Defeating Malaria Together

Partnering to develop new products Siem Reap, Cambodia – 24-26 February 2015 Timothy Wells, PhD ScD Chief Scientific Officer

Defeating Malaria Together

PRODUCTS WITH IMPACT

INVESTING IN OPENNESS

NEW PRODUCTS ON THE HORIZON

WORKING TOGETHER TO INCREASE IMPACT

Resistance against both artemisinin and the partner drug is a concern

Pyramax recrudescence in Pailin (2007-2008) 3.3% day 28; 10.2% day 42 NB: Pursat (2013) piperaquine IC50 increasing, but mefloquine IC50 and PfMDR1 copy numbers decreasing. 3

Day 3: ‘artesunate’

Day 28: ‘partner’

ACT efficacy Pailin,

Cambodia

Approved ACTs: fighting back against resistance

Eurartesim (Sigma-Tau) DHA-piperaquine

EMA approved 2011 Cambodia 2013

NCl

HNN

N O

N

OH

Pyramax (Shin Poong) Pyronaridine-artesunate

EMA article 58 2012 Cambodia 2014

NCl

N

N

NN

N

Cl

Collaborations giving high impact affordable products

25 million vials distributed

Affordable chemoprevention now

Start with the end in mind: Target Product Profiles for the medicine

Long-acting post treatment prophylaxis

Radical cure

Transmission blocking

Long acting Causal liver or slow onset asexual

Different MOA to SERCaP

SERCaP single exposure

radical cure and prophylaxis

SEC single exposure

chemoprotection

Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402 Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)

Fast clearance of parasitaemia

Start with the end in mind Target Candidate Profiles for the molecules

Long-acting post treatment prophylaxis

Radical cure

Transmission blocking

Long acting Causal liver or slow onset asexual

Different MOA to SERCaP

SERCaP single exposure

radical cure and prophylaxis

SEC single exposure

chemoprotection

Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402 Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)

TCP1

TCP3b

TCP2

TCP3a

TCP4 Fast clearance

of parasitaemia

Target Product Profiles Medicines for malaria eradication

Long-acting post treatment prophylaxis

Radical cure

Transmission blocking

Long acting Causal liver or slow onset asexual

Different MOA to SERCaP

SERCaP single exposure

radical cure and prophylaxis

Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402 Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)

TCP1

TCP3b

TCP2

TCP3a

Fast clearance of parasitaemia

Many of the new compounds have both:

they kill fast, with plasma concentrations above

MIC for >7 days

New medicines: building on an existing template

O

OO

OZ03 OZ277/ RBx11160

reduce logP improve solubility

O

OO

NHO

NH2

OZ439

Decrease interaction with ferrous iron (single electron)

O

O OO

OH H

H

O

OO O

N

O

Nature, 2004, 430, 900 PNAS, 2011, 108(11), 4400

Better embryo safety Better granulocyte safety Active vs artesunate resistance

New medicines: building on new templates

KAE609

NH

NH

NH

Br

O

Singleton “Hit” EC50 NF54 90nM

EC50 NF54 9.2nM Clint (hu, m) unstable

NH

NH

NHO

Cl

7- to 6- ring Enantiomer Bromo- to chloro- EC50 NF54 0.7nM

Clint (hu, m) stable ED90 Pb 2.7mg/kg

NH

NH

NHO

Cl

F

ClFix metabolic Instability with halo-substitution

Science, 2010, 1175; J Med Chem 2010, 53, 5155

Data can predict whether compounds kill resistant strains in humans

12

Time after administration (h) 0 24 48 72 96 120 144 168

1

10

100

1000

10000

Dru

g c

once

ntra

tion

(ng/

mL)

800 mg OZ439

OZ439 threshold

DHA threshold

100 mg DHA

NH

NH

NHO

Cl

F

Cl

N

N

N

N

HN

SF5

FF

KAE609 Novartis, Swiss Tropical, Wellcome Trust Development with Novartis

DSM265 Dallas, Swiss Tropical Monash

Development with Takeda, GHIT

Many options for new combinations in phase II studies now

KAF156 Novartis, Swiss Tropical, Wellcome

Development with Novartis

OZ439 Nebraska, Swiss Tropical, Monash

Development with Sanofi

Single Dose 300 mg Tafenoquine Relapse-free Efficacy at 6 months

37.5%

57.7% 54.1% (p=0.16)

89.2% (p<0.0001

)

91.9% (p<0.0001)

77.3% (p=0.0004)

Phase III study currently ongoing including Anlong Veng Referral Hospital, Oddar Meancheay Province. Regulatory Submission planned for 2016

Malaria Box 400 compounds 200 research groups worldwide Sharing our resources with the world

MMV048 University of Cape Town Republic of South Africa

P218 Biotec

Kingdom of Thailand

Partnering with countries to develop medicines

SO2Me

N

NH2NF3C

New mechanism of action: PI-4kinase

Human Volunteer studies Cape Town, May 2014

First time for a new molecule to be tested first in Africa

Next generation DHFR inhibitor: replaces pyrimethamine

Currently in preclinical safety testing

Study in human volunteers in Thailand 2016

The pipeline has moved a long way from 2008

In registration Preclinical

Research Translational Development Patient

exploratory Human

volunteers Lead optimisation Approved* Patient confirmatory

KAE609 NGBS consortium

Falcipains GSK/UCSF

Artimisone UHKST

Artesunate Injection WRAIR

MK 4815 (Merck)

GSK 932121 GSK

Tafenoquine GSK

OZ 439 Monash/UNMC/STI

Pyronaridine AS Shin Poong

DHA-PQP Sigma-Tau

Macrolides GSK

(+) Mefloquine Treague

Artemether Lumefantrine

Novartis

4-pyridone GSK

DHODH UTSW/UW/Monash

DHFR BIOTEC/Monash/

LSHTM

1

APM

20% 68% 10% Submission Probability

2015+ 2013 2017+ >90% 2011

Isoquine LSTH/GSK

to 2015 Research

Miniportfolio Novartis

1 Project Novartis

Miniportfolio GSK

Miniportfolio Sanofi

Aminopyridines UCT

Heterocycles Campinas

Heterocycles St

Jude/Rutgers/USF

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

MMV253 (Astrazeneca)

MMV048 UCT/TIA

P218 DHFR BIOTEC

SJ733 St Jude/Eisai (Rutgers/NIH)

MMV121 (Dundee)

Translational Pr eclinical Human volunteers

OZ439/FQ Sanofi

Rectal Artesunate CIPLA/Strides Acrolab/TDR

Artesunate for injection

Guilin

Artemether- Lumefantrine Dispersible

Novartis

Pyronaridine-Artesunate Shin Poong

DHA- Piperaquine

Sigma-Tau

1

2

3

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

DSM265 Takeda/GHIT

20% 68% 10% Submission Probability

2020+ 2018+ 2022+ >90% 2016

and there are major challenges ahead

SINGLE DOSE CURE TO AUGMENT OR REPLACE ACTS

SAFETY IN EXPECTANT

MOTHERS AND NEW BORN

BABIES

MEDICINES TO PROTECT FOR

EVERYONE

SAFELY PREVENTING THE

RELAPSE OF VIVAX MALARIA

For MMV our network is our intangible asset

Our partnerships are our greatest strength

Defeating Malaria Together

PRODUCTS WITH IMPACT

INVESTING IN OPENNESS

NEW PRODUCTS ON THE HORIZON

WORKING TOGETHER TO INCREASE IMPACT