Novel Antiplatelet Agent Shows Promise for Acute Coronary Syndromes in Safety Study

WASHINGTON – Treatment with the investigational antiplatelet agent atopaxar did not significantly increase bleeding in patients with acute coronary syndromes in a randomized trial, making protease-activated receptor-1 blockade “a promising target” for ACS treatment, the trial’s lead investigator reported.

Drugs that inhibit platelet activation, such as aspirin and P2Y12 inhibitors (clopidogrel, for instance), are the mainstay of therapy for patients with ACS, but these drugs do not inhibit the thrombin receptor as atopaxar does. “Thrombin is known to be the most potent platelet agonist,” explained Dr. Michelle O’Donoghue of Brigham and Women’s Hospital in Boston.

Thrombin acts primarily via the PAR-1 receptor, which has led investigators to wonder whether PAR-1 receptor blockage – in addition to the current antiplatelet therapy – can move clinicians closer to the goal of reducing major adverse cardiac events without increasing the incidence of clinically significant bleeding.

Results from the LANCELOT ACS trial show that the PAR-1 antagonist atopaxar “achieves potent and rapid platelet inhibition ... without a significant increase in bleeding in patients with ACS,” Dr. O’Donoghue reported at the Transcatheter Cardiovascular Therapeutics 2010 meeting, which was sponsored by the Cardiovascular Research Foundation.

In the multicenter, double-blind study, 603 patients with unstable angina or non–ST-elevation myocardial infarction (NSTEMI) were randomized within 72 hours of symptom onset to receive either placebo or a 400-mg loading dose of atopaxar followed by a daily maintenance dose of 50 mg, 100 mg, or 200 mg for 12 weeks. The patients were followed for 4 weeks and, with few exceptions, were treated with aspirin or dual antiplatelet therapy in addition to atopaxar or the placebo drug.

The average rate of bleeding across the three atopaxar groups was 3.1% according to the CURE bleeding classification (1.8% CURE major and 1.3% CURE minor), compared with 2.2% in placebo group (all CURE minor). There was “no evidence of any dose-dependent trend,” Dr. O’Donoghue said.

The study, funded by Eisai Inc., was not powered for efficacy – the primary objective was to establish safety and tolerability – but “numerically, there was a lower incidence of cardiovascular death, MI, or stroke in the active combined group as compared with placebo,” Dr. O’Donoghue said. This difference was not statistically significant, but it shows “favorable trends for efficacy,” she said.

The incidence of Holter-detected ischemia at 48 hours following a 400-mg loading dose also was significantly lower in the atopaxar groups, compared with placebo.

“There was a significant 33% relative risk reduction [in the atopaxar groups combined],” she said. “This is the first time an oral antiplatelet drug was shown to reduce Holter-detected ischemia.”

Overall, the drug was well tolerated, but dose-dependent transaminitis and relative QTc prolongation were observed with the higher doses of atopaxar.

A platelet function substudy showed there was significant inhibition of platelet aggregation 1-3 hours after the loading dose. Platelet inhibition increased further at 3-6 hours to levels that were maintained until the first maintenance dose. Once maintenance doses began, “there was some evidence of a dose-dependent trend, with greater inhibition of platelet aggregation at the higher doses,” said Dr. O’Donoghue.

Dr. David J. Moliterno, who moderated a discussion of the trial, said that atopaxar is “only the second drug to be studied in this class in a phase II fashion.”

“Should we be concerned by the increase [in the rate of major bleeds], from 0 to 1.8%?” said Dr. Moliterno, chief of cardiology at the University of Kentucky, Lexington. “I don’t think we should be discouraged. ... It was a small trial ... and there was no clear dose effect.”

Similar outcomes of treatment with the new agent were reported this year for the J-LANCELOT trial, which tested atopaxar in patients with ACS and high-risk coronary artery disease in Japan (Eur. Heart J. 2010 [doi:10.1093/eurheartj/ehq320]).

The study was funded by Eisai Inc. Dr. O’Donoghue disclosed that she has received research support from Eisai and GlaxoSmithKline, and that she is a consultant for Eli Lilly & Co. and Daiichi Sankyo.

WASHINGTON – Treatment with the investigational antiplatelet agent atopaxar did not significantly increase bleeding in patients with acute coronary syndromes in a randomized trial, making protease-activated receptor-1 blockade “a promising target” for ACS treatment, the trial’s lead investigator reported.

Drugs that inhibit platelet activation, such as aspirin and P2Y12 inhibitors (clopidogrel, for instance), are the mainstay of therapy for patients with ACS, but these drugs do not inhibit the thrombin receptor as atopaxar does. “Thrombin is known to be the most potent platelet agonist,” explained Dr. Michelle O’Donoghue of Brigham and Women’s Hospital in Boston.

Thrombin acts primarily via the PAR-1 receptor, which has led investigators to wonder whether PAR-1 receptor blockage – in addition to the current antiplatelet therapy – can move clinicians closer to the goal of reducing major adverse cardiac events without increasing the incidence of clinically significant bleeding.

Results from the LANCELOT ACS trial show that the PAR-1 antagonist atopaxar “achieves potent and rapid platelet inhibition ... without a significant increase in bleeding in patients with ACS,” Dr. O’Donoghue reported at the Transcatheter Cardiovascular Therapeutics 2010 meeting, which was sponsored by the Cardiovascular Research Foundation.

In the multicenter, double-blind study, 603 patients with unstable angina or non–ST-elevation myocardial infarction (NSTEMI) were randomized within 72 hours of symptom onset to receive either placebo or a 400-mg loading dose of atopaxar followed by a daily maintenance dose of 50 mg, 100 mg, or 200 mg for 12 weeks. The patients were followed for 4 weeks and, with few exceptions, were treated with aspirin or dual antiplatelet therapy in addition to atopaxar or the placebo drug.

The average rate of bleeding across the three atopaxar groups was 3.1% according to the CURE bleeding classification (1.8% CURE major and 1.3% CURE minor), compared with 2.2% in placebo group (all CURE minor). There was “no evidence of any dose-dependent trend,” Dr. O’Donoghue said.

The study, funded by Eisai Inc., was not powered for efficacy – the primary objective was to establish safety and tolerability – but “numerically, there was a lower incidence of cardiovascular death, MI, or stroke in the active combined group as compared with placebo,” Dr. O’Donoghue said. This difference was not statistically significant, but it shows “favorable trends for efficacy,” she said.

The incidence of Holter-detected ischemia at 48 hours following a 400-mg loading dose also was significantly lower in the atopaxar groups, compared with placebo.

“There was a significant 33% relative risk reduction [in the atopaxar groups combined],” she said. “This is the first time an oral antiplatelet drug was shown to reduce Holter-detected ischemia.”

Overall, the drug was well tolerated, but dose-dependent transaminitis and relative QTc prolongation were observed with the higher doses of atopaxar.

A platelet function substudy showed there was significant inhibition of platelet aggregation 1-3 hours after the loading dose. Platelet inhibition increased further at 3-6 hours to levels that were maintained until the first maintenance dose. Once maintenance doses began, “there was some evidence of a dose-dependent trend, with greater inhibition of platelet aggregation at the higher doses,” said Dr. O’Donoghue.

Dr. David J. Moliterno, who moderated a discussion of the trial, said that atopaxar is “only the second drug to be studied in this class in a phase II fashion.”

“Should we be concerned by the increase [in the rate of major bleeds], from 0 to 1.8%?” said Dr. Moliterno, chief of cardiology at the University of Kentucky, Lexington. “I don’t think we should be discouraged. ... It was a small trial ... and there was no clear dose effect.”

Similar outcomes of treatment with the new agent were reported this year for the J-LANCELOT trial, which tested atopaxar in patients with ACS and high-risk coronary artery disease in Japan (Eur. Heart J. 2010 [doi:10.1093/eurheartj/ehq320]).

The study was funded by Eisai Inc. Dr. O’Donoghue disclosed that she has received research support from Eisai and GlaxoSmithKline, and that she is a consultant for Eli Lilly & Co. and Daiichi Sankyo.

WASHINGTON – Treatment with the investigational antiplatelet agent atopaxar did not significantly increase bleeding in patients with acute coronary syndromes in a randomized trial, making protease-activated receptor-1 blockade “a promising target” for ACS treatment, the trial’s lead investigator reported.

Drugs that inhibit platelet activation, such as aspirin and P2Y12 inhibitors (clopidogrel, for instance), are the mainstay of therapy for patients with ACS, but these drugs do not inhibit the thrombin receptor as atopaxar does. “Thrombin is known to be the most potent platelet agonist,” explained Dr. Michelle O’Donoghue of Brigham and Women’s Hospital in Boston.

Thrombin acts primarily via the PAR-1 receptor, which has led investigators to wonder whether PAR-1 receptor blockage – in addition to the current antiplatelet therapy – can move clinicians closer to the goal of reducing major adverse cardiac events without increasing the incidence of clinically significant bleeding.

Results from the LANCELOT ACS trial show that the PAR-1 antagonist atopaxar “achieves potent and rapid platelet inhibition ... without a significant increase in bleeding in patients with ACS,” Dr. O’Donoghue reported at the Transcatheter Cardiovascular Therapeutics 2010 meeting, which was sponsored by the Cardiovascular Research Foundation.

In the multicenter, double-blind study, 603 patients with unstable angina or non–ST-elevation myocardial infarction (NSTEMI) were randomized within 72 hours of symptom onset to receive either placebo or a 400-mg loading dose of atopaxar followed by a daily maintenance dose of 50 mg, 100 mg, or 200 mg for 12 weeks. The patients were followed for 4 weeks and, with few exceptions, were treated with aspirin or dual antiplatelet therapy in addition to atopaxar or the placebo drug.

The average rate of bleeding across the three atopaxar groups was 3.1% according to the CURE bleeding classification (1.8% CURE major and 1.3% CURE minor), compared with 2.2% in placebo group (all CURE minor). There was “no evidence of any dose-dependent trend,” Dr. O’Donoghue said.

The study, funded by Eisai Inc., was not powered for efficacy – the primary objective was to establish safety and tolerability – but “numerically, there was a lower incidence of cardiovascular death, MI, or stroke in the active combined group as compared with placebo,” Dr. O’Donoghue said. This difference was not statistically significant, but it shows “favorable trends for efficacy,” she said.

The incidence of Holter-detected ischemia at 48 hours following a 400-mg loading dose also was significantly lower in the atopaxar groups, compared with placebo.

“There was a significant 33% relative risk reduction [in the atopaxar groups combined],” she said. “This is the first time an oral antiplatelet drug was shown to reduce Holter-detected ischemia.”

Overall, the drug was well tolerated, but dose-dependent transaminitis and relative QTc prolongation were observed with the higher doses of atopaxar.

A platelet function substudy showed there was significant inhibition of platelet aggregation 1-3 hours after the loading dose. Platelet inhibition increased further at 3-6 hours to levels that were maintained until the first maintenance dose. Once maintenance doses began, “there was some evidence of a dose-dependent trend, with greater inhibition of platelet aggregation at the higher doses,” said Dr. O’Donoghue.

Dr. David J. Moliterno, who moderated a discussion of the trial, said that atopaxar is “only the second drug to be studied in this class in a phase II fashion.”

“Should we be concerned by the increase [in the rate of major bleeds], from 0 to 1.8%?” said Dr. Moliterno, chief of cardiology at the University of Kentucky, Lexington. “I don’t think we should be discouraged. ... It was a small trial ... and there was no clear dose effect.”

Similar outcomes of treatment with the new agent were reported this year for the J-LANCELOT trial, which tested atopaxar in patients with ACS and high-risk coronary artery disease in Japan (Eur. Heart J. 2010 [doi:10.1093/eurheartj/ehq320]).

The study was funded by Eisai Inc. Dr. O’Donoghue disclosed that she has received research support from Eisai and GlaxoSmithKline, and that she is a consultant for Eli Lilly & Co. and Daiichi Sankyo.