DMG Deutsche Malaria GmbH, through the financial support of its shareholders, is committed to the development of fosmidomycin as a component of Non-Artemisinin-based Combination Therapy (NACT) for acute uncomplicated Plasmodium falciparum malaria. It is being evaluated in combination with piperaquine with the aim of developing a highly effective, safe and well tolerated treatment having the attributes of rapid schizonticidal activity and prolonged post-treatment prophylaxis to meet the challenge of artemisinin resistance.
As an inhibitor of the enzyme 1-deoxy-D-xylulose 5-phosphate reductoisomerase, resulting in blockade of the non-mevalonate pathway of isoprenoid biosynthesis, fosmidomycin exhibits a unique mode of action. Having no direct homologue in humans who are reliant on the mevalonate pathway of isoprenoid biosynthesis, inhibitors of this enzyme are highly selective and are therefore safe antimalarial agents as has been shown to be the case so far. In contrast, piperaquine inhibits the detoxification of heme within the malaria parasite, its accumulation leading to increased membrane permeability of infected red cells favouring the influx of fosmidomycin and enhancing the additive effect seen in vitro.
The efficacy, safety and tolerance of the combination has been established in a proof of concept study in Gabon in which fosmidomycin, in twice daily doses of 30mg/kg, and piperaquine, in a once daily dose of 16mg/kg, were administered orally for three days to a total 100 subjects, consisting of 10 adults, 40 children aged 5 to 14 years and 50 children aged one to five years. Of the 69 subjects evaluable on Day 28, as the primary efficacy endpoint, the cure rate was 100%. There were no drug related safety issues and tolerance was excellent despite the high dose of fosmidomycin.
Dose optimisation studies with the aim of halving and possibly quartering the daily dose of fosmidomycin within the constraint of a three-day therapeutic regimen of once daily dosing are planned for later this year.