SickleCellDisease

NewTherapeutic
Approaches
MatthewM.Heeney,MD
AssociateChief,Hematology
Director,SickleCellProgram
ChildrensHospitalBoston

ENGAGE
3rd AnnualCanadianConference
onSickleCellDisease
Ottawa,ON
September30th October1st,2016

FacultyDisclosure
MatthewM.Heeney,MD
Personalfinancialinterestsincommercialentitiesthatare
relevanttomypresentation(s)orotherfacultyroles:

EliLilly
AstraZeneca
Pfizer
Sancilio&Co

ResearchFunding
ResearchFunding
ResearchFunding
ResearchFunding

Iwilldiscusstheofflabeluseof

Hydroxyureainchildrenwithsicklecelldisease.

IamCanadian!
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Objectives
Briefoverviewofthepathophysiologyofsickle
celldisease.
Discussnewpathophysiologicallybased
therapiesforsicklecelldisease.

Overview/Pathophysiology
Pathophysiologicallybased
TherapeuticApproaches
ClinicalTrials

Hemoglobin
Fourglobularproteins(globins)
2likeglobins
2likeglobins

Fourhemegroups
Oneperglobinchain
ReversiblybindO2(CO2,NO)

Hbsynthesismustbebalanced
andcoordinated
Allcomponentsarelabileand
toxic
globins,heme,iron

BetaglobinSwitching atBirth

DNA

Protein
Ala
Thr
Glu
Leu
Arg
Ser

Amino Acids

S
HbS(2 2)

S :Singleaminoacid
substitution
Glutamicacid Valine

Valinecreatesahydrophobic
regiononthe globin

10

Hemoglobinchangesshape

11

MolecularPathophysiology

Deoxygenation
resultsinrelaxation
oftheS subunits
Formationofnon
covalentbonds
between S proteins
Formationof14
strandedhelical
polymers.
5/2/14

12

Bunn HF. NEJM 1997

13

Delaytime
Delaytime:periodduringwhichHbS is
deoxygenated,butnotyetpolymerized
Ifpassagethroughthecapillariesexceedsthe
delaytime,hemoglobinwillaggregate,initiate
polymerization,andsickling.

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CellularPathophysiology
Polymerizationleadsto:

Distortionofcellshape
DamagetoRBCmembrane
AbnormalRBCpermeability
Irreversiblesickling

Prematurehemolysis=HemolyticAnemia
ImpairmentofRBCflow=TissueInfarction

15

HemolysisandNitricOxidedepletion

NO
Endothelial
dysfunction

16

16

CellularPathophysiology
Vascularendothelialdysfunction
SickleRBCbindsendotheliummorereadily.
Roleof Reticulocytes
WBC
Platelets
Coagulationcascade(Thrombin)

Dysregulation ofvasculartone(NOmediated)
redbloodcelltransit me
oxygenextrac on
sicklingandvasoocclusion.
17

Vaso-occlusion

Intra-cellular
dehydration

Hemolysis

Reperfusion Injury
Inflammation
Endothelial Activation

Nitric Oxide
consumption

18

ClinicalRiskStratification CSSCD

Miller S et al. NEJM 2000

19

Intravital Microscopy

Cremaster MuscleVenule +TNF

Frenette P et al. Microcirculation 2004

20

LeukocytecontributiontoVOC

Manwani D and Frenette PS Blood. 2013:122(24):3892-3898

21

Overview/Pathophysiology
Pathophysiologicallybased
TherapeuticApproaches
ClinicalTrials

22

FetalHemoglobin(HbF)
FetallifeandearlyinfancyareaHoneymoon
period forsicklecelldisease.
VeryfewVOCcomplicationsobserved.
HigherOxygenaffinity
Doesnotparticipateinpolymerization.

23

PolymerizationblockedbyHbF

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BetaglobinSwitching atBirth

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PharmacologicinductionofHb F
HYDROXYUREA
Olddrug Newindication.
firstsynthesizedin1869
antineoplasticsincethe1960s

Ribonucleotidereductaseinhibitor.
mechanismofactionunclear.

HemoglobinF
HbSpolymeriza onandhemolysis
Hemoglobin
WhiteBloodCells(SideEffect?)

26

Hydroxyurea ClinicalTrials
MultiCenter StudyofHydroxyurea(MSH)(19921995)
Adults
HemoglobinF;Hemolysis&Anemia;whitebloodcells
paincrises by40%;acutechestsyndromeby50%;transfusions by50%
Charache S et al. N Engl J Med 1995;332:1317-1322.

MSHFollowUp(19962001)
40%reductioninmortalityafter9yearsoffollowup
Steinberg MH et al JAMA. 2003;289(13):1645-1651

MSHFollowUp(19962010)
after17.5yearsoffollowup

Steinberg MH et al. Am J Hematol 2010;85: 403408.

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Hydroxyurea ClinicalTrials
HUGKIDS

(19941996)

Children515y.o.withseveredisease.

SimilarlaboratoryandclinicalresultsasMSH
Kinney TR et al. Blood 1999 94:1550-1554

HUSOFT

(19962001)

Age>2y.o.GoodLaboratory&Clinicaleffect.

Normalgrowth/development.

BabyHUG

Hankins JS et al. Blood. 2005 Oct 1;106(7):2269-75.

(20032007)

Age918months.

Doselimitedto20mg/kg/dayfor2years.

Wang WC et al. Lancet. 2011 377(9778):1663-72.

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Effect of Hydroxyurea on ED Utilization of All Patients (n=61)

Annual Visit Frequency per Patient

37%*
2.9
3

1.8

Pre-HU

Post-HU

*=p<0.05
McCullough L et al PAS 2009

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WhoshouldgetHydroxyurea?2016
Indications:
a) ??age HbSS,HbS0 +??HbSC.
b) Frequent paincrises.
c) Acutechestsyndrome.
d) Parentalrequest

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ChronicTransfusion&
Erythrocytapheresis

ProtectionfromCVA,ACS
IatrogenicFeoverload
Allosensitization
UnknownInfectiousRisk

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IronAccumulationinSTOP

Files B et al, JPHO 2002;24:284-90

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Howdowegettheironout?
Deferoxamine
(Desferal)

Deferasirox
(Exjade,Jadenu)

OvernightSubQ infusion

Deferiprone (Ferriprox)
Oncedailyoraldose

Threetimesdailyoraldose
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Overview/Pathophysiology
Pathophysiologicallybased
TherapeuticApproaches
ClinicalTrials

34

ChangingLandscapeinU.S.
PediatricResearchEquityAct(PREA2003)
BestPharmaceuticalsforChildren Act (BPCA2002)
Increase pediatrictrialstoensureadequatetesting,safety,
andefficacyofnewtherapiesforchildren.
Simplegoal developnewandinnovativeevidencebased
therapiestoextend/enhancelivesofchildren.

OrphanDrugAct(ODA1983)
Taxincentives.
Enhancedpatentprotectionandmarketingrights.

RareDiseasesAct(RDA2002)
EstablishOfficeofRareDiseasesatNIH.
35

PathophysiologicallybasedTherapies

ManipulationofOxygendissociationcurve
Leukocyte/Selectininhibition
Plateletinhibition
Antiinflammation
EndothelialDysfunction

StemCellTransplantandGeneTherapy
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ManipulationofOxygenDissociation
AesRx (Aes103)
GlobalBloodTherapeutics(GBT440)

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StudyAes103002(NCT01597401)
Forthosewithmeasurablepainatbaseline
(NPRS2)painwassignificantlyreducedina
dosedependentandtimedependentmanner.

Kato GJ, ASH Annual Meeting 2013 Abstract

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GlobalBloodTherapeutics(GBT440)

A novelsmallmolecule.
Reversiblebindingtoglobin.
StabilizesHb O2 conformation.
DosedependentincreaseinHb O2 affinity.
HighlyselectiveforHemoglobin.
PreventsRBCsicklingandprolongsRBChalf
lifeinamurinemodelofsicklecelldisease.

41

GBT440001(NCT02285088)
Hemoglobin(g/dL)

Reticulocytecount(%)

Relativechangefrombaseline,median,and25th and75th %ile

Lehrer-Graiwer J et al. EHA 2016

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GBT440001(NCT02285088)
Irreversiblysickledcells(smear)

Lehrer-Graiwer J et al. EHA 2016

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Leukocyte/Selectininhibition
Glycomimetics /Pfizer(Rivipansel)
Smallmoleculepanselectin blocker
PhaseII(NCT01119833) complete.
PhaseIIIRESET(NCT02187003)enrolling.

Selexys (SelG1)
Pselectinspecifichumanizedmonoclonal
antibody
Phase2SUSTAIN(NCT01895361)complete.

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SelectinBiology

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Rivipansel(GMI1070)
PhaseIImulticenter,prospective,
randomized,doubleblindstudyinhospitalized
sicklecelldiseasepatientsexperiencingVOC.

N=76patients
22N.A.sites
Ages12to60years
HbSS orHbS0 thalassemiawithVOC.
LoadingdoseIV,followedbyq12hdoses.
Telen M. Blood. 2015 Apr 23;125(17):2656-64

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Rivipansel (GMI1070)
Rivipansel decreasetimetoresolutionofVOC
(p=0.19).
83%reductionincumulativeIVopioiduse(p=0.010).
Theeffectonopioidusewasseenwithin24h.

Telen M. Blood. 2015 Apr 23;125(17):2656-64

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Rivipansel
RESET(NCT02187003)
PhaseIIImulticenter,prospective,
randomized,doubleblindstudyinhospitalized
sicklecelldiseasepatientsexperiencingVOC.
N=350patients
83sites
Ages>6years
HbSS,HbS thalassemia,HbSC orHbSVariant
LoadingdoseIV,followedby8Xq12hdoses.

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Selexys SelG1
SelG1isahumanized
monoclonalantibody
thatbindstohumanP
selectinandblocksthe
interactionswithits
ligandPSGL1.
HumanIgG2heavychain
constantregionwas
exploitedtoeliminate
potentialantibody
effectorfunctionasthe
Humankappalightchain
constantregion.
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Pselectin

http://www.selexys.com/

53

Selexys SUSTAIN(NCT01895361)
PhaseII,multicenter,randomized,placebo
controlled,doubleblind,StudytoAssess
SafetyandEfficacyofSelG1WithorWithout
HydroxyureaTherapyinSickleCellDisease
PatientswithSickleCellRelatedPainCrises.
Age16 65years
2 10VOCwithinthelast12months.
HbSS,HbSC,HbS0 andHbS+thalassemia.
N=174
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Selexys SUSTAIN(NCT01895361)
AdministeredIVover30min.followedby60
min.monitoring
LoadingDose:Day1andDay15 3days
MaintenanceDose:beginningatWeek6and
continuingevery4weeksthroughWeek50
(FinalDose).
Studycompleted Resultspending.

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Plateletinhibition
ADPreleasedfromhemolyzing sicklecells
inducesplateletactivationthroughthe
plateletP2Y12 ADPreceptor.
PlateletP2Y12 ADPreceptorantagonists
EliLilly (Prasugrel)
Phase3DOVEtrial(NCT01794000)completed.

AstraZeneca(Ticagrelor)
Phase2HESTIAtrial(NCT02214121)enrolling.
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Moleculartargetsofantiplateletagents

Michelson AD. Nat Rev Drug Discov. 2010 Feb;9(2):154-69.

58

Prasugrel
MultinationalPhaseIII,DoubleBlind,
Randomized,EfficacyandSafetyComparison
ofPrasugrelandPlaceboinPediatricPatients
withSickleCellDisease.
HbSS andHbS0 thalassemia.
Age2and16years.N=341
9monthsoftreatmentwithanOLE.
51studysitesin14countries.
USA,Canada,Brazil,Lebanon,Egypt,Turkey,Italy,Belgium,France,UK,
Netherlands,Ghana,Kenya,Oman,SaudiArabia,UAE

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RateofVOC
Treatment

No
Patients
w/events
(%)

Totalno
events

Lengthof
followup

Event
rate

Cruderate
ratio

RateRatio
95%CI
(lower,
upper)

pvalue

prasugrel
(N=171)

115(67.3)

328

142.89

2.295

0.830

0.83
(0.66,1.05)

.117

placebo
(N=170)

123(72.4)

408

147.44

2.767

Heeney MM et al. N Engl J Med 2016; 374:625-635

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MeannumberofVOC

Heeney MM et al. N Engl J Med 2016; 374:625-635

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Antiinflammation
Omega3FattyAcids(Fishoils)
Lovaza
Sancilio&Co

(NCT01202812)?Status.
(NCT02604368)?Openingsoon.

Regadenoson
selectiveadenosineA2ARcagonist
Phase2trial(NCT01788631)Enrolling.

65

SickleCellandCytokines

/REGADENOSON

Professional illustration by Eric Smith

67

StudyDesign
PhaseII multicenter,prospective,double
blind,placebocontrolledtrialinSCDpatients
admittedwithpainand/ormildtomoderate
ACS.
Regadenosonvs.Placebo 48hrinfusion
Primaryobjective:
effectoniNKTcellactivation.

Secondaryobjectives:
effectonLOS,respiratorySx,opioiduse,
inflammatorymarkers
68

EndothelialDysfunction
MastTherapeutics(MST188Velpoloxamer)
EPICtrial(NCT01737814) Completed.

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Velpoloxamer Background&Rationale
Vepoloxamer isanonionicmaterialthatreduceserythrocyte
aggregationandcellularadhesiontothevascular
endothelium.
Vepoloxamer adherestodamagedcellmembranes,restoring
thecellsnatural,hydrated,nonadhesivesurfaceand
decreaseswholebloodviscosity.

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EPIC(NCT01737814)
APhaseIIIRandomized,DoubleBlind,
PlaceboControlled,MulticenterTrialof
Vepoloxamer inSickleCellDiseasewithVaso
OcclusiveCrisis.
HbSS,HbSC,HbS0 thal,orHbS+ thal.
Age4 65years.
N=388
77studysitesin14countries.

USA,Canada,Belgium,Brazil,DominicanRepublic,Jamaica,Jordan,
Lebanon,Oman,Panama,Spain,Turkey...

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Velpoloxamer Results
September2016
Velpoloxamer didnotsignificantlyreduceinthe
meandurationofVOCcomparedtoplacebo(82
hoursvs78hours(p=0.09)).
Nostatisticallysignificantdifferencesbetween
Velpoloxamer andplacebofortherateofre
hospitalizationforVOCortheoccurrenceofacute
chestsyndrome.

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Velpoloxamer Ramifications?

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ShiftinTherapeuticFocus
Seriesofchildhoodlifethreateningevents

&
Identification&managementoforgandamage

Cure?
BoneMarrow/StemCellTransplant
GeneTherapy

Whatcanyoudo?
AskQuestions.
BeInvolved.
ParticipateinResearch.

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