Introduction and Background of the Project

Introduction

Severe malaria (SM) is a medical emergency requiring immediate parenteral or enteral treatment. SM affects two million people per year. The current WHO treatment of choice is IV Artesunate (AS), available in 34 developing countries. IV AS is not registered in the US, Europe, Australia, Japan, and many other countries. Other SM treatments have significant liabilities (efficacy/tolerability). SJ733 is an antimalarial entering Phase 2 for oral 3-day treatment of non-severe malaria. In humans, SJ733 is active against blood and sexual stages and possesses an excellent safety profile. SJ733 demonstrated rapid parasite killing in a Phase 1b human challenge. Animal models indicate a lack of embryofetal developmental (EFD) toxicity. SJ733’s clinical profile makes SJ733 a strong candidate for the treatment of SM.

Project objective

The project objectives are:

1) Manufacture a GMP lot of the current SJ733 drug substance to provide enough material to carry out the proposed preclinical and clinical studies.

2) Conduct IND-enabling bridging GLP dog toxicity studies to establish a therapeutic

window when SJ733 is administered via an intravenous route.

3) Carry out formulation studies and manufacture of drug product to support development

of SJ733 for intravenous (IV) bolus and continuous infusion administration.

4) Submit an Investigational New Drug (IND) filing to enable first-in-human studies of IV

5) Carry out a Phase 1a trial using IV SJ733 to establish safety and tolerability of both bolus

and continuous infusion administration routes.

Project design

We will explore SJ733 as a novel treatment for SM. Formulation studies will help select the lead formulation with the optimal dose volume for parental use. Preclinically, the dog was the most sensitive toxicology species. Therefore, GLP dog toxicity studies will bridge from existing IND to the proposed route and schedule. The clinical work will focus on examining safety, tolerability, and pharmacokinetics for two schedules: a bolus IV schedule mirroring AS use and a continuous infusion schedule more closely related to the IV quinine schedule.

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

The current drug of choice for SM is IV AS, which is only available in 34 countries.  Given the relatively narrow availability of IV AS, potential issues with resistance, and the tolerability and safety issues of the older drugs there is an emerging interest in developing drugs for severe disease. While this is a critical issue for high morbidity countries in Africa, it is also a strong need in developed countries that have many fewer cases but a higher proportion of them being severe. Therefore, we see an alignment between development of a drug for use in developed countries, essentially for an orphan indication (severe disease in travelers), and the need to deliver that drug world-wide. This represents an opportunity for leverage of an expedited US registration to meet a global need.

What sort of innovation are you bringing in your project?

SJ733 is novel antimalarial drug currently being developed for the treatment of uncomplicated

malaria. SJ733 has demonstrated very rapid pharmacodynamics, excellent tolerability, excellent potency, and excellent efficacy in preclinical models and has excellent tolerability, safety, and efficacy in humans. SJ733 may also prove useful for severe malaria, and this proposal explores that potential utility.

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 regulatory submissions and coordination of any reporting and publications.

Eisai will be responsible for overseeing the manufacture of the active pharmaceutical ingredient and drug product to be tested.  They will also carry out any new formulation studies.

Final Report

1. Project objective:

Severe malaria (SM) is a medical emergency affecting two million people per year and requiring immediate parenteral or enteral treatment. SJ733 is an antimalarial that recently completed a Phase 2a trial for oral 3-day treatment of non-severe malaria, with excellent efficacy and safety. For this project, we proposed to explore SJ733 as a novel treatment for SM by developing formulations to minimize dose volume for IV parental use and to carry out a Phase 1a study for SJ733 in SM. When we were unable to develop a stable, concentrated IV formulation, we pivoted to developing a rectal suppository (RS) formulation. 

2. Project design:

The project design comprised of the following: 1) manufacture a GMP lot of SJ733 drug substance (DS); 2) carry out formulation studies and manufacture of IV SJ733 drug product (DP); 3) conduct IND-enabling bridging GLP dog toxicity studies for IV SJ733; 4) submit an Investigational New Drug (IND) filing for IV SJ733; 5) carry out a Phase 1a trial using IV SJ733.  When our formulation efforts demonstrated intractability of IV SJ733, we deemphasized items 3-5 and pivoted to 3a) carry out formulation studies and manufacture rectal suppository (RS) SJ733 DP; 4a) conduct IND-enabling bridging GLP dog toxicity studies for RS SJ733.

3. Results, lessons learned:

In the first portion of the program, we fully explored development of IV formulations for SJ733. Extensive work provided several formulations that gave good solubility, but none provided a stable liquid formulation at a concentration appropriate for bolus injection.  Therefore, we abandoned developing an IV product and turned to the alternative of a rectal suppository.

Initial exploration of rectal suppository formulations was conducted using several types of suppositories.  We conducted feasibility studies aimed at improving absorption and stability, and animal PK studies. In addition, experiments were conducted to study manufacturability.  Based on the result of the feasibility study, the team will focus only on advancing the rectal suppository formulation going forward for formulation of clinical trial material and will seek funding for that work in due time.