tim lugo blockbuster opportunities in the dermatology pipeline
TRANSCRIPT
Please refer to important disclosures at the end of the document.William Blair & Company, L.L.C. does and seeks to do business with companies covered in itsresearch reports. As a result, investors should be aware that the firm may have a conflict ofinterest that could affect the objectivity of this report. Investors should consider this report as asingle factor in making an investment decision.
BlockbusterOpportunitiesintheDermatologyPipeline
1
JohnBoyle,[email protected]
January12,2020
Partneringwithclientstodeliverexecutionexcellencethroughasuiteofservicesandnearlyacenturyofexpertise
PremierIndependentGlobalInvestmentBank
(1) AsofSeptember30,2019.3
ASnapshotofWilliamBlair
FirmOverview 2019ECMResults 2019M&AResults 2019FirmResults
Locations
1935Founded
20OfficesWorldwide
100%OwnedbyEmployedPartners
$59BDealValue
30%+Cross-BorderTransactions
>$1BRevenue
~250IBTransactions
$85BAUM(1)
134Transactions
~1,500Employees
91Transactions
~70%HealthcareOfferings
ExecutedasBookrunner
~20%IPOMarketShare
$41BCapitalRaised
NorthAmericaAtlantaBaltimoreBostonCharlotteChicagoNewYorkSanFrancisco
EuropeAmsterdamFrankfurtLondonTelAvivZurich
EastAsiaHoChiMinhCityHongKongSeoulShanghaiSingaporeTokyo
IndiaMumbai
AustraliaSydney
2019IndustryTrends
DermatologySuccessesin20191.LargeStrategicDeals
- Abbvie +Allergan(“Abbv-Gan”)~$63Bmegadeal- AbbVie’splantoseparatethecashpayaestheticsbusinessintoaseparatebusinessunit
2.ProductFocusedDealMakingContinues- AmgenacquisitionofOtezla fromCelgene
- $13.4BdealforanoralcompoundwhichIwouldsayhasprettymodestefficacyandbroughtin$1.96Binrevenuein2019
- Highlightsopportunityforsafecompoundsthatcaneffectivelyslotinbeforebiologicsinpsoriasis- Asastandalonedealitwouldhavebeenoneofthelargestsingleassetdealsinbiotech
- XBiotechdealwithJohnson&Johnsonforbermekimab- $750MacquisitionforPhaseIIassetindevelopmentforHidradenitisSuppurativa andAtopicDermatitis
- EliLillyAcquiringDermira for$1.1billion(announced1/10/2020),gainingaccesstolebrikizumab (IL-13)inatopicdermatitisaswellasthemarketedQbrexa forhyperhidrosis
3.StrongProductLaunches- Skyrizi fromAbbVie
4.Clinicalsuccesses
- Lebrikizumab (Dermira)- Ligelizumab (Roche)- SB206(Novan)
- KB103(Krystal)- PRN1008(Principia)
KeyQuestionsAroundDermatologyPipeline1.Newproductdifferentiationfromstandardofcare
- Eskata fromAclaris hadissuesinthemarketaround“realworld”useanddifferentiationfromstandardofcare
- Businesscaseneedstobestrongintheaestheticsworld(howdoyoucompeteagainsttheprofitabilityofBotox?)
2.Clinicalresultsvs.“realworld”use- AllerganhadsomeissueswithassetstheyacquiredinthepastthreeyearswithKybella revenueof$34millionposted
in2019andawritedownof$1.6billionbackinJanuary
3.Howwillyoucommercialize?- We’vealsoseensomeincrediblystronglaunchesinthedermatologyspacefromcompanieswithanestablished
dermatologypresencesuchasAbbVie’sSkyrizi
- Weseepotentialpathwaystocommercialsuccessinindicationswithsevereunmetmedicalneed- KB103,agenetherapyfordystrophicepidermolysisbullosa(“EB”)
WeseeSeveralBlockbustersinDevelopmentwithBetterBiologics(postTNFinhibitors),BetterOrals,BetterTopicals,BetterScience
InnovationinPsoriasis
PsoriasisOverview
• EnvironmentalfactorstriggerinflammationcharacterizedbyTNFα/IL-23/Th17infiltratesingeneticallydisposedpopulation
• Sustainedinflammationleadstouncontrolledkeratinocyteproliferationanddysfunctionaldifferentiation
• Mostcommonsubtypeisplaquepsoriasis(psoriasisvulgaris)whichaccountsfor~90%ofcases
• Oftendevelopsbetweentheagesof15to25,andtreatmentconsistsoftopicaltreatments,phototherapy,andsystemictherapy
– Topicaltreatmentsaccountfornearly75%ofpsoriasisprescriptionsintheUS,~90%ofwhicharetopicalcorticosteroids1
• Hasseensignificantdevelopmentoverthepastcoupleofdecades,makingitamulti-billiondollarmarket
Psoriasisisachronicinflammatoryskindiseasethataffects~2%oftheglobalpopulation(~8millionpeopleintheUS)
1DermavantcompanyfilingswithSECNationalPsoriasisFoundation(psoriasis.org)
PlaquePsoriasis
SignificantImprovementsinTreatmentinRecentYearsAdvancementsinourunderstandingofdiseasebiologyhaveleadtosignificantimprovementsintreatmentefficacy,asevidencedbyPASI75scoresinclinicaltrials
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%Methotrexate*
Enbrel®
Humira®
Stelara®
Otezla®
Cosentyx®*
Taltz®
Siliq®
Tremfya®
Ilumya®
Skyrizi®
Bimekizumab
BMS-986165
Mirikizumab**
1972 2004 2008 2009 2014 2015 2016 2017 2017 2018 2019 2021E 2021E 2021E
%ofPatientsAchievingPASI75
PASI75ScoresfromPhaseIIb TrialsOverTheYears
InjectionOral
Folic Acid TNFα TNFα IL-12/
23 p40 PDE4 Il-17A Il-17A Il-17R IL-23 p19
IL-23 p19
IL-23 p19
IL-17A/F TYK2 IL-23
p19
FDAApproval^
MOATarget
*BasedonPhaseIIIresults;**ImputedbasedonBMY-986165plusdifferenceinPASI90scores;^Estimatedforproductsthatarenotyetapproved
PASI75scoreshaveshownaclearupwardstrajectoryin
recentdecades
PsoriasisRepresentsaLargeandGrowingMarketPsoriasisisalargemarket,drivenprimarilybyhighlyeffectivebiologics,withsignificantgrowthexpectedoverthecomingyears
Source:EvaluatePharma†Cosentyx,Taltz,Tremfya,Skyrizi,Stelara
>$9B2019globalsalesfortop-5
post-TNFbiologics†
>$16Bconsensus2024globalsalesfortop5post-TNFbiologics
>$14B2018globalsalesoftop10
psoriasistherapies
>$23BEstimated2024globalsalesoftop10psoriasistherapies
Stelara
Cosentyx
Tremfya
Otezla
Skyrizi
Humira
TaltzBMS-986165
Mirikizumab
Enbrel
Other
$0
$5,000
$10,000
$15,000
$20,000
$25,000
$30,000
2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024
WWPsoriasisMarket,2010-2024
Other
Enbrel
Mirikizumab
BMS-986165
Taltz
Humira
Skyrizi
Otezla
Tremfya
Cosentyx
Stelara
TYK2:ANewTargetforTh17DrivenDiseases
• TYK2functionsasaheterodimerwithJAK1orJAK2
– Inhibitionofeithermemberofthedimerblocksreceptorsignaling
• Stronggeneticassociationwithmultipleautoimmunedisordersinhumans
• PotentialtoreplicateefficacyofTh17biologicswhilealsoinhibitingType-Iinterferons(IFN)(α andβ)withasmallmolecule
– Keytargetforseveralchallengingauto-immunedisorders
• NotinhibitedbycurrentJAKinhibitorsliketofacitinibatclinicaldoses
• PotentiallysafertoinhibitcomparedwithJAK1/2/3*
• Outstandingconcerns:JAKclasslabelling?WillweseeJAK-likesideeffects?
TyrosineKinase2(TYK2)isamemberoftheJanusAssociatedKinase(JAK)familyofsignalingkinasesthatplaysanimportantroleinpro-inflammatorysignalpropagation
SelectJanusKinaseSignalingPathways
>$1.2B Consensus2024salesforBMS-986165(leadTYK2)^
*ApprovedJAKinibs haveboxedwarningsforsevereinfectionrisk,heightenedriskoflymphomadevelopment,andthrombosisImagefromBristol-MyersSquibbcompanyreports;^Source:EvaluatePharma
TYK2:Best-in-ClassOralApproachingBiologicEfficacy
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Ote
zla®
BMS-
9861
65
Enbr
el®
Hum
ira®
Trem
fya®
Risa
nkiz
umab
Cose
ntyx
®
Taltz
®
Siliq
®
Bim
ekiz
umab
Bari
citin
ib
Xelja
nz®
PDE4Inhibitor
TYK2inhibitor
anti-TNFα trap
anti-TNFα mAb
IL-23 p19inhibitor
IL-23 p19inhibitor
Il-17Ainhibitor
Il-17Ainhibitor
Il-17Rinhibitor
IL-17A/Finhibitor
JAK 1,2inhibitor
JAK 1,3inhibitor
TYK2oral
anti-TNFα post-IL-23 or IL-17inhibitor
PASI
75
PASI
90
PASI
100
Biologics (injected)
Small Molecules (oral)
† Efficacy data from week 16; § Efficacy data from Phase III report; NR: Not reported; *Annual sales and indication-specific estimates from EvaluatePharma; **Development in psoriasis terminated
(3mgBID)
2018WWPsoriasisSalesbyProduct(USDmillions)*
1,374 N/A 1,180 3,643 544 N/A 2,002 831 32 N/A N/A N/A**
SelectTYK2Inhibitors
BMS-986165• AllostericTYK2inhibitorwithlowaffinityforJAK1/2/3
• PhaseIItrialdemonstratedhighestPASI75scoreforanoralto-date,withnoSAEs
• PhaseIIItrialsvs.Otezla ongoingwithreadoutexpectedin2020
• OngoingPhaseIItrialsinpsoriaticarthritis,lupus,Crohn’sdisease,ulcerativecolitis
Nimbus’TYK2DrugCandidate• PotentallostericinhibitorswithmarkedTYK2functionalselectivity(>1,000xthatofotherJAKsand>100xthatofBMS-986165)
• First-in-humanPhaseIinitiated• HadpartnershipwithCelgene:TBDifBMYkeepitafteracquisition
PASI75/90/100Comparisonat12Weeks,reportedatPhaseIIb
†
§
§ §
NR
NR
** **
Skyrizi:PotentiallyBest-in-Classanti-IL-23Inhibitor
ComparisonofPASI75/90/100at12WeeksFromPhaseIIbTrialsDemonstratesPromisingEfficacy
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Stel
ara®
Ilum
ya®
Trem
fya®
Risa
nkiz
umab
Miri
kizu
mab
Cose
ntyx
®
Taltz
®
Siliq
®
Bim
ekiz
umab
IL-12/23p40
inhibitor
IL-23 p19inhibitor
IL-23 p19inhibitor
IL-23 p19inhibitor
IL23 p19inhibitor
Il-17Ainhibitor
Il-17Ainhibitor
Il-17Rinhibitor
IL-17A/Finhibitor
anti-IL23 or anti-IL-17 inhibitors
PASI 75PASI 90PASI 100
† Efficacy data from week 16; § Efficacy data from Phase 3 report; NR: Not reported; *Annual sales and indication-specific estimates from EvaluatePharma.
2018WWPsoriasisSales($million)*
3,335 3 544 N/A N/A 2,002 831 32 N/A
†
§
§
NR
NR
FDAApprovalApril23,2019
MechanismIL-23p19antagonist
AdministrationSubQ injection(q12w)
Additionalopportunities• Crohn’sdisease• Psoriaticarthritis• Ulcerativecolitis• Atopicdermatitis
Stelara andCosentyx illustratesignificantopportunityinpost-TNFmarket
Skyrizi OffToaStrongStartinPost-TNFPsO MarketEarlylaunchmetricsshowthatSkyrizi isofftoastrongstartinthepost-TNFpsoriasismarket,suggestingitwillholdacommandingpositioninthislargeandgrowingmarket
*IncludespatientsinthebridgeaccessprogramSources:EvaluatePharma;AbbViethirdquarter2019earningscall
~3,500prescribingphysicians
>9,000patientstreated*
>80%commercialaccess
>20%marketshareofin-playpsoriasispatients
$0
$20
$40
$60
$80
$100
$120
$140
Q1 Q2 Q3 Q4
WWSales,First4QuartersPost-Launch
Cosentyx Taltz Tremfya Skyrizi Stelara
Skyrizi’s first2quartersonthemarkethaveoutperformedrecentpeersintheIL-17/IL-23antibodyclass,suggesting
blockbusterpotential
After2quartersonthemarket…
Tapinarof:AhR AgonistforPlaquePsoriasis
• BindingtoAhR downregulatespro-inflammatoryfactorsANDincreasesrestorativeresponses:– DownregulationofTh17andTh2inflammatory
cytokines
– Restoresepithelialbarrierfunctionbyinducingtranscriptionoffilaggrin
– IncreasesproductionofNrf-2toreduceoxidativestress
Dermavant’s tapinarof isatopicalarylhydrocarbonreceptor(AhR)agonistinPhaseIIItrialsforplaquepsoriasis,withpotentialtoexpandintoatopicdermatitisfollowingasuccessfulPhaseIIbtrial
1DermavantcompanyfilingswithSEC;TCS,topicalcorticosteroids
• Topicaltherapiesrepresentasignificantmarket(~75%ofscripts)
• Relativelylittleinnovationintopicaltherapiesascomparedtobiologics– PrimarilyTCS;topicalJAKinibs havebeen
unsuccessfulinpsoriasisto-date
• PromisingdatainPhaseIIb trialsinPsO andmoderate-to-severeatopicdermatitis
• OngoingpivotalprograminPsO (PSOARING)withdataexpectedin2020:– Two12-weekPhaseIIItrials(NCT03956355;
NCT03983980)
– PhaseIIIlong-termopen-labelsafetystudy(NCT04053387)
MarketOpportunity& DevelopmentStatusMechanismofAction
Tapinarof:PromisingPhaseIIb EfficacyinPsoriasisApreviouslycompletedPhaseIIb trialinplaquepsoriasisdemonstrateimpressiveefficacyforatopicalproduct,andsupportongoingPhaseIIIPSOARINGdevelopmentprogram
Proportionofpatientsexperiencinga≥75%improvementfrombaselinePASIscores
*p<0.05;BID,twicedaily;EASI,eczemaareaandseverityindex;IGA,investigatorglobalassessment;QD,oncedaily;PASI,psoriasisareaandseverityindex;PGA,physicianglobalassessment;^NCT03956355,NCT03983980,NCT04053387Sources:PeppersK.etal.,2019. J.Am.Acad.Dermatol.;RobbinsK.etal.,2019. J.Am.Acad.Dermatol.
PASI75of56%atweek12(1%QD)iscomparabletoPhaseIIb efficacyofcurrentlyapprovedorlate-stageoraltherapies(Otezla,41%;baracitinib,54%;BMS-’165TYK2,69%)
Ongoingpivotalprograminpsoriasis(PSOARING^)withdataexpectedin2020
InnovationinAtopicDermatitis
AtopicDermatitisOverview
• Mostoftenoccursearlyinlife;oftendisappearsaschildrenage,butcanreturnasflares
• EstimatedUSprevalenceof~13%inchildrenand7%-10%inadults1
– ~9.6millionchildren(<18)and~16.5millionadultsintheUShaveAD**
• Believedtobecausedwhentheimmunesystemover-reactstoanenvironmentaltrigger– Geneticpredisposition,skinbarrierdysfunction,andaberrant
immuneresponse(especiallyTh2/Th22)
• Significantdiseaseburden,boththroughthedirectsymptomsofAD(e.g.,itch)aswellasanelevatedriskofseveralcomorbidconditions
• Nearly5.9millionworkdaysannuallylostduetoeczema2
• Annualeconomicburden(directandindirect)conservativelyestimatedat$5.3billionin20153
AtopicDermatitis(AD),themostcommon,severe,andlong-lastingformofeczema,isachronicinflammatoryskindiseasecharacterizedbydryskinandpruritus
1Silverbergetal.,2017.Dermatol Clin.; 2NationalEczemafoundationwebsite,accessedDecember18,2019.3Druckeretal.,2017,JInvestDermatol.;*Source:EvaluatePharma;**nationaleczemaassociation(nationaleczema.org)
$0$1,000$2,000$3,000$4,000$5,000$6,000$7,000
2016
2017
2018
2019E
2020E
2021E
2022E
2023E
2024E
WWADSales(USDmillions)*
DiseaseBackground MarketOpportunity
• TheADmarketislessdevelopedthanthePsO market
• Significantgrowthexpectedovernext5-10yearsasseveralnewdrugsexpectedtocometomarket
• 2017approvalofDupixent,thefirstbiologicforADsparkedinflectiontowardsgrowth
SignificantRoomforImprovementRemains
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Eucrisa
Dupixent
abrocitinib
(200mg)
baracitinib
(4mg)
tralokinumab
(300mg)
nemolizumab
(30mg)+TCS
ruxolitinib
(1.5%BID)
lebrikizum
ab(250mgQ2W
)
upadacitinib
(30mg)
delgocitinib
(0.5%BID)**
tapinarof
(1%BID)
tezepelumab
+TCS
bermekimab
(400mg)
ARQ-151
(0.15%
)
LessCompetitiveDevelopmentLandscapethanPsoriasisIGA0or1EASI75
Est.USApproval 2016 2017 2020* 2020* 2020 2020 2022 2023 2023* 2023? 2023? 2024 2024? 2024+?
Target PDE4 IL-4Rα JAK1 JAK1/2 IL-13 IL-31RA JAK1/2 IL-13 JAK1 Pan-JAK AhRagonist Anti-TSL IL-1α PDE4
Admin. Topical Injection Oral Oral Injection Injection Topical Injection Oral Topical Topical Injection Injection Topical
Endpoint Week4 Week16 Week12 Week16 Week12 Week16 Week8 Week16 Week16 Week4 Week12 Week16 Week8 Week4
TSL,thymic stromallymphopoeiten;AhR,Arylhydrocarbonreceptor;*Highestdoseshown,thoughlowerdosesarestillbeingdevelopedinongoingtrials.**DatafromPhaseIIIstudyconductedinJapan.Datafromcompanypresentations.
FewerbiologicsandlowerbarforefficacyascomparedtoPsO illustratetherelativeunderdevelopmentinAD
Thoughdevelopmentactivityhasincreasedinrecentyears,thenumberofdrugsindevelopment,andtheefficacyseeninlate-stagetrialssuggestsalessdevelopedmarketthanpsoriasis
NR
Lebrikizumab:TargetingIL-13forAtopicDermatitis(AD)
• IL-13believedtomediateinflammationandamplifysensoryneuronresponses
• SelectivelypreventsformationoftheIL-13Rα1/IL-4RαheterodimerreceptorsignalingcomplexwhileleavingendogenousregulationofIL-13intact
• AllowsforthesafetyobservedwithotherIL-4/IL-13monoclonalantibodies(e.g.,dupilumab)withpotentiallybetterefficacy
• CurrentlybeingevaluatedinPhaseIIIprogramafterpositiveresultsfromPhaseIIb study– EffectsonitchwereobservedasearlyasDay2inpatientsreceiving
aloadingdose
– Receivedbreakthroughtherapydesignation
• TwopivotalPhaseIIImonotherapystudiesongoing– Top-lineresultsfrom16-weekinductionperiodofbothPhaseIII
studiesexpectedfirsthalfof2021
Dermira’s lebrikizumab selectivelytargetsIL-13topreventreceptordimerizationwhileleavingendogenousregulationofIL-13intact
ADisprojectedtobecomeoneofthelargestmarketsindermatologyby2027
Lebrikizumab Mechanism
Source:Dermira companypresentations
Lebrikizumab DemonstratesPromisingEfficacyInthePhaseIIb study,lebrikizumab demonstrateddose-dependentresponsesacrossallendpoints
EarlyandsustainedimprovementsinEASI
Dose-dependentimprovementsacrosssecondaryendpoints
Robustimprovementsinpruritusscores
*p<0.05,**p<0.0,***p<0.001versusplaceboformpairwiseCochran-Mantel-Haenszel testsLEB,lebrikizumabl;LS,leastsquares;MCMC,MarkovchainMonteCarlo;NRS,numericratingscaleSource:Dermira companypresentations
-41.1
-62.3*-69.2**
-72.1***-80
-70
-60
-50
-40
-30
-20
-10
0
PlaceboQ2W(n=52)
LEB125mgQ4W(n=73)
LEB250mgQ4W(n=80)
LEB250mgQ2W(n=75)
LSMeanChangefrom
Baseline(%)
EASIAtWeek16(PrimaryEndpoint)
-25.4-31.3 -31.0
-40.6-42.4
-53.9
-62.5 -61.5*
-46.5
-61.2
-64.7-69.7**
-50.4
-64.1
-73.5 -72.8***-80.0
-70.0
-60.0
-50.0
-40.0
-30.0
-20.0
-10.0
0.00 4 8 12 16
MeanChangefrom
Baseline(%)
WeekEASIToWeek16
PlaceboQ2W(n=52) LEB125mgQ4W(n=73)
LEB250mgQ4W(n=80) LEB250mgQ2W(n=75)
2.7 16.7 16.624.316.7
30.843.8 43.3
23.4
38.548.3 56.1**
30.4
45.5
66.960.6***
0102030405060708090100
0 4 8 12 16
Patients(%)
Weeks
EASI75
0.5 4.0 5.211.4
3.7 17.3 20.526.17.6
26.0 28.436.1**
14.2
29.836.4 44.0***
0102030405060708090100
0 4 8 12 16
Patients(%)
Weeks
EASI90
0.1 4.8 3.4 15.33.1 14.7 22.1
26.610.024.0
29.9 33.7*
13.9
31.3
42.2 44.6**
0102030405060708090100
0 4 8 12 16
Patients(%)
Weeks
IGA0/1
27.3
41.847.4
70.0***
39.343.5 46.2
67.2**
0
10
20
30
40
50
60
70
80
90
100
PlaceboQ2W(n=22,52)
LEB125mgQ4W(n=55,73)
LEB250mgQ4W(n=57,80)
LEB250mgQ2W(n=50,75)
Patients(%)
NRSChange≥4Points
Noimputation(observedcases)MCMCimputation
4.3
-35.9**
-49.6***-60.6***
-4.6
-36.5**-46.4***
-58.5***
-100
-80
-60
-40
-20
0
20
PlaceboQ2W(n=22,52)
LEB125mgQ4W(n=55,73)
LEB250mgQ4W(n=56,80)
LEB250mgQ2W(n=50,75)
Patients(%)
NRSChange≥4Points
Noimputation(observedcases)MCMCimputation
Rinvoq (upadacitinib):JAK1InhibitionforAD
• Approvedforrheumatoidarthritis(RA);inlatestagedevelopmentforatopicdermatitis(AD),Crohn’sdisease,psoriaticarthritis,ulcerativecolitis,andgiantcellarteritis– AlreadyshownsuperiorityoverHumira inPsO1
• SuccessfullycompletedPhaseIIstudyinAD:– Alldosegroups(30/15/7.5mgonce-daily)mettheprimaryendpointwithdosedependentrelationship
– Nonewsafetysignalsidentified,throughlong-termsafetywillbekeyforadermatologyindicationgiventheclass-wideblackboxwarning
AbbVie’sUpadacitinib isaJAK1inhibitorapprovedforthetreatmentofrheumatoidarthritis,andinlate-stagedevelopmentfornumerousinflammatoryconditionsincludingatopicdermatitis
*p<0.05,^p<0.01,†p<0.001;EASI,EczemaAreaandSeverityIndex;IGA,Investigator’sGlobalAssessment;NRS,NumericalRatingScale;PC,PrimaryCompletion;TCS,topicalcorticosteroids;1ReichKetal.,2019;TheLancet.
23%
10%2% 2%
10%
39%*
29%*
14%* 14%*
40%^
62%†
52%†
26%^31%†
48%†
74%†
69%†
50%† 50%†
69%†
0%10%20%30%40%50%60%70%80%
Mean%∆inEASIscore
EASI75 EASI90 IGAof0or1 %∆inpruritusNRS
StrongEfficacySignalinPhaseII
Placebo(n=41) 7.5mg(n=42) 15mg(n=42) 30mg(n=42)
• ComprehensivePhaseIIIprogramunderway:• MeasureUp1(NCT03569293);
n=810,PC:March2020
• NCT03607422;n=810,PC:Feb2020
• NCT03568318(combowithTCS);n=810,PC:March2020
• NCT03738397(vs.dupilumab);n=650,PC:Sept.2020
Bermekimab:Anti-IL-1α forAD
• DerivedfromnaturalhumanhumoralresponseagainstIL-1α• IL-1α isproducedbyactivatedleukocytesandhasnumerousbiologicaleffects• Single-productassetbeingdevelopinarangeofdermatology,immunology,andoncologyindications• RecentlyacquiredbyJ&Jfor$750millionupfrontwithupto$600millioninmilestones• Promisingdatafromopen-labelPhaseIIstudiesinADandhidradenitissuppurativa (HS)
XBiotech’s Bermekimab,recentlyin-licensedbyJ&J,isananti-IL-1α antibodyindevelopmentforarangeofindications,includingatopicdermatitisandhidradenitissuppurativa
Alsodemonstratedstrongimprovementsinitch(~70%mean%reduction)andpain(>80%mean%
reduction)
Alsodemonstratedstrongimprovementsinpain(54%-64%reductionfrombaseline)
HiSCR,HidradenitisSuppurativa Clinicalresponse;*HiSCR =61%forbiologic-naïveand63%forbiologic-refractorypatients**HumiraStudyIIallowedconcomitantuseofantibiotics
HidradenitisSuppurativaAtopicDermatitis
55%60%65%70%75%80%
abrocitinib(week12)
upadacitinib(week16)
bermekimab(week8)
%achievingEASI75 BestEASI75responserates,
andfastestonsetofcurrenttherapiesindevelopment
0%
20%
40%
60%
80%
Investigatorstudy
Companystudy*
HumiraStudyI
HumiraStudyII**
%achievingHiSCR
InnovationinOtherDermatologyIndications
PF-06651600:SelectiveJAK3InhibitorforAlopecia
• Givenautoimmuneetiology,recentdevelopmenthasfocusedonJAKinibs aspotentialtherapy• PF-06651600istheonlyJAK3-selectiveJAKinib indevelopmentforAA• Bindstoauniquecysteineresidue(Cys-909)inthecatalyticdomainofJAK3thatisnotsharedbyother
JAKisoforms,butissharedby5kinasesintheTECfamily(BTK,BMX,ITK,RLK,TEC)1– Preclinicaldatasuggeststhatofthecytolytic functionofCD8+TcellsandNKcellsisdrivenbyinhibitionofTEC
kinases1
Pfizer’sPF-’600,aJAK3inhibitor,iscurrentlybeingtestedinPhaseIIb/IIItrialsafterasuccessfulPhaseIIa studyinAlopeciaAreata (AA)
1Christophetal.,2000;2XuH.,etal.,ACSChem. Biol.2019,14,6,1235-1242.QD,oncedailyadministration
• 95patientswithmoderate-to-severeAA(≥50%scalphairloss),randomized1:1to200mgQDPF-06651600,orplacebo– Onsetofeffectat6weekswithcontinuedimprovement
outto24weeks– ReceivedbreakthroughtherapydesignationforAA– CurrentlyinongoingPhaseIIb/IIIdose-rangingstudy
(n=660;primarycompletion,September2020)– Despitebetterefficacy,PF-06700841(JAK1/TYK2),was
notprogressedduetosafetyissues(2casesofrhabdomyolysis)
• Concert’sCTP-543(deuteratedruxolitinib)hasalsoshownefficacy,howevercommercializationstrategyisuncertain
PF-06651600PhaseIIa trial
Source: PFE company reports; EADV 2018 presentation
Efficacy analysis for the Phase II trial of Pfizer's JAKinib portfolio for alopecias
**p<0.01, ***p<0.001 vs. placebo; CI = Confidence interval; JAK = Janus-associated kinase; SALT = Severity of alopecia tool; All values are placebo normalized
0 2 4 6 8 12 16 20 24
-10
0
10
20
30
40
50
60 PlaceboPF-06651600 (50-200mg, QD)PF-06700841 (30-60mg, QD)
****
***
***
******
******
*** *** ***
******
Weeks of treatment
Mea
nDS
ALT
scor
efro
m b
asel
ine
(90%
CI)
BiologicstoContinuetoTransformAtopicDiseases
• IL-4Rα monoclonalantibody• Approvedindications:atopicdermatitis,
eosinophilicasthma,chronicrhinosinusitis withnasalpolyposis(CRSwNP)
• Indevelopmentfor:eosinophilicesophagitis(EoE),chronicobstructivepulmonarydisorder(COPD),grass,peanutallergy
• EstimatedWW2024sales:$6.2billion
• Anti-IgE antibody(i.e.,high-affinityXolair)• Indevelopmentfor:chronicspontaneous
urticaria (CSU)• Pivotaldataexpected2021
Dupixent Ligelizumab
• Anti-Siglec-8antibody,directlytargetingcellsurfaceproteinsoneosinophilsandmastcells
• Indevelopmentfor:eosinophilicgastritis/gastroenteritis,chronicspontaneousurticaria,idiopathicsystemicmastocytosis,andsevereallergicconjunctivitis
• Pivotaldataasearlyas2021
• Anti-IL-1α monoclonalantibody• Indicationsindevelopment:pyoderm
gangrenosum,hidradenitissuppurativa,plaquepsoriasis,acnevulgaris,atopicdermatitis,systemicscleroderma,andvariousoncologyindications
• RecentlyacquiredbyJNJfor$750millionupfrontwithupto$600millioninmilestones
Antolimab Bermekimab
Antolimab forAtopicDisorders
• Engagessiglec-8todepleteeosinophilsandinhibitmastcells
• DatafromGIdisorderssuggestsbetterandfastereosinophildepletionthanDupixent
• Hasgeneratedpromisingdatafromanopen-labelPhaseIIstudyinchronicspontaneousurticaria(CSU),andthecompanyhasopenlydiscussedstartingastudyinAD
• Whilenotpuredermatology,urticaria isclearlyrelatedtodermatology,andthedrugmayhavepotentialinadditionaldermatologyindicationssuchasAD
Allakos’antolimab (AK002)isanafucosylated anti-siglec-8monoclonalantibodythatdepleteseosinophilsandinhibitsmastcells
-125
-100
-75
-50
-25
0
25
50
-78%
-100%
-77% -73%
-55%-46% -41% -38%
-23%-13%
-30%
UAS
-7(%
cha
nge
from
bas
elin
e)
IndividualpatientUAS-7scoreresponsesinXolair-refractorypatientstreatedwithantolimab
UCT,urticaria controltest;UAS-7,urticaria activityscore;HSS7,hivesseverityscore(sumofaveragedailyscorefrom7precedingdays)
0%10%20%30%40%50%60%70%80%90%
Ligelizum
ab72mg
Ligelizum
ab240m
g
Omalizum
ab
Antolim
ab(Xolair-naïve)
Antolim
ab(Xolair-refractory)
N= 84 85 85 13 13
ProportionofpatientswithHSS7=0inCSUtrials
Antolimab LooksCompetitiveinCSU
0%10%20%30%40%50%60%70%80%90%100%
UCT(CR) UAS-7%improvementfrombaseline
UAS7<7 UAS7=0 HSS7=0
ComparisontoXolair andLigelizumab inCSU
Xolair* Ligelizumab Antolimab
NR NR
*ShowingbestdataforeachendpointacrossASTERIAI/IIPhaseIIItrials,GLACIALPhaseIIItrial,andPhaseIIb trialofXolair vs.ligelizumabSources:SainiS.etal.,2015.J.InvestDermatol;MaurerM.etal.,2013.NEJM;KaplanA.etal.,2019.JACI;MaurerM.etal.,2018.EAACI;WilliamBlair&CompanyLLCUCT,urticaria controltest;UAS-7,urticaria activityscore;HSS7,hivesseverityscore(sumofaveragedailyscorefrom7precedingdays)
Basedondatafromtheopen-labelPhaseIIstudyinCSU,antolimab comparesfavorablytotheleadingmast-celltargetedbiologicsusedforthetreatmentofpatientswithantihistaminerefractoryCSU
KrystalBiotech:GeneTherapyPlatformforDermatology
• LeadcandidateisKB103(bercolagene telserpavec;B-VEC)forrecessivedystrophicepidermolysisbullosa(dystrophicEB,DEB)– DEBisarare,geneticconnectivetissuediseasethatcausesskintotearandblisterformminorcontact– CausedbymutationsintheCOL7A1genethatcodesfortheCOL7proteinwhichanchorsthedermistoepidermis
• NoapprovedtreatmentsforDEB;palliativetreatmentscost$200k-$400kannually2,3
• WWprevalenceupto125,0001
SkinTARgeted Delivery(STAR-D)Platformusesmodifiedherpessimplexvirus1(HSV)vectorstotreatskindiseases
1DebraInternational2RashidghamatE.,Mellerio J.E.,Managementofchronicwoundsinpatientswithdystrophicepidermolysisbullosa:challengesandsolutions,ChronicWoundCareManagementandResearchVolume2017:4,45-543GENEGRAFTReportSummary.(2015,February16).RetrievedDecember13,2016,fromhttp://cordis.europa.eu/result/rcn/156078_en.htmlSource:KrystalBiotechcompanypresentation
Mechanism of Action
KB103entersthecompromisedskinandtransduceskeratinocytesandfibroblasts
1
KB103entersthenucleusoftransducedcellsandthevectorgenomeisdeposited(episomally)
2
COL7A1 transcriptsaregenerated,allowingproductionandsecretionofCOL7protein
3
SecretedCOL7proteinassemblesintoanchoringfibrilswhichholdthedermisandepidermistogether
4
KB103:ClinicalDataTo-Date
• Notreatmentrelatedadverseevents• Noimmuneresponseorblisteringobservedaroundthesites
ofadministration• Bloodandurinesamplesrevealed:
– Noviralshedding– NoAEsassociatedwithroutinelabs– NoantibodiestoCOL7detected
Combinedresultsfromacombined8patientsinthePhaseI(GEM-1)andPhaseII(GEM-II)studiesdemonstrategoodefficacy,aswellasgoodsafety/tolerability
RMATdesignationPRIMEeligibility
FastTrackDesignationGranted
OrphanDrugDesignationinUSand
EURarePediatricDiseaseDesignationinUS
EligibilityforPriorityReviewVoucher
9/10* woundsclosedcompletelyafterinitialadministrations
17.4 averagetime(days)to100%woundclosure(ofthe9treatedwounds)
113 averageduration(days)ofwoundclosureatlasttimepointmeasured
Pivotalstudyexpectedtobegininfirsthalfof2020;BLAfilingexpectedinthesecondhalfof2020
IllustrativeWoundHealingDatafromPatient05inPhaseIIstudy
Source:KrystalBiotechcompanypresentation*The10thwoundclosedfollowingasecondadministrationofKB103
Summary
DermatologyRemainsaGreatAreaofInnovation• Recentyearshaveseenmajorclinicalimprovementsindermatologydrugdevelopment,as
evidencedbyimprovementinpsoriasiswithPASI100nowbeingarealisticgoalfortreatment• Thelargenumberofhigh-qualityproductsindevelopment,spanningdifferentmechanismsof
actionandroutesofadministration(oral,biologic,topical)aswellasgenetherapyacrosstheindicationsdiscussedillustratesongoinginnovation
• ThesetherapieshavethepotentialtotouchthelivesofmillionsofpatientsintheUSalone(>8millionPsO;>18millionAD;>6millionAA)offeringsignificantimprovementsinhealthandQoL
Indication Drug 2024ESales*
PsO BMS-986165 1,233
PsO Skyrizi 2,616
PsO tapinarof NA
AD lebrikizumab 248
AD Rinvoq NA
AD Dupixent 4,138
AA PF-06651600 112
AA CTP-543 165
CSU ligelizumab 94
CSU antolimab 256^
Multiple bermekimab NA
DEB KB103 275
TOTAL 9,137
• Significantcommercialopportunity– Top10PsO therapiesgenerating2018globalsales>$14
billioninPsO alone
• Newleadersemerging(AbbVie,Pfizer,Merck,Regeneron,Incyte,EliLilly),withseveralsmallerinnovatorsalsoenteringthescene(Dermira,Krystal,Allakos,Nimbus,Concert,Dermavant,Revance,Novan,Principia)
*2024GlobalsalesestimatesforlistedindicationfromEvaluatePharma;^WilliamBlairestimateforCSU
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