Liver Congress.

Results

• At the end of triple therapy at 24 weeks, about 90% of mericitabine recipients had undetectable HCV RNA, compared with about 60% of those taking placebo.
• 60.5% of participants in the mericitabine group had extended RVR and were eligible to stop treatment at 24 weeks, as did 12.9% of placebo recipients.
• 56.8% of patients in the mericitabine arm and 36.5% in the standard therapy arm achieved SVR, a difference of 20.3%.
• SVR rates were higher for mericitabine recipients than placebo recipients when stratified by various factors:

o   Favorable CC IL28B host gene pattern: 77.8% vs 56.0%, respectively;

o   Unfavorable CT or TT pattern: 44.1% vs 16.2%, respectively;

o   Patients without liver cirrhosis: 63.3% vs 41.9%, respectively;

o   Patients with cirrhosis: 38.1% vs 21.7%, respectively.

• Post-treatment relapse rates were 27.7% in the mericitabine arm vs 32.0% in the placebo arm.
• The single participant with partial response showed no evidence of the S282T mutation associated with mericitabine resistance.
• Mericitabine triple therapy was generally safe and well-tolerated.
• The safety profile of mericitabine was similar to that of placebo and side effects were similar to those of people receiving standard therapy, including fatigue, headache, and nausea.
• About twice as many mericitabine recipients experienced serious adverse events (6.2% vs 3.5%), but fewer patients in this group discontinued treatment due to safety reasons.

Based on these findings, the researchers concluded, "A 24-week response-guided combination regimen of mericitabine 1,000 mg twice daily plus peginterferon alfa-2a/ribavirin is well tolerated and more effective than a standard 48-week course of peginterferon alfa-2a/ribavirin."

Mericitabine is also being studied in interferon-free combinations, but results to date have not been as impressive as those for some other regimens. Data from the MATTERHORN trial, presented at the 2012 AASLD Liver Meeting, showed that mericitabine helped reduce post-treatment relapse among hard-to-treat subtype 1a patients when used in a 24-week quadruple regimen with the HCV protease inhibitor danoprevir, pegylated interferon, and ribavirin.

2/12/13

Reference

PJ Pockros, D Jensen, N Tsai, et al (JUMP-C Investigators). JUMP-C: A randomized trial of mericitabine plus peginterferon alfa-2a/ribavirin for 24 weeks in treatment-naive HCV genotype 1/4 patients. Hepatology. January 28, 2012 (Epub ahead of print).