Strategies to support the COVID-19 response in LMICs

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Strategies to support the COVID-19 response in LMICs

Therapeutics Landscape for COVID-19 NatashaMubeenChida,MDMSPHAssociateProgramDirector,InfectiousDiseaseFellowshipProgramAssistantProfessor,DivisionofInfectiousDiseasesJohnsHopkinsUniversitySchoolofMedicine

Objectives

• ReviewbiologicalplausibilityofRemdesivirforSARS-CoV-2treatment• ReviewclinicaldataonRemdesivir• ReviewbiologicalplausibilityofHydroxychloroquineforSARS-CoV-2treatment• ReviewclinicaldataonHydroxychloroquine• DiscusscytokinereleasesyndromeinCOVID-19• DiscussuseofantiIL-6blockadeformanagementofCRS•  StateongoingclinicaltrialsforRemdesivir,hydroxychloroquine,IL-6blockade

Sample of COVID-19 Therapeutic Landscape

Antivirals ImmuneModulators Other

Baloxavir Anakinra ACEI/ARB

Chloroquine/Hydroxychloroquine ConvalescentPlasma AscorbicAcid

DAS-181 Corticosteroids Azithromycin

Favipiravir IVIG Epoprostenol

Interferon Lenzilumab Indomethacin

Lopinavir/Ritonavir Ruxolitinib Ivermectin

Neuraminidaseinhibitors Sarilumab Niclosamide

Remdesivir Sirolimus Nitazoxanide

Ribavarin Tocilizumab Statins

Umifenovir Acalabrutinib

SARS-CoV-2

LiuC,etal.ACSCentSci.doi:10.1021/acscentsci.0c00272(2020).JiangS,HillyerC,DuL.TrendsImmunoldoi:10.1016/j.it.2020.03.007(2020).

“Antivirals”

Remdesivir

•  2013Ebolaoutbreak•  CDC/USAMRIDD/GileadSciencesidentifiednucleosideleadàprodrug,RDV

•  Metabolizedtoactiveform,adenosinenucleosideanalog•  InterfereswithRNApolymerase

•  Evadesviralexoribonucleaseproofreading•  DecreaseinRNAproduction

•  Incell/animalmodelsefficaciousinMERS-CoV,SARS-CoV,Marburg,Nipah,more•  IVformulation

Remdesivir

WarrenTK,etal.Nature.2016;531(7594):381-5.SheahanTP,etal.SciTranslMed.2017;9(396).

Remdesivir

• Clinicaltrials• Compassionateuse:pregnantwomen/children•  Expandedaccessprotocol

Remdesivir Clinical Trials: Examples

Remdesivir Clinical Data

• ReportofpatientsJan-March-61patientsà53•  40(75%)receivedthefull10-daycourseofRemdesivir•  34(64%)ventilatedatbaseline

•  MediandurationofventilationpriortoRemdesivir2days[IQR1-8]

GreinJ,etal.NEnglJMed.doi:10.1056/NEJMoa2007016(2020).


•  18days•  36(68%)showedimprovementinoxygensupport•  57%ventilatedpatientsextubated

• Mostrecentfollowup•  25(47%)discharged•  7(13%)died

•  6(18%)ofthoseventilated,1(5%)notventilated



•  23%seriousadverseevents


Lopinavir/Ritonavir

•  In-vitroactivityagainstSARs-CoV,MERS-CoV•  Hypothesis:inhibitionofSARs/MERSprotease

• BenefitinretrospectivestudiesinSARs-CoV•  SomeinvitrodataSARS-CoV-2,butEC50muchhigherthanlevelsreachedinHIVdosing

•  HIVproteasedifferentproteasefamily•  OptimizedtofitinaspecificpartofthecatalyticsiteofHIVprotease,absentincoronaviruses•  SomebenefitinanimalstudiesMERS-CoV

• WidelyusedinChina•  Numerousretrospectivestudies

LiG,DeClercqE.NatRevDrugDiscov.2020;19(3):149-150.,YaoTT,etal.JMedVirol.doi:10.1002/jmv.2572(2020).,JiangS,HillyerC,DuL.TrendsImmunoldoi:10.1016/j.it.2020.03.007(2020).,ChoyKTetal.AntiviralRes.doi:10.1016/j.antiviral.2020.104786(2020).

Lopinavir/ritonavir

Lopinavir/ritonavir Data

CaoB,etal.NEnglJMed.doi:10.1056/NEJMoa2001282(2020).,YeXT,etal.EurRevMedPharmacolSci.2020;24(6):3390-339

•  Posthocanalysissuggestingearlytreatmentmaybeefficacious

Lopinavir/ritonavir Clinical Trials: Examples

Clinicaltrials.gov

Chloroquine Mechanisms Against SARS-CoV-2

• BlocksviralinfectionbyincreasingendosomalpHrequiredforvirus-cellfusion•  InterfereswithglycosylationofSARS-CoVcellularreceptors• Chloroquineinterfereswithentryandpost-entrystagesofSARS-CoV-2infectioninVeroE6cells

SlidecourtesyMichaelMelia,MD

WangMetal.CellResearch(2020)30:269–271;https://doi.org/10.1038/s41422-020-0282-0.VincentMJetal.VirolJ.2005Aug22;2:69.

Chloroquine Mechanisms Against SARS-CoV-2 • VeroE6cellsinfectedwithSARS-CoV-2atMOI0.05•  EfficacyevaluatedbyquantificationofviralcopynumbersincellsupernatantbyRT-PCR,confirmedwithvisualizationofvirusnucleoproteinexpressionthroughimmunofluorescencemicroscopyat48hpost-infection•  EC90=6.90μM(clinicallyachievable)

SlidecourtesyMichaelMelia,MDWangMetal.CellResearch(2020)30:269–271;https://doi.org/10.1038/s41422-020-0282-0.

CQ versus HCQ in vitro

• CytotoxicityinVeroE6cellsmeasured• HCQlesspotentthanCQatsomeMOI

LiuJetal.CellDiscovery(2020)6:16.https://doi.org/10.1038/s41421-020-0156-0


Hydroxychloroquine Clinical Data (Preprint) • Randomized,parallel-grouptrial•  Inclusioncriteria:

•  Age≥18y•  SARS-CoV-2RT-PCRpositive•  ChestCTwithpneumonia•  SaO2:SpO2>93%orPaO2:FiO2>300mmHg

•  Exclusioncriteria:•  Severe,criticalillness

•  Retinaldisease•  Heartblock•  Severeliverdisease,includingAST>2xULN•  Pregnantorbreastfeeding•  eGFR≤30orRRT

SlidecourtesyMichaelMelia,MDChenZ.medRxivpreprintdoi:https://doi.org/10.1101/2020.03.22.20040758

Hydroxychloroquine Clinical Data (Preprint) •  62patients

•  47%men•  Meanage44.7y±15.3

• Allreceivedstandardtherapy•  Oxygen•  Antiviralandantibacterialagents•  Immunoglobulin±corticosteroids

• RandomizationtoHCQ200mgBIDx5dvsstandardtreatment

• Outcomes•  Timetoclinicalrecovery=afebrileandcoughrelief≥72h•  ChestCTd0vsd6•  InitiallyplannedPCRandT-cellrecoverydatanotreported

• HCQ:9nofever,9nocough• Control:14nofever,16nocough

ChenZ.medRxivpreprintdoi:https://doi.org/10.1101/2020.03.22.20040758


Hydroxychloroquine Clinical Data (Preprint) •  FeverdurationshorterwithHCQ(2.2±0.4dvs3.2±1.3d)• CoughdurationshorterwithHCQ(2.0±0.2dvs3.1±1.5d)• MorepatientshadradiographicimprovementwithHCQ[25/31(81%)vs17/31(55%),p=0.05]• All4patientswhoprogressedtosevereillnesswereincontrolgroup•  2patientswithmildadversereactionsinHCQgroup(rash,HA)



Hydroxychloroquine Clinical Data

•  30patientsatasinglecenterinChina•  RandomizedtoHCQ400mgdailyx5d+conventionaltreatmentorconventionaltreatmentonly•  Bothgroupsreceivedinterferon•  Mostreceivedumifenovirorlopinavir/ritonavir

•  Primaryendpoint:negativeNPswab7dafterrandomization

•  Nodifferenceinprimaryendpointbetweengroups•  13/15(87%)casesnegativeinHCQgroup,14/15(93%)incontrolgroup

•  NodifferenceintimefromhospitalizationtonegativeNPswab,feverresolution,radiographicfindings,diarrheaorabnormalliverenzymes

ChenJ.JZhejiangUniversity.2020:[Epubaheadofprint].https://doi.org/10.3785/j.issn.1008-9292.2020.03.03.https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx.Accessed13April2020.


HCQ + Azithromycin

• Open-label,non-randomizedtrialinFrance• Patientsaged≥12ywithNPSARS-CoV-2carriageonadmission

•  Excluded:retinopathy,G6PDdeficiency,QTintervalprolonged,pregnancy• HCQ200mgTIDx10d±azithromycin500mgx1then250mgQDx4d

•  Controls:untreatedpatientsfromanothercenter,patientsrefusedprotocol

• NPswabVLmeasureddaily•  Endpoint:presenceofvirusatday6post-inclusion

GautretPandLagierJCetal.IntJAntimicrobAgents(2020),doi:https://doi.org/10.1016/j.ijantimicag.2020.105949


HCQ + Azithromycin

•  36*patients•  Meanage45.1±22y•  42%(15/36)men•  4.0±2.6dbetweensymptomonset&inclusion

• Clinicalcharacteristics•  8patientswithLRTIsymptoms(allhadevidenceofpneumoniabyCTscan)•  22patientswithURTIsymptoms(rhinitis,pharyngitis,fever,myalgia)•  6asymptomaticpatients



HCQ + Azithromycin

• Atday6post-inclusion:•  70%HCQ-treatedpatients(vs12.5%controls)testedNPRT-PCRnegative•  100%HCQ+azithromycin-treatedpatients(vs57%patientstreatedwithHCQmonotherapy)testedNPRT-PCRnegative



HCQ + Azithromycin

• OnepatienttreatedwithHCQ+azithromycintestedRT-PCRnegativeatday6andthenpositiveatday8• PatientstreatedwithHCQ+azithromycinhadlowerviralRNAloadsattreatmentinitiationthanHCQandcontrolgroups•  SitesotherthantheprimarysitedidnotperformdailyPCRtesting

•  38%ofdataforcontrolgroupimputed(vs5%fortreatmentgroup)

•  6treatedpatientsomittedfromanalysisowingtoICUtransfer(3),death(1),hospitaldischarge(1),nausea(1)

GautretPandLagierJCetal.IntJAntimicrobAgents(2020),doi:https://doi.org/10.1016/j.ijantimicag.2020.105949.KimAHJ,SparksJAetal.AnnInternMed.Doi:10.7326/M20-1223


HCQ + Azithromycin

•  11consecutivepatients•  7men,4women•  Meanage59y(range20-77)•  8withsignificantcomorbidities

•  HCQ600mgdailyx10d+azithro500mgx1then250mgQDx4d•  Attreatmentinitiation,10/11hadfeverandwerereceivingoxygen• Within5d,onepatientdied,twotransferredtoICU•  Onecoursediscontinuedafter4d(QT405→460-470)•  NPRT-PCRpositivein8/10patientsat5-6daftertreatmentinitiation

MolinaJMetal.MedecineetMaladiesInfectieuses(2020),doi:https://doi.org/10.1016/j.medmal.2020.03.006


HCQ + Azithromycin

•  Caseseriesof80patientsatoneinstitution•  AllpatientstreatedwithHCQ200mgTID+azithromycin500mgx1then250mgQDfor≥3d&followedfor≥6dincluded

•  Excluded:QTc>500ms,ECGsuggestingchannelopathy

•  HCQ200mgTIDx10d±azithromycin500mgx1then250mgQDx4d•  CeftriaxoneaddedforpneumoniaandNEWSscore≥5

•  NPswabVLmeasured~dailybyRT-PCR•  Primaryendpoints:

•  Clinicaloutcome,includingO2therapyorICUtransferafter≥3dtreatment•  ContagiousnessasassessedbyPCRandculture•  Lengthofinpatientstay

GautretPandLagierJCetal.https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf


HCQ + Azithromycin

•  80patients•  Medianage52.5y(IQR42-62)•  52.5%(42/80)men•  57.5%atleastonechroniccondition•  4.9±3.6dbetweensymptomonset&treatmentinitiation

• Clinicalcharacteristics•  54%LRTIsymptoms•  41%URTIsymptoms•  5%asymptomatic•  15%hadfever•  92%lowNEWSscore(0-4)



HCQ + Azithromycin

•  15%(12/80)receivedO2

•  81%(65/80)discharged•  17%(14/80)stillhospitalized•  4%(3/80)transferredtoICU•  1%(1/80)died• Meantimefrominitiationtohospitaldischarge4.1d•  MeanLOS4.6d



HCQ Clinical Trials: Examples

Name/Sponsor PertinentCharacteristics Estimatedcompletion

ACTG5396 Hospitalized Pending

ACTG5395 Outpatients Pending

MultipleProphylaxistrials HCWsorhouseholdcontacts Ongoing

SOLIDARITY/WHO 8.Hospitalized March2020-2022

DISCOVERY/INSERM 9.Hospitalized March2020-2023

On the Horizon Antivirals ImmuneModulators Other

Baloxavir Anakinra ACEI/ARB

Chloroquine/Hydroxychloroquine ConvalescentPlasma AscorbicAcid

DAS-181 Corticosteroids Azithromycin

Favipiravir IVIG Epoprostenol

Interferon Lenzilumab Indomethacin

Lopinavir/Ritonavir Ruxolitinib Ivermectin

Neuraminidaseinhibitors Sarilumab Niclosamide

Remdesivir Sirolimus Nitazoxanide

Ribavarin Tocilizumab Statins

Umifenovir Acalabrutinib

“Antiviral” Key Points

•  RemdesivirhasbiologicalplausibilityandinvitrodatatosupportitscandidacyasaSARS-CoV-2therapeuticagent•  Clinicaltrialdataforthcoming

•  Lopinavir/ritonavirhasminimalsupportiveinvitrodatainSARS-CoV-2•  CurrentclinicaldatadoesnotsupportitscandidacyasaSARS-CoV-2therapeuticagent

•  Clinicaltrialdataforthcoming•  Inpatientswithnon-severedisease,andaspartofmulti-componenttherapy,HCQmay:•  Beassociatedwithshorterdurationsoffeverandcough•  Beassociatedwithradiographicimprovement

•  InadequatedatatocommentonimpactofHCQonviralRNAshedding

Anti IL-6 Agents

COVID-19 Cytokine Release Syndrome

•  SimilartoCRSseeninCART-TTherapy•  DrivenbyIL-6•  AntiIL-6blockade:Tocilizumabutilized

•  LikeinCAR-Ttherapy,appearstobecharacterizedby•  Fever•  Bloodpressureabnormalities•  Progressiverespiratorydecline•  Elevationofcertaininflammatorylaboratories

• ARDS≠CytokineReleaseSyndrome

MehtaP,etal.Lancet.2020;395(10229):1033-1034.

CRS

MooreBJB,JuneCH.Science.doi:10.1126/science.abb8925(2020).

COVID-19 Clinical Course

ZhouF,etal.Lancet.2020395(10229):1054-1062.

Observational Cohorts: Published

• Retrospectiveobservationalstudyof15patientsadmittedtoahospitalinChina•  Classifiedintomoderatelyill(13%),seriouslyill(40%),criticallyill(47%)•  Medianage73[IQR62-80]

• Heterogeneousdosing,timing• Halfreceivedmethylprednisolone

LuoP,etal.JMedVirol.doi:10.1002/jmv.25801(2020).

Observational Cohorts: Published

•  3patientsdied(20%)• Wheninclinicalcoursedidpatientsreceivetocilizumab?• WeretheyARDSordevelopingsignsofCRS?

LuoP,etal.JMedVirol.doi:10.1002/jmv.25801(2020).

Observational Cohorts: Preprint

•  Retrospectiveobservationalstudyof21patientswithprovenCOVID-19admittedto2hospitalsinChina•  Definedas

•  Severe:RR≥30breaths/min,SpO2≤93%onambientair,PaO2/FiO2≤300mmHg

•  Critical:Mechanicalventilation,shock,organfailurerequiringICUadmission

•  Patientsreceivedstandardofcare+tocilizumab•  Standardofcare=lopinavir/ritonavir,methylprednisolone,oxygen

XuX,etal.http://www.chinaxiv.org/abs/202003.00026(Accessed4/19/2020).


•  19%dischargedattimeofpapersubmission• BasedonthisdataNationalHealthCommissionofChinaincludedtocilizumabinCOVID-19therapyrecommendations• Wheninclinicalcoursedidpatientsreceivetocilizumab?• WeretheyARDSordevelopingsignsofCRS?

XuX,etal.http://www.chinaxiv.org/abs/202003.00026(Accessed4/19/2020).


•  21patientswithCOVID-19andARDSinItaly•  Usingnoninvasiveventilation•  PartofSiltuximabcompassionateuseprogram•  Medianage64years[IQR48-75];18(85.7%)men•  MedianIL-6139.5pg/mL,CRP23.4mg/dL•  Comorbidities

•  Hypertension:9(42.3%)•  Diabetes5:(23.8%)•  Cardiovasculardisease4(19.1%)

• Median3dayshospitalizationpriortosiltuximab

GrittiG,etal.https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v2.full.pdf.Accessed4/20/20


GrittiG,etal.https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v2.full.pdf.Accessed4/20/20

Themes Of Current Clinical Data

• Outcomerelatedtotocilizumabornaturalhistory• Heterogeneityinpatients• Variabilityinclinicalcourse• Variabilityinadministration

•  Dosing•  Timingofadministration

• Concomitantuseofotheragents/anti-inflammatories• Heterogeneousoutcomes

Anti IL-6 Clinical Trials: Examples

>7moretrialsbetweenChina,Europe

Anti IL-6 Key Points

•  SomepatientswithCOVID-19maydevelopasyndromesimilartothecytokinereleasesyndromeseeninCAR-Ttherapy•  Characterizedbyspecificclinicalfindingsandinflammatorylaboratories

•  Thereisapaucityofreliablepublisheddata• Clinicaltrialdataforthcoming• Anecdote:earlyadministrationappearsmoreeffectivethanlateinthecourseofillness

Convalescent Plasma

•  IntheUS,IND•  Clinicaltrials,expandedaccess,emergencyindividualuse

• Currentdata:Casereports/series•  Limitations:Plasma•  StudylaunchingatJHH

ConvalescentPlasma


Objectives

• ReviewbiologicalplausibilityofRemdesivirforSARS-CoV-2treatment• ReviewclinicaldataonRemdesivir• ReviewbiologicalplausibilityofHydroxychloroquineforSARS-CoV-2treatment• ReviewclinicaldataonHydroxychloroquine• DiscusscytokinereleasesyndromeinCOVID-19• DiscussuseofantiIL-6blockadeformanagementofCRS•  StateongoingclinicaltrialsforRemdesivir,hydroxychloroquine,IL-6blockade

Documents

Strategies to support the COVID-19 response in LMICs