Preclinical and Clinical Development of (+)-SJ000557733, A Novel Inhibitor of Plasmodium ATP4

SJ733 is a PfATP4 inhibitor that meets MMV TCP1 criteria for treatment of uncomplicated malaria. Trials of SJ733 are ongoing with Phase 1a examining safety and pharmacokinetics and Phase 1b testing pharmacodynamics in the human challenge model. Current Phase 1 human data shows an excellent safety profile and tolerability, good oral availability, and moderate clearance. The most significant adverse events in GLP toxicology studies were methemoglobinemia and mild reversible regenerative anemia, seen only in dogs at high doses. Neither has been seen in human Phase 1 studies. The predicted safety margin for SJ733 at the expected efficacious dose is 8-fold. We propose manufacturing a second batch of our current drug product and carrying out Phase 2a studies. Phase 2a trials with SJ733 alone would determine the PRR, parasite reduction half-life and minimum inhibitory concentration of SJ733 in adults with uncomplicated malaria, assess the exposure-response relationship (PK/PD), and determine potential for transmission blocking. In parallel we would assess best combinations, carry out preliminary formulation studies for tablets, and execute a Phase 1b combination challenge study in volunteers. This will set the stage for subsequent Phase 2 studies to test appropriate combinations and to target special needs groups (children and pregnant women)