- RFP Year2014
- Awarded Amount$2,997,525
- Development StageLead Optimization
- Collaboration PartnersEisai Co., Ltd., Broad Institute
Introduction and Background of the Project
While the global public health community has made significant progress in reducing mortality due to malaria, this mosquito-borne parasite still infects over 200 million people per year. Approximately 625,000 deaths were attributed to malaria in 2012, the majority 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, and the dormant liver stages of Plasmodium vivax and Plasmodium ovale.
The Broad Institute has discovered a series of compounds with an apparently novel mechanism of action and with potent activity against blood-stage Plasmodium falciparum, as well as liver and transmission-stage parasites. Compounds in this series show excellent efficacy in mouse models of malaria. We believe that further development of the current leads, in partnership with Eisai and the GHIT Fund, could yield a clinical candidate with a much-desired therapeutic profile including rapid parasite clearance, activity against drug-resistant strains, and prophylactic and transmission-blocking activity. The goal of this proposal is to further optimize these compounds to yield a preclinical candidate that meets one of the target product profiles defined by MMV (Medicines for Malaria Venture).
How can your partnership (project) address global health challenges?
Elimination of malaria will require concerted and integrated public health measures that include vector (mosquito) control, rapid diagnostics, effective and long-lasting vaccines, and a range of new antimalarial medicines. New therapeutics should include drugs that can address slowing response rates to artemisinin-based endoperoxides, prevent transmission to mosquitoes, and target the dormant liver stage of P. vivax and P. ovale. Unfortunately, the current pipeline not only lacks compounds that meet all of these criteria, but it also has very few compounds with novel mechanisms-of-action that would be useful to combat growing resistance.
Medicines for Malaria Venture (MMV) has targeted development of a Single Exposure Radical Cure and Prophylaxis (SERCaP) for treatment of uncomplicated malaria in adults and children. The target product profile (TPP) for the ideal SERCaP would include rapid blood-stage parasite reduction, transmission blocking activity, and targeting of dormant liver stage parasites. The SERCaP would comprise at least two drugs to reduce the likelihood of resistance emergence. The goal of our partnership is to identify a therapeutic candidate that could be included in a SERCaP combination. The compounds we are developing are active against drug-resistant parasites; in addition, they are active against multiple stages of the parasites, including the blood, liver, and transmission stages. Introduction of drugs with new mechanisms of action and activity against multiple stages of the parasite will be crucial in the campaign to eradicated malaria.
What sort of innovation are you bringing in your project?
The compounds we hope to develop into new malaria therapeutics are novel in two respects. First, the compounds are derived from a unique chemical process termed Diversity-oriented synthesis, which allows us to synthesize complex molecules that have many of the advantages of natural products (e.g. structural diversity) but are also easily modified and optimized in the laboratory. The Broad’s compound library comprises 100,000 such compounds that are not available anywhere else. Secondly, our compounds appear to be inhibiting a component of protein synthesis that is not targeted by any other malaria therapeutics. This novel mechanism-of-action will be useful in the clinic to inhibit malaria parasites that are resistant to all other malaria therapies, including chloroquine and pyrimethamine/sulfadoxine.
Role and Responsibility of Each Partner
Eisai scientists actively participate in the project in the following areas:
- Chemistry: Medicinal Chemistry strategy, synthesis route optimization, scaling up of intermediates and final products
- ADME: metabolic stability of analogs, structure of metabolites, pharmacokinetic evaluation in animals, tissue distribution
- Safety: safety evaluation including rodent and non rodent toxicity, safety pharmacology and genotoxicity studies.
A phenotypic screen of the Broad Institute’s Diversity-oriented synthesis library identified a unique chemical series with novel mechanism of action and with potent activity against blood-stage Plasmodium falciparum, as well as liver and transmission-stage parasites. Building on the modular synthetic pathway utilized in the creation of the library, the Broad scientists lead the medicinal chemistry efforts to improve in vitro potency, physicochemical and pharmacokinetics properties, and the safety profile of the series. Advanced studies conducted at the Broad Institute include target identification/validation as well as a variety of in vivo efficacy studies.