瑞士制药巨头诺华(Novartis)近日收获重磅消息，经历大起大落的抗癌新药Farydak(panobinostat，LBH589)最终获得FDA青睐。FDA已批准Farydak联合Velcade(bortezomib，硼替佐米)和地塞米松(dexamethasone)用于既往接受至少2种治疗方案(包括Velcade和一种免疫调节(IMiD)药物)治疗失败的多发性骨髓瘤(myltiplemyeloma，MM)患者群体。FDA批准Farydak时附带有一项风险评估及减灾策略(REMS)，用于宣传和教育医疗卫生专业人员了解可能与Farydak治疗相关的风险。此次批准，也标志着Faryda成为用于治疗多发性骨髓瘤(MM)的首个组蛋白脱乙酰酶(HDAC)抑制剂，该药的表观遗传学活性，可能有助于恢复多发性骨髓瘤细胞的功能。目前，Farydak在全球其他地区的监管审查正在进行中。

　　Farydak(panobinostat)是一种新型、广谱组蛋白脱乙酰酶(HDAC)抑制剂，具有一种新的作用机制，通过阻断组蛋白脱乙酰酶(HDAC)发挥作用，该药能够对癌细胞施以严重的应激直至其死亡，而健康细胞则不受影响。

　　Farydak通过FDA的加速审批程序批准。该药的获批是基于一项全球III期临床研究(PANORAMA-1)中一项预定义亚组分析(n=193)的疗效和安全性数据。数据显示，在既往接受硼替佐米和一种免疫调节(IMiD)药物治疗的多发性骨髓瘤(MM)群体中，联合标准治疗方案(硼替佐米+地塞米松)治疗时，与安慰剂(PFS=5.8个月，n=99)相比，Farydak延长了中位无进展生存期(PFS=10.6个月，n=94)。此外，Farydak治疗组有59%的患者在治疗后肿瘤缩小或消失，而安慰剂组数据为41%。

　　不过，值得一提的是，Farydak的监管之路可谓波折。在2014年初，诺华提交panobinostat监管申请时，鉴于其良好的疗效，FDA表示将采用快速审批通道审核该药，使审查周期由通常的12个月缩短至8个月。然而，去年11月底，FDA肿瘤药物顾问委员会(ODAC)以5:2的投票结果建议拒绝批准panobinostat。该委员会表示，panobinostat针对经治多发性骨髓瘤(MM)患者群体确实有效，但该药的副作用过于严重，要求FDA慎重考虑。这一建议也迫使FDA将原定于12月份的最后期限推迟至今年3月。之后，诺华提交了额外的分析数据，同时修改panobinostat适应症，用于既往接受至少2种标准疗法(包括硼替佐米和免疫调节剂)的多发性骨髓瘤(MM)群体。FDA经过仔细审查后，最终批准panobinostat。需要指出的是，Farydak带有黑框警告，提示该药严重的腹泻和严重及致命的心脏事件、心律失常及心电图(ECG)变化。

　　多发性骨髓瘤(MM)是一种无法治愈且复发率很高的血液癌症。在过去的11年中，武田的抗癌药Velcade(硼替佐米)作为唯一一种已被证明能够延缓新诊和复发性多发性骨髓瘤(MM)总生存期(OS)的药物，在多发性骨髓瘤(MM)的临床治疗中发挥了重要作用。但该领域仍存在着远未满足的巨大医疗需求。

　　英文原文：NovartisreceivesFDAapprovalofFarydak,thefirstHDACinhibitorforpatientswithmultiplemyeloma

　　-Farydak,anHDACinhibitorwithepigeneticactivity,approvedincombinationforpatientswhoreceivedatleasttwopriorregimensincludingbortezomibandIMiD[1]

　　-FarydakprolongedmedianPFSbenefitwhenusedwithbortezomibanddexamethasonecombinationversuscombinationalone(from6to11months)[1]

　　-Multiplemyelomaisanincurablebloodcancerandthereisanurgentneedfornewtreatments[2]

　　-FarydakisapprovedunderFDA'sacceleratedapprovalprogram;regulatoryapplicationsareunderwayintheEU,Japanandworldwide

　　Basel,February23,2015-NovartisannouncedtodaythattheUSFoodandDrugAdministration(FDA)hasapprovedFarydak(panobinostat,previouslyknownasLBH589)capsulesincombinationwithbortezomib*anddexamethasoneforthetreatmentofpatientswithmultiplemyelomawhohavereceivedatleasttwopriorregimens,includingbortezomibandanimmunomodulatory(IMiD)agent[1].

　　"Farydakrepresentsanexcitingagentwithanewmechanismofactionthatispartofapromisingclassofdrugsinthissetting,"saidstudyinvestigatorPaulRichardson,MD,ClinicalProgramLeaderandDirectorofClinicalResearch,JeromeLipperMultipleMyelomaCenteratDana-FarberCancerInstitute."Importantly,Farydakhasbeenshowntoimproveprogression-freesurvivalinrelapsedmultiplemyelomapatientswhohavereceivedatleasttwopriorregimens,includingbortezomibandanIMiD,whichisanareaofparticularunmetmedicalneed."

　　Farydakhasbeenshowntoextendtheprogression-freesurvival(PFS)benefitofthestandard-of-caretherapyinthispatientpopulation[1].FarydakisapprovedunderacceleratedapprovalbasedonPFS[1].Continuedapprovalforthisindicationmaybecontingentuponverificationanddescriptionofclinicalbenefitinconfirmatorytrials.TheFDA'sacceleratedapprovalprogramgivespatientsaccesstotreatmentsforseriousorlife-threateningillnessesthatprovidemeaningfultherapeuticbenefitoverexistingtreatments.TheFDAhasapprovedariskevaluationandmitigationstrategy(REMS)forFarydak.TheREMSprogramservestoinformandeducatehealthcareprofessionalsabouttherisksthatmaybeassociatedwithFarydaktreatment.

　　ThisFDAapprovalisbasedonefficacyandsafetydatainapre-specifiedsubgroupanalysisof193patientswhohadreceivedpriortreatmentwithbothbortezomibandanIMiDduringthePhaseIII,randomized,double-blind,placebo-controlled,multicenterglobalregistrationtrial,calledPANORAMA-1(PANobinostatORAlinMultipleMyelomA)[1].ThetrialfoundthatthemedianPFSbenefitincreasedinFarydakpatientswhohadreceivedpriortreatmentwithbothbortezomibandanIMiD(10.6months;n=94),ascomparedtotheplaceboarm(5.8months;n=99)(hazardratio=0.52[95%confidenceinterval(CI):0.36,0.76])[1].

　　Themostcommonadversereactions(incidence>=20%)inclinicalstudiesarediarrhea,fatigue,nausea,peripheraledema,decreasedappetite,pyrexiaandvomiting[1].Themostcommonnon-hematologiclaboratoryabnormalities(incidence>=40%)arehypophosphatemia,hypokalemia,hyponatremiaandincreasedcreatinine[1].Themostcommonhematologiclaboratoryabnormalities(incidence>=60%)arethrombocytopenia,lymphopenia,leukopenia,neutropeniaandanemia[1].Farydakcancausefatalandserioustoxicitiesincludingseverediarrheaandcardiactoxicities.Severediarrheaoccurredin25%ofFarydak-treatedpatients.Severeandfatalcardiacischemicevents,includingseverearrhythmiasandECGchangeshaveoccurredinpatientsreceivingFarydak.Seriousadverseevents(SAEs)occurredin60%ofpatientstreatedwithFarydak,bortezomibanddexamethasonecomparedto42%ofpatientsinthecontrolarm.Themostfrequent(>=5%)treatment-emergentSAEsreportedforpatientstreatedwithFarydakwerepneumonia(18%),diarrhea(11%),thrombocytopenia(7%),fatigue(6%)andsepsis(6%).Additionalseriousadversereactionsincludedhemorrhage,myelosuppression,infections,hepatotoxicityandembryo-fetaltoxicity[1].

　　"Novartisiscommittedtodevelopinginnovativefirst-in-classtherapiesforpatientswhoneedtreatmentoptions,"saidBrunoStrigini,President,NovartisOncology."Farydakrepresentsanewdrugclassinmultiplemyeloma,providingthesepatientswithanimportanttreatmentapproachforthisdifficult-to-treatcancer."

　　Farydakisthefirsthistonedeacetylase(HDAC)inhibitoravailabletopatientswithmultiplemyeloma[3].AsanHDACinhibitor,itsepigeneticactivitymayhelptorestorecellfunctioninmultiplemyeloma[4].

　　AdditionalregulatorysubmissionsforFarydakarebeingreviewedbyhealthauthoritiesworldwide.

　　Aboutmultiplemyeloma

　　Epigeneticsisthecellprogrammingthatgovernsgeneexpressionandcelldevelopment[3].Inmultiplemyeloma,thenormalepigeneticprocessisdisrupted(alsocalledepigeneticdysregulation)resultinginthegrowthofcancerousplasmacells,potentialresistancetocurrenttreatment,andultimatelydiseaseprogression[5],[6].

　　Multiplemyelomaimpactsapproximately1to5inevery100,000peopleglobally[7].Multiplemyelomaisacanceroftheplasmacells,akindofwhitebloodcellpresentinbonemarrow-thesoft,blood-producingtissuethatfillsthecenterofmostbones.Thecanceriscausedbytheproductionandgrowthofabnormalcellswithintheplasma,whichmultiplyandbuildupinthebonemarrow,pushingouthealthycellsandpreventingthemfromfunctioningnormally[8].Multiplemyelomaisanincurablediseasewithahighrateofrelapse(whenthecancerreturns)andresistance(whenthetherapystopsworking),despitecurrentlyavailabletreatments[2].Ittypicallyoccursinindividuals60yearsofageorolder,withfewcasesinindividualsyoungerthan40[9].