Development of E-1224 for the Treatment of Chagas Disease.

There is a void of options for the specific treatment of Chagas disease. The only two medicines available benznidazole and nifurtimox are known to cause serious toxicity with unsatisfactory cure rates, especially when used in adult patients with chronic Chagas disease. New treatment alternatives are clearly needed. For about 20 years, ergosterol biosynthesis has been recognized as a potential target pathway for anti-T. cruzi treatment. The pathway has been effectively targeted for antifungal therapy and it shares considerable similarity with the T. cruzi pathway, which is essential for the parasite's growth and survival. Novel antifungal triazole derivatives have arisen as more promising alternative treatments for Chagas disease. They combine potent inhibition of T. cruzi ergosterol biosynthesis and pharmacokinetic properties (long terminal elimination half-life and large distribution volume) suitable for the treatment of this disseminated intracellular infection. The current project evaluates E-1224, a phosphonoxymethyl prodrug of ravuconazole, a new generation triazole compound, as a new tool for the treatment of Chagas disease. The parent drug, ravuconazole, and E1224 have been evaluated extensively in human Phase I and II trials, and have been shown to be safe and with excellent pharmacokinetic profile. Animal efficacy data support Phase II proof-of-principle clinical evaluation for chronic Chagas disease.