activating the power of japan’s unique chemical compounds ... 1_4... · j nat prod. 2016...
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TheNTDDrugDiscoveryBooster:aninnovativecollaborationforhitexpansion
GHITR&DForum,December8th 2017TokyoGardenTerraceKioi Conference
ActivatingthePowerofJapan’sUniqueChemicalCompoundsforNeglectedDiseases
Responding to the Needs of Patients Suffering from Neglected Diseases…
Hep C
DNDi’s PRIORITY:
Neglected Patients
Pediatric HIV
Filarial diseases
Sleeping sickness
Chagas disease
Leishmaniasis
Malaria Mycetoma
…from Bench to Bedside
©"Sco&"Nelson"for"T
he"New
"York"Times!
• Todevelopnewdrugsornewformulationsofexistingdrugs
• Tostrengthencapacitiesinasustainablemanner
• Toadoptadynamicapproachtoportfoliodiseases
DNDi’s Mission
7 new treatments delivered, recommended, implemented
• 30projects,8diseasesareas
• 13entirely newchemical entities (NCEs)
• Over160partnerships,most inendemiccountries
• 160staff,half inendemic countries&700peopleworking onDNDiprojects
• EUR400millionraised equally frompublicandprivate sources
• 4regional disease-specific clinical trialplatforms/networks andseveraltechnology transfers
ü Easy touseü Affordableü Field-adaptedü Non-patented
2016SUPERBOOSTERTHERAPYPaediatric HIV/TB
HIV/TB
DNDi’s success is only possible through innovative partnerships Universities
&ResearchInstitutes
PDPs
Int.Org.&NGOsBiotechs
CROs Pharmaceuticalcompanies
CRITERIAFORSUCCESSü Sharethesamevisionü Mutualunderstandingü Involvementthroughoutthe
wholeprocess
Over160partnerships worldwide
SomecurrentJapanesepartners:
EisaiTakedaShionogiDaiichi-SankyoGeneDesignKitasato InstituteRikenInstituteIMC
GHITFund
7 new treatments available and up to 16 new chemical entities in the pipeline
Screen Hit to Lead Pre-clinical Phase I Phase IIa/PoCLead Opt. RegistrationPhase IIb/III Access
New Chemical Entity (NCE); Fexinidazole (for HAT, VL, and Chagas disease) = 1 NCE; Fosravuconazole = 1NCE
Fosravuconazole
DNDi R&D Portfolio June 2017Research DevelopmentTranslation Implementation
Mycetoma
Ravidasvir/Sofosbuvir
HCV
Two ‘4-in-1’ LPV/r/ABC/3TC
LPV/r pellets with dual NRTI
SuperboosterTherapy
Paediatric HIV/TBPediatric HIV
Screening EmodepsideABBV-4083TylaMac
MacroFilaricide 3
Filaria
New BenzRegimens +/-fosravuconazole
Screening
Biomarkers
ChagasH2L
Fexinidazole
BenznidazolePaediatric Dosage
Form
ChagasLead Opt
Chagas
SSG&PM Africa
New Treatmentsfor HIV/VLScreening
DNDI-5421DNDI-5610oxaborole
LeishH2L
DNDI-0690nitroimidazole New VL Treatments
Asia
New Treatmentsfor PKDL
New VL TreatmentsLatin America
New CLCombinationCpG-D35 (CL)
Aminopyrazoles
DNDI-6148oxaborole
CGH VL Series 1
MF/ParomomycinCombo for Africa
Leishmaniasis
FexinidazoleAcoziboroleSCYX-1330682SCYX-1608210oxaborole
NECT Nifurtimox-EflornithineCombination Therapy
HAT
MalariaFDC ASAQ
MalariaFDC ASMQ
GSK3494245DDD1305143
GSK3186899DDD853651
Projects with Japanese partnerships and support from the GHIT Fund providing NCEs
Screen Hit to Lead Pre-clinical Phase I Phase IIa/PoCLead Opt. RegistrationPhase IIb/III Access
New Chemical Entity (NCE)
DNDi R&D Portfolio June 2017Research DevelopmentTranslation Implementation
Mycetoma
Chagas
Leishmaniasis
CpG-D35 (CL)GeneDesign
Eisai
AminoPyrazolesTakeda
New BenzRegimens +/-FosravuconazoleEisai
FosravuconazoleEisai
Takeda
Daiichi-Sankyo
DNDI-5561Takeda
IMC
Daiichi-Sankyo
Eisai
Takeda
NTD Booster
Kitasato
Eisai,Takeda,Shionogi
Eisai
Takeda
IMC
Daiichi-Sankyo
Eisai
Takeda
Kitasato
NTD Booster
Daiichi-Sankyo
Brd projectRiken
Eisai,Takeda,Shionogi
Growingportfolio• 8Partners• 20projects
Unique compounds from Japan• Screeningofdrug-likesmallmoleculesfromJapanese
pharmaceuticalcompaniesandresearchinstitutes• Someinterestinghitsidentified• NTDDrugDiscoveryBoosterusedtoacceleratethese
newdiscoveries
• Japanesenaturalproducts
PCAplotsofdrugsapprovedbyFDAbetween1981–2010parsedbycompoundorigin
NewmanDJ,CraggGM.NaturalProductsasSourcesofNewDrugsfrom1981to2014JNatProd.201625;79(3):629-61
Stratton etal.,2013,Cheminformaticcomparisonofapproveddrugsfromnaturalproductversussyntheticorigins. Bioorg MedChem Lett.20151;25(21):4802–4807
• DrugdiscoveryfortropicaldiseasessuchasVisceralLeishmanisais andChagasDiseaseisneglected– Littleinterest,limitedinvestment,fewresearchers,fewtools
• Parasitesareverydifficulttokill– HighThroughputScreeninghitrates:
• L.donovani (intracellular)<0.05%• T.cruzi (intracellular)<0.15%
Hitsarescarceandprecious– needtofullyexploitthem
A BIG Experiment in Early Drug Discovery
THP1 cells infected witheGFP-L. donovani (courtesy
of GSK Tres Cantos)
• TheNTDDrugDiscoveryBoosterGoals:– ExpandpreciousHTShitsandenablescaffold-hoppingtofindnewhits– Benefitfromthepoolingofstructuresandinformation– Acceleratediscoveryandreducecosts– Experimentwithanewopeninnovationapproachtodrugdiscovery
Source #hits
Seed S01 1
PartnerA ~90
PartnerB ~90
PartnerC ~90
Partner D ~40
• Complementary compoundcollectionsanddifferent computational approaches efficiently explorechemicalspace around newhits
• RapidSARexpansionandscaffold-hopping before expensive optmimisation chemistry is needed
Booster Process - Representative Example
2Q15 3Q15 4Q15 1Q16 2Q16 3Q16 4Q16 1Q17 2Q17 3Q17 4Q17 1Q18 Status
Hit Series approved
Hit Series approved
HitSeries approved
Abandonned
Hit Series approved
Hit Series approved
Hit Series approved
Hit Series approved
Abandonned
Abandonned
Abandonned
2nd Iteration ongoing
2nd Iteration ongoing
2nd Iteration planned
1st iteration ongoing
1st iterationplanned
OngoingCompleted Abandonned
S01 S01IH1
S02 S02IH1 S02IH2
S03 S03IH1
S04
S05 S05IH1
S06 S06IH1
S07
S08
S07IH1
S11
S09
S10
S03IH2
S08IH1
S02IH3
S12
S07IH2
S13
S14
S11IH1
S15
S12IH1
S16
S13IH1
Hitseriesidentified
Booster: Progress to date
S14IH1
Innovative NTD Booster Project recognised by DNDiProject of the year 2016
NTD Booster Summary• AnovelapproachacceleratingdiscoveryofnewdrugsforNTDs
• AuniquepartnershipofJapanesecompanies,theGHITFundandotherinternationalpartners
• Diversityofchemistryandscientificapproachesalreadyyieldingseveralpromisingprojects
• Usefullearningforgrowingpartnershipwithapplicabilitytootherglobalhealthprojects
• SpecialenvironmentcreatedinJapanbytheGHITFundandJapanesepharmaceuticalcompanies• Globalpartnershipcommittedtopatients’needs• PreciousJapanesecontributionstosyntheticandnaturalcompoundscreening,theNTDBooster,
anddrugdiscoveryanddevelopmentprojects
Acknowledgements
NTD Drug Discovery Booster
IeuanRobertsGarryPairaudeauThierryKogejOlaEngkvistDuncanYoungIainComleyJohnCuff
StacieCananKevinCondroskiTraceyNguyenChuong-ThuThaiJ.P.CasperBlayne Lenoir
Nao-aki WatanabeAtsushi InoueMakoto AsadaKazuya NagaokaMikaAokiKunizo HigurashiAkifumi KimuraNobukoKomuraMakotoMatsuiShuichiSuzukiKappei Tsukahara
RyuYoshidaRinaKakiOsamuYoshidaChiakiFujikoshiAikoYamashitaShujiYonezawaTakashiKawasujiAkiraNaito
Mitsuyuki ShimadaYuichiro AkaoSachiko ItonoMasahiro KamauraNobuo ChoTakashiIchikawaKaori KanekoNaoki TaruiYoshinoriIkeuraTerufumi TakagiAtsukoOchidaTaisukeTawaraishiNaoMorishitaHidekiIgata
BenjaminPerryCharlesE.MowbrayJean-PierrePaccaudDominiqueJunodRachelTisseuilRobDonFumikoHirabayashi
Jean-RobertIosetLeelaPavanTadooriDaisukeImotoTatsuroKuzukiMariMatsumotoMidori Morioka
DavidShumConsantin RaduNakyung Lee
Honggun LeeKideok KimJungjin Lee
Jinyeop KimSooyoung ByunHichul Kim
Starr International Foundation