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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.


HCV viral load decreases were apparent within 1 day after the first dose in all VX-222 dose arms.

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:


250 mg twice-daily: -3.1 log10 IU/mL;

500 mg twice-daily: -3.4 log10 IU/mL;

750 mg twice-daily: -3.2 log10 IU/mL;

1500 mg once-daily: -3.4 log10 IU/mL;

Placebo: no notable decline.

VX-222 demonstrated similar good antiviral efficacy against both genotypes 1a and 1b.

VX-222 was generally safe and well tolerated.

No serious adverse events, significantly laboratory abnormalities, or electrocardiogram changes were observed.

No participants discontinued early due to side effects.

The most common side effects -- typically mild to moderate -- were diarrhea, nausea, headache, and fever.

Pharmacokinetic analysis indicated that VX-222 exposure increased in a dose-proportional manner.

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.



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