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
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