Awarded Amount$3,768,922DiseaseMalariaInterventionDrugDevelopment StagePreclinical developmentCollaboration 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.
1. Project objective
Demonstrate the viability of SJ733 as a rapidly acting component of a combination medicine for the treatment of malaria.
2. Project design
The project design was to first develop and manufacture, under cGMP, a suitable clinical formulation of SJ733; to demonstrate appropriate safety and bioavailability of SJ733 in GLP preclinical studies; to obtain a US-FDA IND for SJ733; to carry out Phase 1a studies with SJ733 in healthy volunteers; and to carry out Phase 1b studies of SJ733 in subjects infected with P. falciparum malaria.
3. Results, lessons learned
The clinical candidate SJ733 was developed by a consortium of researchers in the academic and non-profit sectors including St Jude Children’s Research Hospital, Eisai, Medicines for Malaria Venture, and the University of Kentucky. This grant supported the preclinical and early clinical development of SJ733. A process compatible route was developed to produce kilogram quantities of SJ733 HCl salt and a formulation developed to deliver capsules of this active ingredient manufactured under cGMP. GLP toxicology, pharmacokinetic, and safety pharmacology studies were carried out using rat and dog models to demonstrate that SJ733 was well tolerated at all doses studied, exhibited high oral bioavailability, and that the dose limiting toxicology was production of methemoglobin. The IND enabling experiments also suggested the clinical candidate would have a high therapeutic index and rapid pharmacodynamic effects.
These data were used to successfully file an FDA-IND for SJ733 and Phase 1a studies were initiated with SJ733. All subjects tolerated the study drug well with no serious adverse events or dose limiting toxicities noted in single and repeat doses of up to 1200 mg. AUC increased proportionally with dose up to doses of 600 mg, at which point a plateau in absorption was observed. Based on this data, a Phase 1b was initiated in the human challenge model and fast parasite kill was observed with SJ733 causing roughly a 1,000,000-fold decrease in parasitemia within 48 hours of dosing. SJ733 also blocks the formation of gametocytes in human subjects.
Thus, SJ733 is a novel inhibitor of PfATP4, a critical ion channel in the parasite that causes malaria. In preclinical models SJ733 is orally bioavailable, well tolerated, efficacious against both blood and sexual stages, potent, and extremely fast acting. Phase 1a studies suggest that SJ733 is highly orally bioavailable, safe, and well tolerated in humans. Phase 1b data support the concept that combinations of SJ733 could be efficacious. Based on these data, the selection of appropriate combination drugs and execution of Phase 2a studies to obtain clinical proof-of-concept for such combination drugs is ongoing.
Preclinical and clinical development of (+)-SJ000557733, a novel inhibitor of Plasmodium ATP4