When interferon-based treatment does not appear to be working in patients with hepatitis C virus (HCV) infection, a new once-daily, antiviral oral treatment might be the answer. NM283 (Idenix Pharmaceuticals), which passed its first human clinical trial with flying colors, metabolizes to a form that inhibits HCV RNA polymerase.
In a multicenter trial, 82 patients completed treatment; 68 patients received NM283 and 14 received placebo. All of the patients had chronic HCV infection (genotype 1 strain) and either had not received previous treatment or had not responded to interferon-based therapy.
The groups receiving antiviral therapy were divided into cohorts of 12 patients each. In each group, two received placebo and 10 received the drug at 50, 100, 200, 400, or 800 mg once daily, and one group received 200 mg twice a day.
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Tolerance of higher daily doses was studied in two more cohorts: one patient initially received NM283 at 100 mg/day, advancing progressively to 800 mg/day for the second week of the clinical trial. The second cohort initially received NM283 at 400 mg/day, advancing progressively to 800 mg/day for the second week of the clinical trial. Antiemetic treatment was given together with NM283 for the first two days and for one day in conjunction with each of the two dose escalations.
NM283 consistently reduced serum HCV RNA in a dose-related manner. Patients who had the highest cumulative dose over 15 days experienced the greatest antiviral effect, with a mean HCV RNA reduction of 92%. In this dosing group, HCV RNA decreased in all 10 patients, by 79% to 99%. Nine of the 10 patients had not responded to earlier interferon-based therapies.
For the three highest-dose groups in the clinical trial, antiviral responses over the 15 days of treatment exceeded the average reduction in serum viral level observed in hepatitis C patients who respond to treatment with the current standard of therapy, generic ribavirin plus peg-ylated interferon.
At the higher doses, some patients had mild-to-moderate gastrointestinal side effects, but these usually appeared in the first two days of treatment and typically resolved quickly. None of the patients changed or stopped treatment because of side effects.
NM283 was well absorbed during treatment. There was no significant drug accumulation; drug levels on the 15th day were comparable to those of the first day.
The once-daily 800-mg cohort is ongoing. The next clinical trial will evaluate NM283 combined with pegylated inter-feron over four weeks. Longer-term trials of NM283 are expected later this year.