In Vivo Efficacy
MMV639565 and MMV669844 have both demonstrated parasite clearance in vivo, providing a highly attractive feature of this series.
The therapeutic efficacy of MMV639565 against P falciparum growing in peripheral blood of NODscidIL2Rγnull mice engrafted with human erythrocytes (po dosing, qd for 4 days) is shown below. A rapid parasite clearance - ED90 6.3 mg/kg was recorded.
Values in brackets indicate dose corrected according to quality control of formulation.
The data for MMV669844 show 99.9% inhibition of parasitemia in a snapshot (one dose level of 4 x 50 mg/kg). In an independent study performed at Swiss TPH, at day 7 post-infection, n=2 mice treated with a 4x 50 mg/kg p.o. dosing regimen of MMV669844 were parasite-free (>99.9% activity) compared to n=4 untreated control mice (see SI). The parasite detection limit in that study was 1 parasite in 10,000 erythrocytes (that is, 0.01%). Report is here. Ursula Lehmann, Christoph Fischli and Sergio Wittlin (Swiss TPH, Basel, Switzerland) generated the SCID mouse data for MMV669844.