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Publishing ID: 407 Abstractid ID: 107531
A Phase I/II Dose Escalation Trial Assessing Tolerance, Pharmacokinetics, and Antiviral Activity of NM283, a Novel Antiviral Treatment for Hepatitis C
Eliot Godofsky, Nezam H. Afdhal, Vinod Rustgi, Lawton Shick, Lael Duncan, Xiao-Jian Zhou, George Chao, Christopher Fang, Barbara Fielman, Maureen Myers, Nathaniel Brown
Background: Current therapy for hepatitis C has many side effects and induces a sustained virologic response in fewer than half of patients infected with hepatitis C virus (HCV) genotype 1, the most common genotype (60-70% of patients) in the USA, Europe and Japan. NM283, a novel candidate HCV RNA polymerase inhibitor, has anti-flavivirus activity that is highly synergistic with interferon-α in vitro, and suppresses viremia in chimpanzees chronically infected with human-derived HCV-1 (Standring, EASL2003). Here we report the first clinical data for NM283 in humans. Methods: A phase I/II dose escalation trial is investigating NM283 in the range 50-800 mg/day. Subjects are treatment-naïve or experienced adults with HCV-1 associated chronic hepatitis C, with baseline serum HCV RNA >5 log10. For each dose, 12-patient cohorts are randomized 10:2 to receive NM283 or placebo for 15 days with 14 days of follow-up. Results: Dosing cohorts of 50, 100, 200, and 400 mg/day, involving 48 patients, have been completed with once-daily oral dosing. Dose-related decreases in serum HCV RNA at Day 16 were observed, ranging from a mean 0.15 log10 at the lowest dose (50 mg/day) to 0.73 log10 at 400 mg/day, which is about half of the anticipated clinical dose. Tolerance of study treatment has been satisfactory, with no serious adverse events, dose-limiting toxicities, or pattern of laboratory abnormalities. At 400 mg/day, some NM283-treated patients experienced transient mild nausea (5/10) or vomiting (2/10) on Day 1, but all patients completed treatment without modification. NM283 is well-absorbed, with dose-proportional plasma exposure. Final data concerning higher NM283 doses will be reported at the conference. Conclusions: NM283 exhibits consistent antiviral activity with satisfactory tolerance and linear pharmacokinetics in HCV-1 infected chronic hepatitis C patients. Expanded testing of NM283, alone and in combination with peg-interferon, is anticipated. |
