Download Abstract #5067 The Nonclinical Toxicology Profile

TheNonclinicalToxicologyProfileofPacri3nib,aJAK2/FLT3InhibitorwithnoDoseLimi3ngClinicalMyelosuppression
Abstract#5076
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RebeccaWatson,Ph.D.,D.A.B.T. ;JackSinger,M.D. ;SulimanAl-Fayoumi,Ph.D.,M.B.A. 1CTIBioPharmaCorp,SeaLle,WA
ABSTRACT
Pacri3nibisanorallybioavailablekinaseinhibitorbeingdevelopedforthetreatmentofmyelofibrosis
(MF).Pacri3nibisapotentinhibitorofwild-typeandmutantisoformsofJAK2andFLT3(IC50values<
15nM),anditdoesnotsuppressJAK1atclinicallyrelevantconcentra3ons.Addi3onalkinasestargeted
bypacri3nibandevaluatedinacomprehensivekinomeprofilebyReac3onBiologyCorp.includeIRAK1
(IC50=13.6nM)andc-fms(orCSF1R;IC50=39.5nM).Pacri3nibispharmacologicallyac3vein
nonclinicaltumormodelsdrivenbyJAK2orFLT3overexpressionoroverac3vity,andclinicaltrialshave
demonstratedefficacyofpacri3nibinMFpa3ents.Akeydifferen3a3ngfeatureofpacri3nibover
currentlyavailableJAK2inhibitorsisthelackofdose-limi3ngclinicalmyelosuppression,allowingfor
treatmentofpa3entswithcytopenias.Thecompara3velyreducedmyelosuppressiveac3vityof
pacri3nibisthoughttobeduetoitslackofpharmacologicalac3vityonJAK1,and/oritsinhibi3onof
IRAK1andc-fms,whichmaycontributetoan3-inflammatoryac3vity.Nonclinicalpacri3nibdatafrom
completedrodentandcaninestudieswereevaluatedincomparisontopubliclyavailableinforma3on
forotherJAK2inhibitorstodetermineifdifferencesinnonclinicalendpointsmightcorrelatewiththe
observedclinicaldifferencesinmyelosuppressiveeffects.Thequalita3venonclinicalfindingsseenin
rodentsweresimilarforallJAK2inhibitors,andincludeddecreasesinleukocytes,redcellmass,and
re3culocytes;lymphoiddeple3oninthespleen,thymus,and/orlymphnodes;andhypocellularityof
thebonemarrow.Interes3ngly,plateletdecreaseswerenotobservedinrodentorcaninenonclinical
models,evenwithJAK2inhibitorsassociatedwithclinically-significantthrombocytopeniaAEs.
However,inthedog,pacri3nibisuniqueforitsminimalmyelosuppressiveeffectsinthepivotal30-day
and39-weekstudies.Withpacri3nib,non-adverselymphoidreduc3onwasseeninthespleen,lymph
nodes,Peyer’spatches,and/orthymus;buttherewerenoclinicalpathologyfindingsindica3veof
markedmyelosuppression,norwerethereanytreatment-relatedfindingsindetailedbonemarrow
evalua3ons.Overall,thesecomparisonssuggestthatnonclinicalbonemarrowdataandclinical
pathologyinthedogmaybeinforma3veendpointsfores3ma3ngthemyelosuppressivepoten3alof
JAK2inhibitorsintheclinic.
BACKGROUND
•  Pacri3nibisapromisingdrugcurrentlydevelopedbyCTIBioPharmaCorp.andBaxaltaInc.forthe
treatmentofmyelofibrosis(MF).Pacri3niblacksdose-limi3ngmyelosuppression;thus,itcan
poten3allybepar3cularlybeneficialtopa3entswithcytopeniaswhicharecommonlyseeninMF
pa3ents.
•  Nonclinicalstudydataforpacri3nibwerereviewedtoassesstheconcordanceoftheobserved
nonclinicaltoxici3estopoten3aladverseeffectsintheclinic.Thesedatawerecomparedto
publicallyavailablenonclinicaldata(fromEuropeanMedicinesAgency[EMA],AustralianPublic
AssessmentReports[AusPAR]andCenterforDrugEvalua3onandResearch[CDER]Pharmacology
reviews)forruxoli3nibandtofaci3nib,twocurrentlyapprovedJAKinhibitors.
•  Ruxoli3nib:JAK1/JAK2inhibitorapprovedfortreatmentofMFandpolycythemiavera(PV)
CDERapplica3on20292Orig1s000,2011;AusPARPM-2012-01504-3-4,2014;EMAreport465846,2012
•  Tofaci3nib:JAK1/JAK3inhibitorapprovedfortreatmentofrheumatoidarthri3s
CDERapplica3on203214Orig1s000,2011;AusPARPM-2012-00788-3-3,2015;EMAreport425279,2013
•  Forpacri3nib,ruxoli3nib,andtofaci3nib,pivotalnonclinicalstudieswereperformedinonerodent
modelandonenon-rodentlargeanimalmodel.Thegoalofthesestudieswastoiden3fyano
adverseeffectlevel(NOAEL),ifpossible,andtocharacterizetoxici3esan3cipatedabovethatdose.
•  ConsistentwithJAKinhibi3on,thehematopoie3csystem(spleen,lymphnodes,thymus,bone
marrow)wasatoxicitytargetwithallthreeJAKinhibitors.However,thereweredifferencesinthe
nonclinicalmyelosuppressionandimmunosuppressionprofiles.
PivotalNonclinicalToxicologyStudies
Drug
Pacri3nib
Ruxoli3nib
Tofaci3nib
Rodent
Repeatdosetoxicitystudiesforupto6
mo.intheBALB/Cmouse
Repeatdosetoxicitystudiesforupto6
mo.intheSprague-Dawleyrat
Repeatdosetoxicitystudiesforupto6
mo.intheSprague-Dawleyrat
LargeAnimal
Repeatdosetoxicitystudiesforup
to9mo.intheBeagledog
Repeatdosetoxicitystudiesforup
to12mo.intheBeagledog
Repeatdosetoxicitystudiesforup
to9mo.intheCynomolgusmonkey
NONCLINICALSUMMARY
KeyNonclinicalHistopathologyFindings*
Drug
I.  Dose-LimiJngToxiciJes
Dose-limi3ngtoxici3esforpacri3nib,ruxoli3nib,andtofaci3nibarepresentedbelow.Inrodentmodels,dose-limi3ngtoxici3esarefairlysimilarfor
pacri3nibandruxoli3nib;fortofaci3nib,effectssecondarytoimmunosuppressioncontributedtodoselimi3ngtoxici3es.Inlargeanimalmodels,
adverseGIeffectsweredoselimi3ngwithpacri3nib,whileinfec3onssecondarytoimmunosuppressionwereseenwithruxoli3nibandtofaci3nib.
NonclinicalDoseLimiJngToxiciJes
JAKInhibitor
Rodent
•  Poorclinicalappearance(ruffledcoat,ungroomed)
Pacri3nib
Ruxoli3nib
Tofaci3nib
• 
• 
• 
• 
• 
• 
• 
• 
Decreasedbodyweightandfoodconsump3on
Mortalityathighdoses
Poorclinicalappearance
Decreasedbodyweightandfoodconsump3on
Mortalityathighdoses
Poorclinicalappearance
Decreasedbodyweightandfoodconsump3on
Bacterialinfec3onsofthekidneyandlung
Mortalityathighdoses
LargeAnimal
GI-relatedeffects:Emesis,abnormalfeces,diarrhea
Decreasedbodyweightandfoodconsump3on
Moribundstatusduetoseverelymphadenopathy
Adverseclinicalobserva3ons
Earlydeathsconsistentwithopportunis3cinfec3ons(secondarybacterialskininfec3ons
andpyrogranulomatousinflamma3onassociatedwithintrafollicularmites)
•  Bacterialandviralinfec3ons
•  Lymphomassecondarytotreatment-relatedimmunosuppression.
• 
• 
• 
• 
• 
II.  Myelosuppression
•  ClinicalPathologyData
•  AlltheJAKinhibitorspresentedwithreduc3onsinredcellmass(redbloodcells,hemoglobin,and/orhematocrit)andleukocytepopula3ons.
•  Intherodent,theobservedreduc3onsinredcellmassweremild,andnotconsideredadverse.Decreasedredcellmasswasmorepronouncedin
thelargeanimalstudieswithruxoli3nibandtofaci3nib.
•  Changesinleukocytepopula3onsweremostpronouncedwithruxoli3nibandtofaci3nibcomparedtopacri3nib.
•  HistopathologyData
•  RodentfindingsforallJAKinhibitorsconsistedoflymphoiddeple3onofthespleen,thymusandlymphnodes,indica3veofmildmyelosuppression.
•  Inthelargeanimalstudies,myelosuppressionwasmostpronouncedwithtofaci3nibandleastpronouncedwithpacri3nib
•  Theobservedclinicalpathologyandhistopathologyaltera3onsassociatedwiththeJAKinhibitorsweregenerallyreversible.
•  Resultsfromthelargeanimalstudiesweremorepredic3veofclinicalperformancecomparedtoresultsfromtherodentstudies.
NonclinicalRodentHematologyinPivotalStudies*
PacriJnib:6mo.MouseStudya
RuxoliJnib:6mo.RatStudyb
TofaciJnib:6mo.RatStudyc
Sex
M
F
M
F
M
F
Doses(mg/kg/day)
42.7,142.2,213.4
5,15,30,60
1,10,100
Redbloodcells
upto5.2%↓
upto6.6%↓
NA
NA
1-13%↓
1-15%↓
Hemoglobin
-
-
-
-
upto10%↓
1-10%↓
Hematocrit
-
upto6.5%↓
-
upto12%↓
upto12%↓
Re3culocytes
-
-
NA
NA
NA
NA
Whitebloodcells
-
upto39%↓
5-32%↓
10-38%↓
19-62%↓
19-60%↓
Neutrophils
upto100%↑
-
6-12%↑
-
22-203%↑
31-298%↑
Lymphocytes
upto35%↓
upto56%↓
5-43%↓
18-46%↓
4-38%↓
5-45%↓
Monocytes
-
-
upto14%↓
10-40%↓
upto56%↑
12-134%↑
Eosinophils
-
-
-
11-44%↓
NA
NA
Basophils
-
-
upto57%↓
-
NA
NA
*Resultsreflectthelasthematologysample3mepointpriortotheendofthedosingphaseofthestudy.-:Nonotablechanges.
aNOAELwas71.1mg/kg/daypacri3nibduetomortalityandreducedbodyweight&foodconsump3onathigherdoselevel.
bANOAELwasnotprovided,butnoadverseeffectswereseeninfemalesupto60mg/kgandinmalesupto30mg/kg(malesat60mg/kghadreducedbodyweightgain)
ctheNOAELinthisstudyis<100mg/kg/day,andexactNOAELwasnotprovidedduetotheabsenceofcertainhistopathologydata.
NonclinicalLargeAnimalHematologyinPivotalStudies*
PacriJnib:9mo.DogStudya
RuxoliJnib:6mo.DogStudyb
RuxoliJnib:12mo.DogStudyc
Sex
M
F
M
F
M
F
Doses(mg/kg/day)
4.2,14.4,&28.8
5&10
0.75,1.5,3,&6
Redbloodcells
upto10%↓
-
14-27%↓
8-14%↓
upto17%↓
Hemoglobin
upto15%↓
-
16-33%↓
9-19%↓
upto22%↓
Hematocrit
upto12%↓
-
15-30%↓
9-17%↓
upto18%↓
Re3culocytes
-
-
15-22%↑
32-47%↑
compensatory↑notobserved
Whitebloodcells
30%↓to25%↑ uptoupto32%↑
upto50%↑
83-117%↑
NA
Neutrophils
-
-
9-64%↑
upto10%↑
upto40%↑
Lymphocytes
upto20%↓
upto61%↑
14%↓to28%↑
-
upto35%↓
Monocytes
-
-
31-102%↑
20-76%↑
upto40%↑
Eosinophils
-
-
36-59%↓
73-80%↓
upto55%↓
Basophils
-
-
-
upto50%↑
-
*Resultsreflectthelasthematologysample3mepointpriortotheendofthedosingphaseofthestudy.-:Nonotablechanges.
aNOAELwas14.4mg/kg/dayduetogastrointes3naltoxici3esobservedabovethatdose.
TofaciJnib:9mo.Monkey
Studyd
M
dANOAELcouldbedeterminedinthisstudyduetolymphnodelymphocytehyperplasiaatthelowdose,whichwasconsideredadverse.
LargeAnimal
•  Hypocellularityofthebonemarrowat
thehighdoses
•  LymphoiddepleJoninspleen,thymus,
andlymphnode
•  Slightdecreaseinspleenweights
RuxoliJnib •  MinimaltomildlymphoiddepleJonin
thespleenandlymphnodes
•  SignificantreducJoninspleenand
adrenalglandweights
•  Minimalcor3calatrophyoftheadrenal
glands.
TofaciJnib •  Bonemarrowerythroidandlymphoid
depleJon
•  LymphoiddepleJoninthespleen,
thymus,andlymphnode
•  Enlargedstomachwithmul3focal
necrosis
•  Reducedspleenandthymusweights
*Findingsrelatedtomyelosuppressionareinboldface.
PacriJnib
•  MinimallymphoiddepleJoninthePeyer'spatchesand
spleen,lymphoidhyperplasiaofthethymicmedulla.
•  Notreatment-relatedchangesinthemyeloidanderythroid
populaJonsinthebonemarrow.
•  Slightdecreaseinspleenandthymusweights
•  MarkedlymphoiddepleJoninthespleenandlymphnodes
•  Bonemarrowhypocellularityinsomeearlydeathanimals
•  Granulomatousinflamma3onwithparasi3cmitesinthelymph
nodes,acuteand/orsubacuteinflamma3onofthelung,3ssue
pyrogranulomatousinflamma3onoftheskinandfootpad
secondarytoinfec3on
•  LymphoiddepleJonofthelymphnodes,spleen,and/orgut
associatedlymphoidJssue
•  BonemarrowdepleJon,withreducJoninhematopoieJccells
andrelaJveincreaseinadiposeJssueand/ordecreaseinthe
myeloid:erythroidraJo
•  ReducJonsinthymic,spleen,andreproducJveorganweights
III.Immunosuppression
•  Adverseeffectsofimmunosuppressionwereprimarilyevidentinthelargeanimalstudies.
•  Withpacri3nib,onedeathofahighdoseanimalwaspossiblyexacerbatedbytreatment-related
immunosuppression.
•  Withruxoli3nibandtofaci3nib,secondaryinfec3onswereclearlytreatment-relatedandprevalentin
largenumbersofdogsandmonkeys,respec3vely.
JAKInhibitor
PacriJnib
RuxoliJnib
TofaciJnib
NonclinicalImmunosuppression
LargeAnimalStudyFindings
Inthe30daydogstudy,therewasonehighdoseanimalinwhichdeathaninfec3onsecondaryto
lymphadenopathymighthavebeenexacerbatedbytreatment-relatedimmunosuppression.
Immunosuppressionwasnotseeninthe9monthstudy.
Inthedog,significantimmunosuppressionwasobserved.Thisresultedindemodec3cmangeassociatedbacterialinfec3onsoftheskin,andparasi3cmites.
Inthemonkey,significantimmunosuppressionwasobserved.Inshortertermstudies,thismanifested
insecondaryinfec3onsofopenwoundsandgastrointes3nalerosionsorulcers,inalongertermstudy,
thisresultedinlymphomasassociatedwithlymphocryptovirusinfec3on.
DISCUSSION&CONCLUSIONS
•  Asillustratedbelow,majorclinicaladverseeventsassociatedwithpacri3nib,ruxoli3nib,and
tofaci3nibaregenerallyconsistentwithpreclinicalstudyfindings.
ClinicalAdverseEventsandPreclinicalToxiciJes
JAK
Inhibitor
MajorHumanClinical
AdverseEvent(s)
PacriJnib
Diarrhea,nausea
RuxoliJnib
Anemia,thrombocytopenia,neutropenia,
immunosuppression
TofaciJnib
Suscep3bilitytoopportunis3cinfec3ons,
neutropenia,lymphopenia,hematologic
malignancies,liverdamage,lipidprofile
changes
F
0.5,2,&10
5-20%↓
4-10%↓
4-17%↓
6-11%↓
4-19%↓
5-13%↓
8-67%↑
upto51%↑
1-30%↓
3-30%↓
NA
NA
21-43%↓
26-40%↓
NA
NA
NA
NA
NA
NA
bANOAELwasnotprovided,butabove2.5mg/kg/day,immunologicalcondi3onswereobserved.Onlyhematologydataforthe5and10mg/kg/daydoselevelswereavailable.
cANOAELwasnotprovided,butabove1.5mg/kg/day,generalizeddemodicosiswasobserved
Rodent
PreclinicalAnimalModelCorrelates
GIfindingswerereportedintherodent(thickabdominal
structures,intes3naldilata3on)andvomi3nganddiarrhea
wereobservedinthedog.
Theanemiaandneutropeniawerepredictablebasedon
thepreclinicalhematology(par3cularlyinthedog).
Immunosuppressionwasclearinthedog.
Thrombocytopeniawasnotseeninthepreclinicalstudies.
Opportunis3cinfec3onsuscep3bility,neutropenia,and
lymphopeniaareconsistentwithpreclinicalobserva3ons,
par3cularlyinthemonkey.
•  IncomparisontootherJAKinhibitors,pacri3nibhadmildmyelosuppressiveeffectsinpreclinical
studies,andnoremarkableimmunosuppression.
•  Similarly,intheclinicpacri3nibisnotassociatedwithdose-limi3ngmyelosuppressionor
immunosuppression.
•  Pacri3nib’suniquenonclinicalandclinicalprofilesmaybeduetoitslackofJAK1inhibi3onat
relevantconcentra3ons.JAK1inhibi3onblocksIL2andinterferon
signalingrequiredforahealthyimmuneresponsetoinfec3on.
•  Furtherinves3ga3onscomparingeffectsofJAKinhibitorsonspecific
targetscanpoten3allyhelpdeterminewhichspecificpathwaystotargetin
ordertoop3mizebenefit-risk.
AACR2016