The Medicines Co.’s Slimmer Cangrelor Filing Slated For April Panel Review
This article was originally published in The Pink Sheet Daily
Executive Summary
Company believes it has addressed all of FDA’s concerns in an April 2014 “complete response” letter relative to use during percutaneous coronary intervention, the only indication that will be the focus of a second advisory committee review.
The Medicines Co. is shooting for a narrower approval of its intravenous antiplatelet agent Kengreal (cangrelor), for heart disease patients undergoing percutaneous coronary intervention in cases where oral drugs are not “feasible or desirable,” when it goes for its second review by FDA’s Cardiovascular and Renal Drugs Advisory Committee.
FDA announced plans for the April 15 advisory committee meeting in a Federal Register notice published Feb. 27. According to the company, the filing covers use of Kengreal for “reduction of thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.”
Cangrelor is a rapid-acting, reversible, intravenous P2Y12 platelet inhibitor being targeted for use in acute care settings.
The company is no longer planning to pursue a bridging indication for patients who have to stop oral antiplatelet therapy.
The company had originally sought approval for two indications – use during PCI generally (not just those who were not good candidates for oral platelet inhibitors like clopidogrel) and as a bridging treatment in patients who need to stop taking their oral antiplatelet therapy in preparation for surgery.
However, during a February 2014 review, FDA’s cardio-renal committee voted against approval.
When it came to the PCI indication, advisors were uncomfortable with the margin of efficacy benefit relative to risk in the sole positive pivotal trial, CHAMPION-PHOENIX, which compared cangrelor to generic clopidogrel, especially in light of failures in other Phase III trials (Also see "Cangrelor Can’t Escape Its Past At FDA Advisory Committee" - Pink Sheet, 12 Feb, 2014.).
Panelists also had a number of concerns about use as a bridging antiplatelet therapy, including doubts about the supporting data and the rationale for a rapid-acting replacement drug for oral P2Y12 drugs (Also see "Cangrelor Advisory Cmte. Unsure Whether Plavix Even Needs Replacing" - Pink Sheet, 17 Feb, 2014.). The negative vote was stronger on the bridging indication than on the PCI claim (9-0 vs. 7-2).
New PCI Trial Not Requested
A “complete response” letter in late April 2014 was a blow but provided a silver lining.
Although FDA asked for a new clinical trial to support the bridging indication, when it came to the PCI indication – the use that happens to be most valuable to the company – the agency did not ask for a new clinical trial. Rather, it sought new analyses of efficacy endpoint data (Also see "FDA’s Cangrelor “Complete Response” Leaves Room For Approval Without New Trial" - Pink Sheet, 1 May, 2014.).
The company resubmitted the filing in December 2014 and in its year-end earnings call said that it was expecting a new advisory panel meeting in the second quarter, with a six-month review cycle.
During the call, Chairman and CEO Clive Meanwell suggested that the company was on top of the issues laid out in the “complete response” letter with respect to PCI.
There were three broad categories of issues, he explained. One related to the selection of endpoints and reworking of endpoints to look at a variety of ways of diagnosing a myocardial infarction after PCI. The other two related to internal procedures for data management and clarification of the appropriate patient populations that would benefit most from the products.
“Of course, by and large, that includes patients who were studied in the Phase III trial,” Meanwell said.
FDA also was concerned about the bioequivalence of clopidogrel clinical supplies used by control patients.
“Our submission covered all of those areas. And I think, apparently, suitably so, since the FDA accepted that filing as complete. Whether or not that means they're going to approve the drug, of course, is still open to debate, but certainly, we feel we covered all the necessary areas for the agency,” Meanwell said.
At the time of the “complete response” letter, the exec had described the additional work on the PCI claim as an “advanced number-crunching exercise” that the company was comfortable with. While he suggested that the drug could still get approved, he acknowledged that the letter included “requests for additional subgroup analyses and discussion of the CHAMPION-PHOENIX trial in relation to current American practice,” which could affect labeling.
The Medicines Co. is no longer planning to pursue the bridging indication for patients who have to stop oral antiplatelet therapy.
Cangrelor is one of a number of important cardiology drug filings slated for review and potential approval in 2015, along with two PCSK9 inhibitors – Amgen Inc.’s Repatha (evolocumab) and Sanofi/Regeneron Pharmaceuticals Inc.’s Praluent (alirocumab) – and Amgen’s heart failure candidate Corlanor (ivabradine) (Also see "Cardiovascular Agents Could Be The Heart Of 2015’s New Drug Class" - Pink Sheet, 16 Feb, 2015.).
During The Medicines Co.’s Feb. 18 call, Meanwell said that on top of cangrelor, the company is expecting three other FDA approvals in 2015: Ionsys, a transdermal delivery system for fentanyl; Raplixa, a dry powder formulation of fibrinogen and thrombin; and a new formulation of the antibiotic Minocin (minocycline).