Our mandate with Medicines for Malaria Venture in Geneva comprises exploratory work on novel compounds from various sources. The goal is to identify novel chemical entities showing antimalarial activity in vitro and in rodent models. Our experience during the last decade is that such novel compounds can ultimately become part of the Medicines for Malaria Venture portfolio.
The project on the synthetic trioxolane compounds of the ozonide (OZ) series serves as a prime example in this regard. OZ439 is a novel synthetic ozonide currently undergoing clinical trials. Relative to the artemisinin derivatives, as well as the 'first generation' synthetic ozonide OZ277, OZ439 has significantly improved pharmacokinetic properties, which are very likely the explanation for the dramatic increase in potency.
A single oral dose of 20 mg/kg OZ439 cures mice infected with P. berghei, a result that cannot be reached by chloroquine, mefloquine, OZ277 or the artemisinin derivatives. Phase I clinical trials were performed by Medicines for Malaria Venture in 2009 and showed that OZ439 is well tolerated at all dose levels. So called 'proof of concept' phase II clinical trials with malaria patients showed that the compound holds promise as a much sought one-dose cure for Plasmodium falciparum infection. Following the ozonide project, numerous other major collaborations with Medicines for Malaria Venture were initiated.
The novel compounds involved in two main projects come from the University of Cape Town (South Africa) and Sanofi, Toulouse (France), respectively.