方舟投資 ARKInvest 基因編輯技術(shù)市場(chǎng)機(jī)遇和主要參與者 CRISPR Genome-Editing - Market Opportunity And Key Players

CRISPR

Genome-Editing

MarketOpportunityAndKeyPlayers

Published:August20,2018

Author

ManishaSamy,AnalystatARKInvest

JointheconversationonTwitter

@ARKinvest

2

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

EXECUTIVESUMMARY

Infewerthanfiveyears,ClusteredRegularlyInterspacedShortPalindromicRepeats(CRISPR)-genome-editingtechnologyhastakenthescientificcommunitybystormandhasrevolutionizedthepaceofmodernbiology,promisinganeraofcurativemedicineandrapidbiotechnologicalbreakthroughs.Thankstoitsaccessiblecostandease-of-use,CRISPRhasdemocratizedgenome-editing.ManycompaniesaredeployingtheCRISPRplatformtocommercializenoveltherapiesandtoincreaseresearchanddevelopmentproductivityacrossthedrugdiscoveryprocess,agriculture,diagnostics,chemicals,andmaterialsciences.

ARKbelievesthatCRISPRisbiotech’sbreakthroughofthecenturyandthatitwillhaveaprofoundimpactontheworld’smostsalientissues,especiallyasitstoolboxexpands.Inthenear-term,ARKexpectsthefirstcommercialCRISPRproductswillbeforagriculturalpurposes,asitincreasesglobalfoodsupplyandenhancessustainabilitymeasures.Inmedicine,CRISPR’saddressablemarketinthemonogenicdiseasespacetotalsmorethan$75billionannuallywithnearly$2trillioninlatentdemandfromunaddressedpopulations.Whenjuxtaposedwiththefactthatmonogenicdiseasesonlyaccountforanestimated2%ofallgeneticdiseases,itisevidentthatCRISPRtechnologyisstillinitsinfancy.Thisisaplatforminitsearlieststages.

Thispaperwillelucidatethesignificanceofgenome-editing,theoriginsofCRISPR,howitworksandhowitcomparestolegacygenome-editingtechnologies.Then,itwillexamineCRISPR’smarketopportunityacrossapplicationareasandextrapolatethedirectandindirectinvestableopportunitiesasaresultofCRISPRtechnology.

RESEARCHHIGHLIGHTS

|$250billionannualglobalCRISPR-enabledCAR-Taddressablemarket

|$75billioninannualglobalrevenuepotentialforaddressingall10,000monogenicdiseases|$1.9trillionglobaladdressablemarketformonogenicdiseasesonaprevalencebasis

|$170billioninagriculture-crops,livestock,andaquaculture—valuecreationby2025

|585trillionincreaseincalorieproduction,feedinganadditional800millionpeopleby2025

|35%Aquacultureglobalmarketexpansionby2025

|EmergingtrendsinCRISPR-baseddiagnostics,antibioticresistance,drugdiscovery,datastorage,

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

1THERISEOFCRISPR

WhatisCRISPR?

CRISPRisasimple,powerfulandprogrammablegenome-editingtool.AnacronymforClusteredRegularlyInterspacedShortPalindromicRepeats,CRISPRistheequivalentofa“molecularSwissArmyKnife”composedoftwoparts:first,thebody,orthe‘guideRNA’,thatisolatestheportionoftheDNAthataresearcherwishestomanipulateand,second,thetool,or‘nuclease’,thatperformsanoperationonthatstretchofDNA.Inasimpleexampleoftoday’smostpopularguide-nucleasepairing,CRISPR-Cas9,CRISPRguidesthemolecularSwissArmyKnifetoatargetedspotinthegenomeandusesCas9as“molecularscissors”tocutthedouble-strandofDNA.Othernucleasescanalterthespecificityandcuttingefficiency/patterns,targetRNAandaddressdifferentstretchesofthegenome.Inthispaper,“CRISPR”willencompassallCRISPReditingsystemsandmechanismsofaction.

WhyCRISPR?It’sCheaper,Faster,Easier

CRISPRmakesgenome-editingrelativelysimple.Comparedtoothereditingtechniques,CRISPRismuchfasterandcheaper,asshowninthechartbelow.Ananswertofundingconstraints,itisincreasingtheproductivityofresearchbyloweringthecostperexperiment.CRISPRisdemocratizingsciencebyloweringthelevelofsophisticationrequiredtocarryoutmeaningfulscientificexperimentssothatevenhighschoolstudentsareexperimentingwiththetechnology.

ZFNs1

TALENs2

CRISPR

FirstHumanCellModification

2003

2009

2012

TimetoManufacture(days)

22

10

5

Cost(perpairofnucleases)

~$5,500

~$360

~$30

Source:ARKInvestmentManagementLLCNewerGenome-EditingTechnique>

ARKexpectsthatCRISPRgene-editingcostswilldeclineataratesimilartothatofTALENs-basedediting.TargetingacustomizedstretchofDNA,thecostofaTALENsexperimentdroppedfrom$10,000toroughly$1,400inthe4yearsfrom2012to2016,andalmost10-foldintheeightyearssinceitsdiscovery,asshowninFigure1.

1ZFNs:ZincFingerNucleases

2TALENs:Transcriptionactivator-likeeffectornuclease

3

4

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

Cost

Dollars,USD

FIGURE1

TALENsgeneeditingcostdecline

.PremadeTALENsCustomTALENs

12,000

10,000

8,000

6,000

4,000

2,000

0

2011201220132014201520162017

Source:ARKInvestmentManagementLLC,2018

Inthe6yearssinceitsdiscovery,CRISPR’scostsperreactionalreadyare3-to6-foldbelowthoseforTALENs,dependingonthetypeofmodification,asshowninthechartbelow.

CostperReaction

Dollars,USD

CostDifference

"X"-Fold

FIGURE2

CRISPR:3-6xcheaperbasedongenemodifaction(PerReaction)

TALENsCRISPRDegreeofCostDifferenceperExperiment

GeneKnock-in/Knock-outGeneSilencingUpregulating/Downregulating

GeneExpression

TypeofGeneModification

Source:ARKInvestmentManagementLLC,2018

$180.00

$160.00

$140.00

$120.00

$100.00

$80.00

$60.00

$40.00

$20.00

$-

4

7

6

0

5

3

2

1

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

Inadditiontoitsfavorablecost-efficiencyandmanufacturingprofile,CRISPRisordersofmagnitudeeasiertouse.Researcherscanbetrainedinaslittleasaweek,3andmiddleschoolscienceclassesalreadyareexperimentingwithCRISPR.4Asaresult,itisreinvigoratingcategoriesofresearchthathavebeendormantforyears,importantlystemcells,whilestimulatingdrugdiscoveryandnoveltherapieslikeCAR-T.

BecauseofCRISPR’ssignificantboosttotheirproductivity,scientistsareadoptingCRISPRtechnologyindroves,spendingtheirvaluableresearchanddevelopment(R&D)hoursexpandingitstoolset.IllustratingitsincreasingimportancetoR&Defforts,thenumberofpublicationsfocusedonCRISPRhasrisendramaticallyrelativetoothergene-editingtechnologies,asshownbelow.

PubMedPublications

Count

FIGURE3

A90%CRISPRPubMedpublicationgrowthratefrom2012-2017highlightsitsrapidriseinpopularityfrominitialdiscovery

uZFNsMeganucleaseuTALENsuCRISPR

3500

3000

2500

2000

1500

1000

500

0

20102011201220132014201520162017

ARKInvestmentManagementLLC,2017|DataSource:PubMed

Demonstratingitsprofoundimpactonscientificresearch,morethan50%ofallCRISPRpublicationsareamongstthe10%most-citedpapers,androughly20%areinthetop1%.5Consequently,CRISPRisattractingadisproportionateamountofR&Ddollarsrelativetoothertechnologiesinthespace.

3UsingCRISPRtoEditGenesinInducedPluripotentStemCells.”TheScientist,/lab-tools/using-crispr-to-edit-genes-in-induced-pluripotent-stem-cells-32927.

4Yu,Alan.“HowAGeneEditingToolWentFromLabsToAMiddle-SchoolClassroom.”NPR,NPR,27May2017,/sections/alltech-considered/2017/05/27/530210657/how-a-gene-editing-tool-went-from-labs-to-a-middle-school-classroom.

5Elsevier.“CRISPRInfographic.”1stEdition,Butterworth-Heinemann,/research-intelligence/campaigns/crispr.5

6

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

2CRISPRMARKETOPPORTUNITY:HUMANTHERAPEUTICS

TransformingHealthCare

Assuming“onesizefitsall”,medicinetodaytreatssymptomsratherthantheunderlyingdriversofdisease,aclearlysuboptimalapproachgiventheconsiderablegeneticvariationfrompersontoperson.Asourunderstandingofhumanbiologyincreases,medicinewillbecomepersonalized,enoughsothatintractablediseaseswithastronggeneticbasis,likecancer,mightbecured.

Notonlywillgenomeeditingcorrectmutations,butitalsowillenhanceandaccelerateourunderstandingofbasicbiology.Thehumanbodyismorethanthesumofits3.2billionDNAbasepairs.CRISPRwillhelptoidentifythecomplexconnectionsamonggenesequences,genesynthesis,proteins,metabolism,organs,anddisease.

Insteadoftreatingsymptoms,researchersnowarefocusedonfindingcuresforoncechronicandfataldiseases,potentiallychangingthereimbursementparadigminplacetoday.Asadditionalgenetherapiesareapproved,value-basedpricingcouldbecomemorecommonplace,asnoveltreatmentswithlargestickerpricesrequirepost-commercializationmonitoringofnotonlyinitialefficacy,butongoingdurabilityandothersafetymetrics.

CAR-T:TheFirstApplicationofCRISPRinaCommercialTherapeuticSetting

|IntheUS,CAR-Thasanannualaddressablemarketof$17billionforlatestagecancers,withthepotentialtoexpand6-foldtomorethan$100billiononceitisapprovedforearlystagetherapy.

|CAR-Ttherapyisinitsinfancy,asthenextgenerationwillbenefitfromCRISPRgene-editingbyincreasingitspotency,loweringcostofgoodssold(COGS),andallowingallogeneic6implementations.

ThefirstapplicationofCRISPRinacommercialtherapeuticsettinglikelywilloccurinchimericantigenreceptorT-cell(CAR-T)7therapy,atypeofimmunotherapythatharnessesanindividual’simmunecellstotargetandkillcancerouscellswhileleavinghealthycellsintact.AccordingtoARK’sestimates,theglobaladdressablemarketforCAR-Twillberoughly$40billionannuallyifitsapplicationsremainlimitedtostage3andstage4metastaticcancers.Ifappliedtoallstagesofcancer,themarketcouldscaleto$250billion.Asanovelclassoftherapy,CAR-Twillrequiremanyclinicaltrialsandpost-trialsurveillancetovalidateitssafetyandefficacyinearlierlinesoftreatment.

6Allogeneicdeliveryofatherapeuticproductreferstoadonor-derivedoroff-the-shelfsourceofbiologicalproductsasopposedtoapatient-derivedsource

7CAR-Tmarket-sizinginthispaperdoesnotincludeadvancesandmarketpotentialofCARnaturalkiller(CAR-NK)cells.

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

IntheUS,2017markedahistoricyearforgenetherapy,astheFDAapprovedtwoCAR-Timmunotherapiestargetinghematologic(blood)cancers.ARKestimatesthattheaddressablemarketforimmunotherapiesintheUSwillapproachover$100billion,asshownbelow,validatingtheburgeoningnumberofbiotechcompaniesenteringtheCAR-Tspace.UnderlyingthisestimateistheassumptionthatCAR-Twilladdress70%ofallliquidtumorsbutonly10%ofsolidtumors.

ProjectedAnnualRevenue

Billions,$USD

ProjectedAnnualRevenue

Billions,$USD

FIGURE4FIGURE5

AnnualUSCAR-TTAMGlobalCAR-TTAM

CAR-TTherapy:LiquidTumorsCAR-TTherapy:SolidTumors

$300$250$200$150$100 $50$0

GlobalCAR-TTAMUSDAllStages

Source:ARKInvestmentManagementLLC,2018|TAM=TotalAddressableMarket

$120$100$80$60$40$20$0

CAR-TTherapy:LiquidTumorsCAR-TTherapy:SolidTumors

GlobalCAR-TTAMUSDStage3-4

USCAR-TTAMUSDStage3-4

USCAR-TTAMUSDAllStages

250Billion

105Billion

40Billion

17Billion

CARsarepotentialtargetstowhichmoleculargeneticistscanaddepitopestothereceptorregionofTcellsandgainsignificantcontroloverthehumanbody’simmunesystem.Unliketraditionalchemotherapy,CARproteinsforceTcellstorecognizeandkillcancerouscellsandarmtheimmunesystem’s“memory”cellstorecognizeanyfutureinvasionsofmalignantcellsintheeventofcancerrecurrence,allowingcompletecancerremissionsinupto90%ofpatients.8WhileCAR-Ttreatmentscancauseserioussideeffects,suchascytokinereleasesyndrome(CRS)andneurotoxicity,afterfailingmultiplelinesoftherapy,metastaticcancerpatientsoftenhavenoothertherapeuticoption.

CAR-Tisa“l(fā)ivingdrug”.Inotherwords,notwoCARproductsarethesame.Itsresponseratesvarybyindication,target,composition,manufacturingprocessesandothervariables.

UnlikeearlyCAR-Ttherapies,thenext-generationwillleverageCRISPRtoenhanceboththerapeuticandmanufacturingefficiencies.CRISPRcanaddprecisiontothedeliveryofCARgenes,unlikeviralvectorswhichinsertCARgenesrandomlyintoT-cellDNA.Additionally,ResearchersatMemorialSloanKetteringCancerCenter(MSKCC)haveshownthatT-cellscreatedusingCRISPRarehighlypotent,outperformingtraditionalCAR-Tcells.9

8“ThePromiseofChimericAntigenReceptorT-CellTherapy.”CancerNetwork,15Oct.2016,/oncology-journal/prom-ise-chimeric-antigen-receptor-t-cell-therapy.

9Eyquem,Justin,etal.“TargetingaCARtotheTRACLocuswithCRISPR/Cas9EnhancesTumourRejection.”NatureNews,NaturePublishingGroup,

22Feb.2017,/articles/nature21405.7

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

Further,CRISPR-editingenhancesanti-tumoractivitybydeletinggenesthatinhibitaTcell’sabilitytorecognizetumors.ImmunecheckpointproteinPD-1isaT-cellsurfacereceptorthattumorsoftenexploittodampenaT-cell’sactivitytofightcancerouscells.InatrialattheUniversityofPennsylvania,researchersusedCRISPRtodisruptthegenecodingforPD-1proteintherebycreatingPD-1deficientCAR-Tcellsthatcoulderadicatetumorcells.10BecauseCAR-Tcellsareengineeredoutsideofthebodyandtestedforefficacybeforebeingtransfusedintopatients,cellseditedbyCRISPRareconsideredsafe.

FIGURE6

CAR-Ttherapydevelopmentandinfusionprocess

CRISPRGene-Editing

3.Genetic<Facilitated

1.Apherisis

Modification

Patient

Vein-to-Vein|TurnaroundTime:8-24days4.Expansion

··5.Harvest

Source:ARKInvestmentManagementLLC,2018

2.Target

CellEnrichment&Isolation

7.InfusionBackintoPatient

UndergoingCAR-T

6.Batch

Release

CAR-TrequirestheproliferationoftenstohundredsofmillionsofT-cellswhichcantaketwotothreeweeks.Forthatreason,sourcingT-cellsfromsickpatients,ortheautologousCAR-Tprocess,canfailifthestartingamountistoolow.

MetastaticcancerpatientsdonothavetheluxuryoftimenecessarytogeneratetheirownT-cells.Consequently,cultivatingcoloniesofcancer-fightingT-cells“offtheshelf”,alsoknownasallogeneicCAR-T,oftenismoreproductive,cuttingtimeandcostssignificantly.Ofcourse,introducingsomebodyelse’sT-cellsintoapatient’sbodyposesitsownrisks.IfthebodyinterpretsthoseT-cellsasforeigninvadersitwillfightthemandacceleratethepatient’sdecline.Inorgantransplantsdoctorsseektoavoidthissortofreaction,knownasGraftversusHostDisease,byseekinggeneticallycompatibledonors,aprocessthatistime-consuming,expensiveandsometimesfutile.

Obviatingtheneedforacompatibledonor,CRISPRcanintroducegenesthatencodeCARsintoimmunesystemcellsinanon-majorhistocompatibilitycomplex(MHC).Cellectis(CLLS)isone

8

10Rupp,LeviJ.,etal.“CRISPR/Cas9-MediatedPD-1DisruptionEnhancesAnti-TumorEfficacyofHumanChimericAntigenReceptorTCells.”NatureNews,NaturePublishingGroup,7Apr.2017,/articles/s41598-017-00462-8.

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

ofthecompaniesfocusedontheallogeneicapproach,albeitwithTALENgene-editingtechnology.Kite,nowownedbyGilead,isdevelopingallogeneicCAR-Ttherapiescombininggenome-editingandstemcells.Allogene,aprivatecompanyfoundedbyex-Kiteexecutives,hasannouncedthatitwillcollaboratewithCellectisonthedevelopmentofallogeneicCAR-Ttherapies.

WhileARKestimatesthatapproximately60%ofcancerswillsubmittoallogeneicadministration,someindicationswillbetoocomplexand,aswithbonemarrowtransplants,willbelimitedtotheautologoussourcingofT-cells.Morecostlytodeliverbutmoreeffectiveincomplexcancercases,autologousCAR-Ttherapycouldaccountformorethan60%ofthetotalCAR-Taddressablemarket,asdepictedbelow.Inotherwords,whileallogenictherapiesmightdominatethenumberofcancertreatments,autologoustherapiesprobablywillgarneradisproportionateshareoftherevenues,asshownbelow.

EstimatedRevenue

$USD,Billions

FIGURE7

US:CAR-TTAMprojectionsbydeliverymechanismandlineoftherapy

$120

33Billion105Billion

$100

$80

$60

$40

$20

$-

AutologousDelivery:EarlyStageCancers

Source:ARKInvestmentManagementLLC,2018

AutologousDelivery:LateStageCancers

AllogeneicDelivery:EarlyStageCancers

AllogeneicDelivery:LateStageCancers

TotalAnnualUSTAM

55Billion

11Billion

6Billion

Whilegenetherapiesarebeginningtocurecancer,theyarecausingstickershockintheseearlydays.NovartispricedthefirstapprovedCAR-Ttherapy,Kymriah,at$475,000,payableonlyifthepatientrespondedwithinthefirstmonth,andKitepriceditsCAR-Ttherapy,Yescarta,at$373,000.11

Thatsaid,comparedtotraditionaltherapiesthatsuppresscancer,thecostsrelativetothebenefitsofgenetherapyareinadifferentorbit.Moreover,aswithmostnewtechnologies,thecostsshoulddeclineasthemarketscalesand,asshowninFigure8,thepriceelasticityofdemandassociatedwithgenetherapiesisenormous.

Currently,morethan40companiesaredevelopingincreasinglyadvancedandsafeCAR-Ttherapiesforvariouscancerindications.JunoTherapeutics(JUNO),PoseidaTherapeutics,Cellectis(CLLS),andBellicumPharmaceuticals(BLCM)arecreating“killswitches”forCAR-Ttherapiestoenhanceitssafety.Upondetectionofnegativesideeffects,physicianswillbeabletoturnoffCARactivitywithaneutralizingagent.NowownedbyCelgene,JUNOalsoiscreatingaprotocoltoadministerCAR-Ttherapyonanoutpatientbasis,anindicationoftherapidprogressofthistechnology.

9

11LydiaRamsey,“Acutting-edgenewcancertreatmenthastwodifferentpricetags,anditcouldbethefutureofhowwepayfordrugs”,May7,2018,

/indication-based-pricing-for-novartis-car-t-cell-therapy-kymriah-2018-5

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

ListPricePerCourseofTreatment$USD

FIGURE8

Genetherapypricesbyeligiblepatientsperyear(USD)

$1,200,000

RetinalDystrophy

Glybera

(QURE),10Luxturna

(SPARK),30

$600,000

$400,000

$200,000

Yescarta

$0

Source:ARKInvestmentManagementLLC,2018

SevereCombined

Immunodeficiency(ADA-SCID)

Strimvelis(GSK),20

$1,000,000

$800,000

AggressiveNon-Hodgkin's

Lymphoma(NHL)

PediatricAcute

LymphoblasticLeukimia

Kymriah(NVS),300

LipoproteinLipaseDeficiency

(GILD/KITE),7000

ThreepubliclytradedcompaniesareenhancingvariousCAR-TproductswithCRISPR,whileanotherisworkingwithTALENstechnology.Asshowninthetablebelow,IntelliaTherapeutics(NTLA),EditasMedicine(EDIT),andBluebirdBio(BLUE)havepartneredwithleadingCAR-Tcompanies,whileCRISPRTherapeutics(CRSP)hasoptedtodevelopitsownprogram

BypartneringwithestablishedcompaniesfocusedonCAR-Ttherapies,genetherapycompaniesshouldbenefitfrommanufacturinganddistributionscalewhilemilestone-androyalty-basedrevenuecontinuetofundotherCRISPR-orTALENS-basedtherapeuticinitiatives.BluebirdBio,forexample,iscollaboratingwithCelgeneonthefirstCAR-TprogramtocapitalizeonitsproprietaryMegaTALENSgene-editingplatform.ThebelowchartsummarizestheseCAR-T/gene-editingcollaborations.

GENE-EDITINGCOMPANIES

CAR-T

COMPANIES

COLLABORATIONECONOMICS

IntelliaTherapeutics

Novartis*

-Upto$230Minmilestonepaymentsperproduct

-Upto$50Mincommittedcollaborationfunding

-$18Mequityinvestment

-Mid-singledigittolow-teenroyalties

EditasMedicine

Juno

-$25Mupfrontplus$22Minpotentialresearchsupport

-$230Minmilestonesperprogram

-Low-doubledigitroyalties

CRISPRTherapeutics

N/A

-nocollaborationsasofpublication

BluebirdBio

Celgene

-Undisclosedupfrontpayment

-Upto$225Mperproductinpotentialoptionfeesandclinicalandregulatorymilestones

-50/50co-developmentandprofitshareintheUS

Source:ARKInvestmentManagementLLC

10

*AsofDec.12,2017,NVSreduceditsequitystakeinNTLAby3.61%downto9.76%duetointernalpipelinere-focusingeffortswithacompetingdrug

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

MonogenicDisorders

|Addressingallmonogenicdiseases,CRISPRcouldgenerateupto$75billioninannualrevenuebasedontheincidenceofdisease,andupto~$2trillionbasedontheprevalenceofdisease.

|Monogenicdiseasesaccountforonly2%ofallgeneticdiseases,pointingtosignificantupsideforCRISPRandothergene-editingtechnologiesastheymature.

CRISPR’spotentialtocorrectgeneticmutationsandcurediseaseisprofound.Todate,scientistshaveidentifiedapproximately10,000humanmonogenicdiseases,conditionscausedbyerrorsinasinglegene.12Whileeachisrare,theincidenceofall10,000monogenicdiseasesisexceptionallyhigh:1in100childrenisbornwithsomesortofmonogenicdisease.Huntington’sdiseaseandhemophiliaaretwoofthebetter-knownexamples.IfCRISPRtechnologyweretoaddressall10,000ofthesemonogenicdiseases,theparticipatingcompaniescouldgenerate$75billioninrevenuegloballyperyear.

Whilehistoricallytherapeuticshavefocusedonsymptomsofdisease,genetherapyaimstoaddresstheunderlyingcausesofdiseasebycorrectingthemutationsingenesequencesencodedbyDNA.Inprinciple,correctingfaultygenesshouldrestorenormalgeneandproteinfunction,reversingdisease.Whilevariousgenetherapyandgenome-editingtechnologieshaveevolvedinthelastfewdecadesCRISPRshouldbethemostdisruptivetotraditionaltherapies.

FIGURE9

Addressingallmonogenicdiseasescouldyieldapprox.$75billioninglobalannualtreatmentrevenueonanincidencebasis

US

Global

$0$10$20$30$40$50$60$70$80

USDBillions

Source:ARKInvestmentManagementLLC,2018

75Billion

30Billion

Whileeachmonogenicdiseaseisrare,CRISPRshouldbeabletoaddressthemall,potentiallygeneratingannualrevenuesof$30billionintheUSand$75billionglobally,asshownabove.Today,therapiesthattreatthesymptomsofrarediseasecancostmorethan$100,000peryear.13Logically,atherapeuticcure

12“GenesandHumanDisease.”WorldHealthOrganization,WorldHealthOrganization,7Dec.2010,/genomics/public/geneticdiseases/en/index2.html.

11

13Smith,A.Gordon.“TheCostofDrugsforRareDiseasesIsThreateningtheU.S.HealthCareSystem.”HarvardBusinessReview,7Apr.2017,hbr.org/2017/04/the-cost-of-drugs-for-rare-diseases-is-threatening-the-u-s-health-care-system.

12

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

shouldcommandasubstantialpremium.Whiletheaveragecostprobablywillbe$500,000percure,weestimatethat$2millionwouldbeneutralcomparedtothecurrentcostoftreatingchronicconditions.BasedonARK’sresearch,higherupfrontspendingshouldeliminatefuturehealthcareexenditures.

Importanttonote,theaddressablepopulationsincludenotjustindividualsbornwithdisease–theincidencerateofdiseaseanygivenyear-butalsothosewhowerediagnosedinprioryears-ortheprevalenceofdisease.Thelattergrouptypicallyhasbeentreatedwithexpensiveandinadequatetherapies.IfCRISPRweretotargetmonogenicdiseasesbyprevalenceasopposedtoincidence,itsonetimeglobaladdressablemarketwouldexpandbyanadditional$1.9trillion.

FIGURE10

2021Globalmonogenicmarkettreatmentopportunity

ex-US

PopulationLivingwithMonogenicDiseases

$1.9Trillion

ANNUALONGOINGMARKETOPPORTUNITYLiveBirthsResultinginMonogenicDiseases

$75Billion

Est.AnnualRevenue(Incidence-Basis):CurativePricingEst.One-TimeRevenue(Prevalence-Basis):CurativePricing

Source:ARKInvestmentManagementLLC,2018

INITIALOPPORTUNITY

US

Ofcourse,everydiseaseindicationwillrequireitsownR&DeffortandsubmittodifferentdeliveryvectorsandRNAguides.Consequently,anumberofCRISPR-basedcompanieswillbecomebeneficiariesofthetechnology.Currently,onlythreestockstradedonUSexchangesarefocusedonCRISPRhumantherapeutics:Intellia,Editas,andCRISPRTherapeutics.Thesheersizeofthemarketopportunitysuggeststhatmanycompaniescouldbelargebeneficiaries.

CRISPR—MarketOpportunityandKeyPlayersManishaSamy

ComplexPolygenicDiseases

Causedbyjustonegeneinthehumangenome,monogenicdiseaseshavebecometheprimaryfocusofthefirstgenerationofCRISPRtherapeutics.CRISPRisstillarelativelynewgenome-editingtechnology,soscientistsareproceedingcautiously.Monogenicdiseasescompriseonly2%ofalldiseasesknowntohaveageneticbasis.14Themajorityofotherdiseasesiscausedbymutationsinmultiplegenes.Nearlyallnon-infectiousandinfectiousdiseasesaregeneticinnature,thegenesatfaultbeinginhumancellsintheformerandinbacteriaorvirusesinthelatter.

FIGURE11

Monogenicdiseasescomprise2%offallknowngeneticdiseases

MonogenicDiseasesPolygenicDiseases

10,000