Introduction and Background of the Project

1.Introduction

Malaria continues to be a major public health problem with more than 249 million cases and 608,000 deaths estimated in 2022 worldwide. Because of rapid progression and lethality of malaria, prevention becomes the key to save lives especially when healthcare access is limited. The WHO recommended chemoprevention programs for the most vulnerable populations are widely accepted and rapidly expanding in eligible regions. For example, the seasonal malaria chemoprevention is providing prevention to 49 million children in 2022*1. Although the current first-line oral drugs are generally safe and effective, they face challenges such as parasite resistance and incomplete adherence issues. In addition, monthly distribution of oral drugs to every household requires substantial resources and cost in resource limited settings. Therefore, a highly effective long-acting injectables (LAI) which can cover the whole transmission season by a single injection may prove a simpler and cost-effective option to tackle those issues*2.

2.Project objective

The objective of this project is to identify a preclinical candidate for LAI in malaria chemoprevention. A promising lead series has been identified, in collaboration with Nagasaki University, Shionogi, National Institute of Infectious Diseases, and Medicines for Malaria Venture (MMV), which targets malarial electron transport chain, a well validated target for antimalarial medications. The project aims to optimize the lead and obtain a preclinical development candidate that meet MMV’s preclinical candidate criteria*3.

3.Project design

The project aims to provide a preclinical candidate in two years. A frontrunner compound will be evaluated for the in vivo safety and DMPK studies. In parallel, a lead optimization study will be conducted in search for the second runner candidate with even greater promise than the frontrunner candidate. The most promising compounds will be subjected to extensive in vivo safety and pharmacokinetics studies to satisfy MMV’s preclinical candidate criteria.

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

Malaria is a major public health problem, particularly affecting children under the age of five, and poses significant healthcare and economic burden in afflicted countries. Despite the WHO targets for malaria elimination and eradication, the number of cases and deaths remains persistently high, displaying little reduction^*4. Therefore, there is a critical need for more effective and novel intervention tools. We aim to develop an LAI that could cover the whole high transmission season by single injection with activities against multiple stages of the malaria lifecycle and high barrier against resistance. A highly effective and convenient LAI has the potential to overcome current limitations associated with oral chemoprevention drugs. It may also be useful in perennial transmission settings where chemoprevention programs are currently lacking, or in the remote areas where monthly drug delivery is logistically challenging. We aim to free the most vulnerable people from the threats and burdens imposed by malaria, contributing significantly to the global agenda of malaria elimination and eradication.

What sort of innovation are you bringing in your project?

Our innovation focuses on the development of a LAI for malaria chemoprevention. When a LAI is injected intramuscularly or subcutaneously, the active ingredient is slowly absorbed into the body, ensuring sustained efficacy over an extended duration. This stands in contrast to the current approach, where chemoprevention relies on the monthly distribution of oral drugs to households, contingent on individual’s willingness to complete the regimen every month. Therefore, the proposed LAI introduces a groundbreaking shift by offering a seasonal, single dose solution. Our innovative LAI has the potential to transform current chemoprevention programs.

Role and Responsibility of Each Partner

In the SAR study, Shionogi takes the lead by designing and synthesizing novel compounds, and conducting safety and pharmacokinetics evaluations, including LAI formulations. Complementing this effort, Nagasaki University and National Institute of Infectious Diseases provide parasitological expertise, conducting studies to characterize the properties of the synthesized compounds. MMV supports the project by giving advice based on their extensive expertise in antimalarial drug discovery, and provides essential assays crucial for candidate selection.

Others (including references if necessary)

1, World Malaria Report 2023, WHO

https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2023

2, Macintyre et al., Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria, Malaria Journal, 2018, 17, 402.

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-018-2549-1

3, Preclinical candidate criteria 2021, MMV

https://www.mmv.org/frontrunner-templates

4, Global technical strategy for malaria 2016-2030, 2021 update, WHO

https://www.who.int/publications/i/item/9789240031357