FDA受理勃林格抗凝血剂Pradaxa第4个适应症

2015年4月7日讯/生物谷BIOON/--勃林格殷格翰（BI）近日宣布，FDA已受理抗凝血剂Pradaxa（dabigatran，达比加群酯）的补充新药申请（sNDA）。此次，勃林格寻求批准Pradaxa用于已接受原发性髋关节置换手术的患者，预防性治疗（prophylaxis）深静脉血栓（DVT）和肺栓塞（PE）。如果获批，这将成为Pradaxa的第4个适应症。
据估计，在美国每年开展近30万例全髋关节置换术。若不进行预防性治疗（例如，抗凝治疗预防血栓），深静脉血栓（DVT）在接受择期原发髋关节手术患者群体中的发生率高达40%-60%，而致死性肺栓塞（PE）的发生率约为五百分之一。
全髋关节置换术是一种常规手术，预防性抗凝治疗能显著改善患者的临床结果。PradaxasNDA的提交，是基于2项随机、双盲III期研究（RE-NOVATETM，RE-NOVATETMII）的积极数据。这些研究在接受全髋关节置换术患者中开展，调查了Pradaxa相对于依诺肝素（enoxaparin）在预防静脉血栓栓塞（VTE）和死亡事件的疗效和安全性。
Pradaxa最初于2010年获FDA批准上市，用于降低非瓣膜性房颤(NVAF)患者卒中和全身性栓塞风险。在2014年，FDA批准了Pradaxa2个新的适应症，用于已接受5-10天肠外抗凝剂（parenteralanticoagulant）的患者，治疗深静脉血栓（DVT）和肺栓塞（PE），以及用于既往已治疗过的患者，降低DVT和PE复发的风险。
Pradaxa是德国制药巨头勃林格殷格翰（BI）开发的一款新型抗凝血药物，该药是继华法林之后50年来首个上市的抗凝血口服新药，是抗凝血治疗领域和潜在致死性血栓预防领域的又一个重要里程碑。Pradaxa具有口服、强效、无需特殊用药监测、药物相互作用少等优点，该药在市场上的主要竞争对手是拜耳和强生的拜瑞妥（Xarelto）和辉瑞的Eliquis。
英文原文：FDAFilesSupplementalNewDrugApplicationforBoehringerIngelheim’sPradaxa®(dabigatranetexilatemesylate)fortheProphylaxisofDeepVenousThrombosisandPulmonaryEmbolismAfterHipReplacementSurgery
Ridgefield,CT,April6,2015–BoehringerIngelheimPharmaceuticals,Inc.todayannouncedthattheU.S.FoodandDrugAdministration(FDA)filedasupplementalNewDrugApplication(sNDA)forPradaxa®(dabigatranetexilatemesylate)fortheprophylaxisofdeepvenousthrombosis(DVT)andpulmonaryembolism(PE)inpatientswhohavehadprimaryelectivetotalhipreplacementsurgery.Ifapproved,thiswillbecomethefourthindicationforPRADAXA.
Itisestimatedthatnearly300,000totalhipreplacementsurgeriesareperformedeachyearintheUnitedStates.Withoutprophylaxis(e.g.,anticoagulationtreatmenttopreventbloodclots),theincidenceofDVTdetectedbyvenography(x-rayvisualizationoftheveinsafteradministeringinjectablecontrastdye)rangesfrom40percentto60percentofprimaryelectivehipsurgerypatients,andfatalPEoccursinapproximatelyoneof500patients.
“Totalhipreplacementisacommonprocedure,andpreventiveanticoagulanttreatmentisrecommendedbecauseofthepotentialforDVTandPE,whichcanbelife-threateningforsomepatients,”saidSabineLuik,MD,seniorvicepresident,Medicine&RegulatoryAffairs,BoehringerIngelheimPharmaceuticals,Inc.“TheacceptanceofthissNDAisanothersteptowardexpandingthetherapeuticusesforPRADAXAtoimprovepatientoutcomesinthispopulation.”
ThesubmissiontotheFDAisbasedontheresultsoftworandomized,double-blind,phaseIIItrials,RE-NOVATETMandRE-NOVATETMII.ThestudiescomparedtheefficacyandsafetyofPRADAXAtoenoxaparininpreventingvenousthromboembolism(VTE)anddeathinpatientsundergoingtotalhipreplacementsurgery.
InRE-NOVATE,3,494patientshavingprimaryelectivetotalhipreplacementwererandomizedtothreegroupsreceivingprophylactictreatmentwithoneoftwodosesofPRADAXA(220mgor150mg)oncedailyorenoxaparin40mgoncedailyfor28to35days.ThefirstPRADAXAgroupwasgivenadoseof110mgonthedayofsurgeryand220mgdailythereafter;thesecondPRADAXAgroupreceivedadoseof75mgonthedayofsurgeryand150mgdailythereafter.Theenoxaparingroupwasgivenadoseof40mgthedaybeforesurgeryanddailythereafter.
TheresultsshowedpatientstakingPRADAXA220mghadalowercompositetotalofVTE(VTEcomprisesDVTandPE)andall-causedeath(6.0percent)thanthoseonPRADAXA150mg(8.6percent)andonenoxaparin40mg(6.7percent).Therewasnosignificantdifferenceintheratesofmajorbleedingamongalltreatmentgroups:2.0percentforPRADAXA220mg,1.3percentforPRADAXA150mgand1.6percentforenoxaparin40mg.Themostcommonadverseeventsweregastrointestinaldisorders,withsimilarfrequenciesinalltreatmentgroups(PRADAXA220mg,44.2percent;PRADAXA150mg,44.0percent;enoxaparin40mg,44.8percent).TreatmentwithPRADAXAresultedinhigherratesofwoundsecretionthanenoxaparin(8.9percentwithPRADAXA220mgand8.3percentwithPRADAXA150mgvs.5.5percentwithenoxaparin).
InRE-NOVATEII,2,055patientsundergoingprimaryelectivetotalhipreplacementwererandomlyassignedprophylactictreatmentfor28to35dayswithPRADAXA220mgoncedailyorenoxaparin40mgoncedaily.PatientsreceivingPRADAXAweretreatedwithadoseof110mgonthedayofsurgeryand220mgdailythereafter.Theenoxaparingroupwasgivenadoseof40mgthedaybeforesurgeryanddailythereafter.TheresultsshowedthecompositetotalofVTEandall-causedeathoccurredin7.7percentofpatientsinthePRADAXAgroupvs.8.8percentofpatientsintheenoxaparingroup.Therewasnodifferenceinmajorbleedingratesbetweenthetwotreatments(1.4percentforpatientsonPRADAXAand0.9percentforpatientsonenoxaparin).Gastrointestinaldisorderswerethemostfrequentadverseeventsinthestudy,andweresimilarinbothtreatmentgroups(35.8percentofPRADAXApatientsvs.35.7percentofenoxaparinpatients).TheincidenceofwoundsecretionwasslightlyhigherforpatientsonPRADAXA(2.7percent)thanonenoxaparin(1.2percent).
PRADAXAwasinitiallyapprovedbyFDAin2010toreducetheriskofstrokeandsystemicembolisminpatientswithnon-valvularatrialfibrillation(NVAF).In2014FDAapprovedtwoadditionalindicationsforPRADAXAforthetreatmentofDVTandPEinpatientswhohavebeentreatedwithaparenteralanticoagulantforfiveto10days,andtoreducetheriskofrecurrentDVTandPEinpatientswhohavebeenpreviouslytreated.
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