TCT: LANCELOT-ACS says certain doses of atopaxar can reduce bleeding, CV events

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WASHINGTON, D.C.—Use of certain doses of atopaxar in acute coronary syndrome patients can reduce rates of bleeding, cardiovascular events and better achieve platelet inhibition, according to the results of the LANCELOT-ACS trial presented Sept. 23 as a late-breaking clinical trial during the 2010 Transcatheter Cardiovascular Therapeutics (TCT) annual meeting.

Michelle O’Donoghue MD, MPH, of Brigham and Women’s Hospital in Boston, told Cardiovascular Business News that the “primary intent of the LANCELOT-ACS trial was to evaluate the safety and tolerability of atopaxar (A5555),” in acute coronary syndrome (ACS) patients.

The study enrolled 603 patients presenting with unstable angina or non-STEMI and randomized after 72 hours of the onset of symptoms into four patient groups to receive placebo, or a 50 mg, 100 mg or 200 mg dose of atopaxar daily, on top of a 400 mg loading dose of the drug.

The researchers treated patients for 12 weeks and did patient follow-up for an additional four weeks. CURE major bleeding was used as the primary endpoint of the study and the researchers also evaluated the incidence of cardiovascular events including CV death, MI and stroke.

According to O’Donoghue, results showed that CURE bleeding event rates were similar between the placebo arm and active combined atopaxar arm, 2.2 percent versus 3.1 percent, respectively. It was not statistically significant.

For each of the three atopaxar patient arms, rates of bleeding occurred at 1.3 percent for patients receiving the 50 mg dose, 5.8 percent for those who received a 100 mg dose and 2.1 percent for those who received a 200 mg dose.

For rates of CV death, stroke, MI or recurrent ischemia, these rates were 3.9 percent, 10.8 percent and 9.5 percent, respectively. In comparison, the rates for the placebo arm were 7.8 percent and 8 percent for active combined atopaxar.

“We were a little surprised to see a higher incidence of both CV events as well as bleeding rates in the 100 mg dose arm,” O’Donoghue said in an interview. “But, we essentially don’t believe that that has anything to do with the biology of the drug and suspect that that is likely explained by the fact that the 100 mg dose group was a slightly sicker populations based on the baseline characteristics.”

She noted that the patients in the 100 mg atopaxar group had higher incidence rates of peripheral arterial disease, coronary artery disease and a prior history of CABG.

“We did not see any evidence of dose dependent trend despite the fact the incidence of CV death, MI or stroke was lowest in the 50 mg and 200 mg dose arms,” she said.

Administration of atopaxar, the orally active par-I inhibitor, showed a lower incidence rates of Holter-detected ischemia at 48 hours following the 400 mg loading dose of the drug—a “significant” 33 percent relative risk reduction, said O’Donoghue.

“This is the first time that an oral antiplatelet drug has actually reduced the occurrence of ischemia on Holter monitoring. It is quit promising for a surrogate endpoint for efficacy. We are looking for a new antiplatelet drug that might be able to reduce the incidence of CV events, so that signal in the phase II program is promising,” she noted.

Another component of the LANCELOT-ACS trial evaluated platelet function data. After a 400 mg dose of atopaxar, O’Donoghue said that there was inhibition of platelet activation three hours following the dose. Additionally, the platelet aggression increased further at the three- to six-hour mark and was maintained prior to the first maintenance dose. These numbers were 74 percent at one to three hours, 92 percent at three to six hours and 89 percent two days prior to the dose.

Additionally, O’Donoghue noted that atopaxar achieved “potent and longer platelet inhibition via the PAR-I receptor without a significant increase in bleeding in patients with ACS. Favorable trends for efficacy were supported by a significant reduction in Holter-detected ischemia, a well established surrogate endpoint,” she said.

“Overall, we found that the drug was well tolerated, but we did not observe dose-dependent trends,” she said.

The LANCELOT-CAD trials, the LANCELOT-ACS sister trial, which focuses on a more stable population and compares atopaxar and