Introduction and Background of the Project

1.Introduction

Each year, Plasmodium falciparum causes more than 200 million cases of malaria, and over 400,000 deaths, mostly in children under 5 and pregnant women. Because current antimalarial control is highly dependent on artemisinin combination therapies (ACTs), it is extremely concerning that decreased parasite sensitivity has emerged to all currently used ACTs, leading to significant failure rates in parts of Southeast Asia and more recently Africa, where partner drug resistance is also becoming evident.

Previously, supported by GHIT funding, hit compounds with antimalarial activity were identified from screening a compound library provided by Daiichi Sankyo. Initial profiling of the hit compounds demonstrated that they meet the MMV Confirmed Active criteria¹ are novel, attractive start points for a Hit Validation project and, if successful, a subsequent Hit-to-Lead project with potential to deliver new malaria drug leads.

2.Project objective

The objective of the Hit Validation project is the synthesis and testing of a small array of compounds designed to investigate the minimum pharmacophore, key structural features required for activity and scope to address issues identified through the profiling of the hits identified from the earlier HTS campaign (S2020-113). If a compelling data package is obtained and the series clear potential for further development towards an Early Lead, a GHIT HTLP proposal will be submitted.

3.Project Design

The focus of the array of analogs is to explore the key features required for activity and scope to address potential issues. A feature of the overall design of the array is focused on modifications with potential to improve the metabolic stability of the series in line with potential to deliver a long duration antimalarial (predicted human T1/2 > 120 h). The lipophilicity of the analogues covers a range of values from approximately 1.5 to 4.5 which will help to identify if data (potency, metabolism, cytotoxicity, etc.) correlates with either LogP or LogD.

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

The emergence of drug resistance poses a significant challenge in the battle against malaria a major global health challenge. If it becomes widespread in Africa, where the majority of malaria-related deaths occur, it could lead to a major health crisis. To address this looming threat and work towards eradicating the disease, MMV and Daiichi Sankyo are collaborating to discover, develop, and provide new drugs with innovative modes of action that can tackle the resistance linked to existing treatments. It is particularly crucial to develop compounds that can prevent transmission and be used for both preventive and acute treatment purposes to drive the agenda for eradicating malaria.

MMV has worked with the wider malaria community to establish Target Candidate Profiles (TCPs)² that define the attributes of the next generation antimalarials needed to control and eradicate the disease.

Key characteristics include:

- New drugs for treatment or protection that are fast-acting and have a long duration.

- New drugs with efficacy against all known field resistance and a low risk of resistance generation.

- New drugs that are developable as a cheap, fixed-dose combination drug with no contraindication for use by children and women of childbearing potential.

The initial profiling of the hit compounds identified from the high-throughput screen indicates that the compounds have potential to meet these criteria.

What sort of innovation are you bringing in your project?

The compound series being explored was prioritized based on novelty of the chemotype, life-cycle fingerprint, and the extent to which they fill strategic gaps in the MMV portfolio. The series will only be proposed for Hit to Lead if it fulfills the MMV Validated Hit criteria¹, is differentiated from existing series in the MMV portfolio and has clear potential for further development. The series that will be investigated in this project has a novel drug-like chemotype and mechanism of action, different from current antimalarial drugs in use or compounds in the clinical pipeline.

Role and Responsibility of Each Partner

MMV as designated grantee for this project is responsible for delivering the work plan to the agreed timeline and budget. MMV is also responsible for GHIT reporting.

The project will be conducted by a team comprising of scientists and project managers from Daiichi Sankyo and MMV and it will be this team that is responsible  for managing all activities. The studies will be conducted in collaboration between Daiichi Sankyo, MMV and MMV partner test centers.

• Daiichi Sankyo will be responsible for compound design.

• MMV will subcontract activities to TCG Lifesciences (Kolkata, India) who will be responsible for compound synthesis and ‘critical path’ assays including parasitology (Pf3D7 and PfDd2), cytotoxicity (HepG2) and DMPK (LogD, kinetic solubility, Albumax binding, human liver microsome stability and rat hepatocyte stability).

All other assays will be provided by MMV network test centers or an appropriate CRO.

All project data will be registered in a shared database managed by MMV and accessible by both partners.

Others (including references if necessary)

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

2.Burrows, J. N., et al. New developments in anti-malarial target candidate and product profiles. Malar. J. 16:26 (2017).