Malaria Medicines: a Glass Half Full?
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REVIEWS Malaria medicines: a glass half full? Timothy N. C. Wells1, Rob Hooft van Huijsduijnen1 and Wesley C. Van Voorhis1,2 Abstract | Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compound or product profiles, to assess progress and gaps, and to recommend priorities. Chemotypes Malaria is a human tragedy: by one estimate it may commercial incentives for new malaria medicines has 1 Families of molecules with have killed half of all the people who ever lived and a silver lining: it has created a niche in which academia similar chemical structures that currently claims the lives of hundreds of thousands of and industry can continue to work together to pioneer share biological or therapeutic young children every year2. Stark as the numbers are, new models of collaboration and openness. effects. Many distinct these figures understate the loss of developmental poten- The announcement of the United Nations’ Millennium chemotypes may have the 19,20 same biological activity. tial for malaria-endemic countries, the impact on their Development Goals highlighted the eradication health-care systems and on their economic growth3,4. of malaria as a key target. The goal outlined in this Chemoprotection However, the past decade has seen a renaissance in the announcement is to decrease the incidence of malaria by In the context of malaria, research and development for malaria medicines5–7. 2015. In 2000, malaria was responsible for 350 million to chemoprotection refers to medicines that prevent healthy The critical factors at play here are an increased collabo- 500 million infections and more than 1 million deaths, individuals from contracting ration between academia and industry and a focus on particularly in children under the age of 5 years and in malaria. Such drugs are used finding new chemotypes by screening directly against the expectant mothers21. Progress in the first decade of the by travellers but are also parasite. A call for the eradication of malaria by the Bill new millennium to reduce these frightening statistics was considered for mass and Melinda Gates Foundation in 2007 (REF. 8) identi- steady but slow, with 4% year‑on‑year reductions in deaths eradication campaigns. fied new priorities, such as transmission blocking and driven by the roll out of insecticide-treated bed nets22 and chemoprotection in vulnerable populations9, and new fixed-dose ACTs12. In 2007, the Bill and Melinda Gates target candidate profiles10. The past decade has seen a Foundation, with the support of the Director General transformation of the portfolio of malaria medicines, of the WHO (World Health Organization), announced with a dozen or so new chemical entities entering clinical a campaign to drive the eradication of malaria. The development and breakthroughs in translational research advantages of such a call were obvious; the elimination that have enabled human proof‑of‑concept experiments of malaria would have tremendous benefits for public to be performed rapidly11 (FIGS 1,2). Not only have new health. However, gains made against malaria are frag- classes of molecules been discovered, but so have new ile, and whenever a country has decreased its public 1 Medicines for Malaria ways of collaborating and methods to accelerate drug health focus and funding on malaria control the disease Venture, 20 Route de 23 Pré-Bois, 1215 Geneva 15, development. However, emerging drug resistance threat- prevalence has climbed dramatically . Switzerland. ens all this success. Artemisinin-based combination To eradicate malaria, achievable milestones must be 2Division of Allergy and therapies (ACTs) are used worldwide as the first line of set. The publication of the Global Malaria Action Plan Infectious Diseases, treatments12, but patients with resistance to artemisinin (GMAP) by the WHO24 set some of those milestones; Department of Medicine and Departments of Global and its partner drugs are now being routinely identified for example, a tenfold reduction in malaria incidence 13–18 Health and Microbiology, in Southeast Asia . However optimistic the pipeline and deaths by 2030 (compared with 2015). The first University of Washington, appears, there is still a need for new chemical agents, GMAP was published in 2008 and covered the period 750 Republican Street, Seattle, especially to prevent relapse of Plasmodium vivax infec- until 2015. More recently, input and consultations are Washington 98195, USA. tion and to protect vulnerable populations, especially in being sought from experts and regions for GMAP2. Both Correspondence to T.N.C.W. e‑mail: wellst@mmv.org early pregnancy. Eradication of malaria will take many GMAP2 and the Global Technical Strategy for Malaria doi:10.1038/nrd4573 decades: the challenge is to continually find innovative (co-ordinated by the WHO) will cover the 10 years Published online 22 May 2015 ways of targeting the parasite. Paradoxically, the lack of between 2016 and 2025. All these plans and proposals 424 | JUNE 2015 | VOLUME 14 www.nature.com/reviews/drugdisc © 2015 Macmillan Publishers Limited. All rights reserved REVIEWS (1970s) Chloroquine resistance documented on (Late 1950s) every continent with malaria Chloroquine resistance emerges (Late 1970s) Description of on Thai–Cambodian Resistance to (2700 BCE) Chinchona bark border SP emerges Periodic fevers (quinine) in Peru (2009–2012) Launch of five of malaria and transport Commercialization Eradication (Late 1990s) Mefloquine fixed-dose artemisinin combination described in to Rome for and widespread use efforts resistance emerges in therapies by MMV, DNDi and China malaria therapy of chloroquine halted malaria from Southeast Asia pharmaceutical partners BCE 1631 1891 1946 1947 1955 1969 1972 1990 2000 2006 2007 2009 2010 2012 2015 (284–363) Ge Hong Primaquine, the (1955–1960s) (Mid-1990s) SP Melinda Gates and (2012–2015) Four recommends only marketed Attempted resistance Margaret Chan recently discovered qinghao (Artemisia anti-relapse eradication documented on endorse eradication molecules, OZ439, annua) effusion for agent for P. vivax, of malaria every continent of malaria worldwide KAE609, KAF156 alleviating malaria first synthesized with malaria and DSM265, enter symptoms in the USA Phase II trials CH H 3 Artemisinin isolated P. Guttmann and P. Ehrlich describe from Artemisia annua Artemisinin O O the use of methylene blue against H3C by a Chinese combination therapy Prequalification of malaria, launching efforts for O chemist, Tu Youyou recommended by artesunate injections for H synthetic antimalarials and the path H WHO for first-line severe malaria by Guilin O therapy of malaria that eventually leads to chloroquine CH3 Pharmaceuticals O Figure 1 | Key events in the historical timeline of the discovery of antimalarial therapeutics. Guided by millennia-old Chinese and South-American ethnobotanical knowledge of medicinal plant extracts that relieve fevers, chemists isolated and described two major classes of antimalarials: the quinines and artemisinins. InappropriateNature use Reviews of some | Drugantimalarials Discovery in the mid‑twentieth century resulted in the emergence of drug resistance, halting earlier malaria eradication campaigns in the 1960s. Parasite resistance against chloroquine, sulfadoxine–pyrimethamine (SP), amodiaquine and mefloquine is now widespread. Moreover, emergence of resistance in the greater Mekong region in Southeast Asia against the newest antimalarials, artemisinins, and new partner drugs such as piperaquine threatens to reverse recent gains in the battle against malaria. Recently, novel molecules that act on new targets in the parasite have entered clinical development both for the treatment of acute, blood-stage Plasmodium falciparum infection and conforming to other malaria-related target compound profiles. DNDi, Drugs for Neglected Diseases initiative; P. vivax, Plasmodium vivax; MMV, Medicines for Malaria Venture; WHO, World Health Organization. Images (left to right) courtesy of: Worldwide Picture Library/Alamy (bark); Getty Images/iStockphoto Thinkstock Images (mosquito). call for a transformation of the malaria landscape. That resistant mosquito strains. Currently, only pyrethroid is is, even though substantial progress has been made over approved for use with bed nets, and resistance among 25 Target candidate profiles the past decade with the number of deaths from malaria malaria vectors is increasing . A specific set of quantitative falling by 4% per year, to achieve a 90% reduction by Medicines have also had a tremendous impact on criteria that a molecule must 2030 we need to accelerate progress to as much as a reducing malaria-associated mortality, and ACTs have be predicted of achieving 10–16% fall each year24. As a public health goal, this is been used to treat hundreds of millions of patients, fol- before it is considered for development. These criteria audacious and is clearly not a call to business as usual. lowing the isolation of the active ingredient, artemisinin, typically involve