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ghmm

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Re: dewophile post# 74723

Wednesday, 03/18/2009 8:51:04 PM

Wednesday, March 18, 2009 8:51:04 PM

Post# of 251777
EASL INFORM-1 Abstract:

http://www.abstractserver.com/easl2009/planner/sp.php?go=abstract&action=abstract_iplanner&absno=2661&EASL2009=5idage67e30vqb9he8ufooba44&EASL2009=5idage67e30vqb9he8ufooba44
Abstract


FIRST-IN-MAN DEMONSTRATION OF POTENT ANTIVIRAL ACTIVITY WITH A NUCLEOSIDE POLYMERASE (R7128) AND PROTEASE (R7227/ITMN-191) INHIBITOR COMBINATION IN HCV: SAFETY, PHARMACOKINETICS, AND VIROLOGIC RESULTS FROM INFORM-1

Introduction: The combination of two potent direct-acting antivirals (DAAs), targeting two distinct viral enzymes, may offer advantages over single DAA strategies by enhancing potency, reducing the emergence of drug resistance, and possibly eliminating the need for PEG-IFN +/- ribavirin. The combination of R7128/R7227 offers the potential for a highly potent regimen with a high genetic barrier to resistance.
Methods: INFORM-1 is a randomized, double-blind, ascending dose Phase I trial. Treatment-naïve HCV-infected adults (genotype-1), received up to 14d oral combination therapy. Groups A and B received low dose monotherapy with R7128 (A, n=8) 500mg q12h or low dose R7227 (B, n=9) 100 mg q8h on d1-3, both followed by combination R7128/R7227 on d4-7. Groups C-F (8 active/2 placebo) receive 14d R7128 (mg q12h)/R7227 (mg q8h): 500/100, 1000/100, 500/200, and 1000/200. Safety, viral kinetics, resistance, and pharmacokinetics of R7128/R7227 are evaluated in all cohorts.
Results: Groups A-C (n=27) have been completed with no treatment-related SAEs, dose modifications, or discontinuations. Pharmacokinetic analysis confirmed no drug-drug interaction. The HCVRNA change from baseline for both Groups A and B at d7 was similar (combined mean (SD) -3.0 (0.8) Log10 IU/mL). In Group C after 14d low-dose combination, the mean (SD [range]) change from baseline was -3.9 (0.8 [-5.0 to -2.9]) Log10 IU/mL, with 1 patient undetectable (Figure 1). The combination of R7128 and R7227 provided greater than additive antiviral activity, with no viral rebound (sustained viral load increase > 0.5 Log10).
[
Conclusions: The orally administered combination of low dose R7128 and R7227 provided significant antiviral potency, suppressed viral rebound, and appears safe and well-tolerated for 14 days. Higher doses and twice-daily regimens are being evaluated in additional cohorts. These results confirm for the first time that a protease and nucleoside polymerase inhibitor can be combined in vivo, and remain a promising combination for future treatment.

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