Defeating Malaria Together

New medicines targeting the hypnozoite • Siem Reap, Cambodia – 24-26 February 2015

• Didier Leroy PhD, Director Discovery, MMV

Most of our portfolio is against the blood stages

Included in MMV portfolio post approval

Research

Miniportfolio Novartis

1 Project Novartis

Miniportfolio GSK

Aminopyridines UCT

Heterocycles Campinas

Miniportfolio AstraZeneca

Heterocycles Celgene

3 Projects GSK

Oxaboroles Anacor

Tetraoxanes LSTM/Liverpool

DHODH UTSW/UW/Monash

Orthologue Leads Sanofi

Open Source Drug Discovery

Sydney

Amino-alcohols Merck Serono

Screening Daiichi-Sankyo

Other Projects 15 Projects

Screening Takeda

Screening Eisai

Pathogen Box MMV

Research Lead optimisation Registration Phase IIa Phase IIb/III

OZ439/PQP Sanofi

Tafenoquine GSK

Pyronaridine-Artesunate Paediatric

Shin Poong/Iowa

DHA- Piperaquine

Paediatric Sigma-Tau

KAE609 Novartis

KAF156 Novartis

In registration Development

Patient exploratory Patient confirmatory Phase IV Post Approval

Preclinical Phase I

MMV048 UCT/TIA

DSM265 NIH/Takeda

P218 DHFR BIOTEC (Monash/ LSHTM)

SJ733 St Jude

(Rutgers/NIH)

MMV121 (Dundee)

Translational Pr eclinical Human volunteers

OZ439/FQ Sanofi

Rectal Artesunate CIPLA/Strides/TDR

Artesunate for injection

Guilin

Artemether- Lumefantrine Dispersible

Novartis

Pyronaridine-Artesunate Shin Poong

DHA- Piperaquine

Sigma-Tau

1

2

3

1 Brand name: Coartem® Dispersible 2 Brand name: Artesun® 3 Brand name: Eurartesim® 4 Brand name: Pyramax® 5 Brand names: CoarsucamTM, ASAQ/Winthrop®

* First review or approval by WHO Prequalification, or by regulatory bodies who are ICH members or observers

Research Lead

optimisation

Under review *

Development Patient

exploratory Patient

confirmatory

Translational

Preclinical Human

volunteers

5

4

Access

Artesunate Amodiaquine

Sanofi/DNDi

Artesunate- Mefloquine CIPLA/DNDi

Sulfadoxine Pyrimethamine+

Amodiaquine Guilin

PA92 (Drexel/UW/GNF)

GSK030 GSK

MMV253 (AstraZeneca)

Tafenoquine: a single dose anti-relapse agent against P. vivax

• Discovered by WRAIR (1978); phase IIb collaboration of GSK/MMV since 2012

• Active at all stages of malaria lifecycle including P. vivax hypnozoites

• 300 mg single dose reduces relapse rates by >90%; phase III ongoing

• Risk of hemolysis in severely G6PD-deficient patients, point of care test?

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NH2

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F FF

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3

Llanos-Cuentas A. et al. Lancet. 2014 Mar 22;383(9922):1049-58

Looking for four different types of activity: • Blood stage killers: fast acting and/or long acting • Transmission blocking • Relapse prevention – kills hypnozoites • Chemoprotection – kills liver schizonts

4

Finding new candidates for liver stages

• Initial input 25’000 compounds from blood stage screens

• 2014 started primary screening 600’000 compounds on P. berghei and P yoelii

• Series tested for lysis of G6PD deficient erythrocytes in SCID mouse

5

Finding new candidates for liver stages

Screen asexual stage

P. berghei infected

HepG2/liver cells (25k)

P. cynomolgi infected rhesus

hepatocytes

Proof of concept:

Primate model, Human relapse

New chemical series active against liver schizonts

6

• Testing new chemical series against P cynomolgi infected rhesus hepatocytes

• Many series have activity against liver schizonts, with potential for chemoprotection

• KAF156 and DSM265 being tested in human sporozoite chemoprotection study (2015)

• No hits from initial 25’000 screen have anti-relapse activity

• Initial input 25’000 compounds from blood stage screens • 2014 started primary screening 600’000 compounds on P.

bergei and P yoelii • Series tested for lysis of G6PD deficient erythrocytes in

SCID mouse

7

New Screening cascades for liver stages from 2016

Diversity P vivax infected HepG2

Mouse model with human

liver?

Proof of Concept Travellers or

classical Phase 2

Human microliver infection with P. vivax

8

Day 3 Day 5 Day 7

Day 21 Day 21

anti-PvCSP staining. Scale bar: 10µm and 40µm

• Arrays of primary hepatocytes by microprinting adhesion molecules Sangeeta Bhatia MIT

• 24 and 96 well formats • Persistent small liver forms • Dose response with controls: primaquine and atovaquone • Primary testing in 2016?

Microfluidic Bilayer Device for P vivax infection

9

• Dennis Kyle USF • Uses primary hepatocytes and hepatoma cell lines, maintained

for 21 days • Can identify persistent small liver forms • Possibility to expand to 96 or 384 well format • Primary testing in 2016?

Replacing the primates with murine models

10

• FRG mouse – with engrafted human liver (Stefan Kappe, SRBI) • Infection with 400’000 sporozoites; produces 50% small forms • Similar cost to primate studies, but can be optimised • Alternatives include hepatoma engraftment (Rosemary

Rochford, SUNY)

Day 3 Day 5 Day 7

Next steps

• Increased focus on finding new series active against liver forms • Primary screening now using murine hepatocytes • Primary screening (2016?) with P. vivax cells • Projects with new targets: test in primate model

MMV is grateful for the financial support from the following organizations: