1、eptifibatideTable of Contents2Snapshot.2Development Profile7Literature Review9Development Status12Chemical Structures12Drug Names12Sales and Forecasts15Clinical Trials16Deals and Patents22SWOT Analysis.23Change History.08-Oct-2014Created:Return to Table of Contents2014 Thomson Reuters All rights res
2、ervedeptifibatideSNAPSHOTeptifibatideDrug NameIntegrilin; intrifiban; velofibatide; eptifibatide; Integrelin; C68-22Other Drug NamesOriginator Company COR Therapeutics IncActive Companies Merck GlaxoSmithKline plcInactive Companies COR Therapeutics Inc; Schering-Plough Corp; Schering-Plough Canada;M
3、illennium Pharmaceuticals IncHighest Status LaunchedAcute coronary syndrome; Myocardial infarction; AnginaActive IndicationsStrokeInactive IndicationsTarget-based Actions GP IIb IIIa antagonistOther Actions Platelet aggregation inhibitorIntravenous formulation; Infusion; Biological therapeutic; Pept
4、ideTechnologiesB1C (PLATELET AGGREGATION INHIBITORS); B1C3 (GP IIb/IIIa(glycoprotein) antagonist platelet aggregation inhibitors)EphMRA CodesLast Change Date 14-Aug-2014Added Date 16-Feb-1996DEVELOPMENT PROFILESUMMARYEptifibatide (Integrilin; C68-22) is a synthetic cyclic heptapeptide glycoprotein G
5、PIIb/IIIa antagonist andplatelet aggregation inhibitor, derived from rattlesnake venom, developed and launched by Schering-Plough(now Merck however, inOctober 2003, Millennium discontinued the eptifibatide ADVANCE-MI trial, and it is presumed developmentin acute MI was terminated at that time 509043
6、. In July 2003, an investigator-led phase I/II trial began inthe US to determine if eptifibatide would be effective in treating acute ischemic stroke 858760. However,following disappointing data, no development has been reported on this indication.PATENTS AND GENERICSIn the US, the compound patent i
7、s scheduled to expire in 2014; the patents which cover the formulation anduse of eptifibatide are scheduled to expire in 2015 1393396.In January 2009, Teva Pharmaceutical notified Schering-Plough (now Merck) and Millennium that it had filedan ANDA with the FDA for generic eptifibatide, and was also
8、challenging three Millennium Orange Bookpatents listed for the drug. In February 2009, Schering and Millennium commenced patent infringementlitigation against Teva. The lawsuit would automatically halt FDA approval of Tevas ANDA until August 2011or an adverse court decision 1079416. In February 2011
9、, Merck reported that Teva did not challengecertain eptifibatide patents scheduled to expire in November 2014, and as such, was confident that FDAapproval of Tevas ANDA application would not occur before November 2014 1172264. In October 2011,the parties entered a settlement agreement, allowing Teva
10、 to market its generic eptifibatide beginning June2015 1267460.In November 2012, a patent infringement lawsuit was filed against APP Pharmaceuticals (a subsidiary ofFresenius Kabi), in respect of APPs application to the FDA for generic eptifibatide. The lawsuit automaticallystayed FDA approval of AP
11、Ps ANDA until April 2015 or earlier in the event of an adverse court decision1393396. In March 2013, a settlement agreement between both parties allowed APP to sell a genericversion beginning June 2015 1530886.In September 2013, another patent infringment lawsuit was filed against Ben Venue Laborato
12、ries, doingbusiness as Bedford Laboratories, concerning Bedfords application to the FDA seeking pre-patent expiryapproval to sell a generic version of Integrilin. The lawsuit automatically stayed FDA approval of Bedfordsapplication until February 2016 or earlier in the event of an adverse court deci
13、sion 1530886.REGULATORYTHE USCOR filed eptifibatide for marketing approval in the US in April 1996 to prevent ischemic complications inpatients undergoing percutaneous transluminal coronary angioplasty (PTCA) 195003, 204160. InFebruary 1997, the FDAs Cardiovascular and Renal Drugs Advisory Committee
14、 decided that althougheptifibatide had positive results in the IMPACT II trial as an adjunct therapy in the prevention of acute cardiacischemic complications in patients undergoing PTCA, the results were not compelling enough; the FDArecommended that confirmatory results from another trial should be
15、 submitted for approval 236066,237316, 240112. In May 1998, the FDA approved eptifibatide for the treatment of ACS (unstable anginaand non-Q-wave MI) and PCI and it was launched in June 1998 287360, 311365, 288265, 1484863.Return to Table of Contents2014 Thomson Reuters All rights reserved 3EUROPEIn
16、 April 1997, Schering-Plough withdrew its application for European marketing approval for the treatment ofacute cardiac ischemic complications in patients undergoing PTCA based on discussions with the regulatoryagency 242335. A Centralized Marketing Authorization for eptifibatide was accepted for re
17、view in July 1998292816. Eptifibatide was recommended for approval in February 1999 by the EMEAs CPMP 316719, andapproved in July 1999, for the prevention of early MI in patients with ACS 330662; at that time, the drugwas approved in Denmark, and subsequently launched 1421099; at the same time, the
18、drug was approvedin the Netherlands 1434725, and subsequently launched 1434727. In July 1999, the drug was approvedin the Czech Republic and Latvia 1446687, 1455303 and was subsequently launched 1444818,1454583; at that time, the drug was also approved in Estonia 1461610. By December 1999, the drug
19、hadbeen launched in Germany for MI by Mercks subsidiary, Essex pharma 1341008. In September 1999, thedrug was launched in France 1350158. In April 2000, the drug was approved in Iceland 1452526 andsubsequently launched 1450511. In November 2000, the drug was approved in Croatia 1474224. InNovember 2
20、001, the drug was approved in Bulgaria 1450276. In January 2005, the drug was launched inNorway 1458050. In September 2005, the drug was launched in Switzerland 1575982. In March 2007, thedrug was launched in Portugal 1382915.Eptifibatide was granted technical approval in Switzerland in injection an
21、d infusion solutions as a plateletanti-aggregant 1388440.REST OF THE WORLDCANADACOR filed eptifibatide for marketing approval in Canada in April 1996 195003, 204160. In August 1999,eptifibatide was approved in Canada for the treatment of patients presenting with symptoms of unstableangina or non-Q-w
22、ave MI 335590. By December 2009, Canadian launch had taken place 1079416.ASIA PACIFICIn June 2002, the drug was approved as Integrilin injection in Taiwan. It is indicated for prevention ofexacerbation in patients with unstable angina and non-Q-wave myocardial infarction; as adjuvant therapy topercu
23、taneous transluminal coronary dilation; for the prevention of sudden arterial occlusion and associatedacute ischemic complications 1533772. The product was assumed to be launched shortly after its approvalthere 1530180.POSTMARKETINGIn November 2009, data were presented at the AHA Scientific Sessions
24、 in Orlando, FL. In a study thatassessed the non-inferiority of eptifibatide to abciximab in subjects (eptifibatide n = 3703; abciximab n =10,252) with acute coronary syndromes receiving PCI, 543 and 1607 of eptifibatide- and abciximab-treatedpatients experienced death and myocardial infarction duri
25、ng one year, respectively. Non-inferiority wasdemonstrated for eptifibatide versus abciximab (hazard ratio of 1.07) 1054412.By April 2005, eptifibatide was being evaluated in the REMOVE trial, assessing eptifibatide with or without athrombin inhibitor (heparin or bivalirudin) in low-risk patients un
26、dergoing PCI) 581944, 598184. In October2007, data were published from the REMOVE trial. Patients undergoing elective PCI (n = 159) receivedeither intraprocedural eptifibatide alone or eptifibatide plus heparin. All patients received aspirin (325 mg)and clopidogrel (300 mg) before the procedure. The
27、 primary endpoint was Landefeld bleeding index, withsecondary endpoints of a composite clinical outcome of in-hospital death, myocardial infarction, urgenttarget vessel revascularization, and Thrombolysis In Myocardial Infarction major bleeding, and a compositebleeding outcome of major, minor, and n
28、uisance bleeding. The Landefeld bleeding index was significantlylower for patients treated with eptifibatide alone compared to eptifibatide plus heparin. There was nosignificant difference in the composite clinical endpoint between eptifibatide and eptifibatide plus heparin1081491.Return to Table of
29、 Contents2014 Thomson Reuters All rights reserved 4By April 2005, eptifibatide was being evaluated in the TITAN trial (comparing early use of eptifibatide in STelevation MI compared to eptifibatide given at angioplasty), and EVENT trial (examining use of GPIIb/IIIainhibitors with drug-eluting bare m
30、etal stents) 579885, 581944, 598184. However, by July 2008 TITANhad been terminated due to poor enrollment 954154.Data released in November 2004 from the CLEAR Platelets study, suggested that combined treatment ofclopidogrel with eptifibatide was more effective in achieving optimal platelet inhibiti
31、on and prevention of heartmuscle damage in PCI than clopidogrel alone 581944, 598184.In November 2004, a phase III, 9500-patient study (NCT00089895; P03684AM2; EARLY ACS) began. Itaimed to evaluate whether eptifibatide reduced the occurrence of death, heart attack and urgent cardiacintervention comp
32、ared to placebo in ACS patients with non-ST-segment elevation on first presentation to theER. It was due to be completed in October 2008 954126. In March 2009, results from the study werepresented at the 58th annual ACC Scientific Sessions in Orlando, FL. Patients were randomized assigned toreceive
33、either early-eptifibatide (two iv boluses, each containing 180 microg/kg administered 10 min apart,and a standard infusion (2.0 microg/kg/min) 12 h before angiography) or a placebo infusion with provisionaluse of eptifibatide after angiography (delayed-eptifibatide). Data demonstrated that eptifibat
34、ide failed toachieve either the primary or secondary trial endpoints; the primary endpoint occurred in 9.3% and 10% ofpatients in the early- and delayed-eptifibatide groups, respectively. The rate of death or myocardial infarctionat 30 days were 11.2% and 12.3% for both groups respectively. Signific
35、antly higher rates of bleeding wereobserved in the early-eptifibatide group, however there were no significant differences between the twogroups in the rates of severe bleeding or non-hemorrhagical serious adverse events 996226, 996467.In May 2003, a phase III, randomized, open-label, active-control
36、led, parallel-group study (NCT00250471;PROTECT-TIMI 30) was initiated in the US, to evaluate the safety and efficacy of eptifibatide (with or withoutunfractionated heparin or enoxaparin) versus bivalirudin, for the relative protection against post-PCImicrovascular dysfunction and ischemia in patient
37、s (n = 900) at high risk for heart attack and othercardiovascular complications who were to undergo PCI. The primary endpoints included improved coronaryflow reserve (efficacy) and TIMI (Thrombolysis In Myocardial Infarction) major hemorrhage within 48 h afterrandomization in the trial or hospital d
38、ischarge (safety). The study was completed in September 20041107473. In January 2005, results from the trial were reported. Data showed that eptifibatide increasedmyocardial perfusion in the PCI setting, while bivalirudin increased the coronary flow reserve 600463. Fullresults from the study were pu
39、blished in June 2006. Patients (n = 857) with non-ST-segment elevation ACSwere randomized to eptifibatide plus reduced dose unfractionated heparin (n = 298), eptifibatide plusreduced-dose enoxaparin (n = 275), or bivalirudin monotherapy (n = 284). Data from the 754 evaluablepatients showed that the
40、primary end point of post-PCI coronary flow reserve was significantly greater withbivalirudin (1.43 versus 1.33 for the pooled eptifibatide arms). The TIMI myocardial perfusion grade moreoften was normal with eptifibatide treatment compared with bivalirudin (57.9 versus 50.9%, respectively).Furtherm
41、ore, the ischemia duration on continuous Holter monitoring after PCI was prolonged significantlylonger in patients who received bivalirudin (169 versus 36 min for eptifibatide). Although there was noexcess of TIMI major bleeding among patients treated with eptifibatide compared with bivalirudin (0.7
42、%, n =4 versus 0%, respectively), TIMI minor bleeding (2.5 versus 0.4%, respectively) and transfusion (4.4 versus0.4%, respectively) were both increased. The study concluded that among moderate- to high-risk patientswith ACS undergoing PCI, coronary flow reserve was greater with bivalirudin than ept
43、ifibatide. Eptifibatideimproved myocardial perfusion and reduced the duration of post-PCI ischemia but was associated withhigher minor bleeding and transfusion rates 1107484.PREMARKETINGACS/STEMIPHASE IIIA phase III trial in the treatment of patients with STEMI was initiated in 4Q02. This developmen
44、t was listedas ongoing in July 2003 497207, 497329. However in October 2003, Millennium announced that it haddiscontinued the eptifibatide ADVANCE-MI clinical trial 509043.Return to Table of Contents2014 Thomson Reuters All rights reserved 5In June 2004, Millennium and Schering-Plough initiated a mu
45、lticenter phase IIIb trial to evaluate the benefitof eptifibatide when given early to high risk patients experiencing non-ST segment elevation ACS. This trialwas designed to reflect current treatment guidelines 579885. In August 2004 and November 2004,eptifibatide was listed in the Schering-Plough p
46、ipeline as being in phase III development for early ACS555719, 575533.PHASE IIPhase II trials investigating the use of eptifibatide administered prior to coronary artery bypass graft (CABG)were listed as ongoing by Millennium in July 2003 497207, 497329.In February 2000, enrollment in the ESPRIT stu
47、dy of eptifibatide in patients undergoing coronaryintervention with stenting was halted, after a 50% reduction in death or heart attack at 30 days was observedin an interim analysis 354627. Final data from ESPRIT were published in December 2000. 2064 patientsundergoing stent implantation were enroll
48、ed. Immediately before PCI, patients were randomized to receiveeptifibatide, given as two 180 microg/kg boluses 10 min apart and a continuous infusion of 2 microg/kg/minfor 18 to 24 h, or placebo, in addition to aspirin, heparin and a thienopyridine. The primary endpoint was thecomposite of death, m
49、yocardial infarction, urgent target vessel revascularization, and thrombotic bailoutglycoprotein IIb/IIIa inhibitor therapy within 48 h. The key secondary endpoint was the composite of death,myocardial infarction, or urgent target vessel revascularization at 30 days. The primary endpoint wasreduced from 10.5% of patients on placebo to 6.6% with treatment. The key 30-day secondary endpoint wasalso reduced, from 10.5% to 6.8%. Major bleeding
