Introduction and Background of the Project

Malaria is a disease caused by the Plasmodium parasite, the most deadly of which is Plasmodium falciparum (P. falciparum). Artemisinin is an antimalarial drug identified through the work of Professor Youvou Tu working in China, for which she received the Nobel Prize for Medicine in 2015. Artemisinin based drug combinations are currently recommended as first-line treatments of P. falciparum malaria based on their ability to rapidly reduce parasite numbers.¹ However there are problems with the first generation of these drugs.  They are semi-synthetic, remain in the body for only a short period of time, are poorly absorbed through the stomach and most importantly resistance to these drugs has been identified along the Thai-Cambodian border and is spreading rapidly from this region.² Artemisinin’s anti-malarial activity is due to it containing an endoperoxide group. In the light of these observations there is an urgent need to develop alternative endoperoxide based therapies that can address the shortcomings of current artemisinin based combinations.

Malaria remains a major global health problem that the world wide community wishes to eradicate. To meet these demands the Medicines for Malaria Venture (MMV) (with key opinion leaders) have developed a series of Target Product Profiles (TPP) for these new drugs.³ Central to these plans is the availability of rapidly acting drugs that can be incorporated into a combination product that can deliver Single Exposure Radical Cure and Prophylaxis (SERCAP). In essence they are looking for a combination of drugs that will cure malaria in a single dose.

The loss of the semi-synthetic artemisinins due to resistance and poor drug like properties is a threat to SERCAP. Although there are other fast acting compounds currently under development, new fully synthetic peroxides with improved exposure profiles would be very valuable additions to the armamentarium. It is essential that we have options that could address issues around potential resistance and the need to generate new drug combinations with a range of pharmacological and chemical characteristics going forward.

How can your partnership (project) address global health challenges?

The eradication of malaria is now an accepted global target.⁹ Historical data suggests that effective malaria elimination and control needs highly effective drugs that are available to all populations that need them combined with effective vector control (insecticide treated bed nets, indoor residual spraying of insecticides etc.). It is accepted that current tools are inadequate to meet the demands of the eradication agenda and efforts are in place to address these shortfalls, in the case of drugs these efforts are aligned with MMV's current TPPs. The greatest threat to the current malaria chemotherapy strategy is the emergence of artemisinin resistance. This has already compromised the long term utility of all current artemisinin based combination therapies.¹⁰  Loss of the only registered drug class that offers this rapid rate of parasite clearance will significantly impact on the eradication effort. E209 is not affected by artemisinin resistance and has a safety/ pharmacology profile that suggests it could replace current artemisinins and offer an alternative to the ozonides and ATPase4 inhibitors. Given the existing experience with peroxide based drugs in human use, their utility against all species of human malaria and the normal attrition rates in drug discovery, Liverpool and Eisai are committed to progressing E209 to the first into human transition as a credible alternative fast acting antimalarial for onward development.

What sort of innovation are you bringing in your project?

The global community is committed to the eradication of malaria, a disease that currently kills in excess of 0.5 million people each year.  This will require careful deployment of a range of tools including new drugs. MMV has carried out a careful analysis of the types of drugs that will be required to meet this challenge and have defined Target Product Profiles (TPPs) and associated Target Candidate Profiles (TCPs) in order to coordinate global efforts. TCP1 defines a rapidly acting molecule that can meet the needs of a TPP1 drug combination as exemplified by the artemisinins. Artemisinin resistance, and the need for a pharmacokinetic profile suitable for Single Exposure Radical Cure and Prophylaxis (SERCAP), means that we need new drugs with fast Parasite Reduction ratio’s (PRRs). Although there are molecules in development including OZ439, a synthetic ozonide, and the Pf ATP4 inhibitors, that might meet these requirements, there remains the need for alternatives and back-up molecules that can enhance the robustness of the discovery pipeline and provide options for clinical development and eventual deployment. A lack of genuine alternatives will compromise the eradication effort. Liverpool and Eisai believe that E209 has the potential to become the next generation TCP1 drug, competing with the ozonides and ATPase4 inhibitors.

Role and Responsibility of Each Partner

Eisai will provide toxicology expertise to the project and advice on safety studies related to candidate selection.  Eisai’s formulation team is providing data and advice on salt screening of the lead candidate molecule and other aspects of formulation. Eisai chemists are investigating synthetic routes to allow large scale production of the lead candidate molecule.

LSTM is the designated development partner for the project as a whole. LSTM has a wealth of experience running similar programs developing anti-malarial drugs in collaboration with academic and industrial partners. In the role as designated development partner, LSTM will liaise with all partners on project activities, MMV, and the GHIT Fund.

The University of Liverpool is involved in a number of medicinal chemistry activities, working in collaboration with Eisai on scale-up chemistry, salt screening and formulation, solubility and stability of the lead candidate molecule.

Others (including references if necessary)

1. P. M. O'Neill, G. H. Posner, J. Med. Chem. 2004, 47, 2945.

2. A. M. Dondorp, F. Nosten, N. J. White, New. Engl. J. Med. 2009, 361, 1808.

3. J.N. Burrows, R.H. van Huijsduijnen, J.J. Mohrle, C. Oeuvray et al., Malaria Journal, 2013, 12, 187.

4. Amewu, R.; Stachulski, A. V.; Ward, S. A.; Berry, N. G.; Bray, P. G.; Davies, J.; Labat, G.; Vivas, L.; O’Neill, P. M. Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; synthetic antimalarials with superior activity to artemisinin. Organic & Biomolecular Chemistry, 2006, 4, 4431-4436

5. O’Neill, P. M.; Amewu, R. K.; Nixon, G. L.; ElGarah, F. B.; Mungthin, M.; Chadwick, J.; Shone, A. E.; Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K. S.; Ward, S. A. Identification of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate (RKA 182) with Superior Properties to the Semisynthetic Artemisinins. Angewandte Chemie-International Edition, 2010, 49, 5693-5697

6. Marti, F.; Chadwick, J.; Amewu, R. K.; Burrell-Saward, H.; Srivastava, A.; Ward, S. A.; Sharma, R.; Berry, N.; O'Neill, P. M. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities. Medchemcomm., 2011, 2, 661-665

7. Richard Amewu; O'Neill, Paul Michael; Stachulski, Andrew; Ellis, Gemma; Ward, Stephen Andrew Preparation of dispiro-tetraoxane compounds for the treatment of malaria and/or cancer. 2008, WO 2008038030 A2.

8. Amewu Richard; Marti Francecs; Ward Stephen Andrew; O'Neill Paul. Preparation of dispirocyclohexanyl tetraoxanylcycloalkylphenol derivatives and analogs for use as antimalarials. 2010, WO2010109172 (A1). 

9. http://www.mmv.org/research-development 

10. http://www.who.int/malaria/media/artemisinin_resistance_qa/en/