The failure of any patients treated with the HCV polymerase inhibitor, valopicitabine (NM283), in combination with pegylated IFN-α-2a, to achieve a SVR, in a key Phase IIb clinical trial, proved to be disappointing news for EASL delegates.
Nezam Afdhal (Beth Israel Deaconess Medical Center, Boston, MA, USA) reported results of 178 genotype-1 nonresponders to previous combined pegylated IFN-α and ribavirin therapy.
The five-arm study, which compared pegylated IFN-α-2a and valopicitabine in doses of 400 or 800 mg/day, or valopicitabine 800 mg monotherapy for 48 weeks, with conventional treatment with pegylated IFN-α-2a and ribavirin, had already been adapted following severe gastrointestinal side effects in patients on valopicitabine 800 mg. Patients on this maximum dose of the polymerase inhibitor were reassigned to the 400-mg dose. At this stage, all patients in this arm of the study had completed 40 weeks of treatment.
Despite promising earlier reductions in viral load, no SVRs were achieved in any of the valopicitabine treatment arms, 24 weeks after the end of treatment. Less than a quarter of patients completed treatment, mainly as a result of failure to reach earlier efficacy end points, or as a result of adverse events.
Afdhal concluded that future treatment for previous nonresponders with pegylated IFN-α and valopicitabine will require combinations of novel and complementary agents to achieve optimal outcomes, and he reported that a further Phase II study of triple therapy with pegylated IFN-α, ribavirin and valopicitabine is due to be completed in the next few months.
A key study of valopicitabine in treatment-naive, genotype-1 patients was also reported at the congress. Data from the 48 weeks of the Phase IIb trial of pegylated IFN-α and valopicitabine 200, 400--800 or 800 mg/day, added at a variety of different time points, were presented, but further follow-up is required before SVR results are available.
As in the nonresponder study, patients originally randomized to the 800 mg dose of valopicitabine were rerandomized (to 200 or 400 mg), owing to severe gastrointestinal side effects with the higher doses, when two-thirds of patients had reached week 12 of the study.
More patients completed therapy than in the nonresponder trial -- 44% in the original valopicitabine 800-mg arms and 62% of those treated with 200 mg. Of the patients in the higher-dose arms, 24% discontinued therapy, as did 9% of those in the 200-mg group, owing to side effects.
Efficacy data were presented for patients according to whether they were originally randomized to a treatment arm including valopicitabine 800 mg or valopicitabine 200 mg. In the valopicitabine 800 mg plus pegylated IFN-α group, 50, 47 and 38% were negative for HCV at 12, 24 and 48 weeks, respectively. This compared with 44, 62 and 53% of the valopicitabine 200 mg plus pegylated IFN-α group, respectively.
Eric Lawitz (Alamo Medical Research, San Antonio, TX, USA) concluded that the current end of treatment data suggest a durable antiviral effect of valopicitabine combined with pegylated IFN-α in treatment-naive, genotype-1 patients, and that the 200 mg dose of valopicitabine was better tolerated than the higher dose.
Future Virology. 2007;2(4):331-334. © 2007 Future Medicine Ltd.
Cite this: Where Next for the Treatment of Hepatitis C? - Medscape - Jul 01, 2007.