Atopaxar Passes Early Test in LANCELOT-ACS: No Bleeding Risk Compared With Placebo

September 28, 2010

September 28, 2010 (Washington, DC) — A novel antiplatelet agent, a reversible protease-activated-receptor 1 (PAR-1) thrombin-receptor antagonist, tested in patients with acute coronary syndrome, moved in the right direction last week when investigators reported the drug was not associated with an increased risk of bleeding.

Dr Michelle O'Donoghue

Presenting the results during the late-breaking clinical-trials session at TCT 2010, Dr Michelle O'Donoghue (Brigham and Women's Hospital, Boston, MA) said the drug was well tolerated, achieved rapid platelet inhibition, and also resulted in a significant reduction in Holter-detected ischemia.

The study, known as the LANCELOT ACS trial, tested the safety and efficacy of atopaxar (Eisai, Woodcliff Lake, NJ) in 603 unstable-angina or non-STEMI patients randomized to placebo or to a 400-mg loading dose of atopaxar followed by a daily dose of 50 mg, 100 mg, or 200 mg for 12 weeks. In addition, nearly all patients were treated with aspirin and more than 75% were taking aspirin in combination with clopidogrel or ticlopidine.

During treatment, rates of CURE bleeding, the predefined safety end point, were similar between the placebo- and atopaxar-treated patients. Among those treated with the 50-mg, 100-mg, and 200-mg doses, the rates of any CURE bleeding were 1.3%, 5.8%, and 2.1%, respectively. An analysis that combined all patients treated with atopaxar showed a 3.1% incidence of any CURE bleeding compared with 2.2% among those treated with placebo.

The study also showed a 33% relative reduction in the incidence of Holter-detected ischemia at 48 hours following the 400-mg loading dose. In total, 28.1% of patients treated with placebo had ischemia detected by Holter compared with 18.7% of patients treated with atopaxar. Finally, platelet-function data showed the thrombin receptor-activated peptide (TRAP)-induced inhibition of platelet aggregation was 74% at one to three hours and increased to 92% at three to six hours. Platelet inhibition was maintained until the first maintenance-dose treatment, report investigators.

Like the results from J-LANCELOT, which tested atopaxar in Japanese ACS and high-risk coronary artery disease patients and was reported by heartwire when presented a few weeks ago at the European Society of Cardiology 2010 Congress, there was a dose-dependent increase in liver-function enzymes and a prolongation of the QTc interval at the highest doses, something O'Donoghue said will be monitored as future studies go forward.

Bleeding Stops Evidence-Based Medicine

Commenting on the results of the study during a panel discussion, Dr Michael Gibson (Brigham and Women's Hospital, Boston) said: "You can run, you can hide, but you can't get away from the Holter." He reminded clinicians that ischemia reported on Holter monitoring is associated with significantly higher rates of myocardial necrosis. However, he said, he would like to see more data on atopaxar, particularly how long patients remained positive for Holter-detected ischemia, before the clinical consequences of such ischemia are known.

Regarding the bleeding rates in LANCELOT, Gibson called the LANCELOT data "encouraging," noting that "bleeding results in the cessation of evidence-based medicine," because patients typically stop taking all medications following a bleeding event, including beta blockers and statins, and often fail to restart the drugs.

O'Donoghue said the paradoxical findings in LANCELOT--patients treated with the 100-mg dose had higher, but statistically nonsignificant, rates of CURE bleeding and a higher rate for the underpowered combined end point of cardiovascular death, MI, or stroke, than those treated with the 200-mg dose--are likely the results of differences in baseline characteristics. Individuals treated with the 100-mg dose had more peripheral artery disease, coronary artery disease, and a prior history of coronary artery bypass graft surgery, she said.

O'Donoghue reports research support from Eisai and GlaxoSmithKline and consulting for Eli Lilly and Daiichi Sankyo. Gibson reports research support from Angel Medical, AstraZeneca, Atrium Medical Systems, Bayer, Genentech, Johnson & Johnson, Portola Pharmaceuticals, and Sanofi-Aventis; consulting for Bayer, Johnson & Johnson, Portola, Sanofi-Aventis, Schering-Plough, and the Medicines Company; and speaking for SVELTE Medical Systems, Angel Medical, Schering-Plough, Daiichi Sankyo, Eli Lilly, and the Medicines Company.