New developments in anti-malarial target candidate and product profiles

Abstract

A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

Keywords: Elimination drug discovery; Eradication drug discovery; Malaria; Medicines; Plasmodium; Target candidate profile; Target product profile.

Fig. 1

The role of current and new medicines in driving the reduction of malaria to zero and maintaining elimination in countries ([3, 175] and ‘malERA Refresh’, manuscript submitted). Given that even the most advanced new blood schizonticides will not be approved into policy until the 2020s, much of the initial phase of reduction will be carried out using current medicines, continually optimized for deployment. Transmission blocking will be achieved by the use of insecticides and other vector control methods. As resistance develops there will be a need for new classes of medicines, ideally capable of shortening the treatment course and simplifying therapy (labelled here as SERC, but also including two- or even 3-day regimens). For countries in pre-elimination and elimination, new classes of chemoprotectants will be needed, and this need will arguably increase as the number of countries in pre-elimination increases

Fig. 2

Inter-relationships between the two high-level target product profiles (center) with the individual target candidate profiles (left) for molecules that are part of the product. The uses for each product are summarized on the right

Fig. 3

Probability (P) of delivering two or more new medicines after evaluating n candidate molecules, each with a probability of success (s) of 8 or 16%. The red line indicates an overall delivery success of 90%, with minimal n-values indicated for each curve