Preclinical and Clinical Development of the Next-Generation Antimalaria Prophylactic Agent

Malaria remains the number one infectious disease threat to deployed US troops. This vector-borne disease has a high attack rate, which has been shown repeatedly through history to leave unprotected units completely combat ineffective. Currently in the US Army, our use of prophylactic agents is restricted to doxycycline and atovaquone-proguanil. Both agents must be taken daily to be effective, thus susceptible to poor compliance, and both have limitations with side effects/tolerability (doxycycline) and developing resistance (atovaquone-proguanil). This program is advancing the exploitation of a new class of antimalarial chemoprophylaxis agent protective against Plasmodium falciparum, with a pharmacokinetic profile to support a longer half-life than currently available drugs, and with no demonstrated cross-resistance. Triazines are a novel class developed from earlier studies with imidazolidinedione compounds. In vitro and in vivo malaria efficacy studies have shown triazines to be effective in preventing blood-stage P. berghei malaria in mice (a model for blood stage P. falciparum) as well as suppressive in the Rhesus relapsing model using P. cynomolgi. The first part of this proposal will take the two lead triazine candidates (currently ongoing study) into preclinical pharmacology and toxicity studies investigating general toxicity at various doses, ADME (absorption, distribution, metabolism, and excretion) parameters and drug-drug interaction studies (CYP450 and transporters), as well as specific toxicity concerns including genotoxicity and reproductive toxicity. These data will be used to support an exploratory Investigational New Drug (IND) clinical trial. This trial will determine the compound with the optimal pharmacokinetic profile in humans by introducing 10 healthy volunteer subjects to 1/100th of the minimum effective doses of both compounds (5 subjects per compound) seen in animal studies. The compound with the best pharmacokinetic profile will then be manufactured according to cGMP (current Good Manufacturing Practices) for use in preclinical GLP (Good Laboratory Practices) toxicity studies. The second part of the proposal includes submission of a traditional IND to the Food and Drug Administration (FDA) to begin the clinical phase of development. A Phase 1 trial is planned to investigate the safety and pharmacokinetics of the drug product at six different doses in 12 healthy volunteer subjects (2 subjects per dose), followed by a Phase 1/2a challenge study to investigate three doses for efficacy in preventing P. falciparum infection in 24 healthy volunteer subjects (6 subjects per dosing arm plus 6 infectivity controls). The team prosecuting the project is a unique combination of physicians, clinical pharmacologists, chemists, and toxicologists with extensive experience in malaria drug development. The Walter Reed Army Institute of Research and US Army Medical Research and Materiel Command holds all intellectual property rights to triazines, which will also ensure that this drug could be licensed if this and future studies continue to show promise.

Basic Science
Drug-based Strategies

Sep 2015 — Sep 2019

$3.49M

United States