THE ARTEMISININ ENTERPRISE - GHDonline

More documents

Recommendations

Info

For more information on the Semisynthetic Artemisinin Project, visit: http://www.artemisininproject.org/ or http://www.oneworldhealth.org 3.3 MMV ‐ Synthetic Peroxides: A Viable Alternative to Artemisinin Background Artemisinin‐based Combination Therapies (ACT) form the mainstay in treatments for malaria. Within such combination products there is a heavy reliance on the artemisinin component due to its ability to act rapidly and show high efficacy against both P. falciparum and P. vivax. However, artemisinin derivatives are rapidly cleared and so they are used in combination with a longer‐acting partner drug. Despite the successes of artemisinin there are issues of natural sourcing, supply and cost. Furthermore, were resistance to develop it would challenge the whole position of ACTs in frontline therapy. 16
Synthetic peroxides The first synthetic peroxide project or OZ (an abbreviation of ozonide, which is the peroxide functional group and antimalarial ʺwarheadʺ within the structures) was begun on the premise that a new class of peroxides could be identified that would show greater potency in reducing parasite burden than the best artemisinin derivatives, such that a 3‐day treatment, in combination, could be realised. In addition, due to its being fully synthetic via a simple synthesis, the drug would be available at low cost and without potential supply issues. The fruit of the first project was OZ277 or RBx11160 (Figure 1, ozonide ʺwarheadʺ highlighted with a box). O O O N H N H 2 O Figure 1. OZ-277 or RBx11160 The second generation OZ project extended these goals to include also the provision in combination of a single‐dose oral cure for patients with uncomplicated P. falciparum malaria (and possibly P. vivax) and the potential for prophylactic treatment and intermittent preventative treatment in pregnant women and infants (IPTp and IPTi). RBx11160 itself was shown to be more active than chloroquine, mefloquine, and artemisinin derivatives against P. falciparum in vitro, and P. berghei in mice. It had good physicochemical and pharmacokinetic profile in rats and dogs, though with a short half‐life. The safety profile in rats, dogs and humans was excellent and pharmacokinetic studies in healthy volunteers were reproducible with excellent exposure at doses of 100mg or above. However, the pharmacokinetic studies in malaria patients demonstrated a significant reduction in the drug plasma concentration which was pinned down to greater clearance due to reduced stability in parasite‐infected whole blood. It was postulated that Fe(II)‐mediated cleavage was likely to be a significant contributor to the in vivo clearance of RBx11160 and thus increasing the stability in infected blood became the medicinal chemistry focus of the second generation OZ project. The follow‐up to RBx11160, Next Generation OZ, is significantly more stable in whole blood in vitro (both healthy and infected blood ‐ see Figure 2) than its predecessor and this increased stability contributes to better exposure, a longer half‐life and increased biological activity. 17
Page 1 and 2: THE ARTEMISININ ENTERPRISE REPORT o
Page 3 and 4: 1. Executive Summary The World Mala
Page 5 and 6: An effective, joined‐up communica
Page 7 and 8: artemisinin from plant material by
Page 9 and 10: 3. The Artemisinin Enterprise Partn
Page 11 and 12: Useful genetic diversity does not a
Page 13 and 14: Benefits of new high‐yielding var
Page 15: Partnership has been a key componen
Page 19 and 20: 4. The malaria context Burden of ma
Page 21 and 22: Global targets and tools The Global
Page 23 and 24: The development of Artemisinin Comb
Page 25 and 26: Currently, some seed selection for
Page 27 and 28: ACT and artemisinin market size ‐
Page 29 and 30: Demand versus purchase orders for A
Page 31 and 32: 5. The contributions of the AE tech
Page 33 and 34: Project delivery timelines The timi
Page 35 and 36: 6. Conference recommendations to th
Page 37 and 38: Assess the impact of new variety de
Page 39 and 40: the use of counterfeit drugs, monot
Page 41 and 42: Session 1: Opening and keynote lect
Page 43 and 44: Day 3 October 10 Session 5: Breakou
Page 45 and 46: Philippe Farabolini sanofi‐aventi
Page 47 and 48: Annex 3. Abbreviations Active Pharm

THE ARTEMISININ ENTERPRISE - GHDonline

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?