Invention and deployment of single dose cure and chemoprotective agent for malaria

At a glance

• Malaria kills 400,000 people annually
  
• DDU compound DDD107498 can treat malaria with a single dose costing less than $1
  
• DDD107498 won MMV’s Project of the Year 2014
  
• Merck KGaA licensed DDD107498, renamed M5717, as their flagship anti-malarial for clinical development
  
• M5717 is currently being tested in combination studies in human volunteers

Malaria is a debilitating parasitic disease posing a risk to nearly half the world’s population. The predominant malaria parasite, Plasmodium falciparum, has developed resistance to many drugs and new drugs are therefore urgently needed to effectively treat and eventually eradicate malaria. New anti-malarials must meet several requirements: (a) novel modes of action with no cross-resistance to current drugs; (b) single-dose treatments with activity against blood-stage disease; (c) activity against liver stages that can prevent disease development (chemoprotection or prophylaxis); (d) compounds active against the sexual stages (gametocytes) to prevent transmission of malaria.

In 2009 the Medicines for Malaria Venture (MMV) not-for-profit public-private R&D partnership partnered with DDU to identify new treatments for malaria by phenotypic screening of Dundee’s internal compound collection identifying a promising compound series. A subsequent DDU medicinal chemistry programme optimized properties of the compound series through iterative cycles of designing improvements, making the improved compounds, and biological testing of their potency and metabolic stability [1]. Further rounds of the design-make-test cycle improved their oral bioavailability, permeability, potency and selectivity. This remarkable chemical evolution transformed a series with suboptimal properties into a pre-clinical candidate with approximately 100-fold increase in potency and much improved chemical properties [2]. The final compound was active against drug-resistant parasites with no cross-resistance to current antimalarial drugs. It had remarkable potency, oral bioavailability and a long half-life in malaria mouse models across multiple life cycle stages; cured blood stream infection; had crucial transmission-blocking activity; and could even prevent infection in the first place [1, 2].

The DDU identified that the compound acted through inhibition of protein synthesis, with parasite translation elongation factor eEF2 as its target [2]. After treatment with DDD107498 and consequent inhibition of eEF2, the parasites cannot make essential proteins, and die. This discovery confirmed DDD107498’s completely novel mode of action, one that parasites will not have had a chance to develop resistance to, making it a very attractive prospect for further development. Crucially, it is effective against parasites resistant to current drugs at a dose within MMV’s goal of $1 per treatment, affordable in lower-income countries.

In 2014, MMV formally declared DDD107498 as a candidate for preclinical development [3]. The discovery won MMV’s Project of the Year 2014 [4].

This work, published in Nature in 2015, is highly cited and received significant media coverage [2].

Thanks to the attractive properties of DDD107498, MMV was able to successfully partner the compound with Merck KGaA where it was licensed their flagship anti-malarial for pre-clinical and clinical development and renamed M5717. The compound successfully completed human safety clinical trials (phase 1a) in 2018 and, remarkably, demonstrated single-dose cure in a human volunteer infection model of malaria. In malaria therapy it is important to have at least two drugs in the treatment, to protect against the emergence of resistance, and so M5717 is currently being tested in combination studies in human volunteers, with a view to testing the best combinations in 2022 in African patients.

This huge success in going from fundamental discovery science to a drug in successful clinical trial, highlights the unique on-going capability and impact of the DDU in translating world-class discovery research into new de-risked targets and candidate drugs.

This huge success in going from fundamental discovery science to a drug in successful clinical trial, highlights the unique on-going capability and impact of the DDU in translating world-class discovery research into new de-risked targets and candidate drugs.

1. Baragaña, B, Norcross, NR, Wilson, C, Porzelle, A, Hallyburton, I, Grimaldi, R, Osuna-Cabello, M, Norval, S, Riley, J, Stojanovski, L, Simeons, FRC, Wyatt, PG, Delves, MJ, Meister, S, Duffy, S, Avery, VM, Winzeler, EA, Sinden, RE, Wittlin, S, Frearson, JA, Gray, DW, Fairlamb, AH, Waterson, D, Campbell, SF, Willis, P, Read, KD & Gilbert, IH 2016, 'Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy' Journal of Medicinal Chemistry, vol. 59, no. 21, pp. 9672-9685. https://doi.org/10.1021/acs.jm...
   
2. Baragaña, B, Hallyburton, I, Lee, MCS, Norcross, NR, Grimaldi, R, Otto, TD, Proto, WR, Blagborough, AM, Meister, S, Wirjanata, G, Ruecker, A, Upton, LM, Abraham, TS, Almeida, MJ, Pradhan, A, Porzelle, A, Santos Martinez, M, Bolscher, JM, Woodland, A, Luksch, T, Norval, S, Zuccotto, F, Thomas, J, Simeons, F, Stojanovski, L, Osuna-Cabello, M, Brock, PM, Churcher, TS, Sala, KA, Zakutansky, SE, Belén Jiménez-Díaz, M, Maria Sanz, L, Riley, J, Basak, R, Campbell, M, Avery, VM, Sauerwein, RW, Dechering, KJ, Noviyanti, R, Campo, B, Frearson, JA, Angulo-Barturen, I, Ferrer-Bazaga, S, Javier Gamo, F, Wyatt, PG, Leroy, D, Siegl, P, Delves, MJ, Kyle, DE, Wittlin, S, Marfurt, J, Price, RN, Sinden, RE, Winzeler, EA, Charman, SA, Bebrevska, L, Gray, DW, Campbell, S, Fairlamb, AH, Willis, PA, Rayner, JC, Fidock, DA, Read, KD & Gilbert, IH 2015, 'A novel multiple-stage antimalarial agent that inhibits protein synthesis' Nature, vol. 522, no. 7556, pp. 315-320. https://doi.org/10.1038/nature...
   
3. E1. Press release: Medicines for Malaria Venture 2014, ‘Potential new antimalarial drug identified at the University of Dundee’ MMV.org. 6th February 2014. Available at https://bit.ly/3qeYoCQ
   
4. E2. Press release: Medicines for Malaria Venture 2015, ‘MMV Project of the Year award 2014 - DDD498’ MMV.org. 30th June 2015. Available at https://bit.ly/3q1ZpxS
   
5. Corroboratory testimonial from the Head of Merck Global Health Institute, Merck KGaA and similar interview from 2018. Medicines for Malaria Venture 2018 ‘M5717 (formerly DDD498)’ MMV.org. Available at https://bit.ly/3b5SQ96