On April 30, 2014, the FDA issued a complete response letter (CRL) to The Medicines Company for its intravenous ADP receptor antagonist, cangrelor (The Medicines Company, press release, April 30, 2014). This did not come as a surprise following the negative opinion the FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) adopted regarding the approval of cangrelor for two separate indications: use in percutaneous coronary intervention (PCI) and in bridging to coronary artery bypass graft (CABG) surgery. The filing included data from the trials in the CHAMPION program as well as the BRIDGE trial (see our summary of cangrelor's clinical development: Cangrelor: A New CHAMPION for ACS Patients).

The FDA's reaction to cangrelor's potential bridging indication has been particularly harsh in that it suggested that further trials will be required. But, should this really come as surprise? The evidence supporting use of cangrelor in a bridging indication comes from the small Phase II BRIDGE trial that demonstrated greater platelet inhibition with cangrelor versus placebo in ACS patients awaiting coronary artery bypass graft surgery. Interviewed thought leaders believe that the data supporting the use of cangrelor as a bridging agent are not very strong because of the small size of the BRIDGE trial and the lack of improvements in ischemic complications, a finding which was especially disappointing since cangrelor was being compared to placebo. It is currently uncertain whether The Medicines Company will pursue another trial in bridging but, given the lack of enthusiasm for this potential indication among interviewed thought leaders, we do not believe such a trial will be initiated.

Things look at bit more hopeful for cangrelor's potential PCI indication, however. A press release from The Medicines Company followed by a conference call mentioned a number of suggestions outlined by the FDA. These included the completion of further clinical data analyses of the CHAMPION-PHEONIX study (cangrelor's most recent trial), such as reanalysis of efficacy end points, subgroup analyses, and the implications of these analyses. The agency also suggested that The Medicines Company review certain processes relating to data management and that they provide documentation regarding bioequivalence of the clopidogrel clinical supplies used in the studies. As it currently stands, there do not seem to be any indications that further trials will be required of cangrelor for use in PCI. Another large PCI trial would not only be costly but would push back a potential launch for cangrelor to more closely coincide with the launch of generic prasugrel (Eli Lilly/Daiichi Sankyo's Effient/Efient) and ticagrelor (AstraZeneca's Brilinta/Brilique), two oral ADP receptor antagonists which are considered by many cardiologists to be cangrelor's direct competitors.

While we believe cangrelor will eventually gain approval, its prospects for widespread uptake have been questioned. In the CHAMPION-PHEONIX study, there were indications that cangrelor could fulfill an unmet need by reducing the rate of stent thrombosis. Patients undergoing PCI for an acute coronary syndrome (ACS), particularly those with ST-elevation myocardial infarction (STEMI), are sometimes at risk of peri-procedural stent thrombosis. However, while cangrelor reduced stent thrombosis, this did not translate into a mortality benefit in the study. Patients with stable angina were also represented in the CHAMPION-PHEONIX trial. However, stent thrombosis is less of a concern in this patient population.

So, does cangrelor have the potential to fulfill any unmet needs in the PCI setting Indeed, cangrelor is set aside from the other ADP receptor antagonists by virtue of its advantageous pharmacokinetic profile. Cangrelor's rapid onset of action and intravenous route of administration could be particularly favorable in some ACS patients, like high risk patients (especially STEMI), patients in cardiogenic shock or those with reduced oral bioavailability. There clearly is a niche for cangrelor, although this is more apparent in the ACS rather than the elective PCI setting. An expert interviewed by Decision Resources comments, I can't see cangrelor being adopted in stable coronary artery disease. My belief is it's going to be used for STEMI. That's where the docs are most worried about stent thrombosis, and that was the benefit of cangrelor.

Joseph Dwyer is a business insights analyst in the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

In-depth analysis of cangrelor and other therapies being developed for ACS, with accompanying epidemiology-driven sales forecast models, is presented in Decision Resources Acute Coronary Syndrome (Event Driven) Pharmacor report (Update publishing in May 2014).

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