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Innovative medicines for the control and elimination of malaria

Innovative medicines for the control and elimination of malaria. Defeating Malaria Together. Timothy N.C Wells, ScD Chief Scientific Officer. Malaria: Leading cause of child mortality. 655’000 deaths per year 216 million cases per year 86% in children under five Targets expectant mothers

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Innovative medicines for the control and elimination of malaria

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

  2. 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

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

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

  5. 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

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

  7. 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) 376 1647-57

  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 7:255-60 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.

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

  10. 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 PLoSMed. 2011 Jan 25;8(1) Target Product profiles: see www.mmv.org

  11. 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

  12. Ask the parasite: transforming discovery Chemistry: All available molecules HTS Whole parasite Hits to leads New candidate molecules for development • 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 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)

  13. Discovering, developing and delivering innovative medicines Research Translational Development Lead Gen Lead Opt Preclinical Phase I Phase IIa Phase IIb/III Registration Phase IV Novartis miniportfolio Novartis 2 Projects DSM265 (UTSW/UW/ Monash) GNF156 Novartis OZ439 (Monash/UNMC/ STI) Azithromycin chloroquine Pfizer Coartem®-D Novartis Actelion ACTXXX GSK miniportfolio GSK 2 Projects Aminoindole Broad/Genzyme NITD609 Novartis Tafenoquine GSK Pyramax Shin Poong/University of Iowa Broad/Genzyme miniportfolio sanofi 1 Projects MMV048 (University of Cape Town) Pyramax Paediatric Shin Poong/University of iowa Artesunate for injection Guilin New Chemical Entities Pfizer Screening Anitmalarials St Jude/Rutgers/USF P218 DHFR (Biotec/Monash/LSHTM) Eurartesim® Paediatric sigma tau Eurartesim® sigma tau sanofi Orthologue screen Antimalarials Dundee Pyrazoles (DrexelMED/UW) AstraZeneca Screening ELQ-300 (USF/OHSU-VAMC) DHODH UTSW/UW/ Monash ASAQ Winthrop sanofi /DNDi Kinases Monash Oxaboroles Anacor SP-AQ Guilin Other Projects 15 Projects 2019+ 2018+ 2017+ 2015+ Launch Probability 10% 20% 68% >90%

  14. New fast killers: the front-line of eradication KAE609 EC50 NF54 0.7nM ED90Pb 2.7mg/kg OZ439 EC50 NF54 1.3nM P. berghei oral 1x30mg/kg curative • 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

  15. New medicines for transmission blocking Asymptomatic Carrier study Village based Key compounds from blood stage HTS Membrane feeding in vitro Proof of concept (membrane feeding ex vivo) 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

  16. 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 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

  17. Finding new anti-relapse therapies for P vivax PoC Primate model, Human relapse Screen asexual stage P yoelii infected HepG2/liver cells (25k) P. cynomolgiinfected rhesus hepatocytes 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)

  18. Open Access: Empowering Research Available Now Further details malariabox@mmv.org

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

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

  21. Value through efficiency INNOVATION COMPETENCIES EFFICIENCY PRODUCTIVITY HEALTH IMPACT Leveraging donor funds Committed 2008-2013* $87 million (£53.7 million) $475 million 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 * Total funds received & committed as of March 2013

  22. Value through efficiency INNOVATION COMPETENCIES EFFICIENCY PRODUCTIVITY HEALTH IMPACT Leveraging donor funds Pharma’s ‘in-kind’ support Total £2.50 MMV £1.00 Pharma ‘in-kind’ £1.50

  23. Better medicines for more people at affordable prices UK 23 pence* to cure one child * 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)

  24. Thank you

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