2021 FDA approvals - Nature

The FDA approved 50 novel drugs in 2021, including the first KRAS inhibitor for cancer and the first anti-amyloid antibody for Alzheimer's ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature naturereviewsdrugdiscovery news article TheFDA’sapprovalcountlastyearwasinlinewithrecenttrends,despitethecontinuedimpactofCOVID-19.Theagency’sCenterforDrugEvaluationandResearch(CDER)approved50noveltherapeuticsin2021,downfrom53in2020(Fig.1;Table1).The5-yearaveragesitsat51drugsperyear.Adecadeago,itwas24drugsperyear. Fig.1|NovelFDAapprovalssince1993.Annualnumbersofnewmolecularentities(NMEs)andbiologicslicenseapplications(BLAs)approvedbytheFDA’sCenterforDrugEvaluationandResearch(CDER).SeeTable1fornewapprovalsin2021.ApprovalsbytheCenterforBiologicsEvaluationandResearch(CBER),forproductssuchasvaccinesandgenetherapies,arenotincludedinthisdrugcount(seeTable2).Source:FDA. Table1|CDERapprovalsin2021 Drug(brandname) Sponsor Properties Indication Vericiguat(Verquvo) Merck&Co./Bayer sGCstimulator Chronicheartfailure Cabotegravir;rilpivirine(CabenuvaKit) ViiV INSTIandanNNRTI HIV-1infection Voclosporin(Lupkynis) Aurinia Calcineurininhibitor Lupusnephritis Tepotinib(Tepmetko) EMDSerono METkinaseinhibitor NSCLC Umbralisib(Ukoniq) TGTherapeutics PI3KδandCK1εinhibitor MZL,follicularlymphoma Evinacumab(Evkeeza)a Regeneron ANGPTL3-targetedmAb HoFH Trilaciclib(Cosela) G1Therapeutics CDK4andCDK6kinaseinhibitor Chemotherapy-inducedmyelosuppression Casimersen(Amondys45) Sarepta Exon45-skippingASO DMD Fosdenopterin(Nulibry) BridgeBio cPMP MoCDtypeA Melphalanflufenamide(Pepaxto)b Oncopeptides Peptide-conjugatedalkylatingdrug Multiplemyeloma Dexmethylphenidate;serdexmethylphenidate(Azstarys) CommaveTherapeutics CNSstimulant ADHD Tivozanib(Fotivda) Aveo VEGFRkinaseinhibitor Renalcellcarcinoma Ponesimod(Ponvory) J&J S1Preceptormodulator Relapsingmultiplesclerosis Dasiglucagon(Zegalogue) ZealandPharma Glucagonreceptoragonist Severehypoglycaemia Viloxazine(Qelbree) Supernus SNRI ADHD Drospirenone;estetrol(Nextstellis) MaynePharma Spironolactoneandoestrogenanalogues Topreventpregnancy Dostarlimab(Jemperli)a GlaxoSmithKline PD1-targetedmAb Endometrialcancer Loncastuximabtesirine(Zynlonta)a ADCTherapeutics CD19-targetedADC B-celllymphoma Pegcetacoplan(Empaveli) Apellis ComplementproteinC3inhibitor PNH Amivantamab(Rybrevant)a J&J EGFR×METRbispecificantibody EGFRexon20-mutatedNSCLC PiflufolastatF-18(Pylarify) Progenics RadiolabelledPSMAimagingagent Prostatecancerimaging Infigratinib(Truseltiq) BridgeBio FGFR2kinaseinhibitor FGFR2-mutatedbileductcancer Sotorasib(Lumakras) Amgen KRAS-G12Cinhibitor KRASG12C-mutatedNSCLC Olanzapine;samidorphan(Lybalvi) Alkermes Atypicalantipsychoticandopioidantagonist SchizophreniaandbipolarIdisorder Ibrexafungerp(Brexafemme) Scynexis Triterpenoidantifungal Vulvovaginalcandidiasis Aducanumab(Aduhelm)a Biogen/Eisai Amyloid-β-targetedmAb Alzheimer’sdisease Asparaginaseerwiniachrysanthemi(Rylaze)a Jazz Recombinantasparagine-specificenzyme ALLandLBL,inpatientsallergictoE.coli-derivedproducts Finerenone(Kerendia) Bayer Non-steroidalMRantagonist CKDwithtype2diabetes Fexinidazole(Fexinidazole) Sanofi/DNDi Nitroimidazoleantimicrobial Sleepingsickness Belumosudil(Rezurock) Kadmon ROCK2kinaseinhibitor ChronicGVHD Odevixibat(Bylvay) Albireo IBATinhibitor PruritusinPFIC Anifrolumab(Saphnelo)a AstraZeneca IFNAR-targetedmAb SLE Avalglucosidasealfa(Nexviazyme)a Sanofi Recombinantα-glucosidase Pompedisease Belzutifan(Welireg) Merck&Co. HIF-2αinhibitor vonHippel-Lindaudisease Difelikefalin(Korsuva) CaraTherapeutics κ-Opioidreceptoragonist PruritusassociatedwithCKD Lonapegsomatropin(Skytrofa)a AscendisPharma PEGylatedhumangrowthhormone GrowthfailureduetoGHD Mobocertinib(Exkivity) Takeda EGFRkinaseinhibitor EGFRexon20-mutatedNSCLC Tisotumabvedotin(Tivdak)a Seagen/Genmab Tissue-factor-directedADC Cervicalcancer Atogepant(Qulipta) AbbVie CGRPreceptorantagonist Episodicmigraine Maralixibat(Livmarli) Mirum IBATinhibitor PruritusinAlagillesyndrome Avacopan(Tavneos) ChemoCentryx Complement5areceptorantagonist ANCA-associatedvasculitis Asciminib(Scemblix) Novartis ABL/BCR–ABL1kinaseinhibitor Ph+CML Ropeginterferonalfa-2b(Besremi)a Pharmaessentia PEGylatedinterferonα-2b Polycythaemiavera Vosoritide(Voxzogo) Biomarin CNPanalogue Achondroplasia Maribavir(Livtencity) Takeda CMVpUL97kinaseinhibitor Post-transplantCMVinfection Pafolacianine(Cytalux) OnTargetLabs FluorescentFRimagingagent Ovariancancerimaging Efgartigimodalfa(Vyvgart)a Argenx FcRn-bindingFcfragment Myastheniagravis Tezepelumab(Tezspire)a Astrazeneca/Amgen TSLP-targetedmAb Severeasthma Inclisiran(Leqvio) Novartis/Alnylam PCSK9-targetedsiRNA HeFHorASCVD Tralokinumab(Adbry)a LEOPharma IL-13-targetedmAb Atopicdermatitis aBiologicapproval.bWithdrawnlaterintheyear.A,accelerated;ADC,antibody–drugconjugate;ADHD,attentiondeficithyperactivitydisorder;ALL,acutelymphoblasticleukaemia;ASCVD,atheroscleroticcardiovasculardisease;ASO,antisenseoligonucleotide;B,breakthrough;CKD,chronickidneydisease;CMV,cytomegalovirus;CNP,Ctypenatriureticpeptide;cPMP,cyclicpyranopterinmonophosphate;DMD,Duchennemusculardystrophy;FR,folatereceptor;GHD,growthhormonedeficiency;GVHD,graft-versus-hostdisease;HeFH,heterozygousfamilialhypercholesterolaemia;HoFH,homozygousfamilialhypercholesterolaemia;IBAT,ilealbileacidtransporter;INSTI,integrasestrandtransferinhibitor;LBL,lymphoblasticlymphoma;mAb,monoclonalantibody;MoDC,molybdenumcofactordeficiency;MR,mineralocorticoidreceptor;MZL,marginalzonelymphoma;NSCLC,non-small-celllungcancer;NNRTI,non-nucleosidereversetranscriptaseinhibitor;O,orphan;P,priority;PEG,polyethyleneglycol;Ph+CML,Philadelphiachromosome-positivechronicmyeloidleukaemia;PNH,paroxysmalnocturnalhaemoglobinuria;S1P,sphingosine1-phosphate;sGC,solubleguanylatecyclase;siRNA,smallinterferingRNA;SLE,systemiclupuserythematosus;SNRI,selectivenoradrenalinereuptakeinhibitor;TSLP,thymicstromallymphopoietin.Source:Drugs@FDA. FurtherapprovalsfromtheFDA’sCenterforBiologicsEvaluationandResearch(CBER)additionsincludealandmarkmRNAvaccineandCAR-Tcellproducts(Table2).EmergencyUseAuthorizations(EUAs)madethenewstoo,withantibodiesandrapidlydevelopedoralantiviralsforCOVID-19(Table3).CBERapprovalsandEUAsarenotincludedintheannualnewdrugcount,however. Table2|SelectedCBERapprovalsin2021 Biologic Sponsor Properties Indication Lisocabtagenemaraleucel(Breyanzi) BMS/Juno CD19-targetedCAR-Tcelltherapy DLBCL Idecabtagenevicleucel(Abecma) BMS/Celgene BCMA-targetedCAR-Tcelltherapy Multiplemyeloma Prevnar20 Pfizer Pneumococcal20-valentconjugatevaccine Streptococcuspneumoniaeprevention Vaxneuvance Merck&Co. Pneumococcal15-valentconjugatevaccine Streptococcuspneumoniaeprevention TicoVac Pfizer Tick-borneencephalitisvaccine Tick-borneencephalitisprevention Comirnaty Pfizer/BioNTech COVID-19mRNAvaccine COVID-19prevention Rethymic Enzyvant Allogeneicprocessedthymustissue Congenitalathymia BMS,BristolMyersSquibb;CAR,chimericantigenreceptor;DLBCL,diffuselargeB-celllymphoma.Source:FDA. Table3|SelectedEUAsin2021 Therapeutic Sponsor Properties Indication JNJ-78436735 J&J Viralvectorvaccine COVID-19prevention Bamlanivimabplusetesevimab EliLilly Spike-targetedmAbs Mild-to-moderateCOVID-19 Sotrovimab GlaxoSmithKline Spike-targetedmAb Mild-to-moderateCOVID-19 Tixagevimabpluscilgavimab AstraZeneca Spike-targetedmAbs COVID-19prophylaxis Nirmatrelvirplusritonavir Pfizer MPROinhibitorpluscytochromep450inhibitor Mild-to-moderateCOVID-19 Molnupiravir Merck&Co. Nucleosideanalogue Mild-to-moderateCOVID-19 BMS,BristolMyersSquibb;EUA,emergencyuseauthorization;J&J,JohnsonandJohnson;MPRO,mainproteaseofSARS-CoV-2.Source:FDA. Cancerapprovalsstilldominate,accountingfor15(30%)ofthenewapprovals(Fig.2).The5-yearaverageforcancerapprovalsis28%.Neurologydrugssecuredthesecondmostapprovals,forthethirdyearrunning,with5(10%)ofthenewentrants.Infectiousdiseasesandcardiovasculardiseasestiedforthird,with4(8%)approvalseach. Fig.2|CDERapprovalsbyselectedtherapeuticareas.Indicationsthatspanmultiplediseaseareasareclassifiedunderonlyone.Source:NatureReviewsDrugDiscovery,FDA. CDERapprovalsincludedthe100thantibody,twoantibody–drugconjugates(ADCs),abispecificantibody,aconstrainedpeptideandtwooligonucleotidedrugs(Fig.3).TheFDAhadnotyetreleasedfulldetailsoftheregulatorydesignationsfortheapprovedproductsatthetimeofpublication. Fig.3|CDERapprovalsbymodality.‘Smallmolecules’includesallpeptidesofupto40aminoacidsinlength.Smallmoleculesandoligonucleotidesareapprovedasnewmolecularentities(NMEs).Protein-basedcandidatesareapprovedthroughbiologicslicenseapplications(BLAs).ADC,antibody–drugconjugate;mAb,monoclonalantibody.Source:NatureReviewsDrugDiscovery. Thesalespotentialsoftheseproductscontinuetodrag,however.Analystsexpectonly8CDER-approvedproductstoachieveblockbusterstatus,showaverageforecastsfromClarivateAnalytics’sCortellisdatabase(Table4).Biogen’saducanumabistheonlyoneoftheseforecastedtobreaktheUS$2billionmark,aspeculativebetgiventheheadwindsthatthiscontroversialAlzheimer’sdiseasedrugfaces.NovelCBERapprovalsarecompensating,withaCOVID-19vaccinebreakingrecords. Table4|Selectedblockbustercontendersin2021 Drug(sponsor) Sales(US$billions)a Comirnaty(Pfizer) 35b Prevnar20(Pfizer) 4.4 Aducanumab(Biogen) 4.1 Finerenone(Bayer) 1.9 Sotorasib(Amgen) 1.6 Inclisiran(Novartis) 1.4c Tezepelumab(AstraZeneca/Amgen) 1.4 Avacopan(ChemoCentryx) 1.4 Idecabtagenevicleucel(BMS) 1.3 Atogepant(AbbVie) 1.3 Vaxneuvance(Merck&Co.) 1.2 Lisocabtagenemaraleucel(BMS) 1.1 Lonapegsomatropin(Ascendis) 1.1 a2027averagesalesforecast,fromClarivateAnalytics’sCortellis,unlessotherwiseindicated.b2021salesforecast.c2025salesforecast.BMS,BristolMyersSquibb.Source:ClarivateAnalytics’sCortellis. VaccinevictoriesVaccines—approvedbyCBER—werethestarsofthe2021approvalshow.PfizerandBioNTech’smRNAvaccinetozinameran(Comirnaty),especially,setsnewprecedents.BioNTechstartedworkonthismRNAvaccineforCOVID-19inJanuary2020,andpartneredwithPfizerinMarch.PhaseII/IIItrialswereunderwayinJuly,providingsafetyandefficacydataforanEUAbyDecember2020.FullapprovalcamethroughinAugust2021,just1.5yearsaftertheprogrammestarted.Theaveragevaccinediscoveryanddevelopmenttimelineis10.7years.Tozinameranisalsobreakingcommercialrecords.Analystsforecastsalesofover$35billionin2021,blowingpast$21billionforthesecond-placeseller,AbbVie’s19-year-oldTNF-blockeradalimumab.ThepreviousbestlaunchforwasGilead’santiviralcombinationofledipasvirplussofosbuvir,whichearnedover$10billioninitsfirstyearonthemarketforhepatitisCvirus.High-incomecountrieshavebeencriticizedforbuyinguptoomuchtozinameran,andPfizerhascomeunderfireforitspricinganddistributionpolicies.Moderna’selasomeran(Spikevax)isclosebehindonbothspeedandprofitability.IttoosecuredanEUAforCOVID-19inDecember2020.AfullFDAapprovalisexpectedbyApril2022(seeTable5forothercandidatesupforapprovalin2022).Analystsforecastelasomeransalesofover$17billionin2021. Table5|Selectedapprovalstowatchforin2022 Drug Sponsor Properties Indication ExpectedPDUFA Faricimabb Roche Angiopoietin-2×VEGF-Abispecific nAMDandDME Jan Sutimlimaba Sanofi C1s-targetedmAb AIHA Feb Tebentafuspa Immunocore gp100-targetedTCRfusedtoCD3-bindingFab Uvealmelanoma Feb Lenacapavira Gilead Viralcapsidinhibitor HIV Feb Ciltacabtageneautoleucela J&J BCMA-targetedCAR-Tcelltherapy Multiplemyeloma Feb Relatlimabplusnivolumab BMS LAG3-targetedmAbplusPD-1targetedmAb Melanoma March Vutrisiranb Alnylam Transthyretin-targetedsiRNA hATTR April Elasomeranb Moderna mRNAvaccine COVID-19prevention April Mavacamtena,b BMS Myosininhibitor Cardiomyopathy April Betibeglogeneautotemcela bluebirdbio Lentiviralbeta-globingenetherapy β-thalassemia May Tirzepatideb EliLilly GIP/GLP1co-agonistpeptide Type2diabetes May Lutetium177Lu-PSMA-617a Novartis/Endocyte PSMA-targetedradiopharmaceutical Prostatecancer Firsthalf2022 BMS-986165 BMS TYK2inhibitor Psoriasis Sept NVX-CoV2373 Novavax Proteinsubunitvaccine COVID-19prevention EUAin2022 Donanemaba,b EliLilly Amyloid-β-targetedmAb Alzheimer’sdisease FilingbyQ1 Lecanemaba,b Biogen/Eisai Amyloid-β-targetedmAb Alzheimer’sdisease FilingbyQ2 Adagrasiba,b Mirati KRAS-G12Cinhibitor NSCLC Filingplanned Nirmatrelvirplusritonavir Pfizer MPROinhibitorpluscytochromeP450inhibitor COVID-19infection Filingplanned aBreakthroughtherapydesignated.bForecastedblockbustersalesby2027,accordingtoCortellisdatabase.AIHA,autoimmunehaemolyticanaemia;CAR,chimericantigenreceptor;DME,diabeticmacularoedema;Fab,antigen-bindingfragment;hATTR,hereditarytransthyretinamyloidosis;mAb,monoclonalantibody;MPRO,mainprotease;nAMD,neovascularage-relatedmaculardegeneration;NSCLC,non-small-celllungcancer;PDUFA,PrescriptionDrugUserFeeAct;sGC,solubleguanylatecyclase;siRNA,smallinterferingRNA;TCR,T-cellreceptor.Sources:BioMedTrackerandCortellisdatabase. ThesesuccesseshavedrivenasurgeofinvestmentsinmRNAtechnology—forflu,otherinfectiousdiseasesandcancer.“Wenowhavethefundingtoaccelerateourcancerpipelineandmakeitevenbolder,”saidBioNTechCEOUğurŞahin,whosecompanyisattheforefrontofeffortstodeveloptherapeuticmRNAvaccinesforcancer.Pfizer’sPrevnar20,a20-valentconjugatevaccineforStreptococcuspneumoniaeserotypes,isslatedtohitsalesof$4.4billionby2027.Prevnar20isanext-generationversionofPrevnar13,theworld’stop-sellingvaccinebeforethearrivaloftozinameran.AnalystsalsoforecastblockbusterstatusforMerck&Co.’snewlyapproved15-valentS.pneumoniaevaccineVaxneuvance.CancercapstonesTheapprovalofAmgen’sKRAS-G12Cinhibitorsotorasibwasamajormomentforthecancercommunity.ResearchersidentifiedKRASasaproto-oncogeneover40yearsago,andhavefoundthatitisamongstthemostfrequentlymutatedgenesincancers.ButtheGTP-hydrolysingenzymehaseludeddrugdevelopersforjustaslong,duetotheabsenceoftractablebindingpockets.Thenin2013KevanShokat,achemicalbiologistattheUniversityofCalifornia,SanFrancisco,discoveredanallostericpocketontheG12Cvariantoftheenzyme,providingatoehold.Industryrushedin.“IknewthatoncesomebodycrackedtargetingRASdirectly,therewouldbealotofinterest,”saidShokat.“Ijustdidn'tknowthattherewouldbethismuchinterest.”Amgen’ssotorasibisthefirstoftheKRAScrowdtogainapproval,forKRASG12C-mutatednon-small-celllungcancer(NSCLC).Butdespiteapprovableactivityinthissetting,sotorasibhasyettoliveuptothehopesforthisholygrailofcancertargets.Amgenistestingsotorasibincombinationwithotheragents,invariouscancers.AnalystsforecastsalesofUS$1.6billionby2027.OtherKRAS-targetedtherapeuticsareontheway.MiratiexpectsitsKRAS-G12Cinhibitoradagrasibtobeupforapprovalin2022.Merck&Co.’sbelzutifanadvancesanotherlong-runningcancerstory.TheFDAapprovedthefirst-in-classhypoxia-induciblefactor-2α(HIF-2α)inhibitorfortumoursassociatedwithvonHippel-Lindau(VHL)disease,aninheriteddisorderassociatedwithwell-vascularizedtumours.DecadesofresearchintothebiologyofVHLdiseaseshowedthatHIF-2αisakeydriverofoxygensensing—pavingthewayforanovelanti-angiogenicdrugandearningaNobelPrizeforDana-FarberCancerInstitute’sWilliamKaelinandothers.HIF-2αisatranscriptionfactor,anotherclassoftargetsthatmedicinalchemistsoftenstruggletodrug.Belzutifan,too,wasmadepossiblebythe2009discoveryofanallostericpocket.“Therearenownewwaystodiscoverchemicalsthatbindtovariousnooksandcranniesonproteinsthataren’tnecessarilyactivesites,andanumberofpeopleareusingthesetofindallostericinhibitors,”saidKaelin.OncologistsalsogainedaccesstoaBCMA-targetedCAR-Tcelltherapy,withtheapprovalofBMS’sidecabtagenevicleucelformultiplemyeloma.BCMAisexpressedonthesurfaceofBcells,andhasbecomeaprovinggroundforantibodies,bispecifics,ADCsandcelltherapies.TheFDAapprovedafirstBCMA-targetedbiologic—GlaxoSmithKline’sADCbelantamabmafodotin—in2020.Idecabtagenevicleucelprovidesacelltherapyalternative:Tcellsareharvestedfromapatient,modifiedexvivototargetBCMA,andthenre-infusedintothepatient.OthersBCMA-targetedcandidatesheadedtowardsthemarketincludeJ&J’sCAR-Ttherapyciltacabtageneautoleucel,whichisunderFDAreview.TheFDAhasapproved5otherCAR-Ttherapies,allofwhichhuntanddestroyCD19-expressingcellsforbloodcancers.WiththeFDA’sgreenlightforGlaxoSmithKline’sPD1-targetedmonoclonalantibody(mAb)dostarlimab,theantibodymodalityhitits100thapproval.TheFDAapprovedafirstantibodyin1986,35yearsago.Itnowapprovesaround10antibody-basedproductsperyear.DostarlimabistheseventhPD1/PDL1-targetedantibodytomarket.Salesforecastsforthischeckpointinhibitorreflectitslatecomerstatus.Whereasanalystsforecastsalesofover$30billionby2027forMerck&Co.’sfirst-in-classpembrolizumab,theypredictjust$270millionfordostarlimabin2025.TheFDAisreviewingfourmorePD1/PDL1antibodiesforapprovalin2022.TheFDA’sJuliaBeaverandRichardPazdurrecentlywrotethatcheckpointinhibitorshavebecomeaWildWestofdrugdevelopment,markedby“astampedeofcommercialsponsors,clinicaltrials,andredundantdevelopmentplans.”Theyurgeddrugdeveloperstoworkbettertogether.BMShassubmittedrelatlimab,afirstLAG3-targetedcheckpointinhibitor,forFDAreview.Adecisionisduein2022.TheFDAapprovedtwoADCsin2021.ADCTherapeutics’sloncastuximabtesirineisaCD19-directedADC,forB-celllymphoma.SeagenandGenmab’stisotumabvedotinisatissue-factor-directedADCforcervicalcancer.ThesebringtheapprovedADCcountupto11.TheFDAapproved7oftheseinthepast3years.EmergingclinicaldatafromAstraZeneca’sHER2-targetedADCtrastuzumabderuxtecan,approvedbytheFDAin2019,showsthatnewADCscandeliverconsiderablebenefitoverantibodyandADCforerunners.“Theprogresshereisbecausewe’redesigningADCsaswholesystemsnow,”saidSusanGalbraith,headofOncologyResearch&DevelopmentatAstraZeneca.J&Jscoredanapprovalforamivantamab,abispecificantibodytargetingEGFRandMETforNSCLCwithEGFRexon20mutations,cancersthathavebeenresistanttosmall-moleculeEGFRinhibitors.Whenamivantamabbindstoeitherreceptor’sextracellulardomain,itblocksligandbinding,promotesreceptor–antibodycomplexendocytosisanddegradation,andtriggerstrogocytosisandantibody-dependentcellularcytotoxicity.Amivantamabisthethirdbispecificantibodytomarket.Thisantibodyformataccountsfornearly20%oftheclinical-stageantibodypipeline.TheFDAalsoapprovedTakeda’smobocertinib,asmall-moleculekinaseinhibitordesignedtoselectivelytargetEGFRwithexon20mutationsforthissameindication.Alzheimer’sacrimonyTheFDA’sapprovalforBiogenandEisai’samyloid-β-loweringantibodyaducanumabwastheyear’smostcontroversialdecision.Inearly2019,aninterimanalysisoftwophaseIIItrialsofaducanumabinAlzheimerdiseasefailedtofindevidenceofactivity,promptingBiogentodiscontinueddevelopment.Butthecompanythenre-analysedthedata,foundahintofaneffectandsubmittedforapproval.InNovember2020,anindependentFDAadvisorypanelvoted10to0,with1abstention,againstapproval.TheseexpertsquestionedBiogen’sstatisticalapproachandtheclinicalsignificanceoftheclaimedeffect.TheFDAthenusedtheacceleratedapprovalpathwaytogreen-lightaducanumabonthebasisofitsabilitytoloweramyloidlevels—anunprovensurrogateendpoint.TheFDAgaveBiogenuntil2030toconfirmthattheantibodyprovidesaclinicalbenefit.Thisapprovaldividedthecommunity,andtriggeredmultipleinvestigationsintotheFDA’sdecision-makingprocess.Analystsarestillforecastingblockbustersalesof$4.1billionforBiogenby2027.Butsaleshavestartedslowly,andsometreatmentcentresintheUSAarerefusingtoprescribetheantibody.Biogeninitiallypricedaducanumabat$56,000peryear,buthassincehalveditscost.Europeanregulatorsrejectedtheantibody,andJapaneseregulatorslooksettofollowsuit.ThecommercialsuccessofthisproductwilldependonwhetherMedicare,anationalinsuranceprogrammeforpeopleaged65andolderintheUSA,willcoverit.AdraftdecisionisdueinJanuary.Twomoreanti-amyloidantibodiescouldbecomingin2022.BiogenandpartnerEisaiarefinalizingasubmissionoflenacumab.EliLillyisalsowrappingupasubmissionofitsdonanemab,andhopestohaveconfirmatoryevidenceofbenefitin2023.“Could[theapprovalofaducanumab]havebeendonebetter?Ithinkeveryoneagreesthatthiscouldhaveunfoldedmoreeffectively,”MarkMintun,seniorvice-presidentofneuroscienceresearchanddevelopmentatLilly,toldNature.“Butasthedataaccumulate,peoplewillgetmoreandmoreconvinced,andthedivisions,Ithink,willdisappear.”OtherstandoutsWiththeapprovalofNovartisandAlnylam’sinclisiran,afourthsiRNA-baseddrughasarrived.ThismodalityharnessesRNAinterferencetoreducetheexpressionoftherapeutictargets.InclisiraninhibitsPCSK9tolowerLDL-cholesterol.TheFDAapprovedtwoantibodiesthattargetPCSK9—RegeneronandSanofi’salirocumabandAmgen’sevolocumab—in2015forsubsetsofpatientswithincreasedriskofcardiovasculardisease,buttheseproductshaveyettoliveuptomulti-blockbustersalesexpectations.Inclisiran’sconveniencefactormighthelpitfarebetter.Whereastheantibodiesaredosedevery2–4weeks,inclisirancanbedosedtwiceayear.Alnylamexpectsthatlong-actingsiRNAscouldbetransformativeacrossmultipletherapeuticareas.“Weareataremarkableperiodofarenaissanceintermsofwherethistechnologycouldgo,”saidAlnylam’soutgoingCEOJohnMaraganore.IftheFDAapprovesAnlyam’svutrisiranin2022,itwillbethefifthRNAiapprovalinasmanyyears.Regeneronscoredanotherfirstinthecardiovascularspace,withitsfirst-in-classANGPTL3-targetedmAbevinacumab.Regenerongeneticallyvalidatedthistargetinatheroscleroticcardiovasculardiseasein2017.Ithasnowsecuredanapprovalforhomozygousfamilialhypercholesterolaemia(HoFH),aninheritedconditionthatischaracterizedbyextremelyhighLDL-cholesterollevels.AnotherphaseIIItrialisongoingforthepreventionofacutepancreatitis.AstraZenecaandAmgen’stezepelumabisafirst-in-classTSLP-directedmAbforsevereasthma.TSLPisanIL-7-likecytokinethatmodulatesmultipleinflammatorycascades,andthatcantriggerallergic,eosinophilicandotherformsofinflammationassociatedwiththelungdisease.Tezepelumabistheonlybiologicapprovedforsevereasthmawithoutanyphenotypeorbiomarkerlimitationsonitslabel.Analystsexpectsalesof$1.4billionby2027.AstraZeneca’sanifrolumabisthefirstnewdrugapprovedforsystemiclupuserythematosus(SLE)inadecade.ManySLEpatientshaveelevatedlevelsoftypeIinterferons,andmutationsininterferonsignallinghavebeenlinkedwithdiseasesusceptibility.AnifrolumabblockstheactivityofthesecytokinesbybindingtothetypeIinterferonreceptor.ApellisPharmaceuticals’pegcetacoplanisthefirstcomplementproteinC3inhibitortosecureapproval,showcasingcontinuedinterestincomplement-modulatingdrugs.TheFDAapprovedtheconstrainedcyclicpeptideforparoxysmalnocturnalhaemoglobinuria,arareandpotentiallyfatalblooddisorder.ChemoCentryx’savacopan,approvedbytheFDAin2021forANCA-associatedvasculitis,isthefirstcomplement5areceptorantagonisttogainapproval.“We'regoingtoseealotofactivity[incomplement-modulatingagents],especiallyifdrugdeveloperscansucceedbeyondtherareindications,”saidJohnLambris,animmunologistattheUniversityofPennsylvania.WhereasCOVID-19vaccines,antibodiesandantiviralshaveshownhowfastdrugdeveloperscanmoveunderpressure,Takeda’smaribavirprovidesacounterpoint.PhaseIdatafromthisantiviralwerefirstpresentedin1996.Theantiviralsurviveddeprioritizationandoutlicensing,afailedphaseIIItrial,andtwocompanyacquisitionsbeforeitsapprovalforcytomegalovirus(CMV)infectionsthisyear.Ifatfirstyoudon’tsucceedTheFDArejectedseveralapplicationslastyearaswell(Table6).Someofthesecouldbere-submittedforFDAreviewshortly.ProventionBio,forexample,isworkingtowardsre-submittingitsCD3-targetedmAbteplizumabforthedelayoftype1diabetesinat-riskindividuals.Teplizumabmadeitsclinicaltrialdebutin1997fortransplantrejection,andleadsapackofT-cellmodulatingtherapiesforautoimmunediseases. Table6|Selectedrejecteddrugsof2021 Drug Sponsor Properties Indication Tralokinumaba LEOPharma IL-13-targetedmAb Atopicdermatitis Arimoclomol Orphazyme Chaperoneactivation Niemann–Pickdisease Teplizumab ProventionBio CD3-targetedmAb Type1diabetes Retifanlimab Incyte/MacroGenics PD1-targetedmAb Analcancer Roxadustat AstraZeneca/FibroGen HIF-PHinhibitor Anaemiaduetochronicrenalfailure Oportuzumabmonatox SesenBio EpCAM-targetedimmunotoxin Bladdercancer Narsoplimab Omeros MASP2-targetedmAb TA-TMA Tanezumab Pfizer/EliLilly NGF-targetedmAb Osteoarthritispain Plinabulin BeyondSpring Tubulin-bindingantineoplastic Neutropenia/leukopenia aApprovedlaterintheyear.EpCAM,epithelialcelladhesionmolecule;HIF-PH,hypoxia-induciblefactor-prolylhydroxylase;IL,interleukin;mAb,monoclonalantibody;MASP2,mannose-bindinglectin-associatedserineprotease2;NGF,nervegrowthfactor;NHE3,sodium–hydrogenexchanger3;TA-TMA,transplant-associatedthromboticmicroangiopathy.Source:BioMedTracker. Otherrejectedtherapeuticshavehittheendoftheline.PfizerandEliLillydiscontinueddevelopmentoftheirNGF-targetedmAbtanezumabthisyear,aftertheFDAissuedacompleteresponseletterforuseinosteoarthritispain.TheFDAplacedtheonce-promisinganti-NGFclassonclinicalholdin2010,afterphaseIIIdatashowedthatthesepainkillerscouldcausejointdestruction. doi:https://doi.org/10.1038/d41573-022-00001-9 Jobs FACULTYPOSITIONINMOLECULARTHERAPEUTICS FoxChaseCancerCenter(FCCC),TempleUniversity Philadelphia,PA,UnitedStates JuniorProfessorship(W1)withtenuretrackleadingtoaW2(TenureTrackProfessorship)forPharmacy,withafocusonMedicinalandPharmaceuticalChemistry UniversityofHamburg(UHH) Hamburg,Germany Dean-CollegeofHealthandLifeSciences HamadbinKhalifaUniversity(HBKU) Doha,Qatar TechnicalSpecialist-CellCulture WellcomeSangerInstitute Cambridge,UnitedKingdom SignuptoNatureBriefing Anessentialround-upofsciencenews,opinionandanalysis,deliveredtoyourinboxeveryweekday. 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