Introduction and Background of the Project

This project builds on the screening of a Daiichi-Sankyo 50,000 compound library against the asexual blood and liver and sexual stages of malaria.  The library was made up of high quality, diverse proprietary compounds designed and synthesized by Daiichi-Sankyo.  The screening was performed at the Eskitis Institute in Brisbane, Australia by Prof Vicky Avery, and at the University of California, San Diego (UCSD), in San Diego, USA by Prof Elizabeth Winzeler in collaboration with Daiichi-Sankyo and MMV; this was made possible by support from the GHIT Fund.  The hit compounds were first confirmed as being active selectively against Plasmodium by obtaining concentration-response data against parasites and mammalian cells.  The most interesting frontrunners were then resynthesized and fully tested to ensure the compounds met the stringent GHIT Hit to Lead Platform criteria.  The proposal focuses on three confirmed hit series, though given the likely attrition, particularly in the early stages, there are additional options for chemistry should any series fail quickly.  The objectives for the project are to transform these hits into Lead series with proven in vivo efficacy so as to build a strong Lead Optimisation project for the future, and ultimately deliver a preclinical candidate for malaria.  The chemistry for the project will be lead out of Daiichi-Sankyo India in New Delhi, and the team will consist of scientific experts from Daiichi-Sankyo, Japan and MMV as well as parasitology and DMPK experts from within the MMV network.

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

Malaria is still a devastating disease affecting hundreds of millions of people each year.  Mercifully the number of fatalities due to malaria has been decreasing over the last decade with approximately 630,000 deaths estimated in 2012 by the WHO.  The majority of these deaths are in sub-Saharan Africa and in children under the age of five.  MMV has worked with the wider community to establish five Target Candidate Profiles (TCPs) that emphasise the types of molecule needed to not only control but also eradicate the disease.  This collaborative project is focused on delivering compounds that meet at least one of the five TCPs, namely: i) rapid parasite clearance to relieve symptoms quickly, ii) partner drug to deliver a total cure, ideally with long duration to deliver post-treatment prophylaxis, iii) anti-relapse medicines for patients with Plasmodium vivax and ovale, iv) transmission blocking through targeting the host gametocyte population and preventing infection to the mosquito and v) chemoprotection to protect vulnerable populations from reinfection.

What sort of innovation are you bringing in your project?

Given the maturity of the global pipeline of drugs to tackle malaria, it is critical for future medicines to have something distinct about them.  This collaborative project between Daiichi-Sankyo, MMV and GHIT will focus on compound series having novel mechanisms of action in order to combat the inevitability of resistance; we will also prioritise compound series meeting some of the TCPs that are under represented, in particular those targeting the hypnozoites in Plasmodium vivax and ovale and, hence, have the potential to block relapse, as well as compounds targeting transmission blocking and chemoprotection.  The series covered within the proposal are new to the MMV portfolio and we hope that through the transformation from hits to leads, Daiichi-Sankyo-MMV will deliver a robust Lead optimization project.

Others (including references if necessary)

1. MMV Target Candidate profiles: (Burrows, van Huijsduijnen, Möhrle, Oeuvray, & Wells, 2013

2. Asexual blood stage assay: (Duffy & Avery, 2012)

3. Sexual stage assay: (Lucantoni & Avery, 2012)

4. Liver stage assay: (Meister et al., 2011)