Findings from the ATLAS ACS TIMI 46 study – a Phase II study of the novel oral anticoagulant Xarelto (rivaroxaban) – were presented. Results from this Phase II study support moving rivaroxaban into a pivotal Phase III trial for the secondary prevention of acute coronary syndrome (ACS) later this year.

As a Phase II dose-finding study, the ATLAS ACS TIMI 46 trial was designed to test the safety and efficacy of rivaroxaban at escalating total daily doses, ranging from 5 mg up to 20 mg. Rivaroxaban was administered at once-daily and twice-daily intervals, assessing eight different dosing regimens in total. Nearly 3,500 patients were enrolled in the study and received standard antiplatelet therapy of low-dose aspirin with or without a thienopyridine, such as clopidogrel. Patients were then randomized to additionally receive either rivaroxaban or a placebo for six months.

‘This was a robust study that achieved its main objective of establishing the preferred dosing scenario for further evaluating rivaroxaban in a large Phase III clinical trial of ACS patients,’ said Dr. Gibson. ‘The additional benefit of rivaroxaban over placebo in this study, given on a background of standard antiplatelet therapy, highlights the unmet medical need of this patient population.’

The primary efficacy endpoint was death, myocardiaI infarction (MI), stroke, or severe recurrent ischemia requiring revascularization. Rivaroxaban was associated with an observed 21% Relative Risk Reduction (RRR) for the primary efficacy endpoint (p=0.1) and a statistically significant 31% RRR against the secondary endpoint of death, MI, or stroke (p=0.028), demonstrating a consistent trend for efficacy across doses.

Safety was evaluated by measuring clinically significant bleeding, defined as a composite of TIMI major bleeding, TIMI minor bleeding and any reported bleeding event requiring medical attention. This very sensitive bleeding measure represents a broader definition compared to other standard definitions. As expected, rivaroxaban-treated patients exhibited higher rates of bleeding vs. placebo when administered on a background of antiplatelet therapy, and there was a significant dose trend (p<0.001). However, no study arm was halted due to increased bleeding. Rates of clinically significant bleeding were: Placebo: 3.3%, rivaroxaban 5 mg: 6.1%, 10 mg: 10.9 %, 15 mg: 12.7%, 20 mg: 15.3%. Most bleeding (82%) was classified as bleeding requiring medical attention, rather than TIMI major or TIMI minor. No evidence of drug-induced hepatotoxicity was seen in the study.

Though not statistically significant due to the small sample size, the two doses selected for further evaluation in the pivotal Phase III program – 2.5 mg and 5 mg dosed twice daily – showed the best balance between efficacy and safety with an observed 46% RRR in the composite efficacy endpoint of death, MI or stroke when dosed in addition to aspirin, and an observed 45% RRR when dosed in combination with aspirin and a thienopyridine. Rates of TIMI major bleeding were 1.2% for each stratum.

The global Phase III study, ATLAS ACS TIMI 51, is planned to be initiated in December 2008 with a potential enrollment of up to 16,000 patients. As in the Phase II study, all patients will receive standard antiplatelet therapy and will then be randomly assigned to take either rivaroxaban at doses of 2.5 mg or 5 mg, or placebo, twice daily for at least six months. The primary efficacy endpoint will be a composite of cardiovascular death, MI or stroke. TIMI major bleeding events not associated with coronary artery bypass graft (CABG) surgery will be the primary safety endpoint.

‘Given the encouraging response rates we saw in the ATLAS ACS TIMI 46 trial, we feel very confident in the two doses selected for evaluation in the Phase III study, and we are excited to progress Xarelto to the next level in our clinical development program for this important indication,’ said Dr. Kemal Malik, Head of Global Development and member of the Board of Management of Bayer Schering Pharma AG.

Release Date: November 10, 2008
Source: Bayer HealthCare