Experimental HCV Polymerase Inhibitor GS 9190 Shows Promising Antiviral Activity but Possible Cardiac Side Effects in Phase 1 Study

There is a pressing need for novel agents for the treatment of chronic hepatitis C, especially new compounds with more potent activity against hepatitis C genotype 1 and a more favorable toxicity profile compared with pegylated interferon plus ribavirin.

GS 9190 is an experimental non-nucleoside HCV NS5b polymerase inhibitor that has shown potent antiviral activity in laboratory studies. Initial results from an ongoing single-dose/multiple-dose escalation clinical trial of GS 9190 in HCV-infected volunteers were reported at the 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007).

Study GS 196-0101 is a randomized, double-blind, placebo-controlled trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antiviral activity of single (in Part A) and multiple (in Part B) doses of GS 9190 in treatment-naive patients chronically infected with HCV genotype 1 and without liver cirrhosis.

Part A (completed at the time of presentation) included 31 participants; 5 successive cohorts of 6 subjects each were randomly assigned in a 5:1 manner to receive single ascending doses of GS 9190 (40, 120, 240, 240 mg dosed with food, or 480 mg) or placebo. The participants were mostly men (65%), mostly Caucasian (81%), and had a mean age of about 44 years. They were infected with HCV genotype 1a (77%) or 1b (19%), and the median baseline HCV viral load was 6.6 log₁₀ IU/mL (range 5.2-7.3 log₁₀).

Part B (ongoing at the time of presentation) included 23 participants; 4 successive cohorts of 12 subjects each were randomized in a 10:2 manner to receive multiple ascending doses of GS 9190 (40, 120, or 240 mg twice daily, or 240 mg once daily) or placebo over 8 days. Baseline patient characteristic were similar to those in Part A.

Results from Part A

• All single doses of GS 9190 demonstrated antiviral activity, peaking 24 hours after administration.
  
  
• Median HCV RNA declines at 24 hours ranged from approximately 0.7 to 1.2 log₁₀ IU/mL across GS 9190 cohorts, compared with no significant change in the placebo group.
  
  
• Individual HCV RNA declines among all GS 9190 recipients ranged from 0.2 to 2.5 log₁₀ IU/mL.
  
  
• Median GS 9190 plasma half-life ranged from 10 to 15 hours across the cohorts.
  
  
• Systemic exposure increased approximately 2-fold when GS 9190 was administered with a high-fat meal.
  
  
• The mean GS 9190 concentration 24 hours after administration of the 240 mg fasted dose was about 7-fold higher than the protein binding-adjusted EC50 (50% effective concentration) value using the in vitro HCV GT-1b replicon model.
  
  
• Single doses of GS 9190 were well tolerated, with no serious or treatment-limiting adverse events.
  
  
• All adverse events were mild in severity, except for 1 moderate, with the most common being headache.
  
  
• There were no Grade 3 or 4 (severe or life-threatening) treatment-emergent laboratory abnormalities.  

Based on the results from Part A, the investigators concluded, “This study demonstrates potent dose-dependent antiviral activity of GS 9190, and peak activity was observed in 24 hours and maintained for the duration of 8 days of treatment in HCV-infected volunteers. Single-dose exposure to GS 9190 was well tolerated and demonstrated favorable PK properties that may support [once-daily] or [twice-daily] dosing.

Results from Part B

·    The 40 mg and 120 mg twice-daily doses of GS 9190 produced a sustained antiviral effect over 8 days of treatment.

·    The mean decline in HCV RNA from baseline to Day 8 was approximately 1.4 log₁₀ IU/mL for the 40 mg dose and 1.7 log₁₀for the 120 mg dose, compared with a negligible change in the placebo group.

·    Systemic clearance of the drug at both doses was low, and pharmacokinetics were dose proportional.

·    The median half-life of GS 9190 following multiple-dose administration was 10-13 hours.

·    Twice-daily administration of GS 9190 over 8 days at these doses was generally well tolerated.

QT Elongation

However, the preliminary results from Part B suggested that GS 9190 may be associated with QT elongation, a type of heart rhythm disturbance. Based on routine electrocardiograms (a standard test for cardiac safety in drug trials), the researchers observed “a possible but not confirmed” QT elongation in the second multiple-dose cohort.

Gilead Sciences, the company developing the drug, has initiated a specific QT study to look at the potential cardiac risk of GS 9190 among healthy volunteers without hepatitis C. This study is expected to be concluded by the end of the year.

“These Phase I data support continued evaluation of GS 9190 as a potential therapeutic option for hepatitis C virus,” presenter Ira Jacobson, MD, of Cornell’s Weill Medical College said in a Gilead press release. “New, more convenient and better tolerated medicines for HCV are urgently needed, and we look forward to continuing our assessment of GS 9190 in this clinical program.”

Charles River Laboratories, Northwest Kinetics, Inc., Tacoma, WA; University of Washington, Seattle, WA; Weill Cornell Medical College, New York, NY; Hospital Beaujon, Clichy, France; Saarland University Hospital, Homburg, Germany; Alamo Medical Research, San Antonio, TX; Prism Research, St. Paul, MN; Hospital St. Louis, Paris, France; University of Miami, Miami, FL; Gilead Sciences, Inc., Foster City, CA.

12/11/07

Sources

L Bavisotto, CC Wang, IM Jacobson, and others. Antiviral, Pharmacokinetic and Safety Data for GS 9190, a Non-nucleoside HCV NS5b Polymerase Inhibitor, in a Phase-1 Trial in HCV Genotype 1 Infected Subjects. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, November 2-6, 2007. Abstract 49.