Innovative medicines for the control and elimination of malaria Timothy N.C Wells, ScD Chief Scientific Officer Defeating Malaria Together

Malaria: Leading cause of child mortality 655’000 deaths per year 216 million cases per year 86% in children under five Targets expectant mothers £8 billion African GDP; 40% of health budgets One child dies every minute from malaria

Millenium Development Goals (MDGs) Reducing malaria burden would contribute significantly towards achieving the MDGs 3 Reversal of incidence of malaria and other major diseases by 2015 Reduce Child Mortality Rates Improve maternal health

Unwavering focus on unmet needs Medicines for children Treatment for severe malaria Medicines for pregnant women Medicines for vulnerable populations Facilitating access to gold-standard medicines More simple & effective medicines Better medicines for uncomplicated malaria Transmission blocking Relapse prevention Chemo-protection Medicines for malaria elimination & eradication

Facilitating access to gold standard medicines Pressure on the partner drugs; choice is important Coartem-D: (artemether-lumefantrine with Novartis) 171 million treatments delivered Testing now in children under 5 kg Eurartesim: (DHA-piperaquine, with Sigma-Tau) EMA approved 2011 Now approved in Cambodia, Ghana, Tanzania Pyramax: (pyronaridine artesunate, with Shin Poong) EMA approved 2012 (art 58), WHO prequalified Label extension and granule submission next 12 months

Unwavering focus on unmet needs Medicines for children Treatment for severe malaria Medicines for pregnant women Medicines for vulnerable populations Facilitating access to gold-standard medicines More simple & effective medicines Better medicines for uncomplicated malaria Transmission blocking Relapse prevention Chemo-protection Medicines for malaria elimination & eradication

Artesunate: saving lives in severe malaria Artesunate for injection (with Guilin) WHO prequalified 2010 Mortality reduction: 10.9% to 8.5% Approximately $1 per vial; 6 million vials in first year Next challenge: artesunate suppositories for pre-referral treatment Dondorp AM et al., Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT); an open label, randomised trial Lancet (2010)

8 Protecting children and expectant mothers Seasonal Malaria Chemoprotection: potential 7-8 million less children infected Once per month; cost <50¢ per year Options: Amodiaquine + SP 25 million expectant mothers at risk Protect twice in pregnancy for $1? Options: Azithromycin-Chloroquine low price Mefloquine Chico RM et al., Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy.2008 Malar J 7: Wilson AL. A Systematic Review and Meta-analysis of the Efficacy and Safety of Intermittent Preventive Treatment of Malaria in Children (IPTc). PLoS ONE. 2011;6:e16976.

Unwavering focus on unmet needs Medicines for children Treatment for severe malaria Medicines for pregnant women Medicines for vulnerable populations Facilitating access to gold-standard medicines More simple & effective medicines Better medicines for uncomplicated malaria Transmission blocking Relapse prevention Chemo-protection Medicines for malaria elimination & eradication

New medicines for malaria control and eradication Irresistible Relapse prevention Transmission blocking Single dose Extremely safe Cheap Child friendly A research agenda for malaria eradication: drugs PLoS Med Jan 25;8(1) Target Product profiles: see

Types of medicine we need Target Candidate Profiles 1. Fast killers/blood stage 2. Long persisters/blood stage 3. Relapse prevention, transmission blocking 4. Chemoprotection

Ask the parasite: transforming discovery Chemistry: All available molecules HTS Whole parasite Hits to leads Identify resistance New business model Screened over five million compounds, 25’000 hits Fast: screen to human trials in less than four years Five molecules already in clinical or preclinical Identifies new targets Rottman M., et al, Science (2010) Meister S., et al Science (2011) Gamo FJ, et al., Nature 465 (7296): 305–310 (2010) Guiguemde WA, et al., Nature 465, 311–315 (2010) Wells TNC Science (2010) New candidate molecules for development

Discovering, developing and delivering innovative medicines RegistrationPreclinical ResearchTranslationalDevelopment Lead OptPhase IIaPhase ILead GenPhase IVPhase IIb/III Novartis miniportfolio Novartis 2 Projects MMV048 (University of Cape Town) Artesunate for injection Guilin Coartem®-D Novartis GSK miniportfolio Broad/Genzyme miniportfolio Oxaboroles Anacor Other Projects 15 Projects sanofi Orthologue screen Kinases Monash Pfizer Screening GSK 2 Projects NITD609 Novartis OZ439 (Monash/UNMC/ STI) Azithromycin chloroquine Pfizer Pyramax Shin Poong/University of Iowa ASAQ Winthrop sanofi /DNDi AstraZeneca Screening GNF156 Novartis DSM265 (UTSW/UW/ Monash) Aminoindole Broad/Genzyme Eurartesim® sigma tau Anitmalarials St Jude/Rutgers/USF Tafenoquine GSK P218 DHFR ( Biotec/Monash/LSH TM) Antimalarials Dundee DHODH UTSW/UW/ Monash Pyramax Paediatric Shin Poong/University of iowa Eurartesim® Paediatric sigma tau sanofi 1 Projects Pyrazoles (DrexelMED/UW) ELQ-300 (USF/OHSU-VAMC) Actelion ACTXXX 20%68% 10% Launch Probability >90% SP-AQ Guilin New Chemical Entities

New fast killers: the front-line of eradication OZ439: long acting peroxide; artemisinin replacement Still active when the parasite wakes up KAE609: fast acting, first new target in 20 years Both in Phase II with potential for single dose curative combination OZ439 EC 50 NF54 1.3nM P. berghei oral 1x30mg/kg curative KAE609 EC 50 NF54 0.7nM ED 90 Pb 2.7mg/kg

New medicines for transmission blocking Existing medicines Primaquine kills the gametocytes at safe doses Ivermectin kills the insect forms New medicines 8 molecules in preclinical to phase II Are any of these as good or better than primaquine? Clinical test being validated (Tanzania) 25’000 blood stage hits to follow up on if not Key compounds from blood stage HTS Membrane feeding in vitro Proof of concept (membrane feeding ex vivo) Proof of concept (membrane feeding ex vivo) Asymptomatic Carrier study Village based Asymptomatic Carrier study Village based

Radical Cure of Plasmodium vivax Not benign: high fevers, relapsing, sometimes fatal 80 million cases per year Relapses – infection without a mosquito bite Current treatment primaquine: needs 14 days and G6PD- risk Tafenoquine in phase II efficacy/safety studies (data July 2013) with GSK P. falcip.P. vivax mixed Anaemia Coma RDS Multiple Tjitra E, PLoS Med Jun 17;5(6):e128. Chen, L. H. et al. JAMA 2007;297: Deaths from malaria Tafenoquine Primaquine

Finding new anti-relapse therapies for P vivax Dormant form: hypnozoite Fast track: test exisiting molecules First new class of compounds could enter phase I in 2014 New clinical model to test for relapse directly (Indonesia) Screen asexual stage P yoelii infected HepG2/liver cells (25k) P. cynomolgi infected rhesus hepatocytes P. cynomolgi infected rhesus hepatocytes PoC Primate model, Human relapse PoC Primate model, Human relapse

Open Access: Empowering Research Available Now Further details

Single oral exposure mice PK (140 uM/kg, n=3) Malaria Box: new leads for other diseases In collaboration with DNDi and University of Antwerp (Prof. L. Maes) Unpublished data Plasmodium falciparum EC50 = 50 nM Trypanosoma brucei EC50 <125 nM Leishmania infantum EC50 = 1000 nM

MMV: £29m Industry: £120m Value through efficiency EFFICIENCYPRODUCTIVITYCOMPETENCIES Reducing clinical development costs INNOVATION Total clinical development costs for pyronaridine-artesunate Industry estimates for clinical development of an anti-infective (Tufts) HEALTH IMPACT March 1st 2013 exchange rate

Value through efficiency EFFICIENCYPRODUCTIVITYCOMPETENCIES Leveraging donor funds INNOVATION DFID £ 1.00 Other donors £ 5.46 Total £ 6.46 Benefits to other donors:  MMV manages funds that cannot be provided directly to Pharma by the donor  MMV provides one-stop-shop for donors: strategy, management, reporting Committed * $475 million$87 million (£53.7 million) HEALTH IMPACT * Total funds received & committed as of March 2013

Value through efficiency EFFICIENCYPRODUCTIVITYCOMPETENCIES Leveraging donor funds INNOVATION Pharma’s ‘in-kind’ support MMV £1.00 Pharma ‘in-kind’ £1.50 Total £2.50 HEALTH IMPACT

* cost for one 3-day course of Coartem-dispersible (Novartis public sector price for malaria-endemic countries; weighted average treatment regimen 2012; March 1st 2013 exchange rate) Better medicines for more people at affordable prices UK 23 pence* to cure one child

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