Efficacy of Tecarfarin Mirrors Earlier Studies While Primary Endpoint Missed

ARYx Therapeutics, Inc. (NASDAQ:ARYX), a biopharmaceutical company, today announced results from its Phase 2/3 clinical trial, EmbraceAC, comparing its novel anticoagulant agent tecarfarin (previously ATI-5923) with the leading oral anticoagulant warfarin. In this trial, tecarfarin demonstrated efficacy essentially the same as in earlier Phase 2 studies but did not achieve the primary endpoint of superiority over warfarin, as measured by time in therapeutic range (TTR). This was due to the virtually unprecedented performance of warfarin in this trial. Using the International Normalized Ratio (INR), which is the standard measure of anticoagulation to evaluate TTR, the patients in the trial who were administered tecarfarin stayed within the target therapeutic range 74.0% of the time treated as compared to those patients receiving warfarin who stayed within the target therapeutic range 73.2% of the time (p=0.506). The result for the warfarin group was unexpected based upon the extensive history of prior studies and published literature for the drug. Tecarfarin appeared to be well tolerated by the patients in this Phase 2/3 clinical trial.

"While we are obviously disappointed at the outcome of this trial, tecarfarin achieved the results we anticipated based upon two earlier Phase 2 studies. We continue to demonstrate a time within therapeutic range of INR that remains consistent from trial to trial, whether dosing decisions are made by treating physicians or through a centralized dosing control. In contrast, warfarin patients did much better than we had reason to expect and as a result we did not achieve statistical significance. This appears to be due in no small part to the central dose control center that we established for the trial, and to the ability of the center to anticipate the potential daily pitfalls of warfarin use. Such oversight for warfarin control dosing was necessary for our double-blind trial even though it’s not seen in normal clinical practice. An initial analysis of the data reinforces the importance of comparing normal tecarfarin administration to typical warfarin practice in a so-called real world setting," said Dr. Paul Goddard, chairman and chief executive officer of ARYx. "There are still a lot of data to be analyzed from this trial. Once we have fully analyzed both the efficacy and safety results, we will continue our on-going partnership discussions with several large pharmaceutical companies to determine the best path forward in the future development of tecarfarin. Of course, as we have previously stated, we also remain focused on the licensing of budiodarone and ATI-7505.”

Dr. Linda Bavisotto, a board certified physician in Internal Medicine and Hematology, commented, “I've gained experience with tecarfarin therapy as an Investigator in an earlier study and as a member of the dose control center in the EmbraceAC study. Tecarfarin is relatively easy to administer since it appears to have less dose variability than warfarin, can achieve a time in therapeutic range not usually produced by warfarin in previous studies or in clinical practice, and may confer an advantage relative to warfarin of providing a larger range for titration of dose in situations where the therapeutic window may be tight. The improved performance of warfarin in the EmbraceAC study may be a consequence of the dose control center clinicians' unified approach to dosing, including anticipatory dose adjustments and increased frequency of follow-up monitoring whenever known interactive concurrent medications were introduced by physicians at the study sites. While such proactively adjusted dosing might improve time in therapeutic range for warfarin in an ideally controlled trial, it does not diminish the apparent efficacy of tecarfarin.”

Our Study Design and Implementation

EmbraceAC enrolled 612 patients at 48 clinical study sites in the United States. It was a randomized, double-blind, parallel group, active control study comparing tecarfarin with warfarin in patients who require chronic, oral anticoagulation. The patients who entered this study required anticoagulation therapy to avoid serious blood clotting resulting from their underlying conditions. Each patient was treated for a minimum of six months on either tecarfarin or warfarin and the patients and study site investigators were blind to therapy and dose. Patients included in the study had a variety of underlying conditions including atrial fibrillation; an implanted prosthetic heart valve; a history of venous thromboembolic disease (DVT/PE); a history of myocardial infarction or cardiomyopathy. This is the same patient population for which warfarin is indicated for use and that tecarfarin is intended to treat.

The same target therapeutic range of INR of 2.0 to 3.0 (for heart valve patients the target range applied was 2.5 to 3.5) was applied for patients receiving warfarin therapy as those administered tecarfarin. The primary endpoint of the trial was to demonstrate that patients are maintained within the target INR range a higher percentage of the time when treated with tecarfarin than with warfarin.

The dosing of patients and monitoring of their anticoagulation status was entirely and independently controlled by a central dose control center comprised of clinicians experienced in managing anticoagulation therapy. Since the center was unblinded to each patient’s therapy, history and INR status, factors known to compromise warfarin’s efficacy, including concomitant medications, frequency of INR monitoring and a patient’s genotype, were actively taken into account at time of dosing. Genotype data gives the physician information about the rate at which patients metabolize warfarin. In particular, the CYP2C9 genotype was evaluated to distinguish between “wild type” patients with normal rates of warfarin metabolism and patients with a CYP2C9 “variant” who have slower metabolism. Similar information was gathered on patients’ VKORC1 genotype.