Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.

Abstract

BACKGROUND:

The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease.

METHODS:

This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8).

RESULTS:

In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group.

CONCLUSIONS:

Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

• Authors: Joep de Bruijne, Andre van Vliet, Christine J Weegink, Włodzimierz Mazur, Alicja Wiercinska-Drapało, Krzysztof Simon, Grażyna Cholewińska-Szymańska, Judit Kapocsi, István Várkonyi, Xiao-Jian Zhou, Marie-Francoise Temam, Jeffrey Molles, Jie Chen, Keith Pietropaolo, Joseph F McCarville, John Z Sullivan-Bólyai, Douglas Mayers, Hendrik Reesink
• Journal: Antiviral therapy (Antivir Ther) Vol. 17 Issue 4 Pg. 633-42 ( 2012) ISSN: 2040-2058 [Electronic] England
• PMID: 22427481 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• IDX320
• Macrocyclic Compounds
• Protease Inhibitors
• RNA, Viral

Topics

• Adolescent
• Adult
• Antiviral Agents (administration & dosage, blood, pharmacokinetics, therapeutic use)
• Area Under Curve
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Viral (drug effects)
• Genotype
• Half-Life
• Hepacivirus (drug effects, enzymology, genetics)
• Hepatitis C, Chronic (drug therapy)
• Humans
• Macrocyclic Compounds (administration & dosage, blood, pharmacokinetics, therapeutic use)
• Male
• Middle Aged
• Protease Inhibitors (administration & dosage, blood, pharmacokinetics, therapeutic use)
• RNA, Viral (blood)
• Young Adult