The broad, long-term objective of this proposal is to improve the treatment of drug-resistant malaria.
Its specific aims are to perform Phase 2 human studies (efficacy) of a candidate aminoquinoline antimalarial, AQ-13, in adults (AIM 1) and children (AIM 2). Previous work may have shown that these AQs (including the lead compound, AQ-13) are active in vitro against chloroquine (CQ) resistant and multiresistant P. falciparum, and in vivo against CQ resistant P. falciparum in the squirrel monkey model of human infection with CQ-resistant P. falciparum. Based on that information and preclinical toxicologic and pharmacologic studies, AQ-13 is being studied in humans. The Phase 1 Human Studies performed may have revealed no significant differences in toxicity between AQ-13 and CQ. This proposal requests support to perform Phase 2 (efficacy) studies of AQ-13 in humans in Mali. These studies will begin with a randomized controlled trial dose-finding study in semi-immune adults with uncomplicated P. falciparum malaria (comparing AQ-13 doses of 1400, 1750 and 2100 milligrams of base to Coartem, the currently recommended treatment for uncomplicated P. falciparum malaria in Mali). Using the doses of AQ-13 found effective and safe in adults, these studies will move to studying children 6-14 years of age (who are also semi-immune in Mali), and subsequently to children = 5 years of age (who are not semi-immune). The studies in children 6-14 years of age will begin with milligrams of base per kilogram dose extrapolations from the adult dose (which may have been successful with the close structural analog CQ) and modify those doses as needed based on efficacy (cure rates) and pharmacokinetic (PK) parameters such as bioavailability based on Area Under the Curve (AUC)--part A of AIM 2. Younger non-immune children (= 5 years of age) (part B of AIM 2) will then be studied based on the dose(s) found effective in older children. These studies have the potential to establish clinical efficacy and safety for a new generation of AQs with activity against CQ-resistant and multiresistant P. falciparum, which are administered orally, are as safe as CQ, and would be as economical as CQ to produce for the millions of individuals suffering from CQ-resistant P. falciparum (for example, three dose treatment at roughly $0.03 per dose).
Across the globe, 2 to 3 million children die each year from malaria, because no affordable antimalarials are both active and safe against drug-resistant P. falciparum parasites. Our research has shown that it is possible to make drugs that are economical and are active against drug-resistant parasites. The purpose of this proposal is to test the efficacy of the lead investigational antimalarial (AQ-13) in adults and children, working in collaboration with colleagues at the University of Bamako in Mali, in sub-Saharan Africa.
|Hocart, Simon J; Liu, Huayin; Deng, Haiyan et al. (2011) 4-aminoquinolines active against chloroquine-resistant Plasmodium falciparum: basis of antiparasite activity and quantitative structure-activity relationship analyses. Antimicrob Agents Chemother 55:2233-44|