Introduction and Background of the Project

Introduction

Malaria is a mosquito-borne, life-threating infectious disease caused by Plasmodium protozoa parasites. An estimated 405,000 people died in 2018, mainly children in African countries. The current standard of care for the treatment of malaria typically involves combination therapy with artemisinin derivatives. However, there is evidence of emerging resistance to artemisinin and its partner drugs in some countries such as Cambodia, Thailand, Myanmar and Vietnam. This highlights the urgent need for new classes of compounds with novel mechanisms-of-action (MoA) to treat resistant strains of malaria parasites and support the global malaria eradication strategy.

In this project, we aim to conduct Investigational New Drug(IND)-enabling Good Laboratory Practice (GLP) preclinical studies on an antimalarial candidate compound with a well-characterized and novel MoA.

Glycosylphosphatidylinositol (GPI) is a common moiety in all eukaryotes which has a role in anchoring many proteins to the cell surface. Gwt1p, one of the essential enzymes in the GPI biosynthesis pathway, was identified by Eisai as a novel target for an antifungal drug. After conducting discovery research, Eisai discovered E1210, an antifungal drug clinical candidate, and found that the GWT1 gene encoding Gwt1p enzyme is highly conserved among eukaryotes, including Plasmodium protozoa, the etiological pathogens for malaria. Eisai has screened an internal compound library targeting fungal Gwt1p and found a hit compound with inhibitory activities on plasmodial Gwt1p. This compound showed anti-Plasmodium activities in vitro and in vivo and was subjected to chemical modification in GHIT Hit-to-Lead and Lead Optimization Platforms. MMV and Eisai succeeded in creating the candidate compound with improved anti-Plasmodium activity and the long half-life required for single-dose malaria treatment.

Project objective

The objective of this proposal is to complete preclinical development and IND-enabling GLP studies with a candidate identified in a project funded through the GHIT grant G2017-109.

Project design

The current synthetic route will be optimized in a collaboration between Charles River’s medicinal chemists and Eisai’s process chemists, and a salt form screening will be conducted. Based on the optimized route, Eisai will focus on the following specific objectives:

1. Manufacture the drug substance required for preclinical studies and phase I trials. The drug substance for preclinical studies will be released around year 1.
2. Manufacture drug product for phase I trial by the end of the second year.
3. Conduct preclinical DMPK and safety studies required for First-in-Human (FiH) study submission, such as GLP  preclinical toxicity in rodents and non-rodents, genotoxicity, safety pharmacology, metabolite identification in the second year.
4. Validate the bioanalytical method to support clinical trials.
5. Prepare for submission to conduct FiH studies in March 2022.

MMV will also conduct in vivo evaluations to identify possible partner drugs using a humanized murine model. After these studies, MMV will support the selection of sites for phase I FiH and a Volunteer Infection Study, the preparation of the study protocols, the Investigator’s Brochure, the Investigational Medicinal Product Dossier (IMPD) and other documentation required for FiH submission in collaboration with Eisai.

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

Malaria is still one of the most life-threating diseases and many children still die, especially in sub-Saharan African countries. In these countries, children catch malaria time and time again, due to a low immunity to malaria. This project is proposed to contribute to the eradication of malaria based on its novel and unique mechanism-of-action (MoA), as described below. To control and eliminate infectious diseases, and particularly for eradication, vector control, prevention of infection by vaccines and treatment with drug are all equally important. For malaria, each of them is under evaluation. Antimalarial drugs have shown memorable improvements in last century, but this great footprint is at risk of being washed away by the appearance of resistant parasites. This project is thought to fulfill several of the target profiles set for the next generation of antimalarial drugs targeting malaria eradication. Our novel MoA is highly expected to lead to new antimalarial drugs with novel characteristics, which have never been seen before, and therefore to save many childrens’ lives in the future.

What sort of innovation are you bringing in your project?

The most promising advantage of this project is a novel MoA with an identified target protein. The MoA is inhibition of GPI-biosynthesis and this is a completely novel concept in the treatment of malaria. Furthermore, the target protein Gwt1p, an acyltransferase essential in GPI-biosynthesis, was discovered in Eisai and no other discovery activities targeting this enzyme are reported. Based on its novel mechanism, Gwt1p-inhibitors are expected to act on Plasmodium strains resistant to existing antimalarials, including artemisinins. The existing data suggests that the character of candidate Gwt1p-inhibitor is consistent with TCP1 for malaria treatment, set by MMV, maintaining effective drug concentration due to a sufficiently long half-life. As a second advantage, inhibition of GPI-biosynthesis is expected to lead to anti-Plasmodium activities against multiple parasite life stages, because many kinds of stage-specific GPI-anchored proteins are expressed in each life stage of the malaria parasite. For example, in the sexual stages of P. falciparum, a GPI-anchored protein named Pfs48/45 is expressed in male gametocytes and this protein is essential for sexual mating. These expected efficacies would be consistent with other TCP’s, such as transmission blocking (TCP5) or chemoprotection (TCP4). As a third advantage, in addition to these direct anti-Plasmodium activities, inhibition of Gwt1p is expected to show additional preferable characteristics such as activation of the immunization system of the host or a decrease in the inflammatory response caused by malaria infection.

Role and Responsibility of Each Partner

Eisai will be responsible for preclinical, GLP safety evaluations and CMC studies including the manufacturing of drug substance and drug product. Eisai will also be responsible for synthesis of new compounds and the primary evaluation of synthesized compounds in the back-up activity. Eisai will contract with Charles River, a CRO which is located in Eisai’s facility, for chemistry work.

MMV is responsible for malaria lifecycle profiling and in vivo efficacy evaluation of key compounds toward IND submission, using its research network. MMV is also responsible for SCID studies (monotherapy and combination to select optimal partners for combination development).

Eisai and MMV will collaborate to select the sites for phase I FIH and a Volunteer Infection Study, prepare the study protocols, the IB, IMPD and other documentation required for IND (or equivalent other regulatory) submission. MMV will take the lead for this activity as the expert in malaria drug development using its expertise in early phase clinical studies to characterize novel antimalarial drug candidates.     

Others (including references if necessary)

References

1. http://www.who.int/malaria/publications/world-malaria-report-2016/report/en/

2. Yeung S, Socheat D, Moorthy VS et al. Artemisinin resistance on the Thai-Cambodian border. Lancet 2009; 374: 1418-9.

3. Hawkes M, Conroy AL, Kain KC. Spread of artemisinin resistance in malaria. The New England journal of medicine 2014; 371: 1944-5.

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5. Sagane K, Umemura M, Ogawa-Mitsuhashi K et al. Analysis of membrane topology and identification of essential residues for the yeast endoplasmic reticulum inositol acyltransferase Gwt1p. The Journal of biological chemistry 2011; 286: 14649-58.

6. Tsukahara K, Hata K, Nakamoto K et al. Medicinal genetics approach towards identifying the molecular target of a novel inhibitor of fungal cell wall assembly. Mol Microbiol 2003; 48: 1029-42.

7. Umemura M, Okamoto M, Nakayama K et al. GWT1 gene is required for inositol acylation of glycosylphosphatidylinositol anchors in yeast. The Journal of biological chemistry 2003; 278: 23639-47.

8. Miyazaki M, Horii T, Hata K et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrobial agents and chemotherapy 2011; 55: 4652-8.

9. Burrows et al. New Developments in Anti-Malarial Target Candidate and Product Profiles. Malar J 2017; 16:26