Treating malaria: new drugs for a new era
Authors: G Dennis Shanks, Jörg J Möhrle
Journal: The Lancet Infectious Diseases (2017)

In The Lancet Infectious Diseases, Ousmane Koita and colleagues1Koita OA Sangaré L Miller HD et al.AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial.Lancet Infect Dis. 2017; (published online Sept 12.)http://dx.doi.org/10.1016/S1473-3099(17)30365-1PubMed Google Scholar reported the results of a randomised, phase 2, non-inferiority clinical trial. They compared AQ-13, a next generation 4-aminoquinoline (4-AQ) compound, with artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in 66 Malian men. The per-protocol analysis of this well executed trial showed that both groups had similar proportions cured (28 [100%] of 28 for AQ-13 vs 31 [93·9%] of 33 for artemether plus lumefantrine; p=0·50) and non-inferiority of AQ-13 to artemether plus lumefantrine (difference −6·1%, 95% CI −14·7 to 2·4). The intention-to-treat analysis also showed that proportions cured were also similar between the groups (28 [84·8%] of 33 for AQ-13 vs 31 [93·9%] of 33 for artemether plus lumefantrine; p=0·43); however, this analysis did not show non-inferiority of AQ-13 to artemether plus lumefantrine (difference 9·1%, 95% CI −5·6 to 23·8). The study's suboptimal number of participants was possibly due to civil military disturbances in Mali or improving malaria control in the Sahel. The data presented show AQ-13 to be efficacious in this relatively easy-to-treat population. The next challenge is to understand how well AQ-13 will treat patients who have lower or no immunity to malaria, such as African children. Artemisinin combination therapies with the 4-AQs amodiaquine and piperaquine are approved by stringent regulatory authorities. To justify further development, data are needed to show AQ-13 could fill the gaps left by these drugs. For strengthening the case of AQ-13, two requirements are needed. First, an understanding is needed of the exposure response in non-immune adults (as a surrogate for infants), supporting an argument that a lower dose of AQ-13 could be used as part of combination therapy. This exposure response needs a more rigorous analysis, including data from human challenge studies.2McCarthy JS Marquart L Sekuloski S et al.Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development.Antimicrob Agents Chemother. 2016; 60: 3669-3675Crossref PubMed Scopus (31) Google Scholar Clinical data showed that chloroquine kills parasites very quickly.3Wilson T Edeson JF Studies on the chemotherapy of malaria. VII. The treatment of acute malaria in Malaya.Med J Malaya. 1958; 12: 471-499PubMed Google Scholar Data showing that AQ-13 also rapidly clears parasites clinically would be needed to make a case for its superiority over other aminoquinolines, such as piperaquine or ferroquine.4McCarthy JS Rückle T Djeriou E et al.A phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study.Malar J. 2016; 15: 469Crossref PubMed Scopus (72) Google Scholar, 5Pasay CJ Rockett R Sekuloski S et al.Piperaquine monotherapy of drug-susceptible Plasmodium falciparum infection results in rapid clearance of parasitemia but is followed by the appearance of gametocytemia.J Infect Dis. 2016; 214: 105-113Crossref PubMed Scopus (46) Google Scholar Second, there needs to be an analysis of the best potential partner compound; public health goals would be ill-served by an antimalarial treatment with a single active agent. Ultimately, the case must be made as to why one should invest in a fourth generation aminoquinoline rather than other molecules with novel mechanisms of action.6Medicines for Malaria VentureMMV-supported projects.https://www.mmv.org/research-development/mmv-supported-projectsDate: 2016Google Scholar Potency, exposure of the drug in the patient, and its safety profile should enable its use as a single administration against multiple drug-resistant P falciparum as compared with the current 3-day regimens. Because of 20 years of sustained investment in antimalarial drug development, the pipeline is relatively full of such new drugs with new mechanisms of action,7Wells TN Hooft van Huijsduijnen R Van Voorhis WC Malaria medicines: a glass half full?.Nat Rev Drug Discov. 2015; 14: 424-442Crossref PubMed Scopus (324) Google Scholar largely as a direct result of the continuing commitment of the Bill & Melinda Gates Foundation, Wellcome Trust, and the UK Department for International Development, along with many pharmaceutical industry and academic partners through the public–private partnership of Medicines for Malaria Venture. To move a hit compound from a laboratory screen to a drug candidate, millions of US dollars are involved, whereas moving a drug candidate to the clinic involves tens of millions and transition from clinic to registration involves hundreds of millions. Most compounds do not make it through the pipeline because of toxic side-effects, problems with solubility or bioavailability, or the high-cost of synthesis. The antimalarial drugs that will be needed in the future will be different because of the success of malaria control programmes driven by insecticide-treated bednets and effective combination treatments based on rapid diagnostic tests.8Burrows JN Duparc S Gutteridge WE et al.New developments in anti-malarial target candidate and product profiles.Malar J. 2017; 16: 26Crossref PubMed Scopus (271) Google Scholar One consequence of such public health success is that it is difficult to complete clinical trials in Latin America and Asia because malaria is rarer than it once was. Even in Africa, where the burden of malaria is highest, recruiting patients for thorough studies needed to advance drug candidates has become much harder. Malaria control is the current need but the world is rapidly moving towards malaria elimination. This shift is not just an optimistic illusion, as shown by outstanding success in countries as different as Sri Lanka and China, but malaria elimination does require an evolution in thinking about what drugs are needed.9Feachem RG Phillips AA Targett GA Snow RW Call to action: priorities for malaria elimination.Lancet. 2010; 376: 1517-1521Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar A single exposure treatment will allow directly observed therapy to improve compliance and therefore completely eliminate parasites from a patient. Furthermore, when the mission is to eliminate the last parasite and not just treat the disease, one needs antimalarial drugs safe enough for mass administration to asymptomatic populations and drugs able to kill latent forms in the liver and sexual transmission stages to the mosquito.10Sturrock HJ Hsiang MS Cohen JM et al.Targeting asymptomatic malaria infections: active surveillance in control and elimination.PLoS medicine. 2013; 10: e1001467Crossref PubMed Scopus (237) Google Scholar Malaria parasites have been coevolving with human beings and mosquitoes for a long time; breaking malaria's multiple survival strategies will not be easy and will require new drugs for a new era.11Burrows JN van Huijsduijnen RH Möhrle JJ Oeuvray C Wells TN Designing the next generation of medicines for malaria control and eradication.Malar J. 2013; 12: 187Crossref PubMed Scopus (219) Google Scholar GDS is a member of the Expert Scientific Advisory Committee of the Medicines for Malaria Venture, which is supported by grants from the Bill & Melinda Gates Foundation, Wellcome Trust, UK Department for International Development, and other government and philanthropic sources. JJM is an employee of the Medicines for Malaria Venture. AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trialThe per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended. Full-Text PDF Open Access