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L’ANEMIA FALCIFORME: NUOVI APPROCCI TERAPEUTICI
LuciaDeFranceschi
Dept.diMedicina,AOUIVeronaeUniversita’diVerona-Verona
Treviso17Novembre2017
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Hemoglobinopathies are Emerging Problem of Public Health based on YLD and DALYs (1999-2010; 2010-2055)
YLDs: years lived with disability for hemoglobinopathies (β-thal and SCD): 10.197 vs 21.342 cardiovascular disorders DALYs: disability adjusted life years for hemoglobinopathies (β-thal and SCD): 15.640 vs 75.000 diabetes
MurrayCJetalLancet380:2197,2012;KassebaumNJBlood123:615,2014
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SCD is a Monogenic Disorder but a MulCorgan Disease
Cerebrovascular disease Retinopathy
ACS, PH
Spleen sequestration, Spleen infarts Hepatomegaly
(Cholelithiasis, jaudice)
Microvascular Occlusions (e.g. mesenteric)
Renal Pathology (e.g. hematuria, enuresis, papillar necrosis)
Priapism Bone disease
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Endothelial cells
Exposed Extracellular Matrix
Laminin TSP
BCAM/LU Sulfated Glycolipids
PS
Vesicles PS
PS Erythrophagocytosis
Procoagulant
activity
Endothelial cells
PS
CD36
CD36 TSP
VCAM-1
α4β1 integrin ICAM-4
Abnormal RBC
or Reticulocyte
αVβ3 integrin vWF
MPs
!NO bioavailability
Free Heme
Free Hb
"ROS
Endothelial cells
Endothelial cells
Mac 1
ESL-1
E-Selectin
TF TF
TF TF-MPs
Neutrophils
PS
PS
PLTs
MPs
Activation
coagulation system Cytokine storm:
ET-1
P-Selectin
iNKT iNKT
The high Biocomplexity of SCD Substains MulC-Organ Damage
Modified from De Franceschi L et al. Seminars in Thrombosis, 37: 266; 2011
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Hassel K et al. 38: 5512, 2010
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Available Treatments for SCD
HU(Hydroxyurea) Tranfusion
HSCT
SCD
FreeHemeFreeHb
RBCdehydraQon
Genetherapy
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Endothelial cells
Free Heme Free Hb
éROS
Neutrophils
P-Selectin E-Selectin
Imbalance in vascular tone
ê NO
HbS/HbF
Abnormal Endothelial Activation
Reduction of
Inflammation
Reduction of
Chronic
Hemolysis
HU is a MulCmodal Therapy
Platt OS NEJM 358: 1362, 2008; Saleh AW et al. 102: 31, 1999; Charache S et al. 34: 15, 1997; Yarbro JW et al. 19: 1-10, 1992 ; Maier ER et al Pediatric Res doi 10/1038, 2016;
HU
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InSCD,HUamelioratesmortalityandmorbidityandreduces:
• FrequencyofVOCandrateofhospitalizaQon• ACS• Transfusionrequirements• SeveredacQliQsinSCDpediatricpopulaQon
SCDChildren
SCDAdults
HU
WongTEetalBloodEpubOct2014;CrosbyLEetal.PedriatrBloodCancerEpub2014;VoskaridouEetal.Blood115:2354,2010;WangWCetal.TheLancet377:1663,2011;YawnBPetalJAMA312:1033,2014.
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HU as Acceptable AlternaCve to Chronic Transfusion in SCD Children with History of TCD AbnormaliCes
• InSCDchildrenunderchronictransfusionregime,acareful transiQontoHUmight be consideredwith normal TCD,mantaining every 3monthsTCDfollow-up;
• IdenQfiedpredicQvefactorsforreversiontoabnormalTCDvelocites:• BeforeHU:HighreQccount(>400x109cells/uL)• AgerHU:WBC.
BernaudinFetalBlood127:1814,2016;HeltonKJetalBlood124:891;2014;WareREBlood119:3925;2012;WareREetalLancet387:661-70,2016
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Adherence to HU is a Challenge in SCD
• 35-50%SCDpaQentsachievehighadherencetoHUtherapy;
• MulQplefactors:• ChronicmedicaCon• Socio-economicreasons• AdhesionbarriersrelatedtoadolescenceandtransiConfrompediatriccaretoadultcare
• OngoingstudiesonadherencetoHUtherapy:• ImplementaQonofpharmacyservice• Glowcapdevice• HABITstudy:homevisitsbyCHNandtextmessagingseemtobeeffecQve
InoueSetal.IntJHematol104:2000,2016;HanJetalPharmacotherapydoi10.1002/phar.1834,2016;CerarySetal.JMIRResProtoc5:e193,2016;GreenSetalPediatr.BloodCancer63:2146,2146;2016;GreenNSetalASHposter#1310,2016
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Q: WHY DO WE NEED NEW TREATMENTS FOR SCD?
A: Lack Of Therapeutic Options For Acute Events And Prevention of SCD Related Vasculopathy
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Novel Therapeutic
Targets in SCD
Sickle Red Cells
Membrane ion transports
Anti-sickling agents
HbF inducers
Vasculopathy and adherence events
Molecules targeting heme connection
Agents modulating vascular tone
Agents interfering with RBCs-vascular adhesion
events
Reversal of adhesion mediated vaso-occlusive events
Blockade of adhesive mechanisms
Molecules modulating INFLAMMATORY pathways involved in adhesion events
Anti-PLTs- anti-coagulant therapies
Oxidative stress
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HbS PolymerizaCon and Sickling: TherapeuCc Strategies
• Block intermolecular contacts topreventHbSfibergeneraQon(GBT440)
• DecreaseHbSconcentraQon:o RBCvolumeincreased(CLT,Senicapoc)o HbFinducQon(HU)
• IncreaseHboxygenaffinity
• Weaken fiber contacts (intracellular pHor2-3DPG)LiQetalPNAS11:e689,2017;
DeFranceschiLetalHaematologica89:348,2004
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GBT440 (Originally named GTx011) and SCD
• GBT440 is an oral available potent and direct anC-sicklingagent
• GBT440 binds to HbS and promotes a leK shiK inp50 of HbS, delaying HbS polymerizaQon andsickling
• GBT440 ameliorates in vitro red cell deformabilityand viscosity and improves sickle mouse red cellsurvivalwithreducQoninreQculocytecount
DufuKetal..Blood.2014;124:217;OderEetal.BJH175:24,2016;OksenbergDetalBJH175:141,2016;LiQetalPNAS11:e689,2017;
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GBT440andClinicalImpactinSCD
• InPhaseI/IIstudydoubleblindplacebocontrolledtrialinhealthyvolunteersandSCDpaQents(SS-Sβ°pts),GBT440showed:o Tobewelltoleratedwithoutmajoradverseeventso Tomodify10-30HbSo ToreduceRBCshemolysiso TodecreasereCculocytecountso TodecreaseEPOlevels
• PhaseIIopenlabelstudyinSCDadolescent:GBT440pharmacokineQcsimilartoadultSCDpaQentsOderEetalBJH175:24,2016;OksenbergDetalBJH175:141,2016;Lehrer-GraiwerJetalBlood126:542,2015;WashingtonCetal.EHAabstract#P620,2017
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Novel Therapeutic
Targets in SCD
Sickle Red Cells
Membrane ion transports
Anti-sickling agents
HbF inducers
Vasculopathy and adherence events
Molecules targeting heme connection
Agents modulating vascular tone
Agents interfering with RBCs-vascular adhesion
events
Reversal of adhesion mediated vaso-occlusive events
Blockade of adhesive mechanisms
Molecules modulating INFLAMMATORY pathways involved in adhesion events
Anti-PLTs- anti-coagulant therapies
Oxidative stress
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Molecules Interfering with
Sickle-RBCs-Endothelial Adhesive Mechanisms:
Selectin and SCD
• Endothelial cell P-selectins are cell adhesion molecules • P-selectins play a key role in leukocyte recruitment and sickle red cell
adhesion to endothelium • P-selectin values are increased in plasma of SCD patients
PanJJBC273:10058,1998;MatsuiNMBlood98:1955,2001;TurhanAPNAS99:3047,2002;KatoGJBrJHaematol130:943,2005;BlannADJThrombThrombolysis25:185,2008.
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TherapeuCc Strategies to Block SelecCn-mediated processes in SCD
• ToblockallselecQns:• Pan-SelecCnantagonist(GMI-1070,Rivipansel)(ChangJetal.Blood116:1779-86,2010;Telen
MJetal.Blood125:2656-64,2015;WuTetal.PlosOne2014:9:e101301,2014)
• TotargetonlyP-selecQn:• HumanizedanC-P-SelecCnanCbody(SelG1)(MandarinoDetalBlood122:abstract#970,2013;
AtagaKIetalabstract#1,2016ASH)
• Sevuparin(TelenMJBJHdoi10.111/BJH14303,2016)
• P-selecCnaptamer(GustaevaDRetal.Blood117:727-35,2011)
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Pan-Selectin Antagonist (Rivipansel)
• GMI-1070-RivipanselisaglycomimeQcpan-selecQnantagonist• Inphase1/2,GMI-1070showed:
– asafeprofileandtolerability– reducedE-SelecQnlevelsduringacuteVOCs– StudylimitaQon:failureofprimaryendpoint,enrolmentofSCpaQents
• OngoingphaseIII(NCT02187003)foracuteVOCs.ChangJetal.Blood116:1779-86,2010;TelenMJetal.Blood125:2656-64,2015;WuTetal.PlosOne2014:9:e101301,2014
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Humanized Monoclonal Ab against P-selecCn (Crinalizumab) and Acute events in SCD
Inadoubleblindplacebo-controlledmuQnaQonaltrial:• wassafeandwelltollerated• Induceda1monthP-selecQnblock• Reducedpaincrisis• IncreasedtheQmebetweenpaincrisis
Mandarino D et al Blood 122: abstract 970, 2013; TelenMJ Blood 127: 810-19,2016;AtagaKIetalBlood-ASH1,2016;KutlarAetalHaematologicaS454,2017
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• SUSTAIN:doubleblindplacebocontrolledphaseIIstudy(NCT0185361)withP-selecQninhibitor-Crizanlizumab
• Genopyte:SS,SC,S/β0,S/β+
• 66ptson2.5mg/Kgevery4weeksand67ptson5mg/Kgevery4weeks
• Crizanlizumab(5mg/Kgevery4):• increasesthelikelihoodofSCDadultpaQentsbeingsicklecellpaincrisisfree• iseffecQvealsoinpaQentsunderHU
KutlarAetalHaematologicaS454,2017
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Sevuparin: blocking mulCple adhesion targets in SCD
• SevuparinisaderivaQveoflow-molecularweightheparin,lackinganQcoagulantacQvity
• Sevuparinblocks:
• PandL-selecQns• Thrombospondin-FibronecQn-VonWillebrandfactor
• OngoingphaseIImulQcenterinternaQonaltrialonsevuparininacuteVOCs
TelenMJBlood127:810-19,2016;TelenMJBJHdoi10.111/BJH14303,2016
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RBCdehydraQon
Vasculopathy
InflammaQon
PLTsandcoagulaQon
FreeHbFreeheme
ROS
SCDRequiresMulQtargetTreatment
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PerspecCves: CombinaCon Therapies for SCD
• HUincombinaQonwith:-ChronicP-selecQnblockade(AtagaKIetal.abstract#1,2016;TelenMJetaldoi10.111/BJH14303,2016)
-NutriQonal/dietarysupplementaQon(i.e.:ω-3faryacid,Mg2+supplementaQon)(KalisBetalHaematologica100:870-80,2015;DaakAAetal.AJCN97:37,2013;HankinsJSetal.BJH140:80,2008)-AnQ-inflammatoryagents(Regadenoson)(FieldJJBlood121:3329,2013;FieldJJBlood122abstract#977,2013)
• CombinaQontreatmentwithoutHU:
• AnQ-sicklingagent(s)combinedwithP-selecQnblockade(SwigRetalabstract#121,2016;LehrerJetal.abstract#2488,2016;AtagaKIetal.abstract#1,2016;TelenMJetaldoi10.111/BJH14303,2016)
• AnQ-sicklingagent(s)andanQ-inflammatoryagentssuchasRegadenoson(SwigRetalabstract#121,2016;LehrerJetal.abstract#2488,FieldJJBlood121:3329,2013;FieldJJBlood122abstract#977,2013)
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CONCLUSIONS
• New therapeuQc strategies for SCD involve pathophysiology-basedtargets;
• Noveltreatmentsaredirectedtomodifynaturalhistoryofthe
disease such as acute VOC and related chronic organcomplicaQonsinSCD
• A new field of combinatorial therapy for SCD will require aholisQcapproach,consideringtheimprovementofpaQentQoLasanimportantoutcomeindesigningnewclinicalstudies.
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Studio SITE per la Mappatura dei Pazienti con SCD e in Trattamento Medico Intensivo con
HU
Rigano P et al. Blood Mol and Disease Epub 2017