Future

Fig. 3

(Adapted from the MMV-supported project's webpage [58])

Snapshot of the projects supported by MMV at different stages of the drug discovery and development pipeline.

Since its establishment in 1999, the Medicines for Malaria Venture has been front lining the discovery and development of new medicines for the treatment of malaria. The potential for these compounds to act as new antimalarials is judged by several requirements: novel modes of action with no cross-resistance to current drugs; single-dose cures (artesunate and chloroquine are unable to do this); activity against both the asexual blood stages that cause disease and the gametocytes responsible for transmission; compounds that prevent infection (chemoprotective agents); and compounds that clear P. vivax hypnozoites from the liver (anti-relapse agents) [59, 60]. MMV has been aiding the fight against malaria by partnering with universities and pharmaceutical companies around the world to bring new antimalarials to market (Fig. 3).

Besides the traditional drug discovery and development methods for the identification of new antimalarials that will be described below, there are a number of other ways in which a new anti-malarial drug may be discovered. One way, as previously mentioned, is through the exploration of new combinations and formulations of current anti-malarial drugs. This may help overcome issues with resistance to a particular component or may assist in the delivery of the drug allowing it to be more effective. Alternatively, existing drugs used for other purposes may be found efficacious against malaria and subsequently be repurposed as a new anti-malarial treatment. This can be advantageous since these compounds may have already shown good biological properties and may also reveal novel MoAs. Examples include those shown in Fig. 4.

Fig. 4

New anti-malarial compounds in development as a result of drug repurposing. Original indications for the drugs are shown in parentheses. Many of these repurposed drugs are already in Phase II trials as new potential antimalarials.

Methylene blue, a drug for the treatment of methaemoglobinaemia. Last completed Phase II trials in 2017 (NCT02851108) as a combination with primaquine. Fosmidomycin, an antibiotic. Most recently in Phase II trials in 2015 (NCT02198807) as a combination with piperaquine. Rosiglitazone, an antidiabetic drug. Currently in clinical trials as adjunctive therapy for severe malaria (NCT02694874). Imatinib, a cancer therapy drug. Currently in Phase II trials (NCT03697668) as a triple combination with dihydroartemisinin-piperaquine. Sevuparin, a drug for the treatment of sickle cell disease. Last in Phase I/II trials in 2014 (NCT01442168) as a combination with atovaquone-proguanil.

The following seven compounds were discovered and developed with the hope of progressing into clinical trials as potential new anti-malarial candidates (Fig. 5). However, over the past two years, progress in the development of these compounds has slowed, making the fate of these drug candidates less clear.

Fig. 5

New anti-malarial drug candidates that have reported no significant progress in the last 2 years. These compounds may have encountered issues during preclinical or early clinical studies.

The chiral 8-aminoquinoline derivative, NPC1161B was developed at the University of Mississippi and was still in preclinical studies in 2014 [61, 62, 63, 64]. MK4815 was developed in 2012 at Merck but is still in preclinical studies due to safety issues [65]. CDRI 97/78 is a fast-acting novel trioxane anti-malarial first synthesized in 2001 by a team at the Council of Scientific and Industrial Research in India [66]. Having passed all preclinical studies, it was last seen to have completed first-in-human Phase I trials in 2014 [67]. Developed at the Liverpool School of Tropical Medicine in 2009, N-tert butyl isoquine/GSK369796 was designed as an alternative to amodiaquine [68, 69]. It completed preclinical studies [70], and was last in Phase I trials in 2008 (NCT00675064). Artemisone is a second-generation semi-synthetic artemisinin derivative developed at the Hong Kong University of Science and Technology, that has previously been shown to be as efficacious as artesunate, with minimal neuro- and cytotoxicity and a comparably low cost of production [71]. It was withdrawn from Phase II/III trials in 2010 (NCT00936767). The bisthiazolium salt, SAR97276, was discovered and developed by Sanofi in 2005 [72], however, further investigation was terminated in 2012 after Phase II trials (NCT01445938). AQ-13 is a chloroquine derivative that was first described in 1946 [73]. While only differing to CQ in the amine side-chain, this difference has been linked to its increased efficacy against CQ-resistant strains [74]. It has a MoA and pharmacokinetic properties similar to that of CQ [75, 76]. AQ-13 last completed Phase II trial at the end of 2017 (NCT01614964) [77], however there has been no mention of any following active trials so the ongoing status of this compound is unclear.

The compounds in the remainder of this section are currently still actively being pursued. For ease of visualisation throughout in this section, a graphical summary of each compound structure and its code will be displayed, along with key physical and biological properties identified during the hit to lead campaigns (Additional file 2).