Abstract 4415: The Utility of Genotyping in the First Evaluation of a Novel Vitamin K Antagonist: ATI-5923

Abstract

(S)-Warfarin, the most active enantiomer of warfarin, is metabolized by CYP2C9. Genetic variations of the CYP2C9 gene result in slower metabolism and are major contributors to inter-patient dose variability with resultant INR instability, especially in patients on multiple medications. This leads to higher hemorrhagic and thrombotic complications. ATI-5923 (ARYx therapeutics Inc.) is a novel VKOR inhibitor that undergoes metabolism by human carboxyles-terase and not by CYP2C9. We hypothesize that time in therapeutic range (TTR) based on Rosendaal method is better for ATI-5923 than for historic warfarin and that maintenance dose is independent of CYP2C9 polymorphism, but dependent on VKOR haplotype. This was a multi-center, open-label, 3 month study of 66 patients with AF treated with ATI-5923. All except two patients were on prior warfarin. Periodic INR testing occurred twice weekly for the first 3 weeks and then weekly during the maintenance phase. Genetic testing for the CYP2C9 and VKORC1 polymorphism was performed on all patients. Drug dosing was performed using a standardized nomogram. Pre-study INRs and warfarin dose data were collected for up to one year prior to study entry. 77 % of patients were in therapeutic range (INR 2–3) after 7 days and 80% had stable INR (3 consecutive INR values within range without dose adjustment) by 3 months. For the maintenance phase the mean TTR was 71.5 and 59.3% for ATI-5923 and warfarin respectively (12.2% improvement; p=0.0009). Patients with the VKOR AA haplotype required lower maintenance doses than VKOR GA or GG haplotype (8.6 vs 15.8 and 18.7mg; p < 0.0001). CYP2C9 genotype had no influence on maintenance dose. CYP2C9 variants (n=20), showed a trend toward better control compared to warfarin; 16% improvement vs. 11% for wild type CYP2C9 (n =42). ATI-5923 has better INR control than prior warfarin therapy. VKOR AA patients require a significantly lower maintenance dose. CYP2C9 variants show a trend to added improvement compared to the CYP2C9 wild type, suggesting that, unlike warfarin, ATI-5923 is not influenced by CYP2C9 genetic variations.