The limited efficacy and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection have spurred investigators to study several novel drugs that directly target various stages of the viral lifecycle -- an approach known as "STAT-C."

In a set of presentations at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers reported data on one such agent, InterMune and Roche's investigational HCV NS3/4A serine protease inhibitor ITMN-191 (also known by its Roche designation, R7227).

Healthy Volunteers

A Phase 1a single-ascending-dose (SAD) study in healthy volunteers demonstrated that ITMN-191 was safe and well-tolerated when given to 64 HCV negative adults at single doses ranging from 2 to 1600 mg (poster 871).

The pharmacokinetics of ITMN-191 were linear over a dose range of 100 to 800 mg, and administration with food increased the expected trough and overall concentrations by 40%-50% compared with an empty stomach. This food effect has led InterMune and Roche to explore lower doses in subsequent clinical trials.

Adverse events (AEs) were generally mild and transient, and were similar between treatment groups -- with the exception of a higher frequency of mild diarrhea and abdominal pain in the highest-dose (1600 mg) ITMN-191 group. No serious AEs or clinically significant laboratory or ECG abnormalities were reported.

Intermune, Inc, Brisbane, CA; ICPD/Ordway Research Institute, Inc., Albany, NY; Biotrial, Rennes, France.

Monotherapy in Genotype 1 Patients

A randomized Phase 1b multiple ascending dose (MAD) study assessed ITMN-191 in 4 cohorts of treatment-naive patients with HCV genotype 1, plus 1 cohort of genotype 1 prior non-responders (poster 1847). A total of 50 participants received ITMN-191 as monotherapy at doses of up to 600 mg, or else placebo, for 14 days.

ITMN-191 reduced HCV RNA in a dose-dependent manner when administered every 8 or every 12 hours. Viral load reductions occurred rapidly and were typically sustained through day 14. The greatest median decrease in HCV RNA -- 3.8 log10 -- was seen in patients receiving 200 mg every 8 hours.

In the exploratory non-responder cohort, participants who failed to achieve at least a 2.0 log10 reduction in HCV RNA with prior standard-of-care therapy, or who still had detectable HCV RNA after 24 weeks of treatment, received ITMN-191 at a dose of 300 mg every 12 hours (twice-daily). By day 14, viral load fell by a median 2.5 log10.

ITMN-191 appeared safe and well-tolerated. AEs were generally mild and transient and did not correlate with dose level. A single serious AE (benign paroxysmal positional vertigo) was observed, but was deemed unrelated to the study drug. Resistance mutations were detected in patients who experienced virological rebound, but not those with a continued decline in HCV RNA.

JW Goethe Universität, Frankfurt, Germany; CHU, Montpellier, France; Pontchaillou Hospital, Rennes, France; Hôpital Beaujon, Clichy, France; Centre CAP, Montpellier, France; Biotrial, Rennes, France; Intermune, Inc, Brisbane, CA.

ITMN-5489

Intermune also presented very early data on a new agent, ITMN-5489, another NS3/4A protease inhibitor (poster 1909). The performance characteristics of this non-macrocyclic compound compared favorably with those of ITMN-191.

In laboratory studies, ITMN-5489 had a 50% effective concentration (EC50) of approximately 1 nM against a genotype 1b HCV replicon model, and 81 nM produced replicon clearance in 14 days. ITMN-5489 exhibited significant stability in liver cells derived from rats, monkeys, and humans. The drug's plasma concentration 24 hours after dosing was higher than the concentration of ITMN-191 after 12 hours, and the overall area under the curve was 5- to 10-fold higher, suggesting that once-daily dosing of ITMN-5489 may be feasible.

Intermune, Inc, Brisbane, CA.

11/14/08

References

N Forestier, DG Larrey, D Guyader, and others. Treatment of Chronic Hepatitis C Virus (HCV) Genotype 1 Patients with the NS3/4A Protease Inhibitor ITMN-191 Leads to Rapid Reductions in Plasma HCV RNA: Results of a Phase 1b Multiple Ascending Dose (MAD) Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1847.

WZ Bradford, C Rubino, S Porter, and others. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics (PK) of Single Ascending Oral Doses of the NS3/4A Protease Inhibitor ITMN 191 in Healthy Subjects. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1871.

BO Buckman, L Pan, L Huang, and others. Identification of Novel Non-Macrocyclic Inhibitors of HCV NS3/4A Serine Protease Activity. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1909.

Other source
InterMune, Inc. InterMune to Present Four Abstracts on HCV Protease Inhibitor ITMN-191 at the AASLD Meeting. Press release. September 24, 2008.