Introduction and Background of the Project

Introduction

SJ733 is a PfATP4 inhibitor that meets 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.

In the next phase of the project we will carry 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, examine alternative formulations, 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)

Project objective

The project objectives are:

1. Manufacture a GMP lot of the SJ733 drug substance and drug product

2. Carry out a Phase 2a trial using SJ733 as a monotherapy at an established clinical site in Peru to evaluate its effectiveness in the field setting

3. Carry out laboratory studies to support selection of the final combination partner from among the existing development candidates within the MMV portfolio

4. Carry out a combination Phase1 challenge study, using a similar design to that employed by MMV to study the combination of DSM265 and OZ439 with SJ733 and the optimal selected combination partner.  This will be carried out using co-administered but physically separate doses of the two drugs from the existing clinical stocks.

5. Carry out preliminary formulation studies to support development of the final combination drug

Project design

The scientific rationale for this project is the development of a novel chemical entity meeting both the fast parasite clearance and transmission blocking requirements that acts on a new target for which there are not yet existing resistant strains of Plasmodium in the field. Briefly, the molecule must be potent and efficacious, highly orally bioavailable, safe, and possess a low propensity for resistance.  The dihydroisoquinolones (DHIQ’s), a chemically novel class of antimalarials, that target PfATP4, afforded SJ733, which is a clinical candidate meeting these.

We propose in this application to study for the first time the parallel validation of the field efficacy of a development candidate and its validation as a combination with another novel drug in the challenge model.  This approach could significantly shorten the development timeline of the targeted combination while still providing a better evidence base for the best combination. Both drugs will have been individually investigated in the CHMI model, the combination of both compounds will provide information on drug interactions in healthy subjects and subjects with an induced malaria infection and antiparasitic effects in combination. Importantly the study can confirm whether antiparasitic effects are additive, synergistic or antagonistic when given in combination to the human host. This information will have a direct impact on the decision whether a combination will be further pursued (in case of synergy and additivity) or discontinued (antagonism). Furthermore, the PK/PD analysis can provide a better estimation of the doses of both drugs to be investigated in a subsequent Phase IIb trial.

How can your partnership (project) address global health challenges?

Despite being an entirely preventable and treatable disease, malaria still places 3.2 billion people at risk in 97 countries, killing an estimated 438,000 people each year in 2015. The WHO estimates that 90% of all malaria deaths occur in sub-Saharan Africa, killing 482 000 children under five years of age. Furthermore, the emergence of resistance to insecticides and malaria medicines currently being used in endemic countries is a growing concern. Parasite resistance to artemisinin – the core compound of ACTs – has been detected in four countries in South-East Asia: in Cambodia, Myanmar, Thailand and Viet Nam. At this time the key goal is to develop a suitable replacement for artemisinin that will not be subject to the emerging resistance.

What sort of innovation are you bringing in your project?

This project has a number of innovations including the innovative use of parallel Phase 2 monotherapy and Phase 1 combination therapy trials to streamline derisking the new drug; a novel PfATP4 inhibitor with very strong safety profile; and a new approach to selection of partner drugs relying upon increased total cidality of the partners. 

Role and Responsibility of Each Partner

The University of Kentucky (UK) will be responsible for managing the overall project, ensuring completion and planning to work around any issues that arise.  They will also have responsibility for coordination of any reporting and publications. Finally, UK will also carry out in vitro testing to guide selection of potential partner drugs.

The Medicines for Malaria Venture (MMV) will be responsible for overseeing the Phase 1a/1b combination drug trials and the Phase 2a single agent drug trial. They will also have responsibility for coordinating any regulatory submissions with the FDA. Finally, MMV will coordinate in vivo studies to confirm potential partner drug choices

Eisai will be responsible for overseeing the manufacture of the active pharmaceutical ingredient and drug product to be tested.  They will coordinate contract research organizations to produce the clinical material.  They will also carry out any new formulation studies aimed at developing a tablet or slow release formulation.