HCV Polymerase Inhibitor VX-222 Demonstrates Good Safety and Antiviral Activity in Treatment-naive Genotype 1 Hepatitis C Patients
While the protease inhibitors telaprevir and boceprevir are the directly-targeted anti-HCV agents furthest along in the development pipeline, HCV polymerase -- an enzyme responsible for copying viral genetic material -- is also a promising target. VX-222 is a novel non-nucleoside HCV NS5B polymerase inhibitor with potent in vitro activity.
Maribel Rodriguez-Torres and colleagues conducted a Phase 1b/2a trial to evaluate the short-term antiviral activity, safety, tolerability, and pharmacokinetics of VX-222.
This international multicenter dose-ascending study included 32 previously untreated patients with chronic genotype 1 HCV infection (75% with genotype 1a, the rest with 1b). Most (about 80%) were men, a similar proportion were white, and the mean age was about 50 years.
Participants were randomly assigned to receive VX-222 at doses of 250 mg twice-daily, 500 mg twice-daily, 750 mg twice-daily, or 1500 mg once-daily, or else placebo, for 3 days. At the end of the 3-day period, they were offered the opportunity to receive standard therapy using pegylated interferon alfa-2a (Pegasys) plus ribavirin for up to 48 weeks.
Results
HCV viral load decreases were apparent within 1 day after the first dose in all VX-222 dose arms. |
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Between baseline and the end of the 3-day treatment period, HCV RNA viral load decreased by at least 3 log IU/mL in all VX-222 arms: |
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VX-222 demonstrated similar good antiviral efficacy against both genotypes 1a and 1b. |
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VX-222 was generally safe and well tolerated. |
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No serious adverse events, significantly laboratory abnormalities, or electrocardiogram changes were observed. |
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No participants discontinued early due to side effects. |
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The most common side effects -- typically mild to moderate -- were diarrhea, nausea, headache, and fever. |
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Pharmacokinetic analysis indicated that VX-222 exposure increased in a dose-proportional manner. |
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The drug's half-life in the body was 4-6 hours. |
"VX-222 was well tolerated and a mean HCV RNA decline of > 3 log10 at day 4 was observed in each cohort," the investigators concluded. "These results support further evaluation of VX-222 in combination with peginterferon and ribavirin in the treatment of HCV."
Vertex is now starting a Phase 2 trial to test VX-222 in combination with its lead HCV protease inhibitor, telaprevir, both as an all-oral regimen and in combination with pegylated interferon/ribavirin.
"In this Phase 1b clinical trial, treatment with VX-222 for three days resulted in a reduction in viral load across all the dose groups studied," Dr. Rodriguez-Torres, MD, said in a press released issued by Vertex. "I am pleased that additional development efforts for VX-222 are advancing, including the first trial to evaluate a two-drug regimen of VX-222 dosed in combination with the HCV protease inhibitor telaprevir."
Fundacion de Investigacion de Diego, Santurce, Puerto Rico; Alamo Medical Research, San Antonio, TX; University of British Columbia, Vancouver, BC, Canada; University of Manitoba, Winnipeg, MB, Canada; GI Specialists of Georgia, Marietta, GA; The Liver Institute at Methodist Dallas, Dallas, TX; ACLIRES, Buenos Aires, Argentina; University of Ottawa, Ottawa, ON, Canada; Hospital Universitario Austral, Buenos Aires, Argentina; Vertex Pharmaceuticals Incorporated, Cambridge, MA; ViroChem Pharma Inc., Laval, QC, Canada; Duke University Medical Center, Durham, NC.
M Rodriguez-Torres, E Lawitz , B Conway, and others. Safety and antiviral activity of the HCV non-nucleoside polymerase inhibitor VX-222 in treatment-naive genotype 1 HCV-infected patients. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna , Austria . April 14-18, 2010. Abstract 137.