ARYx Therapeutics (NASDAQ:ARYX) announced today that clinical data for ATI-5923, a novel vitamin K epoxide reductase (VKOR) inhibitor in Phase 2/3 development for the treatment of patients at risk of forming dangerous blood clots, were presented this week at the American Heart Association (AHA) Scientific Sessions 2008 in New Orleans, LA. The data featured in these presentations indicate that ATI-5923 has potential advantages over the leading drug warfarin, including possible reduction of drug-drug interactions (DDIs), more predictable dosing and better anticoagulation control.
An oral presentation entitled, “The CYP450 Inhibitor Fluconazole Increases Plasma Concentrations of both (R)-and (S)-Warfarin, but not ATI-5923, a Novel VKOR Inhibitor,” described results of a clinical pharmacokinetic (PK) study conducted by ARYx. The study compared drug exposure and elimination rates of ATI-5923 and warfarin when given to subjects who also were administered the CYP 2C9/3A4 inhibitor fluconazole (FCZ). Data from this study suggest that exposure and elimination rate of ATI-5923, which undergoes esterase-mediated metabolism, are unaffected by FCZ treatment. In contrast, drug levels of warfarin, which undergoes CYP450-mediated metabolism, were dramatically increased by FCZ treatment.
“These data are significant because, in the clinical setting, DDI-induced increase in warfarin exposure is associated with increased anticoagulant effect and risk of bleeding,” noted Peter Milner, M.D., president, research and development of ARYx. “ATI-5923 was designed to have an alternative metabolic pathway, so it should avoid metabolic DDIs with other drugs that inhibit or induce CYP450 enzymes. This could give ATI-5923 a distinct advantage over the current standard of care.”
ARYx also presented a poster entitled, “The Utility of Genotyping in the First Evaluation of a Novel Vitamin K Epoxide Reductase (VKOR) Inhibitor: ATI-5923.” This poster described results from a 3-month clinical study of ATI-5923 in 66 patients with atrial fibrillation that included analysis of genetic variations of CYP2C9 (a gene involved in warfarin metabolism) and VKORC1 (the enzyme targeted by ATI-5923 for therapeutic effect). It has been established that individuals with CYP2C9 genetic subtype variants are among the most difficult to maintain at a proper level of anticoagulation while on warfarin. The expectation that ATI-5923 could have a particularly beneficial effect on these patients due to ATI-5923’s avoidance of the CYP metabolic pathway is suggested by the results from this clinical study. The study data indicate that patients had more stable control of anticoagulation (measured with international normalized ratio, or INR) with ATI-5923 than with prior warfarin therapy, and that patients with CYP2C9 genetic variations exhibited even greater improvement in the control of anticoagulation when on ATI-5923 than when on warfarin.
“The results from this clinical study reflect what we had hypothesized, based on the unique attributes of ATI-5923,” noted Dr. Milner. “Because ATI-5923 is designed to undergo metabolism by human carboxylesterase and not by CYP2C9, it shouldn’t be influenced by CYP2C9 genetic variations. This genotyping analysis tells us that ATI-5923 is behaving as expected, and that it may provide more stable control of anticoagulation as a result of its unique metabolism.”
ARYx is currently conducting a Phase 2/3 clinical trial of ATI-5923 against warfarin. Recently, ARYx completed patient enrollment in this study, and based on recent interactions with the FDA, ARYx believes that this trial could be positioned as one of the pivotal trials needed for registration. ARYx expects data from this trial to be available by the end of the first half of 2009.
About the Clinical Trials
In the PK study referenced in ARYx’s oral presentation, two groups (n=10/group) of healthy volunteers were randomized to receive a single equieffective oral dose of either warfarin (17.5 mg) or ATI-5923 (50 mg). ATI-5923, ATI-5900 (the inactive metabolite of ATI-5923), R-warfarin and S-warfarin concentrations were measured in serial plasma samples collected over a seven-day period and the PK parameters (AUC, Cmax, Tmax and T1/2) were determined. On day seven, subjects were given FCZ (400 mg/day) for 14 days, and on day 21, subjects received a second dose of either warfarin or ATI-5923. FCZ co-administration was continued for seven days and the PK study was repeated.
The clinical trial referenced in ARYx’s poster presentation is a multi-center, open-label study of 66 patients with atrial fibrillation. Patients were dosed with ATI-5923 for a period of three months. Periodic INR testing occurred twice weekly for the first three weeks and then weekly during the maintenance phase. Genetic testing for the CYP2C9 and VKORC1 polymorphisms were performed on all patients. Pre-study INR values and warfarin dose data were collected for up to one year prior to study entry. Seventy seven percent of patients treated with ATI-5923 reached therapeutic range (INR 2-3) after seven days, and 80% of patients treated with ATI-5923 had reached a stable dose (three consecutive INR values within range without dose adjustment) by three months. For the maintenance phase, the mean time patients were within the target INR time in therapeutic range (TTR) was 71.5 and 59.3% for ATI-5923 and warfarin, respectively (12.2% absolute difference; 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 variant patients (n=20) treated with ATI-5923 showed a 16% improvement in TTR as compared to warfarin treatment, while patients with wild type CYP2C9 genotype (n=42) showed an 11% improvement in TTR while treated with ATI-5923 as compared to warfarin treatment. About ATI-5923 ATI-5923 is modeled on the drug warfarin as an oral anticoagulation therapy for patients who are in danger of forming life-threatening blood clots as a result of atrial fibrillation, prosthetic heart valve replacement or venous thromboembolism. There are at least an estimated 3.5 million patients requiring anticoagulation therapy in the United States alone. Patients with implanted mechanical heart valves are also among those requiring anticoagulation therapy. ATI-5923, like warfarin, is a selective inhibitor of VKOR, or vitamin K epoxide reductase enzyme, and has the same mechanism of anticoagulation action as warfarin. Unlike warfarin, which is dependent upon cytochrome P450 enzymes for metabolism, ATI-5923 was designed to avoid drug-drug interactions through its alternative metabolic pathway. ARYx expects that the avoidance of cytochrome P450 metabolism will cause the dosing and response to ATI-5923 to be more predictable than with warfarin, avoiding the dangers of over-or-under therapeutic anticoagulation that have long been associated with that therapy. About ARYx Therapeutics, Inc. ARYx Therapeutics is a biopharmaceutical company focused on developing a portfolio of internally discovered products designed to eliminate known safety issues associated with well-established, commercially successful drugs. ARYx uses its RetroMetabolic Drug Design technology to design structurally unique molecules that retain the efficacy of these original drugs but are metabolized through a potentially safer pathway to avoid specific adverse side effects associated with these compounds. ARYx currently has four products in clinical trials: an oral anticoagulant agent for patients at risk for the formation of dangerous blood clots, ATI-5923; an oral anti-arrhythmic agent for the treatment of atrial fibrillation, ATI-2042; a prokinetic agent for the treatment of various gastrointestinal disorders, ATI-7505; and, an agent for the treatment of schizophrenia and other psychiatric disorders, ATI-9242. Please visit our web site at aryx for additional information. Forward-looking Statements This press release contains forward-looking statements, including, without limitation, statements related to the potential safety and efficacy and further development of ATI-5923, the timing and availability of our clinical results, the initiation of new clinical trials, the ability of ATI-5923 to be more predictable than currently available therapies regarding dosing and response to treatment, and the ability of ATI-5923 to avoid the dangers existing in currently available therapies. Words such as “indicate,” “suggest,” “should,” “could,” “may,” “expects,” “will,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon our current expectations. Forward-looking statements involve risks and uncertainties. ARYx’s actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, the risk that our product candidates may not demonstrate safety and efficacy or lead to regulatory approval, the risk that we will need substantial additional funding and may be unable to raise additional capital when needed which would force us to limit or cease our operations and related product development programs, the risk that any failure or delay in commencing or completing clinical trials for our product candidates could severely harm our business, the risk that we depend on collaborative arrangements to complete the development and commercialization of each of our product candidates and we may have to alter our development and commercialization plans if collaborative relationships are not established for ATI-5923, ATI-2042 and ATI-7505, the risk that any potential collaborative arrangements will likely place the development of our product candidates outside of our control and will likely require us to relinquish important rights or may otherwise be on terms unfavorable to us, and the risk that third party manufacturers could delay or prevent the clinical development of our product candidates. These and other risk factors are discussed under “Risk Factors” and elsewhere in our Annual Report on Form 10-K for the year ended December 31, 2007, in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2008 and our other filings with the U.S. Securities and Exchange Commission. ARYx expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein. ARYx Therapeutics, Inc. View drug information on Warfarin Sodium tablets.