R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.
R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions.


CONCLUSIONS
A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway.
Pockros
Paul J
PJ
Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, CA 92037, USA.
Nelson
David
D
Godofsky
Eliot
E
Rodriguez-Torres
Maribel
M
Everson
Gregory T
GT
Fried
Michael W
MW
Ghalib
Reem
R
Harrison
Stephen
S
Nyberg
Lisa
L
Shiffman
Mitchell L
ML
Najera
Isabel
I
Chan
Anna
A
Hill
George
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003562:Cytidine / Q000031:analogs & derivatives / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D009705:Nucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009705:Nucleosides; D011355:Prodrugs; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D003562:Cytidine; D000410:Alanine Transaminase; C508950:4'-azidocytidine; C100416:peginterferon alfa-2a; C530825:balapiravir