2015年6月22日,美国食品药品监管局(FDA)批准Kengreal(坎格雷洛[cangrelor])，一种静脉抗血小板药预防在供应心脏血流的血管冠状动脉中有害的血凝块形成。它被批准为进行经皮冠状动脉介入治疗(PCI) 成年患者，一种操作用于打开一个被阻塞或狭窄冠状动脉改善对心肌血流。
按照美国疾病控制和预防中心，在美国每年约 500,000人进行PCI。冠状动脉在狭窄部位被充气气球打开，通常接着通过放置一个小网管，被称为支架，保持动脉打开。
通过预防血小板积聚，Kengreal与操作相关的严重凝血的并发症风险，包括心脏发作和支架的凝血(支架血栓形成)。
FDA的药品评价和研究中心心血管和肾脏药部主任Norman Stockbridge，M.D.，Ph.D.说：“对进行经皮冠状动脉介入治疗患者，凝血可致严重问题，”， “Kengreal的批准为患者提供另外治疗选择。”
如同其他FDA-批准的抗血小板药，出血，包括危及生命出血，是Kengreal的最严重风险。
在一项超过10,000例参加者临床试验中Kengreal与Plavix(氯吡格雷[clopidogrel])比较，Kengreal显著减低心脏发作的发生，需要进一步操作打开动脉和支架血栓形成。用Kengreal比用氯吡格雷严重出血的总发生低但更常见。严重出血每170例Kengreal患者约一例有相比在每275例氯吡格雷患者中约一例。
Kengreal是由总部设在新泽西州Parsippany的Medicines公司制造。
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm452172.htm
Kengreal Approval History
•FDA approved: Yes (First approved June 22nd, 2015)
•Brand name: Kengreal
•Generic name: cangrelor
•Company: The Medicines Company
•Treatment for: Percutaneous Coronary Intervention
Kengreal (cangrelor) is an intravenous P2Y12 platelet inhibitor indicated for use in patients undergoing Percutaneous Coronary Intervention (PCI) to reduce the risk of periprocedural thrombotic events.
New Drugs Online Report for cangrelor
Information
Generic Name: cangrelor
Trade Name: Kengrexal (EU), Kengreal (US)
Entry Type: New molecular entity
Development and Regulatory status
UK: Approved (Licensed)
EU: Approved (Licensed)
US: Recommended for approval (Positive opinion)
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
May 15: The Medicines Company hope to launch Kengrexal in the UK in the coming weeks or months [25].
01/05/2015 12:58:41
Apr 15: US advisory committee votes 9-2 with one abstention in favour of recommending cangrelor for approval [24].
17/04/2015 17:15:45
Apr 15: Ahead of an advisory committee meeting on 15 Apr, FDA reviewers conclude that the benefit of cangrelor compared to clopidogrel is small, but the risk is smaller. Treating 171 patients prevents one clinically meaningful periprocedural MI. In comparison, treating 1106 patients causes one GUSTO severe bleed. They recommend that cangrelor be approved as an adjunct to PCI for reducing risk of periprocedural ischaemic complications including MI & stent thrombosis in patients in whom treatment with an oral P2Y12 platelet inhibitor prior to PCI is not feasible and when glycoprotein IIb/IIIa receptor antagonists are not anticipated to be used [23].
14/04/2015 09:49:33
Mar 15: The Medicines Company is seeking potential partners to support supply during 2015 and beyond [22].
02/04/2015 09:17:28
Mar 15: A new drug application for Kengreal (cangrelor) is under active review by the FDA [22].
02/04/2015 08:58:07
Mar 15: Approved in the EU. The marketing authorisation is valid in the 31 countries of the European Economic Area, which includes all 28 EU Member States, plus Norway, Iceland and Liechtenstein [22].
02/04/2015 08:49:54
Jan 15: EU positive opinion for Kengrexal, co-administered with acetylsalicylic acid, for reduction of thrombotic CV events in adult patients with coronary artery disease undergoing 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 [21].
23/01/2015 14:06:55
May 14: The FDA has not approved cangrelor. It has requested further analysis of data from the PIII PCI study, reviewing processes and double-checking clinical supplies, and has also requested a new study for the bridge indication as the results of the 210-patient trial did not clarify the drug´s risk-benefit profile [20].
02/05/2014 21:55:58
Feb 13: An FDA advisory panel voted 7 to 2 against recommending approval for cangrelor to prevent cardiovascular events in patients undergoing PCI. The panel also voted unanimously against recommending its use in maintaining antiplatelet therapy in patients with ACS or those with stents who are at increased risk for thrombotic events when oral P2Y12 therapy is interrupted due to surgery [19].
14/02/2014 15:07:55
Feb 14: FDA reviewers are divided on cangrelor ahead of an advosry panel meeting. One claims there are no data to demonstrate superiority or noninferiority of cangrelor over clopidogrel and states that cangrelor may be harmful to some patients and shouldn´t be approved. The reviewer criticises the use of different doses of the two drugs and says that the studies included work done unethically and that another study is needed to correct the flaws of the previous work. However another FDA reviewer concludes that the company has presented a convincing case that the drug met the main goal of the study, warranting an approval [18].
10/02/2014 20:48:41
Dec 13: European Medicines Agency (EMA) has accepted for review a marketing authorisation application (MAA) [17]
24/12/2013 08:40:46
Jul 13: Filing in EU expected Q4 2013 [15].
02/07/2013 11:29:53
Jul 13: Filed in the US for use in patients undergoing PCI and those that require bridging from oral antiplatelet therapy to surgery [15].
02/07/2013 11:28:55
Mar 13: EU & US filings will take place in the 2Q 13 [14].
12/03/2013 07:54:08
Jan 13: Company plan to file in EU and US in 2013 based on the Chamion Phoenix and Bridge studies [13].
10/01/2013 09:50:56
Apr 12: PIII CHAMPION PHOENIX (NCT01156571) continues to recruit pts [11].
19/04/2012 16:34:38
Company report for 1Q 2011 states: Cangrelor (and oritavancin) PIII trials are each ahead of enrollment schedule. This implies that development of cangrelor is ongoing [8].
19/04/2012 16:20:04
May 09: PIII CHAMPION programme discontinued. Interim analysis indicates that the programme will not meet efficacy endpoints (3).
25/05/2009 17:12:29
PIII enrollment commenced (1)
Trial or other data
Apr 15: Re-eva luation of the pivotal Champion-Phoenix trial suggests that cangrelor reduced the risk of death, heart attack, repeat procedures and stent thrombosis compared with clopidogrel due to its fast action and clearance. The data indicated that patients on Kengreal were 22% less likely to have those complications 48 hours after the stent procedure than patients who were given clopidogrel. The primary change in the recent eva luation of the study was to differentiate between heart attacks associated with cangrelor and heart attacks that may have been caused by the angioplasty itself.
14/04/2015 10:10:13
Sep 13: A pooled analysis of patient-level data from CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX was presented at the European Society of Cardiology on the 3/9/13 and concurrently published in The Lancet [16].
06/09/2013 11:17:24
Apr 13: Results of the PIII CHAMPION PHOENIX study published in New Engl J Med 2013: 368; 1303-13 (4 Apr).
23/04/2013 11:07:49
Mar 13: In the PIII CHAMPION PHOENIX study, 4.7% of pts taking cangrelor either died, had a heart attack, experienced a repeat procedure or had a blood clot develop on their stent 48 hours after surgery (stent thrombosis) vs. 5.9% in the clopidogrel group (22% reduction in risk). For stent thrombosis at 48 hours, a secondary endpoint, the reduction in risk was 38% [14].
12/03/2013 07:53:27
Jan 13: Company reports the PIII CHAMPION PHOENIX study met its primary composite efficacy endpoint of death, myocardial infarction, ischemia driven revascularization and stent thrombosis at 48 hours vs clopidogrel [13].
10/01/2013 09:50:32
Jul 12: The Company expects to complete patient enrollment in CHAMPION PHOENIX trial in Q4 2012. Following a pre-specified interim analysis on data from ~ 7,700 patients, the independent data safety monitoring board agreed that10,900 patients was an adequate sample size; it was thought that a sample size of 15,000 might be needed which would have extended enrollment over a further year [12].
23/11/2012 08:56:22
Oct 10: PIII CHAMPION PHOENIX trial (NCT01156571) comparing cangrelor to clopidogrel for preventing ischaemic events in 10 900 pts who require PCI starts. The primary outcome is the composite incidence of all-cause mortality, MI, ischaemia-driven revascularisation & stent thrombosis. The trial will be conducted in the US & is expected to be completed in Sep 12 [9].
19/04/2012 16:19:35
April 10: In the CHAMPION PLATFORM (n=5,362) study cangrelor was less effective than placebo when 600mg of clopidogrel was given at the time of PCI. Assessment of bleeding risk was complicated by the use of more than one rating scale. (7)
06/04/2010 15:54:46
April 10: CHAMPION PCI study results (n=8877). Intravenous cangrelor has failed to show a benefit on the primary end point of a composite of death, myocardial infarction (MI) or ischaemia-driven revascularisation 48 hours after percutaneous coronary intervention (PCI) when compared with clopidogrel 600mg administered before PCI. (7)
06/04/2010 15:54:38
Nov 09: NeJM Editorial (6)
16/11/2009 08:36:40
Nov 09: CHAMPION-PLATFORM results: Doubl-blind, placebo-controlled study,5362 patients who had not been treated with clopidogrel randomly assigned to either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point. The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas. (5)
16/11/2009 08:36:01
Nov 09: CHAMPION-PCI results: RCT comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in 8716 patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14). (4)
16/11/2009 08:33:36
May 09: Company announced that it is discontinuing its PIII CHAMPION clinical trial programme of cangrelor in patients undergoing PCI as it showed no significant differences vs clopidogrel in measures of clinical effectiveness in an interim analysis. The independent Interim Analysis Review Committee (IARC) recommended that enrollment in both trials be discontinued. The IARC also recommended that the company might focus on short-term use of cangrelor in settings where oral drugs cannot be used or when a short half-life is highly desirable. The company had previously begun studying cangrelor in this setting in the BRIDGE study, which aims to establish the dose of cangrelor that achieves ≥ 60% inhibition of platelet aggregation for 5 days. They plan to enroll 200 patients who discontinue clopidogrel in preparation for cardiac surgery. The aim is to show safe bridging of patients during the pre- and post-surgical period of risk. If successful, this approach may form the basis for regulatory filings (3)
25/05/2009 17:13:21
Two PIII trials underway: CHAMPION-PCI began in March 2006, and will enrol approximately 9,000 patients. It is comparing the effect of cangrelor vs. clopidogrel on all-cause mortality, myocardial infarction, and ischemia in subjects requiring PCI; CHAMPION-PLATFORM started in October 2006 and is comparing cangrelor + usual care vs. usual care in around 440 patient requiring PCI (2)
26/03/2009 16:47:45
Evidence Based eva luations
EPAR http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003773/WC500188100.pdf
NICE scope
NHSC
Available only to registered users
Category
BNF Category: Antiplatelet drugs (02.09)
Pharmacology: P2Y12 recepter blocker
Epidemiology: In the UK, about 114,000 pts with ACS are admitted to hospital each year [10].
Indication: Coronary artery disease
Additional Details: for reduction of thrombotic CV events in adults undergoing PCI
Method(s) of Administration
Intravenous
Company Information
Name: The Medicines Company
US Name: The Medicines Company
Further Information
Anticipated commissioning route (England) NHSE
High cost drug list? No
Tariff Healthcare Resource Group included.
In NICE timetable: Yes
When: Aug / 2015
Note: www.nice.org.uk/Guidance/InDevelopment/GID-TAG464
Implications Available only to registered users |
