Developing next-generation malaria medicines to address drug resistance and increase the operational feasibility of malaria elimination efforts

Aims: In 2015 the World Health Assembly endorsed the WHO Global Technical Strategy for Malaria 2016-20301, which aims to reduce global malaria incidence and mortality rates by 90%. While progress towards malaria reduction and elimination can be made using existing tools, there is general consensus the operational feasibility and impact of malaria elimination efforts will be enhanced by the availability of improved interventions, including drugs. Furthermore, new drugs are needed to address the increasing prevalence of drug resistant parasites. The Malaria Eradication Research Agenda (malERA) published a target profile for the 'ideal' malaria elimination/eradication drug2 – a Single Encounter Radical Cure and Prophylaxis (SERCaP) intervention capable of achieving rapid reduction in parasitemia, sterilizing the human host of all forms of the parasite, reducing/preventing onwards transmission and providing some degree of post-treatment protection against reinfection. The aim of this talk is to provide an update on the strategy and progress of the Medicines for Malaria Venture (MMV) and its partners in developing novel anti-malarial medicines that meet these requirements.

Methods: MMV's current efforts focus on delivering improved interventions for children and pregnant women, including chemo-prevention, drugs to address resistance and improved drugs for relapsing malaria, all ideally as single dose medicines. MMV works with a consortium of partners to screen chemical libraries, initially via high throughput screening (HTS) against whole parasites. Compounds that are confirmed as active in the HTS are then 'finger-printed' using a selection of assays covering the various lifecycle stages of the parasite3. PK/PD data obtained in a humanized SCID mouse model for P. falciparum are used within lead optimization to support the first human dose prediction required at preclinical candidate selection4. Clinical development of novel malaria agents now utilizes a controlled human infection model5 for blood stage Pf infection, allowing early assessment of PK/PD in humans, facilitating early portfolio de-risking and dose selection.

Results: To date more than 7 million compounds have been screened against whole parasites. Over 25,000 compounds with EC50< 1 uM have been identified. Importantly, many of these compounds are active against targets different from the currently approved anti-malaria medicines. To date, drug candidates covering six novel targets have been selected for development. Twenty-five compounds have been identified where no drug-resistance phenotypes could be generated. The most recent compound to enter Phase IIa studies is DSM265 a triazolopyrimidine-based highly selective inhibitor targeting Plasmodium's dihydroorotate dehydrogenase (DHODH). Data obtained from the HuSCID mouse model and the controlled human infection model for Pf malaria were used to estimate the MIC and efficacious dose for DSM265. Data obtained from the Phase IIa monotherapy study in malaria-infected patients showed strong concordance with predictions, with a single 400mg dose of DSM265 sterilizing the majority of patients of Pf infection out to 28 days follow-up.

Conclusion: MMV and its partners have bought forward a portfolio of novel antimalarial drugs focused on addressing key unmet medical needs, including compounds to address drug resistance and support malaria elimination efforts. Through these efforts, pathways to kill the parasite have more than doubled over the last 10 years, providing the potential to address drug resistant parasites. Early PK/PD assessment in the HuSCID mouse model, coupled with the use of the controlled human model for Pf blood-stage infection has identified potent compounds with rapid parasite clearance kinetics and long half lives, supporting their potential inclusion into future SERCaP regimens for malaria elimination.

References:

1. Global Technical Strategy for Malaria 2016-2030. World Health Organisation. 2015. http://apps.who.int/iris/bitstream/10665/176712/1/9789241564991_eng.pdf?ua=1&ua=1

2. The malERA Consultative Group on Drugs (2011) A Research Agenda for Malaria Eradication: Drugs. PLoS Med 8(1)

3. Delves M, et al. (2012) The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites. PLoS Med 9(2).

4. Diaz BJ-D, et al. Improved Murine Model of Malaria Using Plasmodium falciparum Competent Strains and Non-Myelodepleted NOD-scid IL2Rnull Mice Engrafted with Human Erythrocytes, Antimicrob. Agents and Chemother., 2009, 53(10), 4553-4536.

5. McCarthy JS, et al. (2011) A Pilot Randomised Trial of Induced Blood-Stage Plasmodium falciparum Infections in Healthy Volunteers for Testing Efficacy of New Antimalarial Drugs. PLoS ONE 6(8)