Malaria Global update, progress, priorities Steve Taylor GLHLTH701 Sept 2 2014.

MalariaGlobal update, progress, priorities

Steve TaylorGLHLTH701Sept 2 2014

Overview

• Malaria– Microbiologically, epidemiologically– Historically, clinically

• Malaria today• Progress• Hot topics

– Vaccines– Drug resistance

What is malaria?

What is malaria?

Homo sapiens and Plasmodia

• > 3000 yrs old– Chinese, Assyrian, Indian medical texts

• European wars• European colonialisation• Cinchona bark

H. sapiens and P. falciparum

Hay Nat Comm 2010Fairhurst NEJM 2004

Where was malaria?

memory.loc.gov

How big of a problem is malaria?

Malaria J 2011; 10: 378

P. falciparum

P. vivax

How big of a problem is malaria?

Plos Med 2010; 7: e1000290

How big of a problem is malaria?

Lancet 2012; 379: 2151

U5 deathsTotal: 7.6mMalaria: 564,000

Who gets malaria?People in Africa and S. Asia

Plos Med 2010; 7: e1000290

60%

Who gets malaria?Children

Nat Immunol 2008; 9: 725Lancet 2014 (in press)

Asymptomatic infection

Mild malaria

Severe malaria

?

?

Who gets malaria?Pregnant women

http://www.cdc.gov/malaria/malaria_worldwide/reduction/iptp.htmlPLoS Med 2010; 7(1): e1000221

Who gets malaria?Travelers

MMWR 2012; 61

Malaria today

Who is working on malaria?

How is malaria treated?

Artemisinin combination therapies:e.g. Coartem

Bark of Cinchona tree:Quinine

ChloroquineMefloquine

SP(Fansidar)

Artemisinin combination therapies

New malaria drugs? Sept 2013RegistrationPreclinical

Research Translational DevelopmentLead Opt Phase IIaPhase ILead Gen Phase IVPhase IIb/III

MiniportfolioNovartis

1 ProjectNovartis

Artesunate for injection

Guilin

Coartem®-DNovartis

MiniportfolioGSK

MiniportfolioSanofi

AminopyridinesUCT

Other Projects19 Projects

HeterocyclesCelgene

MiniportfolioAstraZeneca

4 ProjectsGSK

KAE609Novartis

OZ439(Monash/UNMC/

STI)

Azithromycin chloroquine

Pfizer

PyramaxShin Poong/

University of Iowa

OxaborolesAnacor

ELQ-300(USF/

OHSU-VAMC)

21A092(DrexelMed/UW)

KAF156Novartis

DSM265(UTSW/UW/

Monash)

Eurartesim® Sigma-Tau

Whole Cell LeadsAstraZeneca

TafenoquineGSK

P218 DHFR(Biotec/Monash/

LSHTM)

2 ProjectsLiverpool

STM/Liverpool Uni

DHODHUTSW/UW

PyramaxPaediatricShin Poong/

University of iowa

Eurartesim® PaediatricSigma-Tau

Orthologue LeadsSanofi

HeterocyclesDundee

Included in MMV portfolio post registration

SP-AQGuilin

ASAQ Winthropsanofi /DNDi

Nauclea pobeguinii

DRC/Antwerp

Argemone mexicana

Mali/Geneva

MMV390048(UCT)

SJ557733St Jude/Rutgers

Global Malaria Portfolio, 2Q 2014Classified by therapeutic type

ELQ300Takeda(USF/

OHSU-VAMC)

21A092(DrexelMed/UW)

DSM265NIH/Takeda

P218 DHFRBIOTEC(Monash/LSHTM)

MMV048UCT/TIA

RKA182LSTM/Liverpool

NPC-1161-BMississippi

BCX4945Biocryst/Albert Einstein

College of Medicine

SAR116242Palumed

AQ13Immtech

ACT840Actelion

DF02Dilafor

CDRI 97-78Ipca

N-tert butyl isoquine

LSTM/Liverpool/GSK

SJ733St Jude

(Rutgers/NIH)

Artesunate MefloquineCIPLA/DNDi

Artesunate for injection

Guilin

Artemether- LumefantrineDispersible

Novartis

Pyronaridine-ArtesunateShin Poong

Dihydroartemisin- Piperaquine

Sigma-Tau

Artesunate AmodiaquineSanofi /DNDi

Artemether- Lumefantrine

Novartis 1

2

6

7

3

4

5

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

OZ439/FQSanofi

KAE609Novartis

OZ439/PQPSanofi

KAF156Novartis

TafenoquineGSK

Pyronaridine-Artesunate Paediatric

Shin Poong/Iowa

DHA Piperaquine PaediatricSigma-Tau

Sulfadoxine Pyrimethamine +

AmodiaquineGuilin

SAR97276Sanofi

FosmidomycinPiperaquine

Jomaa Pharma GmbH

Methylene Blue /AQHeidelberg

Rectal Artesunate CIPLA/Strides/TDR

ArtemisoneUHKST

Co-trimoxazole Bactrim

Inst. of Trop. Med.

Artemisinin Naphthoquine

KPC

Arterolane/PQPRanbaxy

Artemether sub-lingual spray

ProtoPharma Ltd

8

4

5

9

10

1 Brand name: Coartem®, Generics by Ajanta, Cipla, Ipca, Strides, Macleods Pharma Ltd, Mylan Laboratories2 Brand name: Coartem® Dispersible, Generic by Ajanta3 Brand name: Artesun® 4 Brand name: Eurartesim® 5 Brand name: Pyramax® 6 Brand names: CoarsucamTM, ASAQ/Winthrop®, generics by Ajanta, Ipca, Guilin, Cipla, Strides (co-blistered)7 Also Acino/Mepha product (co-blistered)8 Brand name: SynriamTM

9 Brand name: ARCO® 10 Brand name: ArTiMistTM

Non MMV

Included in MMV portfolio post registration

ACT’s

Endoperoxides

Severe Malaria

Antibiotics

P. vivax

Molecular Mechanisms

Cell Based Mechanisms

Natural Products

On Hold

ResearchResearchLead

optimisationPhase IIa Phase IIb/III

Under review *

DevelopmentPatient

exploratoryPatient

confirmatoryPhase IVPost

Approval

AccessTranslational

PreclinicalHuman

volunteers

MMV121(Dundee)

Number of Preclinical – Phase IV candidates

21

10

20

30

409

4

2

4

8

7

2

Currentpipeline ACT’s Endoperoxide

SevereMalaria

Antibiotics P.vivax MolecularMechanisms

Cell BasedMechanisms

On holdNatural Products

3

0

39

ACT’s

Endoperoxides

Severe Malaria

Antibiotics

P. vivax

Molecular Mechanisms

Cell Based Mechanisms

Natural Products

On Hold

How do we prevent malaria?

Vector insecticide resistance

Parasite drug resistance

Parasite drug resistance

Vector insecticide resistance

Prevention in pregnant women

Lancet ID 2011; 11: 190

Progress?

• “Malaria mortality rates have fallen by more than 25% since 2000”

• “Off 99 countries with ongoing malaria transmission, 43 recorded decreases of more than 50%... Between 2000 and 2010”

• 2004-2010-2012: LLINs 6m 145m 66m• 2010 – 2011: RDTs 88m 155m• 2005-2011: ACTs 11m 278m

WHO, World Malaria Report 2011

Progress?Zanzibar Ethiopia Fajara

Kilifi

Limpopo, SASao Tome &Principe

Bioko I.

Lancet ID 2010; 10: 545

Progress?

Lancet 2008; 372: 1555Lancet 2014 (in press)

What about a vaccine?

Annu Rev Med 2011; 63: 345

Malaria vaccines?

www.malariavaccine.org

What about a vaccine?

NEJM 2011; 365: 1863Plos Med 2014; 11: e1001685

Wall St J 7/24/2014

Drug resistance

Antimalarial Drug

Year Introduced

First Reported

Resistance

Difference (years)

Quinine 1632 1910 278

Mepacrine 1935 1945 10

Chloroquine 1945 1957 12

Proguanil 1948 1949 1

Fansidar 1967 1967 0

Mefloquine 1977 1982 5

Atovaquone 1996 1996 0

Artemisinin 1980 2009 ?

Drug resistance

NEJM 2009; 361: 455NEJM 2014; 371: 411

Drug resistance

Nature 2014; 505: 50JID 2014 (in press)

Drug resistance

JID 2014; 210: 335www.wwarn.org

What’s next?• Preventive measures• Vector control• New drugs

– Combinations– Adjunctive

• Better diagnostics– Surveillance

• New vaccines– Antigens– Adjuvants

• Molecular pathogenesis

Parting words

“Be sure to give the poor the aid they most need. There are a thousand hacking at the branches of evil to one who is striking at the root, and it may be that he who bestows the largest amount of time and money on the needy is doing the most by his mode of life to produce the misery which he strives in vain to relieve.”

-- H.D. Thoreau