- Awarded Year2014
- Awarded Amount$3,768,922
- Development StageClinical Phase1
- Collaboration PartnersEisai Co., Ltd., Medicines for Malaria Venture (MMV), St. Jude Children’s Research Hospital
Introduction and Background of the Project
Malaria remains a global health problem. Continued resistance to the currently available antimalarial drugs and developing resistance to the artemisinins enforces a need to discover new anti-malarial therapies. Recently, substantial effort has been put into defining the desired Target-Product Profiles (TPP) to drive another global eradication campaign. The backbone product for the ongoing campaign is defined as the Single Exposure Radical Cure and Prophylaxis (SERCAP) – a single, multi-component drug that would cure a treated patient after one exposure and provide substantial post treatment protection from reinfection and recrudescence. The drug is envisaged to have three main components: a fast parasite clearance ingredient, a long duration ingredient, and a transmission blocking / relapse prevention ingredient.
The scientific rationale for this project is the development of a novel chemical entity capable of meeting both the fast 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, producing a 6-log drop of parasitemia with one or two oral doses. The molecule must be highly orally bioavailable, safe (especially with no enhanced risk for G6PD deficient patients), and possess a low propensity for resistance.
Screening of a large diversity library revealed the dihydroisoquinolones (DHIQ’s), as a chemically novel class of antimalarials targeting PfATP4.
A clinical candidate has emerged from these studies, (+)-SJ000557733, (+)-SJ733 for short, that meets or exceeds all of the requirements for a SERCaP fast acting component.
How can your partnership (project) address global health challenges?
The (+)-SJ733 project aligns with the MMV Target Product and Candidate Profiles that were established in 2013 to better define the needs of the eradication agenda. As such, (+)-SJ733 fulfills the criteria for a rapid acting antimalarial (TCP1) for use in a combination therapy for treatment (TPP1). The compound acts via PfATP4, a clinically validated pathway based on the data from Novartis’ KAE609. Furthermore, the clinical rate of parasite clearance for this mechanism is extremely rapid, so assuming (+)-SJ733 works in a similar way then the principle efficacy requirements are significantly de-risked. (+)-SJ733 is a remarkably ‘clean’ compound with safety margins projected to be between better than 40-fold, coupled with the fact that the dose limiting toxicity is still relatively innocuous.
Thus (+)-SJ733 offers not only a high likelihood of excellent efficacy but also good tolerability and lack of drug-drug interactions – a quality that is particularly important given the targeted patient population, the state of the health care systems in endemic regions and the times of co-morbidities (and resultant drug regimens) that patients are often on. The risk with (+)-SJ733 pertains to the human pharmacokinetics. If in the expected range, a single dose treatment is likely; at worst, an acceptable 3 day treatment will be targeted. Thus (+)-SJ733 will be positioned to either replace artemisinin, which is particularly relevant given observed decreased parasite clearance times with ART in SE Asia or, at best, to be a new fast acting component in a single dose combination treatment.
What sort of innovation are you bringing in your project?
The team brings state of the art drug discovery and development science to the problem of tailoring a novel PfATP4 inhibitor to use for treatment of malaria.
The project is based on a completely new scaffold that targets a clinically validated target; if successful it would be the second PfATP4 inhibitor to go to the clinic. We will utilize an integrated approach, including chemical sciences, pharmacological sciences, and clinical sciences to prove the compound safe and efficacious in humans.
Role and Responsibility of Each Partner
Eisai will be responsible for developing a process for manufacture of the active pharmaceutical ingredient and drug product to be tested. They will coordinate contract research organizations to produce this clinical grade material. Eisai will also carry out GLP toxicology studies, particularly in the dog, and coordinate the toxicology evaluation for the active ingredient. Finally, they will assist in preparation of the CMC and toxicology portions of the IND.
St. Jude will manage the overall project, ensuring completion and planning to work around any issues that arise. They will also have responsibility for coordinating the assembly of the IND and filing the IND application with the FDA. St. Jude will carry out the Phase 1a studies at a local clinical site and will be responsible for initiating the Phase 1b site once an appropriate tolerated dose is found.
MMV will review the IND and assist in its preparation and submission. Once a tolerated dose has been found, MMV will oversee the Phase 1b study, which will be completed at Queensland Institute of Medical Research (QIMR) using the human challenge model. They will work with QIMR to define the protocol, and coordinate submission of information to the Australian regulatory authorities.