The NTD Drug Discovery Booster:an innovative collaboration for hit expansion

Charlie MowbrayDiscovery Director

GHIT R&D Forum, December 8th 2017Tokyo Garden Terrace Kioi Conference

Activating the Power of Japan’s Unique Chemical Compounds for Neglected Diseases

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

NelsonforTheNewYorkTim

es

• To develop new

drugs or new

formulations of

existing drugs

• To strengthen

capacities in a

sustainable manner

• To adopt a dynamic

approach to

portfolio diseases

DNDi’s Mission

7 new treatments delivered, recommended, implemented

• 30 projects, 8 diseases areas

• 13 entirely new chemical entities (NCEs)

• Over 160 partnerships, most in endemiccountries

• 160 staff, half in endemic countries & 700 people working on DNDi projects

• EUR 400 million raised equally frompublic and private sources

• 4 regional disease-specific clinical trial platforms/ networks and severaltechnology transfers

✓ Easy to use✓ Affordable✓ Field-adapted✓ Non-patented

2016

SUPERBOOSTERTHERAPYPaediatric HIV/TB

HIV/TB

DNDi’s success is only possible

through innovative partnershipsUniversities& ResearchInstitutes

PDPs

Int. Org.& NGOs

Biotechs

CROs Pharmaceutical companies

CRITERIA FOR SUCCESS✓ Share the same vision✓ Mutual understanding✓ Involvement throughout the

whole process

Over 160 partnerships worldwide

Some currentJapanese partners:

EisaiTakedaShionogiDaiichi-SankyoGeneDesignKitasato InstituteRiken InstituteIMC

GHIT Fund

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 2017

Research DevelopmentTranslation Implementation

Mycetoma

Ravidasvir/

SofosbuvirHCV

Two ‘4-in-1’

LPV/r/ABC/3TC

LPV/r pellets

with dual NRTI

Superbooster

Therapy

Paediatric HIV/TB

Pediatric

HIV

Screening EmodepsideABBV-4083

TylaMacMacro

Filaricide 3Filaria

New Benz

Regimens +/-

fosravuconazole

Screening

Biomarkers

Chagas

H2L

Fexinidazole

Benznidazole

Paediatric Dosage

Form

Chagas

Lead OptChagas

SSG&PM

Africa

New Treatments

for HIV/VLScreeningDNDI-5421

DNDI-5610

oxaborole

Leish

H2L

DNDI-0690

nitroimidazole New VL Treatments

Asia

New Treatments

for PKDL

New VL

Treatments

Latin America

New CL

CombinationCpG-D35 (CL)

Amino

pyrazoles

DNDI-6148

oxaborole

CGH VL

Series 1

MF/Paromomycin

Combo for Africa

Leishmaniasis

FexinidazoleAcoziboroleSCYX-1330682

SCYX-1608210

oxaborole

NECT

Nifurtimox-Eflornithine

Combination Therapy

HAT

Malaria

FDC ASAQ

Malaria

FDC ASMQ

GSK3494245

DDD1305143

GSK3186899

DDD853651

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 2017

Research DevelopmentTranslation Implementation

Mycetoma

Chagas

Leishmaniasis

CpG-D35 (CL)

GeneDesign

Eisai

Amino

Pyrazoles

Takeda

New Benz

Regimens +/-

Fosravuconazole

Eisai

Fosravuconazole

Eisai

Takeda

Daiichi-

Sankyo

DNDI-5561

Takeda

IMC

Daiichi-

Sankyo

Eisai

Takeda

NTD Booster

Kitasato

Eisai, Takeda, Shionogi

Eisai

Takeda

IMC

Daiichi-

Sankyo

Eisai

Takeda

Kitasato

NTD Booster

Daiichi-

Sankyo

Brd project

Riken

Eisai, Takeda, Shionogi

Growing portfolio• 8 Partners• 20 projects

Unique compounds from Japan• Screening of drug-like small molecules from Japanese

pharmaceutical companies and research institutes

• Some interesting hits identified

• NTD Drug Discovery Booster used to accelerate these new discoveries

• Japanese natural products

PCA plots of drugs approved by FDA between 1981–2010 parsed by compound origin

Newman DJ, Cragg GM. Natural Products as Sources of New Drugs from 1981 to 2014 J Nat Prod. 2016 25;79(3):629-61

Stratton et al., 2013, Cheminformatic comparison of approved drugs from natural product versus synthetic origins. Bioorg Med Chem Lett. 2015 1; 25(21): 4802–4807

• Drug discovery for tropical diseases such as Visceral Leishmanisais and Chagas Disease is neglected

– Little interest, limited investment, few researchers, few tools

• Parasites are very difficult to kill

– High Throughput Screening hit rates:

• L. donovani (intracellular) <0.05%

• T. cruzi (intracellular) <0.15%

Hits are scarce and precious – need to fully exploit them

A BIG Experiment in Early Drug Discovery

THP1 cells infected with

eGFP-L. donovani (courtesy

of GSK Tres Cantos)

• The NTD Drug Discovery Booster Goals:

– Expand precious HTS hits and enable scaffold-hopping to find new hits

– Benefit from the pooling of structures and information

– Accelerate discovery and reduce costs

– Experiment with a new open innovation approach to drug discovery

Source # hits

Seed S01 1

Partner A ~90

Partner B ~90

Partner C ~90

Partner D ~40

• Complementary compound collections and different computational approaches efficiently explore chemicalspace around new hits

• Rapid SAR expansion and scaffold-hopping before expensive optmimisation chemistry is needed

Booster Process - Representative Example

2Q15 3Q15 4Q15 1Q16 2Q16 3Q16 4Q16 1Q17 2Q 17 3Q17 4Q17 1Q18 Status

Hit Series approved

Hit Series approved

Hit Series 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 iteration planned

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

Hit series identified

Booster: Progress to date

S14IH1

Innovative NTD Booster Project recognised by DNDiProject of the year 2016

NTD Booster Summary

• A novel approach accelerating discovery of new drugs for NTDs

• A unique partnership of Japanese companies, the GHIT Fund and other international partners

• Diversity of chemistry and scientific approaches already yielding several promising projects

• Useful learning for growing partnership with applicability to other global health projects

• Special environment created in Japan by the GHIT Fund and Japanese pharmaceutical companies

• Global partnership committed to patients’ needs

• Precious Japanese contributions to synthetic and natural compound screening, the NTD Booster, and drug discovery and development projects

Acknowledgements

NTD Drug Discovery Booster

Ieuan RobertsGarry PairaudeauThierry KogejOla EngkvistDuncan YoungIain ComleyJohn Cuff

Stacie CananKevin CondroskiTracey NguyenChuong-Thu ThaiJ. P. CasperBlayne Lenoir

Nao-aki WatanabeAtsushi InoueMakoto AsadaKazuya NagaokaMika AokiKunizo HigurashiAkifumi KimuraNobuko KomuraMakoto MatsuiShuichi SuzukiKappei Tsukahara

Ryu YoshidaRina KakiOsamu YoshidaChiaki FujikoshiAiko YamashitaShuji YonezawaTakashi KawasujiAkira Naito

Mitsuyuki ShimadaYuichiro AkaoSachiko ItonoMasahiro KamauraNobuo ChoTakashi IchikawaKaori KanekoNaoki TaruiYoshinori IkeuraTerufumi TakagiAtsuko OchidaTaisuke TawaraishiNao MorishitaHideki Igata

Benjamin PerryCharles E. MowbrayJean-Pierre PaccaudDominique JunodRachel TisseuilRob DonFumiko Hirabayashi

Jean-Robert IosetLeela Pavan TadooriDaisuke ImotoTatsuro KuzukiMari MatsumotoMidori Morioka

David ShumConsantin RaduNakyung Lee

Honggun LeeKideok KimJungjin Lee

Jinyeop KimSooyoung ByunHichul Kim

Starr International Foundation