The good news on the antimalarial development front is that scientific and technological advances will allow for more rapid identification of effective therapy and new targets.
The sequencing of various Plasmodium genomes [36
] has accelerated target identification and expression analysis. Orthologues (genes that evolved from a common ancestral gene in different species that generally retain the same function) for targets of interest can be easily identified and small molecules against these targets tested in vivo
(animal models) or in vitro
. High throughput screening in vitro
can identify active molecules that can be further optimized for preclinical testing [38
]. The molecular-based search for targets is referred to as the “rational design approach.” This approach has not yet delivered a product, in part because the time from molecular target identification to clinic testing is great. One problem with this approach is that it favors identification of drugs with one rather than multiple targets, making these more likely to induce parasite resistance.
Others have advocated the “whole parasite screening” approach: molecules are selected from available chemical data, and hits (molecules) are identified through high throughput screening with whole parasites. Molecular targets are then established by generating mutant parasites that are resistant to the active or “hit” molecule. If a particular antimalarial has many targets, it has a lower chance of encountering resistant parasites. This method recently resulted in the identification of a new candidate antimalarial, the spiroindolone NITD609, by Rottman et al. [39
], which has been shown to be safe for testing in humans [40
Mass screening of chemical libraries has yielded a wealth of potential antimalarial compounds, and many are active at sub-micromolar concentrations with minimal toxicity to human cell lines. Screening assays in 1536-well formats exist for asexual blood stage P. falciparum
, and assays are under development for the dormant liver hypnozoite and transmission stages. In a screen of 2816 registered or approved compounds, 32 compounds were recently found to be active against 45 parasite lines sourced from around the world with IC50 values ≤ 1 µM, including 10 compounds not previously known to have anti-malarial activity. Genome-wide association and linkage analysis then identified compounds that had similar or distinct mechanisms of action, which might predict cross-resistance and therefore guide combination therapy [41
To manage such large quantities of data being generated by different groups, a centralized database of high throughput screening results to “facilitate assimilation, integration, and mining of data” has been started by the WHO, the United Nations, and the World Bank-sponsored Tropical Disease Research group. Also, public-private partnerships and non-profit organizations, such as Medicines for Malaria Venture, Drugs for Neglected Diseases Initiative (DNDi), and African Network for Drugs and Diagnostics Innovation (ANDI), have been developed with the idea of maximizing collaborations and developing new therapies [4
The current pipeline
Medicines for Malaria Venture, a non-profit group that supports scientists and companies to develop new antimalarials, highlights a number of compounds considered leads in optimization, as well as antimalarials in the pipeline (preclinical through Phase IV development) on their website, (http://www.mmv.org/research-development?gclid=CJPY--7e96oCFWUTNAod80I-Pg
). Many of these compounds are newly identified or novel in their application to antimalarial therapy.
The initial approach to tackling drug resistance was to develop drugs based on structures of existing antimalarials, and this has been a profitable endeavor. Antimalarials developed based on chloroquine include lumefantrine, piperaquine and pyronaridine developed in China, each of which are now components of artemisinin combination therapys in use or in advanced trial stages. In the United States, other chloroquine-like antimalarials include amodiaquine (also used in artemisinin combination therapy), mefloquine, and halofantrine, although the last of these is not widely used clinically today [4
]. Drugs with indirect or direct disruption of pyrimidine metabolism (e.g. pyrimethamine, sulfonamides, atovaquone) have inspired the development of new drugs targeting another aspect of the pyrimidine pathway: dihydroorotate dehydrogenase [42
]. Some of the lead candidates based on already successful antimalarials [40
] are highlighted below:
Pyronaridine, a chloroquine relative, is being used in combination with artesunate as a promising new artemisinin-based combination therapy. Pyronaridine-artesunate has been studied in Phase II and Phase III clinical trials, and has been shown to be effective against uncomplicated P. falciparum
and blood stage P. vivax
]. As increasingly chloroquine-resistant strains of P. vivax
emerge, and as the need to treat P. falciparum
and P. vivax
co-infection expands in certain areas, such a regimen is welcome. Pyronaridine-artesunate is available as Pyramax® tablets and pediatric granule formulations, and manufacture of this compound is being undertaken by Shin Poong Pharmaceuticals [40
Tafenoquine is a lead candidate drug aimed at a radical cure of P. vivax
(i.e. elimination of dormant stage hypnozoites), and is being studied in a Phase II/III tafenoquine/chloroquine combination study this year [40
]. A fixed dose artemisinin combination therapy, artesunate-amodiaquine (Coarsucam/ASAQ, Winthrop) has been approved by WHO and developed by Sanofi-Aventis and the DNDi, and is undergoing Phase IV field assessment [40
The endoperoxide feature of artemisinins, which confers antimalarial activity, is shared by ozonide OZ439, a synthetic endoperoxide. OZ439 carries the hope of providing a single dose oral cure in humans when used in combination. OZ439 is a rapidly acting agent against asexual stage parasites, and will likely be developed for use in combination with a partner drug with a longer half-life than its own. Studies are underway to identify such a partner. This drug is currently undergoing Phase IIa trials. [44
For all of these drugs, the caveats regarding antimalarial resistance and ease of dosing and administration remain. Pharmacokinetic trials in adults, once done, must be followed by appropriate pharmacokinetic studies in children, as it is well known that certain antimalarials (such as piperaquine and sulfadoxine-pyrimethamine) have differing pharmacokinetics in children compared with adults, which will modify their efficacy [45
]. Drug efficacy is also influenced by the degree of pre-existing antimalarial immunity, acquired as children get older and are exposed to malaria over and over again [46
]. Thus, drug efficacy must be evaluated in children and must take into account these additional factors.