Phase IIa
Project Leader: Dr Fiona Macintyre, MMV
Partners: University of Nebraska Medical Center, USA; Monash University, VIC, Australia; Swiss Tropical and Public Health Institute, Switzerland
Fully synthetic peroxides are an exciting prospect as they could provide an alternative to currently-used artemisinin derivatives. They contain the peroxide bond that is believed to confer the antimalarial activity to artemisinin; additionally, being fully synthetic, they are not reliant on the vagaries of agriculture for their production.
Preclinical studies and clinical trials in human volunteers have demonstrated that OZ439 has a higher potency and longer plasma exposure compared to artemisinin – which might imply greater efficacy at lower doses.
In 2009, the first Phase I dose-escalation trial demonstrated that the molecule was safe and well tolerated up to 1600mg. On this basis, the Phase II trial to evaluate the efficacy and stability of OZ439 in malaria patients was initiated in 2010. Preliminary results with a single dose of OZ439 have confirmed that the plasma exposure is similar to the one observed in healthy volunteers with similar efficacy as artemisinin against both P. falciparum and P. vivax. These results confirm OZ439’s potential to be developed as a single-dose combination therapy for acute malaria.
The active site of the molecule (endoperoxide bond) is consistent with that of the artemisinin derivatives, however, the molecule itself is believed to be structurally distinct enough to not be jeopardized by currently emerging artemisinin-resistant strains. To determine is this is the case, further efficacy studies are planned to compare OZ439 with artesunate in areas where resistance to artemisinin derivatives is emerging.
Additionally, three potential combination partner drugs have been selected, and the development plans and the non-clinical work to evaluate which are compatible with OZ439 are underway.
