GHITR&DForumSession4:PropellingR&Dforlate-stageprojects

ClinicalDevelopmentofE1224“ANewTreatmentforChagasDisease”&“Mycetoma Treatment,FosravuconazoleClinicalTrial”

DaisukeImotoHeadofOfficeDNDi Japan

Chagas Disease – Unmet Medical NeedDistributionofcasesofT.cruzi infection,basedonofficial

estimates,worldwide,2010–2013(WHO,3rd NTDreport,2015)

<18,000patientstreated/year

¨ Most common parasitic disease in the Americas

¨ Endemic in 21 countries / 6-8M infected / 70M at risk

¨ Largest disease burden in chronic indeterminate patients

¨ 20-30% will evolve to cardiomyopathy with importantmorbidity and mortality

¨ Currently only 2 registered compounds: BZN and nifurtimox

Estimated prevalence segmented by age group Region Age group 2010

Endemic Area

< 1 year 10,584 1 to 5 years 113,424 5 to 15 years 420,801 15 to 20 years 331,607 Adults 2,643,920

Total Endemic Area 3,520,337

Non-endemic

< 1 year 6,099 1 to 5 years 82,072 5 to 15 years 429,058 15 to 20 years 397,059 Adults 2,988,189

Total Non-Endemic Area 3,902,477

Endemic + non-endemic

< 1 year 16,683 1 to 5 years 195,496 5 to 15 years 849,859 15 to 20 years 728,667 Adults 5,632,109

Total Endemic + Non-endemic Area 7,422,814

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ImprovedTreatmentOptionsareNeededforallStagesofChagasInfection

• Currentavailabletreatmentsaremorethan40yearsoldü Goodefficacyintheacutephase,butneedtobeusedinlongregimens

andcausesignificantsideeffects

à Theefficacyandsafetyofshortertreatmentcoursesand/oratlowerdosesneedtobeexplored

à Newdrugsandnewcombinationsarealsoneeded

DNDi aimstodeliver:§ Alternativeregimensofexistingdrugs (lowerdoses,shorterduration,combinations)

§ Asafeandefficaciousnewdrugtreatment ofchronicChagaspatients,ideallyefficaciousforacuteChagaspatients,alsosafetouseduringpregnancy

§ Anearlytestofcureand/ormarkersoftherapeuticresponse

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On-goingProject:AnewtreatmentforChagasDisease(inBolivia)

Objective&Goal

Evaluatenewtherapeuticregimensofbenznidazole,inmonotherapyandincombinationwithfosravuconazole,forthetreatmentofadultpatientswithchronicindeterminateChagasdisease

PartnershipEisaiCo.,Ltd.(Japan),CollectiveofAppliedStudiesandSocialDevelopment(CEADES)(Spain/Bolivia),PlatformofIntegralCareforPatientswithChagasDisease,(Bolivia),UniversidadMayordeSanSimon,Bolivia;UniversidadAutónomaJuanMisaelSaracho,(Bolivia)v EisaiandDNDi signedacollaborationandlicenseagreementfortheclinical

developmentofChagasDiseasein2009à TheLancetpublishedin2009anarticlethatannouncesthestartoftheclinicaltrial

highlightingthepartnershipbetweenEisaiandDNDi (Vol.374,October31.2009)

“The1st drugin40yearsofanewdrugforthisdisease”

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BENDITAoveralldesign4

rand

omis

atio

n

Screen

ingpe

riod

BZN3004W BZNPBO4W

E1224PBO8W

BZNPBO4W

BZN3008W

E1224PBO8W

E1224PBO8W

BZN3002W BZNPBO6W

BZNPBO8W

E1224PBO8W

BZN1504W

E1224PBO8W

BZNPBO4W

BZN1504W

E12248W

BZNPBO4WBZNPBO4W

IT

IT

IT

IT

IT

IT

E12248W

Follow-upat10wk,12wk,4M,6M,12M

§ Futility stopping rule§ 10 and 12-week interim

analysis (safety and efficacy) 2 months treatment phase

Primary endpoint at 6M

Follow-up until 12M

§ Adults (18 – 50 years old) at Chronic Indeterminate CD stage

§ 210 subjects - 30 patients/arm

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Recruitment Finalized

AllPatientsfinalizedtreatment Patientsinfollow-up:208(treatmentcompleted)

2 1028

51

81

110

148175

210

2 1030

55

90120

140170

200 210

0

50

100

150

200

250

nov/16 Dec16 jan/17 Feb17 Mar17 Apr17 May17 Jun_17 Jul_17 Aug_17

Patie

nts

Bendita- Recruitment

Actual

Planned

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Jul Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun Jul >>> Dec Jan Feb Mar

Nextsteps6

DSMB Safety IA (20% at 10 weeks)

DSMB Efficacy andSafetyreview

End of 6M Follow-up

Go/ No go for Phase 3

6M analysis End of 12M F-up

Toplinereport

CSR

2017 2018 2019

Publicationaround Q4 2019

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Definition:Chronicinfectionofsubcutaneoustissuesthathastwodifferentforms:1) Actinomycetoma: bacterialinfectionwitha>90%curerateusingantibiotics2) Eumycetoma: fungalinfection,endemicinAfrica,ismuchmoredifficulttotreat

[Symptoms]§ Feetbecomeveryswollenanddisfigured.Thisslow-growingdiseasecauses

littlepainandconsequentlypeopledelayseekingtreatmentuntilthediseasehasreachedthelaterstages,whenamputationisoftennecessary- stigmatized

§ Ifuntreated,itgraduallydeterioratesintoaseriouscondition,whichcanbefatal.[Impact]§ Basicepidemiologicalinformationislacking,globalburdenremainsunknown§ TheMycetoma ResearchCentre(MRC)inKhartoum,Sudan,hasrecordedaround

6,500patientssince1991– mostpatientsareyoungandpoor§ Actinomycetoma (bacterialform)hasa90%cureratewhilethe

eumycetoma(fungalform)curerateisonly25-35%

In2016,Mycetoma wasaddedtothe18th diseaseoftheWHOlistofNTDs

DNDi stronglyadvocatedforMycetoma tobeincludedinthelist

Mycetoma – NeglectedUnmetMedicalNeed

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[Geography]

§ Endemicintropicalandsubtropicalregions– casesreportedin50countries

§ “Mycetoma Belt”between

latitude30°Northand15°South

Mycetoma – NeglectedUnmetMedicalNeed

[Transmission]

§ Currentlynodefinitivetheoryabouttherouteoftransmission

§ Theinfectionmaycomefromthesoiloranimaldung,anditisthoughtthatitentersthebodyaftertheskinhasbeenpricked(e.g.byathorn)

[PatientNeeds]

§ Thecurrenttreatmentislong,ineffective,expensiveandhaveserioussideeffects(themediantreatmentdurationis12months,andmorethan$2,000/year)

§ Nopoint-of-carediagnostictest

DNDi aimstodeliver:Anewsafe,effective,andaffordabletreatmentforpatientswithlimitedeumycetoma

On-goingProject:Mycetoma Treatment,Fosravuconazole ClinicalTrial(inSudan)

Objective&GoalConductarandomizedcontrolledclinicaltrial(phaseIIstudy)toinvestigatetheefficacyofFosravuconazole (E1224)comparedtothecurrenttreatment,Itraconazolev Fosravuconazole,underdevelopmentforChagasdisease,whichhasbeenshowntohavepotentin

vitro acitivity againstMadurella mycetomatis

v Itspharmacokineticpropertiesarefavorableanditstoxicityislow

Additional 12months follow-upifsuccess /maintenanceofresponse

Primaryend-pointwillbecompletecureatthe12-month asevidencedby:• clinicalassessmentshowingabsenceofmass,sinusesanddischarge• normalultrasonic/MRIexamination, or• thepresenceoffibrosisonly+negativefungalculturefromasurgicalbiopsy

Measurements:Clinical: diameterofthelesion,numberofsinuses,presenceofdischargeImaging:3DscanningwithindependentreviewRadiological:MRI,ultrasoundMicrobiology:demonstrationofM.mycetomatis byPCRthroughfineneedleaspirationandculture.PK/PD

Studydesign Ntotal=138

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Mycetoma Treatment,Fosravuconazole ClinicalTrialConductofStudyandNextSteps

Conduct§ Mycetoma ResearchCentreKhartoum,aWHOCollaborativeCentre

§ Subjects18yearsorolder

§ Singleeumycetomalesion≥2cmand<10cmindiametercausedbyMadurellamycetomatis confirmedbyPCR

§ Target:6-10participantspermonth->fieldvisitsbymobileteams/activescreening

§ StartedenrollingpatientsinMay2017

§ Nosurgicalmedicaltreatmentbefore

Nextsteps§ Eisaiintends tocontinuesupporting thedevelopment ofE1224including thedrug

product supply (clinical trials)needed forregulatory approval

§ Continuing toengagewith endemic countriesNRAs andPolicymakers formostappropriate approval strategy /unmet medical need

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Mycetoma Treatment,Fosravuconazole ClinicalTrial

PartnershipEisaiCo.,Ltd.(Japan),Mycetoma ResearchCentre(MRC)/InstituteofEndemicDiseases(IEND),KhartoumUniversity,Khartoum,Sudan,ErasmusMedicalCenter(TheNetherlands)

v EisaiandDNDi signedacollaborationandlicenseagreementfortheclinicaldevelopmentofeumycetomain2015:Long-standingpartnershipwithEisaiwasessential

v TheMRChasbeencollaboratingwithWHO(MRCisaWHOCentre)thatgavethediseasepoliticalprominencein2016byaddingittothelistofNTDs

v KnowledgeandinsightsrelativetothediseaseandtheaffectedpopulationprovidedbytheMRCarecriticaltohaveabetterideaofwhatisactuallyneededinthefield

Challenges

§ Enrollmentofpatientshasbeenslowduetovariousreasonsincludingtherainyseason,theinclusioncriteriathatarequitestrict

§ Informedconsentformisdifficultforlocalpatientstounderstand(8pages)weareexaminingawaytomakeitmorepatient-friendly

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CommentstoGHITFund

§ DNDi wishestocongratulateGHITFundforitsbravedecisiontoletustakethefirststeptogethertowardfindinganewtreatmentforpatientswithMycetoma,forwhichnoglobalsurveillancesystemsexistandthereforeverylittleisknowncurrently

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Thank youtoallour Donors andPartners

www.dndi.orgwww.dndijapan.org

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