Phase 2 Trial of SJ733, a Novel PfATP4 Inhibitor for Malaria

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) Milestone 1 – Phase 2a & 1a/ab Go’s – Manufacture of Clinical DS/DP – Eisai The costs for milestone 1 are mostly associated with manufacture of the SJ733 drug product to be tested in the Phase 2a, 1a, Phase 1b studies, regulatory compliance with that product and distribution of the product for clinical trials. In addition these costs include initiation of long-term stability studies with the drug product – a critical component in registration if this product is to go forward. Finally preliminary tablet formulation work is included herein. Costs are based on experience of the Eisai group in similar projects. The work will either be carried out in house at Eisai or contracted to a CRO (at equivalent costs). Milestone 2 – Phase 2b Go – Selection of SJ733 Combination Partners (UK) The costs for Milestone 2 are associated laboratory modeling to select the combinations of SJ733 that provide enhanced cidality and minimize negative drug interactions from among the potential partners that are currently in development or registered. The costs are based on the experience of the Guy group in similar projects. Milestone 3 -Phase 2b Go – Completion of SJ733 Monotherapy Phase 2a (MMV) The costs for milestone 3 are related to the execution of the Phase 2a trial in Peru. The projected costs are based on MMV experience with the GHIT funded DSM265 trial recently carried out. Milestone 4 Phase 2b Go - Completion of SJ733 Combination Phase 1a/b (MMV) The costs for milestone 4 include all associated with the Phase 1a/b trials previously carried out at QIMR, including startup of the trial, clinical costs, pharmacokinetics, monitoring, and analysis. The costs are based on the current ongoing costs for similar trials overseen by MMV.