The VX-222+Telaprevir phase-2 trial is notable in several ways:
• There is no SoC control arm. (Although not having an SoC arm is novel, it can’t be called surprising because it’s what I predicted in #msg-46326087.)
• Patients are required to have undetectable virus as early as two weeks from the start of treatment in order to discontinue treatment after 12 weeks. To my knowledge, no HCV trial has ever had such a stringent timing requirement for stopping therapy.
• The threshold for undetectability is <10 IU/ml, which reflects the sensitivity of the latest assays and reduces the likelihood of seeing cases of faux viral rebound.
• All arms in the trial use BID rather than TID Telaprevir, based on the positive outcome of JNJ’s C208 study (#msg-43114192).
M. Rodriguez-Torres1, E. Lawitz2, B. Conway3, K. Kaita4, A.M. Sheikh5, R. Ghalib6, R. Adrover7, C. Cooper8, M. Silva7, M. Rosario9, B. Bourgault10, L. Proulx10, J.G. McHutchison11 1Fundacion de Investigacion de Diego, Santurce, PR, 2Alamo Medical Research, San Antonio, TX, USA, 3University of British Columbia, Vancouver, BC, 4University of Manitoba, Winnipeg, MB, Canada, 5GI Specialists of Georgia, Marietta, GA, 6The Liver Institute at Methodist Dallas, Dallas, TX, USA, 7ACLIRES, Buenos Aires, Argentina, 8University of Ottawa, Ottawa, ON, Canada, 9Hospital Universitario Austral, Buenos Aires, Argentina, 10Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA, 11ViroChem Pharma Inc., Laval, QC, Canada, 12Duke University Medical Center, Durham, NC, USA. *rodztorres@coqui.net
Background and aims: VX-222 is a novel non-nucleoside hepatitis C virus (HCV) polymerase inhibitor with potent in vitro activity. Safety, tolerability, pharmacokinetics and antiviral activity of VX-222 were assessed in a phase Ib/IIa multicenter, randomized, double-blinded, placebo-controlled, dose-ascending study in HCV-infected patients. Methods: Treatment-naïve HCV genotype 1 patients were randomized to receive VX-222 at doses of 250 mg BID, 500 mg BID, 750 mg BID, 1500 mg QD or placebo for 3 days in a treatment:placebo ratio of 6:2 (8 patients/cohort). Peginterferon-alfa-2a (P) plus ribavirin (R) was offered to patients at end of study (day 4) for up to 48 weeks, as judged appropriate by the investigator. PR treatment was discontinued in patients who had not experienced a =2 log10 HCV RNA level decline at week 12. VX-222 plasma levels were assessed at multiple time points over 12 hours, on days 1 and 3. Results: Twenty-four patients were enrolled in the first three cohorts. VX-222 exposure increased in a dose-related manner. On day 3, the mean AUC0-12h and Cmax values were 19,490 ng*h/mL (CV 41%) and 2,959 ng/mL (CV 29%), 29,848 ng*h/mL (CV 54%) and 5,044 ng/mL (CV 36%), and 62,952 ng*h/mL (CV 112 %) and 10,288 ng/mL (CV 112%) for the 250 mg, 500 mg, and 750 mg BID groups, respectively. The mean HCV RNA decline achieved on day 4 with placebo, 250 mg, 500 mg, and 750 mg VX-222 BID was 0.1 log10 (range: 0.3 increase to 0.5 decline), 3.1 log10 (range: 2.0 to 4.2), 3.4 log10 (range: 3.2 to 3.6), and 3.2 log10 (range: 2.3 to 3.8), respectively. All AEs reported were mild to moderate, and the most frequently reported AEs by patients that received either active drug or placebo were diarrhea (25%), headache (20%) and nausea (12%). No clinically relevant laboratory abnormalities were reported. Conclusions: VX-222 was well tolerated and a mean HCV RNA decline of >3 log10 at day 4 was observed in each cohort, results of the fourth cohort evaluating QD dosing will also be presented. These results support further evaluation of VX-222 in combination with peginterferon and ribavirin in the treatment of HCV.
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