Introduction and Background of the Project

Introduction

Malaria continues to be a major burden for the people in Tropical and subtropical regions, causing 619,000 deaths, mostly children under five, and 247 million cases in 2021¹. The artemisinin-based combination therapy (ACT) is the current first-line therapy, however, the rise and spread of drug- resistant parasites threaten this effective treatment. Therefore, the need for novel, safe, and effective drugs to overcome drug resistance is paramount for global health. Shionogi & Co., Ltd. and Nagasaki University have been working together to provide a novel treatment option for drug resistance in malaria since 2019². In this partnership, 80,000 compounds from Shionogi’s chemical library were screened with a novel phenotypic method established at Nagasaki University against the asexual blood stage of P. falciparum. With the support of Medicines for Malaria Venture (MMV), 5 structurally novel hit series with fast-acting properties were identified. In this project, Hit to Lead study for these hits will be conducted to identify a novel lead series that could overcome the drug resistance issue and provide single dose treatment.

Project objective

The objective of this project is to identify a novel lead series that could overcome the drug resistance issues and satisfy the MMV’s early lead criteria³ by conducting structure activity relationship (SAR) study for five novel hit series.

Project design

This project will be divided into two parts. In the first part, all 5 hit series will be explored to understand their potential for higher potency, safety and the activity on known drug resistance strains within 6 months. In the second part, one or two series will be prioritized, and we will continue the SAR study for further potency and characterization of the series. A promising series will be subjected to in vivo efficacy study in mice.

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

According to WHO, children under 5 accounted for about 80% of all malaria deaths in 20211. This project aims to provides a novel drug that is safe for high-risk populations, such as children under 5 and pregnant women, and effective on drug resistant parasites. By delivering a novel treatment option for patients, we would like to commit the global health toward the malaria control and elimination.

What sort of innovation are you bringing in your project?

The novel hit series in this project have novel chemical structures as antimalarials and are potentially working with novel mechanism of action, which is important to ensure the activity on drug resistant parasites. The hit series were also confirmed to have fast-acting properties, which is desired for a novel treatment drug. In this project, we aim to identify a novel lead series by utilizing novel pharmacological assays established at Nagasaki University in the SAR study.

Role and Responsibility of Each Partner

Shionogi leads the SAR study by designing and synthesizing novel compounds, and conducts pharmacokinetics and safety evaluations. Nagasaki University provides parasitological expertise and conducts studies to characterize the compounds. MMV supports the project by giving advice based on their expertise in antimalarial drug discovery and provides some essential assays to differentiate our series from the existing drugs.

Others (including references if necessary)

1. WHO fact sheets (8 December 2022)

https://www.who.int/news-room/fact-sheets/detail/malaria

2. Shionogi & Co., Ltd.　Press release　(28 February 2019)

https://www.shionogi.com/content/dam/shionogi/jp/news/pdf/2019/190228_012.pdf

3. MMV Frontrunner template: early leads

https://www.mmv.org/research-development/information-scientists

Final Report

1. Project objective:

This project aimed at obtaining a novel lead series that is effective to existing drug resistant malaria and satisfies MMV’s early lead criteria through structure activity relationship (SAR) studies of five phenotypic screening hit series.

2. Project design:

All five hit series were explored in the initial six months to prioritize the promising series in terms of the pharmacology, safety and DMPK. The prioritized series were further explored in the next 18 months for higher potency and pharmacological characterization.

3. Results, lessons learned:

One most promising series was prioritized from initial five hit series through the SAR studies. The series was structurally novel and showed promising properties such as high potency, fast rate of kill and high metabolic stability. The series did not show cross-resistance to resistant parasites for drugs with known mechanisms, implying potential novel mechanism of action. In resistance risk assessment studies, some compounds in the series were resistance refractory, while some others generated low-grade resistant parasites. The target identification studies by using those compounds are underway. Overall, the series is satisfying target criteria, but some of the key data, such as in vivo efficacy, was not obtained with the most promising compounds yet, thereby further research is needed.

One of the challenges we faced in the project was the difficulty in doing research without knowing the mechanism, where inconsistent results, such as in rate of kill and resistance risk studies, were seen even in the same series, which could be typical in phenotypic screening projects. Even with these challenges, the relationship between some of the structural features and pharmacology were being found in the SAR studies. This could have been only achieved by efficient international collaboration that allowed access to various assays and sufficient number of compounds screened.

The research is continuing for further characterization, and the proposal to next step is under consideration with patient needs and differentiation in mind.