ki h fLooking to the future:MMV’s discovery and d l t i iti fdevelopment priorities for malaria eradicationTimothy Wells ScDChief Scientific Officer

Strong pipeline of artemisinin combination therapiesNo ‘one size fits all’ solutionNo one size fits all solution

Coartem-D Coarsucam Eurartesim Pyramax AS/MQ

Compounds ArtemetherLumefantrine

Artesunate Amodiaquine

DihydroartemisininPiperaquine

ArtesunatePyronaridine

Artesunate Mefloquine

75% 25%Partner Novartis sanofi aventis/DNDi sigma-tau/Pfizer Shin Poong Farmanguinhos

DNDi/CIPLA

75% 25%

Launch 1Q’09 4Q’08 4Q’10 1Q’11 2Q’08Key Selling Point

Market LeaderSafety: >250

First line therapy in West Africa>20 million

Very long half life Once per day; Field experience

Long half life: protection at

Simple regimen for children and adultsSafety: 250

million treatments

20 million treatments per year

Field experience80% post treatment protection at Day 63

protection at Day 42 P. vivax clinical data

adults

Paediatric Formulation

Dispersible tablet

Dissolves Crushed tabletDispersible in 2013

Sachet of granules in 2012

Crushed tablet

Eurartesim® (dihydroartemisinin/piperaquine)The ACT with the longest post treatment protectionThe ACT with the longest post treatment protection

Partners: sigma-tau, Pfizer g ,Status:• Submitted: European Medicines Agency July 09• Additional studies ongoing – QTc prolongation and

PK comparison• Registration expected 4Q’10Registration expected 4Q 10

Future:• EDCTP Longitudinal study (3Q’10)• Paediatric dispersible formulation (2011)

INESS I l t ti t d i M bi d

DRAFT

• INESS Implementation study in Mozambique and Burkina Faso (2011)

PYRAMAX® (pyronaridine/artesunate)First ACT labelled for both P falciparum and P vivaxFirst ACT labelled for both P. falciparum and P. vivax

Partners: Shin Poong Pharmaceutical Iowa UniversityPartners: Shin Poong Pharmaceutical, Iowa UniversityStatus:• Submission to the European Medicines Agency

(article 58) for tablets (> 15 kg) in May ‘10 • First publication accepted by Lancet

Future:• Drug-drug interaction study (Pyramax-Ritonavir) DRAFTg g y ( y )• P. vivax studies in Papua New Guinea (chloroquine

resistant area, 2010), then in Brazil/Peru (2011)• EDCTP Longit dinal st d (3Q’11)• EDCTP Longitudinal study (3Q’11)

Azithromycin/chloroquine (AZCQ) in IPTpA new medicine protecting pregnant womenA new medicine protecting pregnant women

Partners: Pfizer, London School of Hygiene and Tropical MedicineRationale:• Need therapy Intermittent Preventive Treatment in

P (IPT )Pregnancy (IPTp)• AZCQ safe and efficacious in pregnant women

• Azithromycin reverses chloroquine resistanceAzithromycin reverses chloroquine resistance • Non artemisinin based • Antibacterial activity of azithromycin improves

maternal STDsStatus:

PK ffi 166 t ti t t ti S t’10• PK-efficacy: 166 pregnant patients starting Sept’10• IPTp study in 5000 pregnant women (composite

endpoint; live births and low births starts 2011)endpoint; live births and low births starts 2011)

OZ439: single dose synthetic peroxide?Ready to start phase IIaReady to start phase IIa

Background:S d ti th ti

Plasma conc. time curves after single oral • Second generation synthetic

peroxide • Goal: single-dose cure

doses of OZ439 solution

1000

10000

c (n

g/m

L)

400 mg 800 mg1600 mgExpected MIC

Progress:• Completed pre-clinical and phase I

in 18 months1

10

100

OZ4

39 c

onc p

Future:• Does it work in patients? 2Q’10• Does it work in artemisinin resistant

10 12 24 36 48 60 72

time (h)

• Does it work in artemisinin resistant malaria? 2011

• Find the best partner for a combinationcombination• piperaquine, ferroquine,

naphthoquine • launch planned for 2015launch planned for 2015

TafenoquinePotential ≤ 3 day radical cure of P vivaxPotential ≤ 3 day radical cure of P. vivax

Status:Ai i f ‘b tt th P i i ’• Aiming for ‘better than Primaquine’• Shorter treatment, better compliance• Safety in G6PD deficient patientsy p

• Clinical safety study in G6PD-deficient patients ongoing in Thailand

F tFuture:• Innovative pivotal phase II/III design (faster and

cheaper) – starts Jan ‘11• Protocol review with US FDA scheduled for Mar

´10

Pre-clinical Phase I Phase IIa Phase II/III Registration

2011 2015

Preventing relapse of P.vivaxNew assay formats for testing moleculesNew assay formats for testing molecules

primaquine• Cell culture assay developed by Dutch

Primate Centre using related parasite P. cynomologi 60

80

100

120Total EEFDeveloping EEFHypnozoites

EEF

• Validated with known drugs – 0

20

40

#

gprimaquine, atovaquone 0.01 0.1 1 10 100 1000 10000

ng/ml

• Testing 100 key antimalarials in 2010 Schizonts (developing EEF)

• Future: Identifying hypnozoite biomarkers to make better assay

Hypnozoites

Tools to develop better drugs fasterDesigning inhibitors to overcome resistanceDesigning inhibitors to overcome resistance

• Resistance due to point mutations identified in DHFR

• Structural information used to design new compound P218 which inhibits both normal and mutant DHFR

• Compound entering preclinical development –fi t ti i h 2011 Pf Pf

IC50 (nM)first time in human 2011 Pf sens. Pf res.

Pyr 58 > 100,000P218 4.6 56

NO

NH2O

CO2H

N

N EtH2N

Phenotypic ScreeningRapidly identifying new classes of antimalarialsRapidly identifying new classes of antimalarials

• MMV and partners have tested 5 pmillion compounds against parasite.

B i f j ll b ti ith• Basis of major collaborations with pharmaceutical companies

• Treasure trove of actives with over 20’000 highly potent starting points

• Moves the drug discovery bottle neck closer to the patientp

Hits-to-Leads chemistryCollaborations to solve the clinical bottleneckCollaborations to solve the clinical bottleneck

Hi L d b d i h• Hits-to-Leads can be done in house or with dedicated external resource

• Dedicated teams, in disease endemic ,countries – India, South Africa

• World class industry experts acting as mentorsmentors

• In vivo pharmacology by centres of excellence 80

90 Mouse modelSingle oral dose

• Partnering with government for training and capacity building 30

40

50

60

70

Dos

e (m

g/kg

)

New compoundartemether

Single oral dose

training and capacity building

0

10

20

30

50% reduction 90% reduction 99% reduction

Parasitaemia

KAE609 Project of the YearSpiroindolone a new chemotype for malariaSpiroindolone, a new chemotype for malaria

• Novartis ‘miniportfolio’: consortium, p ,cosponsored with Wellcome Trust

• 2.1 million compounds screened -Spiroindolone scaffold declared ‘lead’Spiroindolone scaffold declared lead Dec ‘07

• Early pre-clinical studies in 2009 NVC-KAE609• Excellent drug-like properties

• Highly bioavailableHi hl ti di t d h d• Highly active - predicted human dose 30 mg

• Active in transmission blocking assaysg y• First in Man Jan 2011

Priorities for malaria eradication

• Bringing the pipeline to the patient

• Towards the single dose cure

• Collaboration networks bringing exciting new medicines for the eradication agendanew medicines for the eradication agenda

Back-upsp

Coartem®-Dispersible (artemether/lumefantrine)The first ACT designed for childrenThe first ACT designed for children

Partner: NovartisPartner: NovartisStatus:• Approved: Swissmedic in Dec ’08, US-FDA ’09• WHO prequalified• Registered in 26 African countries, 16 million

treatments in ’09treatments in 09Future:• Study in asymptomatic subjects to assess y y p j

community morbidity• Expert meeting in March to refine concept

St d t t i N b ’10• Study starts in November ’10• INESS Implementation study in Tanzania

Coarsucam® (artesunate/amodiaquine) A model for drug safety monitoringA model for drug safety monitoring

Partners: sanofi aventis DNDiPartners: sanofi aventis, DNDi Status:• WHO Prequalification Oct ‘08• Registered in 24 African countries, over 20

million treatments in 2009Future:Future:• Phase IV program to determine safety and

effectiveness in Agboville, Côte d’Ivoire(Nov ’09)(Nov 09)• Implementation study: open-labeled

(15,000 patients) to detect rare adverse eventsevents

• Pre- and post-studies with 290 patients: effectiveness and safety at 2 year-intervals

Research and DevelopmentStrong diverse portfolio for the eradication challengeStrong diverse portfolio for the eradication challenge

RegistrationPreclinical

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

Novartisminiportfolio

KAI407 seriesNovartis

MK 4815(Merck)

GSK 932121GSK

Iv artesunateGuilin

Eurartesim™sigma-tau

Coartem®-DNovartis

Arterolane/PQPRanbaxy

GSK Pyridone KAE 609 Tafenoquine Artemisone AZCQ Pyramax®Shi P /U i it

Coarsucam®miniportfolio

Broad/Genzymeminiportfolio

Pfi

yGSK

DHODHUTSW/UW/Monash

A i i d l

Novartis

P218 DHFR(BIOTEC/Monash/

LSHTM)

qGSK

OZ 439(Monash/UNMC/STI)

UHKST Pfizer Shin Poong/University of Iowa sanofi aventis/DNDi

sanofi aventisOrthologue screen

PfizerWhole cell screen

AminoindoleBroad/Genzyme

Ozonide backupMonash/UNMC/STI

Natural Products5 Projects

KinasesMonash

DHODHBroad/Genzyme

QuinolineMethanols

WRAIR

Whole Cell HitsSt Jude/Rutgers

Other Projects13 Projects

KAC776 seriesNovartis

KA558 seriesNovartis