L’ANEMIA FALCIFORME: NUOVI APPROCCI TERAPEUTICI

LuciaDeFranceschi

Dept.diMedicina,AOUIVeronaeUniversita’diVerona-Verona

Treviso17Novembre2017

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

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

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

Hassel K et al. 38: 5512, 2010

Available Treatments for SCD

HU(Hydroxyurea) Tranfusion

HSCT

SCD

FreeHemeFreeHb

RBCdehydraQon

Genetherapy

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

InSCD,HUamelioratesmortalityandmorbidityandreduces:

•  FrequencyofVOCandrateofhospitalizaQon•  ACS•  Transfusionrequirements•  SeveredacQliQsinSCDpediatricpopulaQon

SCDChildren

SCDAdults

HU

WongTEetalBloodEpubOct2014;CrosbyLEetal.PedriatrBloodCancerEpub2014;VoskaridouEetal.Blood115:2354,2010;WangWCetal.TheLancet377:1663,2011;YawnBPetalJAMA312:1033,2014.

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

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

Q: WHY DO WE NEED NEW TREATMENTS FOR SCD?

A: Lack Of Therapeutic Options For Acute Events And Prevention of SCD Related Vasculopathy

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

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

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;

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

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

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.

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)

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

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

•  SUSTAIN:doubleblindplacebocontrolledphaseIIstudy(NCT0185361)withP-selecQninhibitor-Crizanlizumab

• Genopyte:SS,SC,S/β0,S/β+

•  66ptson2.5mg/Kgevery4weeksand67ptson5mg/Kgevery4weeks

• Crizanlizumab(5mg/Kgevery4):•  increasesthelikelihoodofSCDadultpaQentsbeingsicklecellpaincrisisfree•  iseffecQvealsoinpaQentsunderHU

KutlarAetalHaematologicaS454,2017

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

RBCdehydraQon

Vasculopathy

InflammaQon

PLTsandcoagulaQon

FreeHbFreeheme

ROS

SCDRequiresMulQtargetTreatment

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)

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.

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