InterMune Inc. (ITMN)

[ghmm]

ITMN-191 Phase 1b

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
N. Forestier1; D. G. Larrey2; D. Guyader3; P. Marcellin4; R. Rouzier5; A. A. Patat6; W. Z. Bradford7; S. Porter7; S. Zeuzem1
1. J.W. Goethe Universität, Frankfurt, Germany.
2. CHU , Montpellier, France.
3. Pontchaillou Hospital, Rennes, France.
4. Hôpital Beaujon, Clichy, France.
5. Centre CAP, Montpellier, France.
6. Biotrial, Rennes, France.
7. Intermune, Inc, Brisbane, CA, USA.


Background: ITMN-191 is an oral, highly potent, selective inhibitor of the HCV NS3/4A serine protease. Emerging evidence suggests combination regimens including direct inhibitors of viral enzymes will improve virologic response rates relative to the current standard of care. In order to identify doses for subsequent studies of ITMN-191-based combination regimens, we evaluated the safety, pharmacokinetics, and effects on plasma HCV RNA of multiple ascending doses of ITMN-191 in patients with chronic HCV infection.

Methods: In a double-blind, randomized, placebo-controlled study, 4 cohorts of treatment-naïve HCV genotype 1 patients and one cohort of non-responders (NR) were randomized to receive ITMN-191 or matched placebo for 14 days. Cohorts consisted of 8 and 2 patients receiving ITMN-191 and placebo, respectively. Patients were sequestered in a Phase 1 unit for 16 days and completed standardized clinical and laboratory evaluations.

Results: Fifty patients were randomized and all completed the study. ITMN-191 was safe and well-tolerated. Adverse events were generally mild and transient and without association to treatment group or dose level. A single serious adverse event of benign paroxysmal positional vertigo was observed in a patient with a history of similar symptoms. The event was deemed unrelated to study drug and resolved rapidly without study drug discontinuation. ITMN-191 reduced HCV RNA in a dose dependent manner with both q8 and q12 hour schedules; reductions occurred rapidly and were typically sustained through day 14. Viral variants with reduced drug sensitivity were observed in the subset of patients that experienced virologic rebound but not in those who experienced a continual decline in HCV RNA.

Conclusion: ITMN-191 was safe and well tolerated. Treatment resulted in rapid and sustained reductions in HCV RNA, with a median reduction at day 14 of 3.8 log10 in patients receiving 200 mg q8h. Treatment response was lower in the NR cohort; this observation will inform regimen selection in future studies in this population. Based on these findings, a Phase 1b study to assess the safety and efficacy of ITMN-191 in combination with peginterferon α-2a plus ribavirin is currently underway.

 
 Change from baseline in Log10 (IU/mL) HCV RNA 
 Cohort 	        Dose            N               Median Change 
                                                 HCV RNA Log10 (IU/mL) 
                                                 Day 14 
 P (naïve)       Placebo         8               0.0 
 P (NR)          Placebo         2               0.0 
 1 (naïve)       100 mg q12h     8               -0.7 
 2 (naïve)       100 mg q8h      8               -1.7 
 3 (naïve)       200 mg q12h     5               -3.1 
 4 (naïve)       200 mg q8h      8               -3.8 
 5 (NR)          300 mg q12h     8               -2.5