Introduction and Background of the Project

Malaria, a mosquito-borne parasite, can still infect over 200 million people per year. There were an estimated 584,000 malaria deaths worldwide in 2013 with 78% of global malaria deaths which were estimated to occur in children under 5 years of age. Whilst advances have been made in reducing the numbers of cases and deaths, it is clear that if the global heath community wants Malaria to be eradicated world wild, a strategy including multi-pronged approach is required, including vector (mosquito) control, effective vaccines, and new chemotherapeutics that can target drug-resistant parasites, the infectious and transmission stages of the parasites, and the dormant liver stages of Plasmodium vivax and Plasmodium ovale. Moreover, resistance to artemisinin (ART), the WHO recommended treatment for Malaria, resulting in a decreased parasite clearance times in response to ART derivative treatment has been reported and combatting it is the immediate threat and outline the urgent need for new and highly effective antimalarials.

This project builds on the screening of a Takeda 50,000 compound library against the asexual blood, liver and sexual stages of malaria. The library was made up of high quality, diverse proprietary compounds designed and synthesized by Takeda. 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 Takeda and MMV; this was made possible by support from the GHIT Fund. The team is now working on three confirmed chemical hit series inhibiting the asexual blood and the liver stages of the parasite life cycle. 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 eradication of malaria. The team will consist of scientific experts from Takeda, Japan and MMV as well as parasitology and DMPK experts from within the MMV network.

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

In the fight against malaria new medicines are an essential weapon. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made: for example combination medicines which allow for single dose regimens, cheaper, safer and more effective medicines, or improved stability under field conditions. For new medicines to be optimal in malaria control they must also be able to reduce transmission and prevent relapse of dormant forms: additional constraints on a combination medicine. In the absence of a highly effective vaccine, new medicines are also needed to protect patient populations. Unfortunately, the current pipeline not only lacks compounds that meet all of these criteria, but it also has very few compounds with novel mechanisms-of-action that would be useful to combat growing artemisinin resistance. This collaborative project is focused on delivering compounds that meet at least one of those criteria, 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?

As outlined previously it is critical to develop new drugs for malaria with novel chemical scaffolds and novel mechanism of action. Those would be useful in the clinic to inhibit malaria parasites that are resistant to all other malaria therapies, including artemisinin, chloroquine and pyrimethamine/sulfadoxine. This collaborative project between Takeda, MMV and GHIT will therefore focus on compound series with such profiles. We will also prioritize compound series meeting some of the key areas 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, Takeda and MMV will deliver a robust Lead optimization project.

Role and Responsibility of Each Partner

Takeda Pharmaceutical Company Limited (Takeda) has provided over 20,000 compounds among proprietary screening libraries for the assays of asexual blood, liver and sexual stages of malaria in order to discover hit chemical series for the research collaboration project with MMV, and as a result, several hit compounds have been found among them. Takeda's current role is to make scientific advices in the medicinal chemistry plans and the selection of analogue compounds for further studies and profiling of the hit chemical series with scientists in MMV, Eskitis Institute and CDCO, to generate lead compounds as anti-malarial drug candidates. Takeda is also planning to provide advices on DMPK, physicochemical profile, and safety pharmacology utilizing Takeda's experience and expertise to drug discovery and development.

Dr. Brice Campo is a biologist/in vitro pharmacologist and MMV Project Director providing drug discovery expertise and strategic input to the project.  MMV also has the responsibility to connect the team with partners in the MMV network (such as GSK, UCSD, BPRC, Mahidol, USF, TropIQ, Imperial College, STPH and Columbia University) so that data on selected project compounds is available to aid decision making. Dr. Benoit Laleu is a medicinal chemist and currently the Project Leader providing input in the medicinal chemistry plans and analyzing the data received on the parasitological profile of each compounds.

Prof Vicky Avery (Eskitis Institute, Griffiths University) and Prof Susan Charman (CDCO, Monash University) are MMV partners on the team with the responsibilities to deliver in vitro blood stage parasitology data and in vitro/ in vivo DMPK data, respectively, on selected compounds agreed by the project team.

Others (including references if necessary)

WHO World Malaria Report:

http://www.who.int/malaria/publications/world_malaria_report_2014/report/en/

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

Asexual blood stage assay: Duffy & Avery, 2012

Sexual stage assay: Lucantoni & Avery, 2012

Liver stage assay: Meister et al., 2011

Final Report

1. Project objective

The objectives of this project were to transform the hits identified among the high-throughput screening performed on the Takeda library, into Lead series with proven in vivo efficacy in the animal disease models. The goal was to deliver at least one compound series meeting the GHIT/MMV criteria for progression to Lead Optimization stage.

2. Project design  

During the first phase of the project, frontrunner compounds from the three series selected for hit-to-lead progression have been profiled in the parasite life cycle assays to confirm their Target Candidate Profile (TCP) – Milestone 1 achieved. In parallel, medicinal chemistry has been carried out and analogues have been profiled in parasitology and cytotoxicity assays. The physicochemical properties, stability and ADMET characteristics have also be determined in order to design analogues with optimized properties. A mitigation risk strategy had also been defined to identify possible back-up series in case of the ones initially selected were found to be not tractable.

3. Results, lessons learned 

In this program, we have prosecuted 3 hit series as seeds and 1 as back-up. Unfortunately all these series were abandoned 7 months after the start of the project due to poor developability potential. Fortunately, a mitigation risk strategy had already been anticipated and has allowed us to identify 6 new chemical series after further investigation of the GHIT Screening Platform data. While these series were not prosecuted at the beginning of the current proposal, Takeda has now additionally released and made them available to the project team showing the potential of those series as new starting points. We have also identified and repurposed another chemical series from the Takeda portfolio for which the biological target is known. As we have only started chemistry in August 2016 on 3 of the most attractive new series, another application to GHIT for a hit-to-lead funding was submitted by Takeda and MMV, and now accepted by GHIT. This will allow a 1 year extension of our current program to be able to further optimize their properties and select a couple of lead molecules which can be the basis for a new proposal to GHIT for a Lead Optimization program in 2018.

This project has shed light on the importance to have a well-defined mitigation risk strategy to be able to exploit valuable back-up series already identified. Besides, repurposing Takeda chemical series towards antimalarial drug discovery has allowed to benefit not only from in-house knowledge at Takeda but also from a number of analogues readily available in stock. This was found to be critical in order to catch up part of the delays due to the abandon of the series initially picked.