Drugs in Development for Malaria

Abstract

The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.

Fig. 1

Schematic representation of intra-erythrocytic trophozoite showing sites of action of newer antimalarials. Agents in red are still in development

Fig. 2

Graph representing comparative parasite clearance rates after treatment with different antimalarial classes. Adapted from White NJ [150] with permission

Fig. 3

Developmental time-line of currently deployed ACTs versus leading compounds. Information sourced from [11, 31, 148, 149]. Single asterisk: Dihydroartemisinin–piperaquine (WHO pre-qualification refers to Eurartesim^® by sigma tau in 2015); approved by EMA in 2011. Double asterisk: Artemether–lumefantrine (WHO pre-qualification for Coartem^® by Novartis in 2004, products by Ipca and Cipla in 2009; others have followed since then). Triple asterisk: Artesunate–amodiaquine (WHO pre-qualification for Sanofi’s ASAQ Winthrop^® in 2008, Ipca and Guilin products in 2012, Ajanta in 2013 and Cipla in 2014)