PROPEL: A randomized trial of mericitabine plus peginterferon alpha‐2a/ribavirin therapy in treatment‐naïve HCV genotype 1/4 patients

Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment‐naïve HCV genotype 1 or 4 patients were randomized to double‐blind treatment with oral mericitabine at a dosage of 500 mg twice‐daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), o...

Full description

Saved in:
Bibliographic Details
Published inHepatology (Baltimore, Md.) Vol. 58; no. 2; pp. 524 - 537
Main Authors Wedemeyer, Heiner, Jensen, Donald, Herring, Robert, Ferenci, Peter, Ma, Mang‐Ming, Zeuzem, Stefan, Rodriguez‐Torres, Maribel, Bzowej, Natalie, Pockros, Paul, Vierling, John, Ipe, David, Munson, Marie Lou, Chen, Ya‐Chi, Najera, Isabel, Thommes, James
Format Journal Article
LanguageEnglish
Published United States Wolters Kluwer Health, Inc 01.08.2013
Subjects
Adolescent
Adult
Aged
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Deoxycytidine - therapeutic use
Dose-Response Relationship, Drug
Double-Blind Method
Drug Therapy, Combination
Female
Genotype
Hepacivirus - genetics
Hepatitis C, Chronic - drug therapy
Hepatology
Humans
Interferon-alpha - pharmacology
Interferon-alpha - therapeutic use
Interferons
Interleukins - genetics
Male
Middle Aged
Polyethylene Glycols - pharmacology
Polyethylene Glycols - therapeutic use
Recombinant Proteins - pharmacology
Recombinant Proteins - therapeutic use
Ribavirin - pharmacology
Ribavirin - therapeutic use
RNA, Viral - drug effects
RNA, Viral - genetics
Treatment Outcome
Young Adult
Online AccessGet full text
ISSN0270-9139
1527-3350
1527-3350
DOI10.1002/hep.26274

Cover

More Information
Summary:Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment‐naïve HCV genotype 1 or 4 patients were randomized to double‐blind treatment with oral mericitabine at a dosage of 500 mg twice‐daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha‐2a (Peg‐IFNα‐2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A‐C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A‐E) continued Peg‐IFNα‐2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow‐up; SVR‐24). VR rates were higher in arms A‐D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non‐CC IL28B genotypes. However, the overall SVR‐24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response‐guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine‐resistance mutations (S282T) were observed during mericitabine therapy. Conclusion: Treatment with mericitabine plus Peg‐IFNα‐2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN‐free and IFN‐containing trials of mericitabine of longer treatment duration are ongoing. (HEPATOLOGY 2013;58:524–537)
Bibliography:Potential conflict of interest: Heiner Wedemeyer – Consulting: Roche, MSD, Gilead, Bristol ‐ Myers Squibb, Novartis, Transgene, Abbott, Janssen ‐ Ciliag; Advisory arrangements: Roche, MSD, Gilead, Bristol ‐ Myers Squibb, Novartis, Transgene, Abbott, Janssen ‐ Ciliag; Speakers' bureau: Roche, MSD, Gilead, Bristol ‐ Myers Squibb, Novartis, Transgene, Abbott, Janssen ‐ Ciliag; Grants/contracts: research: Roche, MSD, Gilead, Bristol ‐ Myers Squibb, Novartis, Transgene, Abbott, Janssen ‐ Ciliag; Travel grants: Roche, MSD, Gilead, Bristol ‐ Myers Squibb, Novartis, Transgene, Abbott. Donald Jensen – Consulting: Abbott, Bristol ‐ Myers Squibb, Boehringer Ingelheim, Genentech/Roche; Tibotec/J&J, Astex, Biotica, Vertex, Gilead/Pharmasset, Inhibitex, Merck; Grants/contracts: research: Abbott, Bristol ‐ Myers Squibb, Boehringer Ingelheim, Genentech/Roche; Tibotec/J Other interests: Consensus Medical Communications, Clinical Care Options. Peter Ferenci – Consulting: Roche, Vertex, Tibotec, MSD; Advisory arrangements: Roche, Vertex, Tibotec, MSD; Speakers' bureau: Roche, MSD; Grants/contracts: unrestricted: Roche, MSD; Travel grants: Roche. Stefan Zeuzem – Consulting: Roche; Advisory arrangements: Roche; Speakers' bureau: Roche. Maribel Rodriguez ‐ Torres – Consulting: Akros Pharmaceutical, Bristol ‐ Myers Squibb, Genentech, Hoffman ‐ La Roche, Inhibitex, Janssen R&D Ireland, Merck Sharp & Dohme Corp., Pharmasset, Santaris Pharma. A/S, Vertex Pharmaceutical Inc.; Grants/contracts: research: Abbott Laboratories, Akros Pharmaceutical, Anadys Pharmaceutical, Beckman Coulter, Beohringer Ingelheim, Bristol ‐ Myers Squibb, Genetech, Gilead Pharmaceuticals, GlaxoSmithKline, Hoffman ‐ La Roche, Human Genome Sciences, Idenix Pharmaceutical, Idera Pharmaceutical, Inhibitex, Johnson & Johnson, Merck Sharp & Dohme Corp., Mochida Pharmaceutical, Novartis, Pfizer, Pharmasset, Santaris Pharma. A/S, Scynexis, Inc., Siemens Healthcare Diagnostics, Vertex Pharmaceutical Inc., Zymogenetics. Natalie Bzowej – Consulting: Abbott, Zymogenetics; Advisory arrangements: Gilead, Vertex; Grants/contracts: research: Bristol ‐ Myers Squibb, Eiger, Gilead, Pharmasset, Roche/Genentech, Vertex, Zymogenetics. Paul J. Pockros – Consulting: Genentech, Vertex, Merck; Advisory arrangements: Genentech, Vertex, Merck; Speakers' bureau: Genentech, Vertex, Merck; Grants/contracts: research: Genentech, Vertex; Grants/contracts: unrestricted: Genentech, Vertex, Merck. John M. Vierling – Consulting and advisory arrangements: Abbott, Bristol ‐ Myers Squibb, Excalenz, Gilead, GlobeImmune, HepQuant, Hyperion, Immuron, Janssen, Novartis, Roche, Schering (now Merck), Salix, Sundise, Vertex, HepaLife Technologies, Herbalife, Ocera; Speakers' bureau: Chronic Liver Diseases Foundation; Grants/contracts: research: Abbott, Bristol ‐ Myers Squibb, Conatus, Excalenz, Gilead, GlobeImmune, Hyperion, Idenix ‐ Novartis, Ikaria, Intercept, Merck (formerly Schering), Mochida, Novartis, Ocera, Pfizer, Pharmasset, Roche, Sundise, Vertex, Zymogenetics. David Ipe – employee of Genentech. Marie Lou Munson – employee of Genentech. Ya ‐ Chi Chen – employee of Roche. Isabel Najera – Stock ownership or equity: Roche; employee of Roche. James Thommes – Medical Director at Genentech.
See Editorial on Page
Additional PROPEL Investigators are listed in the Appendix.
488
This research was funded by F. Hoffmann‐La Roche Ltd. Support for third‐party writing assistance for this manuscript was provided by F. Hoffmann‐La Roche Ltd.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
ObjectType-Article-2
ObjectType-Feature-1
content type line 23
ObjectType-Undefined-3
ISSN:0270-9139
1527-3350
1527-3350
DOI:10.1002/hep.26274