FDA Advisory Committee Meeting

The data on cangrelor support approval of the fast-acting antiplatelet drug for reducing thrombotic cardiovascular events in patients with coronary artery disease who are undergoing percutaneous coronary intervention – one of two indications being reviewed by the Food and Drug Administration, according to the agency’s clinical reviewers of the application.

Cangrelor is a platelet P2Y12 inhibitor administered intravenously, and is fast acting and has a short half-life, compared with clopidogrel, the oral P2Y12 inhibitor. The clinical effects of cangrelor persist for about an hour after the infusion is stopped – compared with days after doses when oral antiplatelet drugs are stopped.

In briefing documents filed 2 days before an FDA advisory panel is scheduled to meet to review the data on cangrelor, the reviewers wrote that they recommended approval for the percutaneous coronary intervention (PCI) indication, "the reduction of death, MI, stent thrombosis, and ischemic driven revascularization (IDR) in patients who have not been recently treated with a thienopyridine and who are undergoing PCI." This is based on the results of the CHAMPION PHOENIX study that compared cangrelor to oral clopidogrel in more than 11,000 patients undergoing PCI, which found the primary endpoint – death, MI, IDR, and stent thrombosis at 48 hours post-PCI – was significantly reduced, by 22%, among those treated with cangrelor, compared with those on clopidogrel (N. Engl. J. Med. 2013;368:1303-13).

But they do not recommend approval for the second indication proposed by the manufacturer, the Medicines Company, to "maintain P2Y12 inhibition in patients with acute coronary syndrome or with stents who are at increased risk for thrombotic events (such as stent thrombosis) when oral P2Y12 inhibitor therapy is interrupted due to surgery."

BRIDGE, a pharmacodynamic study, compared cangrelor to placebo in 210 patients with acute coronary syndrome or who were treated with a coronary stent and were at increased risk of thrombotic events after discontinuing an oral platelet inhibitor before coronary artery bypass graft surgery. Levels of platelet inhibition associated with a low risk of thrombotic events such as stent thrombosis were maintained in 99% of those treated with cangrelor, vs. 19% of those on placebo, a statistically significant difference. (JAMA 2012;307:265-74).

Their reasons for not supporting approval include the "lack of clinical data" from this study that support the pharmacodynamic effect at the dose proposed for the bridging indication and that the clinical efficacy results in the PHOENIX study could not be applied to the bridging indication because the cangrelor dose used in the BRIDGE study was fivefold lower than that in the PHOENIX study, the reviewers wrote.

The briefing documents were posted on Feb. 10, 2 days before the agency’s Cardiovascular and Renal Drugs Advisory Committee will meet to review and discuss the data on cangrelor and vote on whether to recommend approval for the indications proposed by the manufacturer.

In the documents, a divergent opinion on approval was expressed by Dr. Thomas A. Marciniak, clinical team leader in the FDA’s division of cardiovascular and renal products. He wrote that he recommended against approval for the PCI indication until another trial successfully corrected what he considered flaws in the cangrelor studies. Among the flaws he cited are the use of the 300-mg loading dose of clopidogrel allowed only in the clopidogrel arm and the "exclusive use" of the 600-mg clopidogrel loading dose in the cangrelor arm, which he commented ‘may explain some of the superiority’ of that arm." (He did not comment on the bridge to surgery indication).

But the clinical reviewers, Dr. Fred Senatore and Nhi Beasley, Pharm.D., of the same division, wrote that while the imbalance in the cangrelor-treated patients who received the higher loading dose "might have played a role in cangrelor achieving its efficacy endpoint," they noted that the 300-mg loading dose is recommended in the clopidogrel label. And the ACCF/AHA 2012 (American College of Cardiology Foundation/American Heart Association) guidelines note that the "optimal clopidogrel loading dose has not been rigorously established and that trials examining the higher loading dose vs. the standard dose ... have only generated a hypothesis suggesting a greater benefit for the higher dose," they added.

The FDA panel will be asked to vote on whether to recommend approval of the two indications, and will be asked to discuss several other questions, including the effect the patient’s diagnosis on entry into the PHOENIX study on the results, and the drug’s overall benefit-risk. In the PHOENIX study, the rates of bleeding events were 15.6% among those on cangrelor vs. 11% of those on clopidogrel.

[email protected]

The data on cangrelor support approval of the fast-acting antiplatelet drug for reducing thrombotic cardiovascular events in patients with coronary artery disease who are undergoing percutaneous coronary intervention – one of two indications being reviewed by the Food and Drug Administration, according to the agency’s clinical reviewers of the application.

Cangrelor is a platelet P2Y12 inhibitor administered intravenously, and is fast acting and has a short half-life, compared with clopidogrel, the oral P2Y12 inhibitor. The clinical effects of cangrelor persist for about an hour after the infusion is stopped – compared with days after doses when oral antiplatelet drugs are stopped.

In briefing documents filed 2 days before an FDA advisory panel is scheduled to meet to review the data on cangrelor, the reviewers wrote that they recommended approval for the percutaneous coronary intervention (PCI) indication, "the reduction of death, MI, stent thrombosis, and ischemic driven revascularization (IDR) in patients who have not been recently treated with a thienopyridine and who are undergoing PCI." This is based on the results of the CHAMPION PHOENIX study that compared cangrelor to oral clopidogrel in more than 11,000 patients undergoing PCI, which found the primary endpoint – death, MI, IDR, and stent thrombosis at 48 hours post-PCI – was significantly reduced, by 22%, among those treated with cangrelor, compared with those on clopidogrel (N. Engl. J. Med. 2013;368:1303-13).

But they do not recommend approval for the second indication proposed by the manufacturer, the Medicines Company, to "maintain P2Y12 inhibition in patients with acute coronary syndrome or with stents who are at increased risk for thrombotic events (such as stent thrombosis) when oral P2Y12 inhibitor therapy is interrupted due to surgery."

BRIDGE, a pharmacodynamic study, compared cangrelor to placebo in 210 patients with acute coronary syndrome or who were treated with a coronary stent and were at increased risk of thrombotic events after discontinuing an oral platelet inhibitor before coronary artery bypass graft surgery. Levels of platelet inhibition associated with a low risk of thrombotic events such as stent thrombosis were maintained in 99% of those treated with cangrelor, vs. 19% of those on placebo, a statistically significant difference. (JAMA 2012;307:265-74).

Their reasons for not supporting approval include the "lack of clinical data" from this study that support the pharmacodynamic effect at the dose proposed for the bridging indication and that the clinical efficacy results in the PHOENIX study could not be applied to the bridging indication because the cangrelor dose used in the BRIDGE study was fivefold lower than that in the PHOENIX study, the reviewers wrote.

The briefing documents were posted on Feb. 10, 2 days before the agency’s Cardiovascular and Renal Drugs Advisory Committee will meet to review and discuss the data on cangrelor and vote on whether to recommend approval for the indications proposed by the manufacturer.

In the documents, a divergent opinion on approval was expressed by Dr. Thomas A. Marciniak, clinical team leader in the FDA’s division of cardiovascular and renal products. He wrote that he recommended against approval for the PCI indication until another trial successfully corrected what he considered flaws in the cangrelor studies. Among the flaws he cited are the use of the 300-mg loading dose of clopidogrel allowed only in the clopidogrel arm and the "exclusive use" of the 600-mg clopidogrel loading dose in the cangrelor arm, which he commented ‘may explain some of the superiority’ of that arm." (He did not comment on the bridge to surgery indication).

But the clinical reviewers, Dr. Fred Senatore and Nhi Beasley, Pharm.D., of the same division, wrote that while the imbalance in the cangrelor-treated patients who received the higher loading dose "might have played a role in cangrelor achieving its efficacy endpoint," they noted that the 300-mg loading dose is recommended in the clopidogrel label. And the ACCF/AHA 2012 (American College of Cardiology Foundation/American Heart Association) guidelines note that the "optimal clopidogrel loading dose has not been rigorously established and that trials examining the higher loading dose vs. the standard dose ... have only generated a hypothesis suggesting a greater benefit for the higher dose," they added.

The FDA panel will be asked to vote on whether to recommend approval of the two indications, and will be asked to discuss several other questions, including the effect the patient’s diagnosis on entry into the PHOENIX study on the results, and the drug’s overall benefit-risk. In the PHOENIX study, the rates of bleeding events were 15.6% among those on cangrelor vs. 11% of those on clopidogrel.

[email protected]

The data on cangrelor support approval of the fast-acting antiplatelet drug for reducing thrombotic cardiovascular events in patients with coronary artery disease who are undergoing percutaneous coronary intervention – one of two indications being reviewed by the Food and Drug Administration, according to the agency’s clinical reviewers of the application.

Cangrelor is a platelet P2Y12 inhibitor administered intravenously, and is fast acting and has a short half-life, compared with clopidogrel, the oral P2Y12 inhibitor. The clinical effects of cangrelor persist for about an hour after the infusion is stopped – compared with days after doses when oral antiplatelet drugs are stopped.

In briefing documents filed 2 days before an FDA advisory panel is scheduled to meet to review the data on cangrelor, the reviewers wrote that they recommended approval for the percutaneous coronary intervention (PCI) indication, "the reduction of death, MI, stent thrombosis, and ischemic driven revascularization (IDR) in patients who have not been recently treated with a thienopyridine and who are undergoing PCI." This is based on the results of the CHAMPION PHOENIX study that compared cangrelor to oral clopidogrel in more than 11,000 patients undergoing PCI, which found the primary endpoint – death, MI, IDR, and stent thrombosis at 48 hours post-PCI – was significantly reduced, by 22%, among those treated with cangrelor, compared with those on clopidogrel (N. Engl. J. Med. 2013;368:1303-13).

But they do not recommend approval for the second indication proposed by the manufacturer, the Medicines Company, to "maintain P2Y12 inhibition in patients with acute coronary syndrome or with stents who are at increased risk for thrombotic events (such as stent thrombosis) when oral P2Y12 inhibitor therapy is interrupted due to surgery."

BRIDGE, a pharmacodynamic study, compared cangrelor to placebo in 210 patients with acute coronary syndrome or who were treated with a coronary stent and were at increased risk of thrombotic events after discontinuing an oral platelet inhibitor before coronary artery bypass graft surgery. Levels of platelet inhibition associated with a low risk of thrombotic events such as stent thrombosis were maintained in 99% of those treated with cangrelor, vs. 19% of those on placebo, a statistically significant difference. (JAMA 2012;307:265-74).

Their reasons for not supporting approval include the "lack of clinical data" from this study that support the pharmacodynamic effect at the dose proposed for the bridging indication and that the clinical efficacy results in the PHOENIX study could not be applied to the bridging indication because the cangrelor dose used in the BRIDGE study was fivefold lower than that in the PHOENIX study, the reviewers wrote.

The briefing documents were posted on Feb. 10, 2 days before the agency’s Cardiovascular and Renal Drugs Advisory Committee will meet to review and discuss the data on cangrelor and vote on whether to recommend approval for the indications proposed by the manufacturer.

In the documents, a divergent opinion on approval was expressed by Dr. Thomas A. Marciniak, clinical team leader in the FDA’s division of cardiovascular and renal products. He wrote that he recommended against approval for the PCI indication until another trial successfully corrected what he considered flaws in the cangrelor studies. Among the flaws he cited are the use of the 300-mg loading dose of clopidogrel allowed only in the clopidogrel arm and the "exclusive use" of the 600-mg clopidogrel loading dose in the cangrelor arm, which he commented ‘may explain some of the superiority’ of that arm." (He did not comment on the bridge to surgery indication).

But the clinical reviewers, Dr. Fred Senatore and Nhi Beasley, Pharm.D., of the same division, wrote that while the imbalance in the cangrelor-treated patients who received the higher loading dose "might have played a role in cangrelor achieving its efficacy endpoint," they noted that the 300-mg loading dose is recommended in the clopidogrel label. And the ACCF/AHA 2012 (American College of Cardiology Foundation/American Heart Association) guidelines note that the "optimal clopidogrel loading dose has not been rigorously established and that trials examining the higher loading dose vs. the standard dose ... have only generated a hypothesis suggesting a greater benefit for the higher dose," they added.

The FDA panel will be asked to vote on whether to recommend approval of the two indications, and will be asked to discuss several other questions, including the effect the patient’s diagnosis on entry into the PHOENIX study on the results, and the drug’s overall benefit-risk. In the PHOENIX study, the rates of bleeding events were 15.6% among those on cangrelor vs. 11% of those on clopidogrel.

[email protected]