Artefenomel: a promising new antimalarial drug
2015; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês
10.1016/s1473-3099(15)00343-6
ISSN1474-4457
Autores Tópico(s)Research on Leishmaniasis Studies
ResumoNew drugs are needed to treat malaria. Artefenomel (OZ439), a trioxolane that shares the peroxide pharmacophore of highly effective artemisinins,1Charman SA Arbe-Barnes S Bathurst IC et al.Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria.Proc Natl Acad Sci USA. 2011; 108: 4400-4405Crossref PubMed Scopus (304) Google Scholar has been progressing through development, and results reported by Aung Pyae Phyo and colleagues2Phyo AP Jittamala P Nosten FH et al.Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial.Lancet Infect Dis. 2015; (published online Oct 5.)http://dx.doi.org/10.1016/S1473-3099(15)00320-5PubMed Google Scholar in The Lancet Infectious Diseases add to its promise. As with every new potential antimalarial drug, artefenomel has advantages and disadvantages. Before considering these issues, it is appropriate to ask fundamental questions, such as why do we need new drugs for malaria and what drug characteristics are most needed? First, available drugs are limited by drug resistance. Artemisinin-based combination therapy is recommended for the treatment of falciparum malaria and is effective against other plasmodial species. Artemisinin resistance, manifested as delayed parasite clearance after therapy, is established in southeast Asia.3Ashley EA Dhorda M Fairhurst RM et al.Spread of artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2014; 371: 411-423Crossref PubMed Scopus (1442) Google Scholar Less publicised is decreased activity of partner drugs, with decreased parasite sensitivity and changing sensitivity patterns over time documented for several drugs in different regions.4Rosenthal PJ The interplay between drug resistance and fitness in malaria parasites.Mol Microbiol. 2013; 89: 1025-1038Crossref PubMed Scopus (91) Google Scholar Recently in Cambodia, delayed parasite clearance as well as actual high failure rates have been seen after treatment of uncomplicated malaria with dihydroartemisinin plus piperaquine, presumably because of decreased responsiveness to both drugs.5Chaorattanakawee S Saunders DL Sea D et al.Ex vivo drug susceptibility testing and molecular profiling of clinical Plasmodium falciparum isolates from Cambodia from 2008 to 2013 suggest emerging piperaquine resistance.Antimicrob Agents Chemother. 2015; 59: 4631-4643Crossref PubMed Scopus (58) Google Scholar, 6Leang R Taylor WR Bouth DM et al.Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western Cambodia: dihydroartemisinin-piperaquine open-label multicenter clinical assessment.Antimicrob Agents Chemother. 2015; 59: 4719-4726Crossref PubMed Scopus (219) Google Scholar New antimalarial drugs that are not affected by current resistance mechanisms are needed. Second, available drugs require multiple doses. Artemisinin-based combination therapies are given once or twice daily for 3 days. An effective single-dose regimen, offering improved compliance and cost, would be a huge advance. The identification of new agents effective after a single dose is a high priority. Third, most available drugs are not highly active against non-erythrocytic and sexual stages. Treatment of malaria requires action against asexual erythrocytic parasites, which are responsible for all disease manifestations. Added benefit would come from action against other stages to facilitate chemoprevention (by killing liver stages before they elicit clinical illness) and transmission blocking (by killing sexual stages before they infect mosquitoes). Fourth, artemisinins are natural products, complicating maintenance of stable drug supplies and pricing. This challenge has been partly overcome with the development of bioengineered artemisinic acid in yeast.7Paddon CJ Westfall PJ Pitera DJ et al.High-level semi-synthetic production of the potent antimalarial artemisinin.Nature. 2013; 496: 528-532Crossref PubMed Scopus (1410) Google Scholar Bioengineered artemisinin has contributed to the worldwide supply of artemisinin-based combination therapies since 2014, but most available therapies include artemisinin derivatives from agricultural sources. Compounds readily produced by simple and inexpensive synthetic methods are clearly preferred. Finally, some antimalarial drugs have safety limitations. Ideal antimalarial drugs must be safe in young children and pregnant women to enable treatment and also use of these drugs for malaria control and elimination, including intermittent preventive therapy, seasonal malaria chemoprevention, and mass drug administration. Key advantages of artefenomel are its lack of reliance on natural product starting materials, ease of synthesis,8Dong Y Chollet J Matile H et al.Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.J Med Chem. 2005; 48: 4953-4961Crossref PubMed Scopus (115) Google Scholar excellent absorption, distribution, metabolism, and excretion (ADME) properties,9Wang X Dong Y Wittlin S et al.Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres.J Med Chem. 2013; 56: 2547-2555Crossref PubMed Scopus (72) Google Scholar and, in limited studies, apparent safety10Moehrle JJ Duparc S Siethoff C et al.First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials.Br J Clin Pharmacol. 2013; 75: 524-537Crossref PubMed Scopus (79) Google Scholar and antimalarial efficacy.2Phyo AP Jittamala P Nosten FH et al.Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial.Lancet Infect Dis. 2015; (published online Oct 5.)http://dx.doi.org/10.1016/S1473-3099(15)00320-5PubMed Google Scholar In their phase 2a dose-ranging study, Phyo and colleagues show that the drug has excellent efficacy against falciparum and vivax malaria on the basis of parasite clearance rates; true efficacy was not assessed, because patients received definitive therapy after 36 h. Safety results were reassuring, although a study of 80 patients is obviously limited in uncovering uncommon toxic efects. Importantly, artefenomel has a long half-life (46–62 h compared with about 0·5–4 h for artemisinins), and drug exposure did not seem to be decreased in acute malaria (as was the case with the earlier trioxolane arterolane [OZ277]11Valecha N Looareesuwan S Martensson A et al.Arterolane, a new synthetic trioxolane for treatment of uncomplicated Plasmodium falciparum malaria: a phase II, multicenter, randomized, dose-finding clinical trial.Clin Infect Dis. 2010; 51: 684-691Crossref PubMed Scopus (61) Google Scholar), leading to confidence that single-dose therapy will be feasible.10Moehrle JJ Duparc S Siethoff C et al.First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials.Br J Clin Pharmacol. 2013; 75: 524-537Crossref PubMed Scopus (79) Google Scholar But, artefenomel is not the perfect antimalarial drug. Its similarity to artemisinins suggests that it might share safety concerns; these drugs have proven to be very safe in routine use, including in young children, but they may be embryotoxic,12Ades V Safety, pharmacokinetics and efficacy of artemisinins in pregnancy.Infect Dis Rep. 2011; 3: e8Crossref PubMed Google Scholar complicating use during pregnancy, and delayed haemolysis after therapy has been reported.13Jaureguiberry S Thellier M Ndour PA et al.Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011–2013.Emerg Infect Dis. 2015; 21: 804-812Crossref PubMed Scopus (40) Google Scholar As with artemisinins, artefenomel does not seem to have activity against liver stages, but it might offer at least partial transmission-blocking activity against sexual stages.14Delves M Plouffe D Scheurer C et al.The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites.PLoS Med. 2012; 9: e1001169Crossref PubMed Scopus (271) Google Scholar Additionally, it remains unclear whether artefenomel will be subject to the same resistance concerns as artemisinins. In the current study, patients infected with artemisinin-resistant parasites (based on genotypes) cleared parasitaemia slightly (but not significantly) more slowly than did those infected with sensitive parasites,2Phyo AP Jittamala P Nosten FH et al.Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial.Lancet Infect Dis. 2015; (published online Oct 5.)http://dx.doi.org/10.1016/S1473-3099(15)00320-5PubMed Google Scholar a result that is better than would be expected for artemisinins. However, with limited available data it remains uncertain whether artefenomel will circumvent artemisinin resistance. In summary, artefenomel will probably be a long-acting artemisinin-related drug, offering single-dose therapy, which is a major advance. Possibly, it will be equally active against wild-type and artemisinin-resistant parasites, a second major advance. Combination therapy is needed, and potential combinations are under investigation. The list of potential partner drugs remains short, and so continued work towards identifying additional new antimalarial drugs meeting the criteria discussed above is a high priority. I declare no competing interests. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trialArtefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs. Full-Text PDF Open Access
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