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

2. Overview Malaria – Microbiologically, epidemiologically – Historically, clinically Malaria today Progress Hot topics – Vaccines – Drug resistance

3. What is malaria?

5. Homo sapiens and Plasmodia > 3000 yrs old – Chinese, Assyrian, Indian medical texts European wars European colonialisation Cinchona bark

6. H. sapiens and P. falciparum Hay Nat Comm 2010 Fairhurst NEJM 2004

7. Where was malaria? memory.loc.gov

8. How big of a problem is malaria? Malaria J 2011; 10: 378 P. falciparum P. vivax

9. How big of a problem is malaria? Plos Med 2010; 7: e1000290

10. How big of a problem is malaria? Lancet 2012; 379: 2151 U5 deaths Total: 7.6m Malaria: 564,000

11. Who gets malaria? People in Africa and S. Asia Plos Med 2010; 7: e1000290 60%

12. Who gets malaria? Children Nat Immunol 2008; 9: 725 Lancet 2014 (in press) Asymptomatic infection Mild malaria Severe malaria ? ?

13. Who gets malaria? Pregnant women http://www.cdc.gov/malaria/malaria_worldwide/reduction/iptp.html PLoS Med 2010; 7(1): e1000221

14. Who gets malaria? Travelers MMWR 2012; 61

15. Malaria today

16. Who is working on malaria?

17. How is malaria treated? Artemisinin combination therapies: e.g. Coartem Bark of Cinchona tree: Quinine Chloroquine Mefloquine SP (Fansidar)

18. Artemisinin combination therapies

19. New malaria drugs? Sept 2013 RegistrationPreclinical ResearchTranslationalDevelopment Lead OptPhase IIaPhase ILead GenPhase IVPhase IIb/III Miniportfolio Novartis 1 Project Novartis Artesunate for injection Guilin Coartem®-D Novartis Miniportfolio GSK Miniportfolio Sanofi Aminopyridines UCT Other Projects 19 Projects Heterocycles Celgene Miniportfolio AstraZeneca 4 Projects GSK KAE609 Novartis OZ439 (Monash/UNMC/ STI) Azithromycin chloroquine Pfizer Pyramax Shin Poong/ University of Iowa Oxaboroles Anacor ELQ-300 (USF/ OHSU-VAMC ) 21A092 (DrexelMed/UW) KAF156 Novartis DSM265 (UTSW/UW/ Monash) Eurartesim® Sigma-Tau Whole Cell Leads AstraZeneca Tafenoquine GSK P218 DHFR ( Biotec/Monash/ LSHTM) 2 Projects Liverpool STM/Liverpool Uni DHODH UTSW/UW Pyramax Paediatric Shin Poong/ University of iowa Eurartesim® Paediatric Sigma-Tau Orthologue Leads Sanofi Heterocycles Dundee Included in MMV portfolio post registration SP-AQ Guilin ASAQ Winthrop sanofi /DNDi Nauclea pobeguinii DRC/Antwerp Argemone mexicana Mali/Geneva MMV390048 (UCT) SJ557733 St Jude/Rutgers

20. Global Malaria Portfolio, 2Q 2014 Classified by therapeutic type ELQ300 Takeda (USF/ OHSU-VAMC) 21A092 (DrexelMed/UW) DSM265 NIH/Takeda P218 DHFR BIOTEC (Monash/ LSHTM) MMV048 UCT/TIA RKA182 LSTM/Liverpool NPC-1161-B Mississippi BCX4945 Biocryst/Albert Einstein College of Medicine SAR116242 Palumed AQ13 Immtech ACT840 Actelion DF02 Dilafo r CDRI 97-78 Ipca N-tert butyl isoquine LSTM/Liverpool/ GSK SJ733 St Jude (Rutgers/NIH) Artesunate Mefloquine CIPLA/DNDi Artesunate for injection Guilin Artemether- Lumefantrine Dispersible Novartis Pyronaridine- Artesunate Shin Poong Dihydroartemisin- Piperaquine Sigma-Tau Artesunate Amodiaquine Sanofi /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/FQ Sanofi KAE609 Novartis OZ439/PQP Sanofi KAF156 Novartis Tafenoquine GSK Pyronaridine- Artesunate Paediatric Shin Poong/Iowa DHA Piperaquine Paediatric Sigma-Tau Sulfadoxine Pyrimethamine + Amodiaquine Guilin SAR97276 Sanofi Fosmidomycin Piperaquine Jomaa Pharma GmbH Methylene Blue /AQ Heidelberg Rectal Artesunate CIPLA/Strides/TDR Artemisone UHKST Co-trimoxazole Bactrim Inst. of Trop. Med. Artemisinin Naphthoquine KPC Arterolane/PQP Ranbaxy 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 Laboratories 2 Brand name: Coartem® Dispersible, Generic by Ajanta 3 Brand name: Artesun® 4 Brand name: Eurartesim® 5 Brand name: Pyramax® 6 Brand names: Coarsucam TM, ASAQ/Winthrop®, generics by Ajanta, Ipca, Guilin, Cipla, Strides (co-blistered) 7 Also Acino/Mepha product (co-blistered) 8 Brand name: Synriam TM 9 Brand name: ARCO® 10 Brand name: ArTiMist TM 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 Research Lead optimisation Phase IIaPhase IIb/III Under review * Development Patient exploratory Patient confirmatory Phase IV Post Approval AccessTranslational Preclinical Human volunteers MMV121 (Dundee)

21. Number of Preclinical – Phase IV candidates 21 10 20 30 40 9 4 2 4 8 7 2 Current pipeline ACT’s Endoperoxide Severe Malaria Antibiotics P.vivaxMolecular Mechanisms Cell Based Mechanisms On hold Natural Products 3 0 39 ACT’s Endoperoxides Severe Malaria Antibiotics P. vivax Molecular Mechanisms Cell Based Mechanisms Natural Products On Hold

22. How do we prevent malaria? Vector insecticide resistance Parasite drug resistance Vector insecticide resistance

23. Prevention in pregnant women Lancet ID 2011; 11: 190

24. 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

25. Progress? ZanzibarEthiopiaFajara Kilifi Limpopo, SA Sao Tome & Principe Bioko I. Lancet ID 2010; 10: 545

26. Progress? Lancet 2008; 372: 1555 Lancet 2014 (in press)

27. What about a vaccine? Annu Rev Med 2011; 63: 345

28. Malaria vaccines? www.malariavaccine.org

29. What about a vaccine? NEJM 2011; 365: 1863 Plos Med 2014; 11: e1001685

30. Wall St J 7/24/2014

31. Drug resistance Antimalarial Drug Year Introduced First Reported Resistance Difference (years) Quinine16321910278 Mepacrine1935194510 Chloroquine1945195712 Proguanil194819491 Fansidar1967 0 Mefloquine197719825 Atovaquone1996 0 Artemisinin19802009?

32. Drug resistance NEJM 2009; 361: 455 NEJM 2014; 371: 411

33. Drug resistance Nature 2014; 505: 50 JID 2014 (in press)

34. Drug resistance JID 2014; 210: 335 www.wwarn.org

35. What’s next? Preventive measures Vector control New drugs – Combinations – Adjunctive Better diagnostics – Surveillance New vaccines – Antigens – Adjuvants Molecular pathogenesis

36. 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