Introduction and Background of the Project

1. Introduction

SJ733 is a PfATP4 inhibitor that meets criteria for treatment of uncomplicated malaria. Three clinical trials of SJ733 have been completed. Phase 1a examined safety and pharmacokinetics of SJ733. Phase 1b tested pharmacodynamics in the human challenge model. Phase 2a determined the parasite reduction ratio, parasite reduction half-life and minimum inhibitory concentration of SJ733 in adults with uncomplicated malaria and assessed the exposure-response relationship (PK/PD). Current Phase 1a, 1b, and 2a human data shows an excellent safety profile and tolerability, good oral availability, and moderate drug clearance.

In the next phase of the project, we will conduct a Phase 2b study examining the potential for radical cure of uncomplicated P. vivax malaria in adults with a 1, 2, or 3 day schedule of the SJ733-tafenoquine (TQ) combination. This will set the stage for subsequent pivotal Phase 3 studies.

2. Project objective

The overall objective of this project is to examine the clinical safety and efficacy of the combination of SJ733 and TQ for radical cure of P. vivax malaria. The purpose is to develop an SJ733-TQ combination drug suitable for treatment of all patients with uncomplicated P. vivax malaria. The targeted results for this study are data that support 1 to 3 doses of an SJ733-TQ fixed dose combination for radical cure of P. vivax mono-infected patients.

3. Project design

First, we will consider toxicology associated with administration of the combination of SJ733 and TQ to support the proposed Phase 2b studies. Next, we will carry out a clinical trial to establish safety and efficacy of a fixed-dose combination of SJ733-TQ in adults with P. vivax malaria mono-infection to examine the safety and efficacy of the combination of SJ733 and TQ in uncomplicated P. vivax malaria mono-infection in Peruvian adult patients. The primary objectives are to assess the safety, tolerability, efficacy, and pharmacokinetics of an orally administered combination of SJ733 and TQ. Concurrently, we will explore options to reduce the overall cost of goods of SJ733.

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

The global malaria eradication campaign reduced malaria mortality by 60% but recently stalled with malaria still causing >200 million annual cases, mostly from Plasmodium falciparum and P. vivax infections. Although P. falciparum accounts for > 90% of the total cases, due to extremely high burden in Africa, in many parts of the world P. vivax accounts for 20-100% of cases. P. vivax malaria is the most widespread, covering the entire world. Although artemisinin combination therapies (ACTs) drove early success, ACT resistance is rising, and backup drugs are urgently needed. Additionally, current drug combinations that both cure and prevent relapse of P. vivax malaria – a “radical cure” – require extended treatment schedules (7-14 days) and have poor adherence and modest efficacy (< 80% cure rates). Therefore, there is a strong need to develop safe, rapidly acting combination treatments for malaria. SJ733 is a novel, orally bioavailable, rapidly acting antimalarial acting on both blood and sexual stages of P. falciparum and P. vivax. Phase 2a trials demonstrated SJ733 clears blood stage P. vivax disease with fewer than 3 doses, 1-2 doses for most patients. This proposal aims to obtain clinical proof-of-concept that an SJ733-TQ drug combination would radically cure P. vivax malaria with 1, 2, or 3 doses, representing a substantial improvement in schedule and likely significantly better efficacy than current radical cure drugs.

What sort of innovation are you bringing in your project?

SJ733 is a novel antimalarial drug currently being developed for the treatment of uncomplicated malaria. SJ733 has demonstrated rapid pharmacodynamics, excellent tolerability, safety, and efficacy in human clinical trials. We will assess the safety, tolerability, efficacy, and pharmacokinetics of an orally administered fixed-dose combination of SJ733 and TQ with the aim of showing the combination would radically cure P. vivax malaria with a substantial improvement in schedule and better efficacy than current radical cure drugs.

Role and Responsibility of Each Partner

Eisai is the Designated Development Partner. Eisai and the University of Kentucky have collaboratively designed the proposed safety and pharmacokinetics studies, which will be contracted to rigorously qualified CROs and overseen by Eisai’s subject matter experts.

Eisai will manage the formulation of a new batch of SJ733 clinical trial material, as well as combination toxicology evaluation.

The University of Kentucky will oversee the regulatory filings to amend the current US-FDA IND (held by Prof. Guy) for development of SJ733 and the Phase 2b clinical trial work, including the local ethics and regulatory submissions.