Malaria: New Medicines for its Control and Eradication

1.1 Introduction

Malaria is caused by protozoan parasites of the genus Plasmodium that infect and destroy red blood cells, leading to fever, severe anaemia and, if untreated, cerebral malaria and death. Plasmodium falciparum is the dominant species in sub-Saharan Africa, and is responsible for almost one million deaths each year. The disease burden is heaviest in sub-Saharan African children under 3 years old (who have frequent attacks and little immunological protection), and also in expectant mothers. Malaria is both a cause and a consequence of poverty: in countries with intense malaria transmission, the economic impact of the disease results in a slowing of economic growth of 1.3% per year, translating to a reduction of the Gross Domestic Product in sub-Saharan Africa estimated to be US$12 billion per year.

The global fight to control malaria requires a multifaceted approach. At present, we have a wide range of effective tools. Medicines can be used to prevent as well as to cure, especially in vulnerable populations such as infants or pregnant women. Insecticides and larvicide spraying and the use of insecticide-impregnated bed nets to protect against infection by mosquitoes have dramatically increased in recent years. This success brings with it the need for the development of the next generation of insecticides, since resistance to the current gold standard, the pyrethroids, is already an issue. Developing a vaccine is proving especially challenging, as the parasite has sophisticated mechanisms for avoiding the host immune system. The best candidate currently is GSK 257049, known as RTS,S/AS202, where phase III trials are expected to finish in July 2013. Phase II studies suggest that it will reduce risk of clinical malaria, and decrease mortality in severe malaria by 50%.

In November 2007, the Bill and Melinda Gates Foundation set an agenda with the final goal of completely eradicating malaria, an objective supported by both the World Health Organization (WHO) and its Roll Back Malaria (RBM) partnership. Commentators have described this objective as 'worthy, challenging, and just possible', but one which must be pursued with balance, humility, and rigorous analysis.

The addition of this new goal has implications for the global malaria R&D agenda, which have been discussed in a variety of different working groups. Future antimalarial medicines must not only be able to treat the asexual blood stages of P. falciparum, but also to block the transmission of the parasite to other persons via the mosquito vector and, in the case of P. vivax infection, to target the dormant liver-stage of the parasite. In this chapter, we discuss the current pipeline of antimalarial medicines, and the target product profiles for the generation of such products.

1.2 The Challenges of the Different Plasmodium Species

Four main species of the malaria parasite infect humans. P. falciparum is responsible for the vast majority of the malaria-linked deaths in sub-Saharan Africa and is therefore the most important target. P. vivax constitutes as much as 25–40% of the global malaria burden, particularly in South and Southeast Asia, and Central and South America. It does not normally progress to cerebral malaria, and has been traditionally labelled benign. However, P. vivax causes a greater host inflammatory response than P. falciparum at equivalent parasitaemia. Mortality from P. vivax is most likely underreported, as recent analyses in Papua (Indonesia), have shown similar mortality figures in children to those found with P. falciparum.

Medicines that are active on the asexual erythrocyte stages of P. falciparum, such as the artemisinin-based combination therapies (ACTs), are assumed to be fully active against the other species. The formal clinical database supporting this assumption is relatively thin but is well supported by empirical observation. Historically, mixed infections of P. falciparum and P. vivax are rarely reported, possibly because P. falciparum suppresses the development of P. vivax, but PCR detection methods have shown that these can be as high as 30%.14 The other two species are P. malariae and P. ovale. Currently, these are diagnosed by microscopy, and represent a small percentage of infections. Diagnosis based on Polymerase Chain Reaction (PCR) will undoubtedly lead to a re-evaluation of the presence of mixed infections, since it is able to quantify low parasite numbers, and is often more definitive as a diagnostic.

From a treatment and eradication perspective, there are 3 key differences between the species. The first difference occurs in the liver. Following infection of the patient, parasites rapidly progress to infect hepatocytes, undergo asexual schizogony, and release large numbers of merozoites into the host bloodstream. In P. vivax and P. ovale, some of the liver parasites become dormant (a form known as the hypnozoite). These forms can be reactivated after periods that vary from 3 weeks to several years, dependent on the strain of parasite and the status of the host. Unless the hypnozoites are eliminated, malaria will continue to relapse periodically. Since P. vivax transmission is rarely intense, activation of hypnozoites is thought to be a major contributor to disease frequency.

The second difference between the species is in the time taken for the parasite to replicate in the host. The time between febrile paroxysms varies from around 48 hours for P. falciparum and P. vivax to 72 hours for the more benign P. malariae. There has been a recent interest...