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New medicines to drive the control and eradication of malaria

New medicines to drive the control and eradication of malaria. Defeating Malaria Together. Timothy Wells CSO Medicines for Malaria Venture APPMG December 11 th 2013. MMV Portfolio: October 2013. Research. Translational. Development. APM. Human volunteers. Patient exploratory.

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New medicines to drive the control and eradication of malaria

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  1. New medicines to drive the control and eradication of malaria Defeating Malaria Together Timothy Wells CSO Medicines for Malaria Venture APPMG December 11th 2013

  2. MMV Portfolio: October 2013 Research Translational Development APM Human volunteers Patient exploratory Patient confirmatory In registration Approved* Lead optimisation Preclinical Oxaboroles Anacor 1 Project Novartis P218 DHFR (Biotec/Monash/LSHTM) DSM265 (UTSW/UW/ Monash) OZ439 (Monash/UNMC/ STI) Tafenoquine GSK Rectal Artesunate MMV / WHO-TDR Artemether Lumefantrine Novartis 1 DHODH UTSW/UW/Monash 4 Projects GSK ELQ-300 (USF/ OHSU-VAMC) KAE609 Novartis DHA-PQP Pediatric Sigma-Tau 4 Sulfadoxine Pyrimethamine + Amodiaquine Guilin A-L Dispersible Novartis 2 Pyrazoles DrexelMed/UW Orthologue Leads Sanofi 21A092 (DrexelMed/UW) KAF156 Novartis Pyronaridine AS Pediatric Shin Poong 5 Artesunate for injection Guilin 3 Heterocycles Dundee Whole cell leads AstraZeneca MMV390048 (UCT) 1 Dihydroartemisinin Piperaquine (DHA-PQP) Sigma-Tau 4 2 Projects Liverpool STM/Liverpool Uni SJ557733 St Jude/Rutgers Pyronaridine-ArtesunateShin Poong 5 Aminopyridines UCT Artesunate Amodiaquine Sanofi /DNDi 6 Artesunate Mefloquine Cipla/DNDi 7 1 Brand Coartem®, Generics Ajanta, Cipla, Ipca, Strides 2 Brand Coartem® Dispersible. Generic by Ajanta 3 Brand Artesun® 4 Brand Eurartesim® 5 Brand Pyramax® 6 Brand CoarsucamTM, ASAQ/Winthrop® 7 Also, Acino/Mepha product (co-blistered). First approval by regulatory bodies who are ICH members or observers or WHO Prequalification Included in MMV portfolio post registration *

  3. MMV Portfolio: October 2013 Research Translational Development APM Human volunteers Patient exploratory Patient confirmatory In registration Approved* Lead optimisation Preclinical Oxaboroles Anacor 1 Project Novartis P218 DHFR (Biotec/Monash/LSHTM) DSM265 (UTSW/UW/ Monash) OZ439 (Monash/UNMC/ STI) Tafenoquine GSK Rectal Artesunate MMV / WHO-TDR Artemether Lumefantrine Novartis 1 DHODH UTSW/UW/Monash 4 Projects GSK ELQ-300 (USF/ OHSU-VAMC) KAE609 Novartis DHA-PQP Pediatric Sigma-Tau 4 Sulfadoxine Pyrimethamine + Amodiaquine Guilin A-L Dispersible Novartis 2 Pyrazoles DrexelMed/UW Orthologue Leads Sanofi 21A092 (DrexelMed/UW) KAF156 Novartis Pyronaridine AS Pediatric Shin Poong 5 Artesunate for injection Guilin 3 Heterocycles Dundee Whole cell leads AstraZeneca MMV390048 (UCT) 1 Dihydroartemisinin Piperaquine (DHA-PQP) Sigma-Tau 4 2 Projects Liverpool STM/Liverpool Uni SJ557733 St Jude/Rutgers Pyronaridine-ArtesunateShin Poong 5 Aminopyridines UCT Artesunate Amodiaquine Sanofi /DNDi 6 Artesunate Mefloquine Cipla/DNDi 7 New presentations of existing molecules New chemical entities since 2007

  4. MMV Portfolio: October 2013 Research Translational Development APM Human volunteers Patient exploratory Patient confirmatory In registration Approved* Lead optimisation Preclinical Oxaboroles Anacor 1 Project Novartis P218 DHFR (Biotec/Monash/LSHTM) DSM265 (UTSW/UW/ Monash) OZ439 (Monash/UNMC/ STI) Tafenoquine GSK Rectal Artesunate MMV / WHO-TDR Artemether Lumefantrine Novartis 1 DHODH UTSW/UW/Monash 4 Projects GSK ELQ-300 (USF/ OHSU-VAMC) KAE609 Novartis DHA-PQP Pediatric Sigma-Tau 4 Sulfadoxine Pyrimethamine + Amodiaquine Guilin A-L Dispersible Novartis 2 Pyrazoles DrexelMed/UW Orthologue Leads Sanofi 21A092 (DrexelMed/UW) KAF156 Novartis Pyronaridine AS Pediatric Shin Poong 5 Artesunate for injection Guilin 3 Heterocycles Dundee Whole cell leads AstraZeneca MMV390048 (UCT) 1 Dihydroartemisinin Piperaquine (DHA-PQP) Sigma-Tau 4 2 Projects Liverpool STM/Liverpool Uni SJ557733 St Jude/Rutgers Pyronaridine-ArtesunateShin Poong 5 Aminopyridines UCT Artesunate Amodiaquine Sanofi /DNDi 6 Artesunate Mefloquine Cipla/DNDi 7 2022+ 2020+ 2018 2016 Launch Probability 10% 20% 68% >90%

  5. MMV Portfolio: October 2008 Research Translational Development APM Human volunteers Patient exploratory Patient confirmatory In registration Approved* Lead optimisation Preclinical DHFR BIOTEC/Monash/ LSHTM OZ 439 Monash/UNMC/STI Tafenoquine GSK Artesunate Injection WRAIR Artemether Lumefantrine Novartis DHA-PQP Sigma-Tau DHODH UTSW/UW/Monash MK 4815 (Merck) Artimisone UHKST Isoquine LSTH/GSK Pyronaridine AS Shin Poong GSK Pyridones 2 compounds (+) Mefloquine Treague 1 Novartis 2 compounds 2017+ 2015+ 2013 2011 Launch Probability 10% 20% 68% >90%

  6. Every second a child’s life is transformed • Coartem-D: Collaboration with Novartis • Taste masked, sweet cherry flavour, dispersible • Twice a day for three days • Approved in 2009; 200 000 000 treatments delivered • Ongoing study of activity in under 5kg patients

  7. Critical Success FactorMultiplechild-friendly treatment options ftreatment is critical • DHA-piperaquine • Collaboration with Sigma- Tau (Italy) • Approved EMA (2011) • Approved in Cambodia, Ghana, Burkina Faso, Tanzania, Mozambique • Superior post-treatment prophylaxis • Pyronaridine-artesunate • Collaboration with Shin- Poong (Korea) • Approved EMA article 58 (2012), and Korea • WHO prequalified: targeting the Mekong • Repeat use study for submission 2014

  8. Multiple ACTs: providing options 65% 35%

  9. Emerging multidrug resistant malaria strains in Western Cambodia

  10. Medicines can be used against malaria to treat … and to protect Protection

  11. Sulfadoxine-pyramethamine plus amodiaquine Once per month; cost <50¢ per year 82% reduction of infection; 57% less all-cause mortality Manufacturing and Product Access collaboration with Guilin (China) to support prequalification One million treatments in first year (2013) 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. Cairns M. et al SMC symposium ASTMH (2011) Protecting small children:Seasonal Malarial ChemoprotectionCost-effective protection of children Draft

  12. Artesunate: Providing options in severe malaria • Artesunate for injection: WHO prequalified 2010 • Mortality reduction: 10.9% to 8.5% • Approximately $1 per vial; 12 million vials 2012-3 • Managing pharmacovigilance of late onset hemolysis • Next step: artesunate suppositories for pre-referral treatment (UNITAID, WHO-TDR, WHO-prequalification) 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) 376 1647-57

  13. New medicines for Malaria Eradication Replacing three days ACT and 14 days primaquine with a simpler therapy Overcoming concerns about resistance Post treatment Protection Fast killing Radical cure Transmission blocking SERCaP single exposure radical cure and prophylaxis Alonso P et al.,(2011) A research agenda for malaria eradication: drugs PLoS Med. Jan 25;8

  14. Strong portfolio of single dose killers:A new medicine needs two

  15. New compounds to stop Plasmodium vivaxrelapse • Not benign: high fevers, relapsing, sometimes fatal • Relapses – infection without a mosquito bite • Current treatment primaquine: needs 14 days and G6PD- risk • Tafenoquine in phase II Safety and Efficacy • Single dose cure mixed P. falcip. P. vivax Deaths from malaria Anaemia RDS Coma Multiple Primaquine Tjitra E, PLoS Med. 2008 Jun 17;5(6):e128. Chen, L. H. et al. JAMA 2007;297:2251-2263 Tafenoquine

  16. Single Dose TafenoquineRelapse-free Efficacy at 6 months 91.9% (p<0.0001) 89.2% (p<0.0001) 77.3% (p=0.0004) 54.1% (p=0.16) 57.7% 37.5%

  17. Transforming drug discoveryEngineered phenotypic screens Chemistry: All available molecules HTS Whole parasite Hits to leads New candidate molecules for development • New business model • Screened five million compounds: 25’000 hits (1 uM) • Fast: screen to human trials in less than four years • Seven molecules already in clinical or preclinical • Identifies previously overlooked new targets Identify resistance Rottman M., et al, Science 325 1175-1180 (2010) Meister S., et al Science 334 1372-1377 (2011) Gamo FJ, et al., Nature 465 (7296): 305–310 (2010) Guiguemde WA, et al., Nature 465, 311–315 (2010) Wells TNC Science 329 1153-1154 (2010)

  18. MMV collaborateswith a majority of pharma and biotechcompanies 1 Exact definitions variable – usually confirmed hit is non-cytotoxic and has IC50 < 2mM 2Compounds selected inhibited human targets that have orthologues in Plasmodium Building a Bayesian model to predict actives from theoretical diversity

  19. Open Access:Empowering neglected disease drug discovery • From 20’000 hits to 400 reference compounds • Open access: supplied to over 150 groups • 40% malaria • 60% other diseases • PK and metabolism data • Stringent quality controls malariabox@mmv.org

  20. Malaria Box: transforming open access drug dsicovery in disease endemic countries 23 www.mmv.org/malariabox

  21. MMV partners with a global network of study sites O O O O O O O O O O O * relapse prevention Oproof of concept patients transmission blocking Ovolunteers fielddemonstration fast clearance, long duration volunteers Opatients chemoprotection Ovolunteers *

  22. EnhancingCapacity in Pailin, Cambodia (2007)Testingmedicineswhereresistanceishighest

  23. Enhancingcapacity in Bagamoyo, TanzaniaCardiology, challenge models, transmission

  24. The future: KollaDiba, Gondar, EthiopiaPreparing for P vivaxtesting in Africa

  25. PDPs REDUCE DISEASE AND SUFFERINGby focusing international health R&D efforts and funding on the development of EFFECTIVE AND AFFORDABLE NEW PRODUCTS for those diseases that primarily affect developing country populations. REDUCE DISEASE AND SUFFERING EFFECTIVE | AFFORDABLE | IMPACTFUL MEDICINES EFFECTIVE AFFORDABLE

  26. EFFECTIVE|AFFORDABLE |IMPACTFUL MEDICINES

  27. COARTEM DISPERSIBLE ARTESUN INJECTED EURATESIM PYRAMAX 4 medicines registered from 2009-2013

  28. 94-99% efficacy* for 3 ACTs developed with MMV COARTEM DISPERSIBLE ARTESUN INJECTED EURARTESIM PYRAMAX 4 medicines registered from 2009-2013 * PCR-adjusted; day 28

  29. 22-33%greater survival with injected artesunatevs. iv quinine COARTEM DISPERSIBLE ARTESUN INJECTED EURARTESIM PYRAMAX 4 medicines registered from 2009-2013

  30. Eurartesim-dispersible Pyramax-granules Tafenoquine OZ439 KAE609 KAF156 DSM265 7 new medicines in clinical development

  31. 1x CHILDREN & PREGNANT WOMEN SINGLE DOSE CURES PREVENTION OF RELAPSE TRANSMISSION BLOCKING CHEMO PREVENTION Addressing unmet medical needs

  32. 25 new chemical entities in pre-clinical development & hit-to-lead / lead optimization

  33. 12 WITH ACADEMIA 25 new chemical entities in pre-clinical development & hit-to-lead / lead optimization

  34. 13 WITH PHARMA 25 new chemical entities in pre-clinical development & hit-to-lead / lead optimization

  35. Providing researchers with 400 anti-malaria compounds to further R&D in other NTDs

  36. 3 chemical series Providing researchers with 400 anti-malaria compounds to further R&D in other NTDs

  37. 2 tropical diseases Sleeping sickness Leishmaniasis Providing researchers with 400 anti-malaria compounds to further R&D in other NTDs

  38. EFFECTIVE |AFFORDABLE|IMPACTFUL MEDICINES

  39. PHARM A PHARMA ‘IN-KIND’ ‘IN-KIN D ’ T O T AL TOTAL MMV MMV = + + = $1.00 $1.00 $1.50 $2.50 $1.50 $2.50 Leveraging donor funds Leveraging donor funds

  40. Before GLP preclinical GLP preclinical Phase I Phase II Phase III Launched Active 34 5 1 4 2 4 42 9 4 3 2 Terminated Focusing resources through early project prioritisation

  41. INDUSTRY $180 MILLIONS Industry estimates for clinical development of an anti-infective (Tufts) 70% REDUCTION MMV $54 MILLIONS* Total clinical development costs for pyronaridine-artesunate Reducing costs in clinical development * Includes direct internal project costs, CRO costs and MMV management & administration costs.

  42. INITIAL COST PROPOSAL Reducing partner & vendor costs e.g. non-clinical toxicology study

  43. INITIAL COST PROPOSAL 73% REDUCTION CRO BID Reducing partner & vendor costs e.g. non-clinical toxicology study

  44. INITIAL COST PROPOSAL 50% OF CRO BID 13% OF INITIAL PROPOSAL CRO BID MMV SHARE Reducing partner & vendor costs e.g. non-clinical toxicology study

  45. >$800 CURRENT COST API $400 IMPROVED SYNTHESIS 1KG MEFLOQUINE Cutting production costs by improving routes of synthesis

  46. ACT AFTER NEGOTIATION WITH MMV 40% REDUCTION + Obligation to launch in malaria-endemic countries + Price targets & cost audits Negotiating affordable pricing

  47. INJECTABLE ARTESUNATE 92% REDUCTION Ensuring competitive pricing by qualifying generic producers

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