First Sustained Response Data for Polymerase Inhibitor Mericitabine

By Liz Highleyman

Hepatitis C virus (HCV) protease inhibitors will be the first direct-acting antivirals to emerge from the development pipeline, but polymerase inhibitors are not far behind. Mericitabine is a nucleoside analog NS5B RNA-dependent RNA polymerase inhibitor being developed by Roche/Genentech. The drug works by disabling an enzyme required to copy HCV RNA. Preclinical studies indicated that it has a high barrier to drug resistance.

Paul Pockros from the Scripps Clinic and colleagues designed the JUMP-C study to compare a response-guided therapy regimen of mericitabine plus pegylated interferon alfa-2a (Pegasys) and ribavirin versus standard therapy with pegylated interferon/ribavirin alone.

This Phase 2b trial included 166 previously untreated chronic hepatitis C patients with hard-to-treat HCV genotypes 1 or 4. About 60% were men, 78% were white, 12% were black, and the average age was 50 years. About 60% had HCV genotype 1a, 30% had 1b, and 6% had genotype 4. About one-quarter had advanced liver fibrosis or cirrhosis (Metavir stages F3-F4).

Participants were first randomly assigned to receive the mericitabine combination or standard therapy. Within the former group, those who experienced extended rapid virological response (eRVR, or HCV RNA < 15 IU/mL from week 4 to 22) received 1000 mg twice-daily mericitabine plus standard doses of pegylated interferon and ribavirin for 24 weeks. Those who did not achieve eRVR received 24 weeks of mericitabine triple therapy followed by a further 24 weeks of pegylated interferon/ribavirin alone. Everyone in the standard therapy control group received only pegylated interferon/ribavirin for 48 weeks.

Results

	At week 4, 63% of patients receiving mericitabine triple therapy achieved RVR, compared with just 14% in the standard therapy arm.
	At week 12, 89% of those taking mericitabine and 51% of those on standard therapy achieved early virological response.
	At week 24, 91% of mericitabine recipients and 62% of standard therapy recipients had undetectable HCV RNA.
	60% of participants in the mericitabine group had extended RVR were eligible to stop treatment at 24 weeks:
	76% of these patients still had undetectable HCV viral load 12 weeks after the end of treatment (sustained virological response or SVR-12); 24% experienced viral relapse by 12 weeks post-treatment.
	Triple therapy recipients who did not achieve extended RVR and patients in the standard therapy arm continued treatment; overall, 56% had undetectable HCV RNA at week 36, but treatment assignment remained blinded.
	SVR-12 rates for mericitabine recipients who stopped treatment at 24 weeks were similar regardless of IL28B gene pattern:
	CC (favorable): 80%; CT or TT (unfavorable): 72%.
	Safety and tolerability of mericitabine triple therapy were comparable to standard therapy.
	No side effects were significantly more or less common in the mericitabine group.
	Blood cell deficiencies and signs of impaired kidney function were uncommon in both groups.
	No resistance-associated variants were observed among mericitabine recipients.

"In this interim analysis, mericitabine plus [pegylated interferon/ribavirin] for 24 weeks was associated with very high rates of virological suppression (91%) and high SVR-12 (76%) in patients with eRVR (60%)," the researchers stated.

They added that mericitabine appeared to overcome the disadvantage of having an unfavorable IL28B gene pattern.

"A good safety and tolerability profile, strong antiviral potency and no evidence of resistance-related breakthrough makes mericitabine highly desirable for further study, including combinations with other [directing-acting antivirals]," they concluded.

Investigator affiliations:

Scripps Clinic Research Center, La Jolla, CA; Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL; Hawaii Medical Center, Honolulu, HI; University of Kansas Hospital Medical Center, Kansas City, KS; Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada; Ottawa Hospital, Ottowa, ON, Canada; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Infections Limited Hawaii, Honolulu, HI; Roche, Nutley, NJ; Genentech, South San Francisco, CA; Baylor College of Medicine, Houston, TX.

The JUMP-C study was funded by Roche.

4/5/11

Reference
P Pockros, D Jensen, N Tsai, et al. First SVR data with the nucleoside analogue polymerase inhibitor mericitabine (RG7128) combined with peginterferon/ribavirin in treatment-naive HCV G1/4 patients: interim analysis from the JUMP-C trial. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 421.