Investment

Details

Preclinical development of a novel mechanism-of-action antimalarial drug with multistage activity

Introduction and Background of the Project

Introduction

Treatment and ultimately elimination of malaria remains a massive challenge due, mainly, to the emergence of drug-resistant strains of Plasmodium falciparum, the most lethal species in humans. It is therefore necessary to discover lead candidates unaffected by existing mechanisms of resistance to traditional antimalarial chemotypes. Additionally, while prophylaxis and transmission-blocking drugs are needed to prevent epidemics and to protect vulnerable populations, standard-of-care antimalarials do not address all of the requirements for pan-lifecycle activity. The Broad Institute, in collaboration with Eisai Ltd., has discovered a series of antimalarial compounds with a novel mechanism of action (targeting Plasmodium falciparum cytosolic phenylalanine tRNA synthetase (PfcPheRS)) (Nature, doi:10.1038/nature19804). Our unique bicyclic azetidine series exhibits potent activity both in vitro and in vivo against blood-, liver- and transmission-stage P. falciparum parasites.

 

Project objective

The current proposal builds on the progress made with GHIT support (G2014-107 and G2016-219) that delivered multiple compounds with excellent therapeutic profiles and improved synthetic routes. These advances will enable completion of preclinical development studies and Investigational New Drug (IND)-enabling Good Laboratory Practice (GLP) studies, with the goal of nominating a candidate for Phase I clinical studies aligned with the target candidate profiles defined by Medicines for Malaria Venture (MMV). 

 

Project design

The project is designed to generate in-depth preclinical data around the most promising candidate of the bicyclic azetidine chemical series, with the goal of nominating an antimalarial candidate for Phase I clinical studies. The main objectives of the project include: 1) physicochemical profiling of the candidate and selection of salt form; 2) preparation of material in accordance with Good Laboratory Practice (GLP) guidelines; 3) development of dosage form; 4) Investigational New Drug (IND)-enabling non-clinical safety studies. 

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

While the global public health community has made significant progress in reducing mortality due to malaria, this mosquito-borne parasite still infects over 212 million people per year. Approximately 435,000 deaths were attributed to malaria in 2017, the majority (61%) of them in children under the age of five. In order to further decrease the morbidity and mortality associated with malaria, a multi-pronged approach is required, including vector (mosquito) control, effective vaccines, and new chemotherapeutics that can target drug-resistant parasites, the infectious and transmission stages of the parasites (sporozoites and gametocytes, respectively), and the dormant hypnozoite stages of P. vivax and P. ovale. Medicines for Malaria Venture (MMV) has proposed the development of a Single Exposure Radical Cure and Prophylaxis (SERCaP) for the treatment of uncomplicated malaria in adults and children. The target product profile (TPP) for the ideal SERCaP would include rapid asexual blood-stage parasite reduction, transmission-blocking activity, and targeting of hypnozoites. We anticipate that a candidate from the proposed work would not only meet the requirements of at least one MMV TCP, but due to the known activity against gametocytes and liver-stage parasites, would provide a significant advantage to patients. 

What sort of innovation are you bringing in your project?

Effective eradication strategies for the treatment of malaria have been elusive, primarily owing to the complex life cycle of Plasmodium and the emergence of drug-resistant strains of P. falciparum, the most lethal Plasmodium species in humans. The majority of the current antimalarial drugs target the asexual blood stage of Plasmodium, in which they parasitize and replicate within erythrocytes. Even though liver and transmission-stage parasites do not cause malarial symptoms, prophylaxis and transmission-blocking drugs are essential for the proactive prevention of disease epidemics and to protect vulnerable populations. Unfortunately, the current antimalarial drugs do not address all of the requirements for the targeting of pan-life-cycle activity. Our unique bicyclic azetidine series exhibits potent activity both in vitro and in vivo against blood-, liver- and transmission-stage P. falciparum parasites with a novel mechanism of action (targeting Plasmodium falciparum cytosolic phenylalanine tRNA synthetase (PfcPheRS)). 

Role and Responsibility of Each Partner

Project members from the Broad Institute and Eisai will collaborate closely in order to execute on the project plan:

– Broad is the designated development partner for the project. Broad will contribute to project management and leadership, and to the optimization of the synthesis of the Active Pharmaceutical Ingredient.

– Eisai will contribute to project management and leadership. Additionally, Eisai will be responsible for toxicology studies, physicochemical characterization studies, preparation of the candidate compound and preliminary development of the dosage form, as well as for monitoring IND-enabling non-clinical safety studies. 

Others (including references if necessary)

Nature, doi:10.1038/nature19804