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. If resistance becomes widespread in Africa (where most deaths occur), a major health crisis is possible. In response to this impending crisis and with the eventual aim of eradicating the disease, MMV and Astellas as a collaboration partner seek to discover, develop, and deliver new drugs with novel modes of action which address resistance associated with existing therapeutics. Development of compounds which can block transmission and be used in chemoprotection/chemoprevention, in addition to acute treatment, are especially valuable to drive the eradication agenda.

Previously, supported by GHIT funding, hit compounds with antimalarial activity were identified from screening a compound library provided by Astellas. Initial profiling of the hit compounds demonstrated that they are novel, attractive start points for a Hit Validation and subsequent Hit-to-Lead project with potential to deliver new malaria drug candidates.

2. Project objective

The objective of the project is to identify at least 1 novel compound series meeting MMV Early Lead Criteria (1) that has clear potential for further development and progression to Lead Optimization.

3. Project design

The project will consist of two phases. The first 6-month phase will involve the synthesis and profiling of small set of compounds designed around each of the four hit compounds identified in the previous project. The compounds will be designed to explore both structure activity relationships (SAR) and scope for structural modification to improve the compound profile (potency, DMPK, safety, etc.). Two series will be selected for Hit-to-Lead studies. The second 18-month phase of the project will involve the optimization of the series (prioritizing the series with the greatest potential) with the goal of identifying a series with a frontrunner compound meeting the MMV Early Lead criteria.

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

MMV has worked with the wider malaria community to establish Target Candidate Profiles (TCPs) that define the attributes of the next generation antimalarials needed to not only control but also eradicate the disease (2).

Key characteristics are:

• New drugs for treatment or protection that are fast acting and have 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 contra-indication for use by children and women of child-bearing potential.

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

What sort of innovation are you bringing in your project?

All the compound series being explored have been prioritized based on novelty of the chemotype, life-cycle fingerprint, and the extent to which they fill strategic gaps in the MMV portfolio. Compound series will only be proposed for Lead Optimization if they fulfill the MMV Early Lead criteria (1) and are differentiated from existing series in the MMV portfolio at the time of the LO proposal. All series have novel drug-like chemotypes and mechanism of action, different from current antimalarial drugs in use or compounds in the clinical pipeline.

Role and Responsibility of Each Partner

TCGLS will be responsible for compound synthesis and, in vitro parasitology (asexual blood stage growth inhibition and rate of kill), cytotoxicity and DMPK. All other assays will be provided by MMV network test centers or the appropriate CRO. MMV will lead project strategy, medicinal chemistry (data analysis and compound design) and ensure alignment with global malaria elimination goals. Astellas will contribute to the design of new analogues and interpretation of the data using state of the art computer-aided drug design techniques.

Others (including references if necessary)

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

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