評(píng)估報(bào)告評(píng)估-抗體驅(qū)動(dòng)的細(xì)菌偶聯(lián)物-EVALUATING ANTIBODY DRUG CONJUGATES

EVALUATING

ANTIBODYDRUGCONJUGATES

ADCMarket

Landscape

ADCMarketLandscape

Antibody-drug

conjugates(ADCs)arethehottestrealestateinoncology.

Bigpharmaaredishingoutbillionstobuyorlicensethem:in2023,Pfizerpaid$43billionforSeagen,AbbViestumpedup

over$10billionforADCpioneer

ImmunoGen,andMerckforkedout$4

billionup-front–andpotentiallyupto

$22billion–toDaiichiSankyoforashareofthreeofitsADCs.Theactioncontinuesin2024,withJohnson&Johnson’s$2

billioncashdealforAmbrxPharmaandRoche’slicensingdealwithSuzhou,

China-basedMediLinkTherapeuticsinJanuary.

ThetotalvalueofADC-focusedM&Aandpartnershipactivitywascloseto$100

billionintotalin2023–morethanthreetimesthevalueofsimilardealsin2022,andninetimesthedealtallyin2019,

accordingtoEvaluatePharma.

Despiteachock-fullADCpipeline,

accessingevenearly-stageassetsisnowtrickyforallbutthebiggestandrichest:onebiotechCEOinSeptemberdeclaredbeing“pricedout”ofADClicensing

negotiationsdespitehavingraisedcloseto$200million.

What’sthefuss?ADCscombinethe

specificityofmonoclonalantibodieswiththepotencyofcytotoxicdrugstocreatewhatisineffectprecisionchemotherapy.

Thescientificandcommercialpromise

arereal:overadozenADCsareapprovedintheUS.Thebiggest,Daiichi/

AstraZeneca’sEnhertu,soldmorethan$1.6billionin2022andisforecasttotop

$9billionby2028,accordingtoEvaluateconsensusforecasts.Bythen,theADCcategory–includingdevelopment

candidateswithsalesforecasts–willbeworthalmost$30billion.

RochetopstheADCpilein2023,with

breastcancerADCKadcylaand

lymphomatherapyPolivybringinginover$3billionincombinedannualsales.But

DaiichiSankyoisforecasttotakethelead

by2028,withcloseto$10billion

combinedsalesfromEnhertuand

Phase3

hopeful

datopotamabderuxtecanwhosepositiveresultsinSeptembertakeitclosetoregulatorysubmission.Bothare

partneredwithAstraZeneca.Pfizerwillbe

insecondplacein2028,thankstothe“

gooselayingthegoldeneggs

”–akaSeagen.

2023’s

EuropeanSocietyofMedical

Oncology

(ESMO)congresswasa-buzzwithADCtales,includingadoublingofmediansurvivalshownbyAstellas/

Seagen’sPadcev

incombinationwith

Merck’scheckpointinhibitorKeytrudainadvancedbladdercancer.

TOPFIVECOMPANIESBYCOMBINEDADCSALES,2023AND2028

Company

2023ADCsales($m)

2028ADCsalesforecast($m)

DaiichiSankyo

2,459

9,998

Pfizer/Seagen

1,952

5,277

Gilead

1,071

3,423

Roche

3,072

3,128

AstraZeneca*

295

1,702

*sharesofDaiichi’sEnhertuanddatopotamab

TheADCpipelineisburstingwithnext-generationhopefulsplusnewindicationsandcombinationsforexistingtherapies.

Thereareover150clinicalstage

programs,includingalmostfortyinPhase2andadozeninPhase3,accordingto

BioMedtracker.Currentdevelopment-

stageprogramswithforecastsattached–

typicallythemostadvanced–willbeworthcloseto$6billionby2028,

accordingtoEvaluate.

TheideabehindADCs–usingantibodies’targetingabilitytoferrytoxicmedsto

cancercells–soundssimpleenough.Butfindingtherightcombinationofantibody,linkertechnologyandwarheadisdifficult.Linkersdeterminehowmuchpayloadcanbecarried(the“drug-to-antibody”ratio),andwhenandwhereitisreleased.

Droppingthepayloadearly,oroff-target,willlimitADCefficacy(atbest)or,at

worst,damagehealthytissue.

Thechoiceoflinkerandpayloadmatters:EnhertuandKadcylausethesame

antibody,trastuzumab(soldseparatelyasHerceptin).Yettheirlinkersandpayloads

differ.Enhertu,whichcarries

chemotherapydrugDXdviaacleavablelinker,ismoreeffectiveatprolonging

survivalthanemtansine-carryingKadcyla,withitsnon-cleavablelinker.Hencethe$7billiongapinpeaksales:ten-year-oldKadcylaisexpectedtomaxoutatjust

over$2billionthisyear.

Pfizerhadtore-designandrelaunchthefirsteverADC,Mylotarg(approvedin

2000)duetotoxicityresultingfroman

unstablelinker.AbbViepaidnearly$6

billionfor

Stemcentrx

in2016,butstar

ADCRova-Tfailedtwoyearslater.So

AbbVie’splayeditsaferwithImmunoGen,whosefirstADC,Elahere,received

conditionalapprovalin2021forovariancancerandisgrowingfast.

Hiccupscontinue:GlaxoSmithKline

withdrewmultiplemyelomadrugBlenrep(belantamabmafodotin)fromtheUS

marketinlate2022afterafailed

confirmatorytrial(thoughit’s

having

bigpharmaboughtMablinktoo,withits

ChinarightstoHansohPharma’sovarian/

aprogramco-designedbyMediLink.

anothergo

),andADCTherapeutics’

platformpromisingtargetedpayload

endometrialtumorADC.Thedrugisin

(NonaisownedbyHong-Kong-based

CD-19targetingZynlonta,whichnabbed

releaseandahigherdrug-to-antibody

Phase1trialsinChina,anotherregion

HBMHoldingsLtd.)

anacceleratedapprovalin2021forB-celllymphoma,thisyear

failed

aPhase2

ratio.Alsoin2023,BristolMyersSquibbpaid$23millionforaccesstoTubulis’

enjoyinganADCboom.

conjugationtechnologyandanother

$100millionforSouthKoreanfirmOrumTherapeutics’Phase1antibody-protein

degraderconjugate.InDecember,theBigPharmaplungedintoADCsdeeperstill,

withan$800millionup-frontdealforex-ChinarightstoSystImmune’sPhase2

bispecificADCtargetingEGFRandHER3.

GSKisalsodippingitstoesbackinto

ADCs,withan$85millionup-front

licensingdealinDecember2023forex-

combinationtrialwithrituximabduetoadverseevents.ZynlontaisalsobeinghitbycompetitionfromPolivy.

EliLillyandBristolMyersSquibbhave

kittedupwithADCsandlinker

technologiesviasmalleracquisitions.InJune2023,Lillypaidafewmillionfor

Germanstart-upEmergence,whosepre-clinicalNectin-4targetingADCusesa

linkertechnologylicensedfromLyon,

France-basedMablinkBioscience.Sothe

InotherWestern-ChineseADCtie-ups,

BioNtechinApril2023handedover$170

milliontoShanghai-basedDualityBiofor

accesstotwopipelineADCsincludinga

HER2-targetedtopoisomeraseinhibitor-

basedADCinPhase2,andsixmonths

laterlicensedaHER3-directedADCfrom

MediLink.AstraZenecalicensedapre-

clinicalADCfromShanghai-based

LaNovaMedicinesandPfizerpaid$53

millionforNonaBiosciences’mesothelin-

targetedADCinthefinalweeksof2023–

TheideabehindADCs–usingantibodies’targetingabilitytoferrytoxicmedstocancercells–soundssimpleenough. Butfindingtherightcombinationofantibody,linker

technologyandwarheadisdifficult.

EVALUATING

KeyPlayers

ImmunoGen

Roche’sKadcyla(whichlinksantibody

Herceptintocytotoxicagentemtansine)usesImmunoGen’stargetedcytotoxin

technology.OxfordBioTherapeuticsisanothercollaborator;itcouplesnew

targetswithImmunoGen’sADClinker-payloadtechnology,whichfeatures,

alongwithaDM4payload,inOBT’sleadPhase1program.

Forty-yearoldImmunoGen,whichwas

workingonfirst-generationADCsinthe

1980s,sawitssharesreachaten-year

highin2023afterElahere,whichreceived

acceleratedapprovalinNovember2022,

showeda

35%reductioninrisk

ofdisease

progressionordeathversus

chemotherapyinsomeformsofresistant

ovariancancer.Thatwasalsoenoughto

attractAbbViewithits$10billion;the

drugsgianttherebyleapfrogsontothe

market,carvingatrailforitsownADC

pipeline,whichincludesPhase3lung

cancercandidatetelizotuzumabvedotin.

ADCTherapeutics

TwootherADCsdevelopedusingthe

PBD-basedpayloadtechnologyhave

Zynlontasaleshavefallen–alongwith

ADC’sshares–duetoafailedPhaseII

combinationtrialwithrituximaband

competitionfromRoche’sPolivy,whichisalsoapprovedforDLBCL.Phase2

Hodgkin’slymphomacandidate

camidanlumabtesirinewasshelved

followingan

FDAfilingrebuttal

inlate

2022andafailedcombinationstudywithKeytruda.

failed:Seagen’svadastuximabandRova-

T,theone-timecrownjewelofAbbVie’s

$6billionStemcentrxacquisitionin2016.

Doubtsoverthetechnology’s

effectivenessmayexplainwhyno-one

hassnappedupADCTherapeutics(yet).

DaiichiSankyo

ADCsarethemaingrowthengineforthismid-sizedJapanesepharma,whose

overseassalessurpasseddomesticforthefirsttimein2022.

Thecompanyexpectsitsoncology

businesstogrowto$6billion(JPY

900bn)in2025,makingupalmosthalfthegroup’soverallrevenues.

WereitscrownjewelADCsnotalready

spokenfor,DaiichiSankyowouldbeabig

mouthful,evenforcash-richWesternbig

pharma.

WWW.DAIICHISANKYO.COM/RD/PIPELINE/

EVALUATING

OnestoWatch

OnestoWatch

profoundBio

PrivateADC-focusedcompanybasedinSeattlewiththreeearlyclinical-stage

programsincludingaleadtargetingFR“,thesametargetasImmunoGen/

AbbVie’sElahere.Claimssuperiorlinkertechnologymayallowmorepotent

payload,greaterADCefficacyandlowerdrugresistance.

Private,

preclinical

-stageGermanADCcompanyfocusedonconjugation

technologies,withatopoisomeraseinhibitorpayloadplatform.Claimssuperior

ADCdesignwithflexiblelinkersthatenablesafeandeffectiveuseofawider

rangeofpayloads.Multi-targetpartnershipwithBMS.

WWW.TUBULIS.CO