Introduction and Background of the Project

Introduction

Malaria, a mosquito-borne parasite, can still infect over 200 million people per year. There were an estimated 445,000 malaria deaths worldwide in 2016 (1). Novel classes of antimalarial medicines targeting different parasite stages are urgently needed to provide both effective alternatives when resistance to current therapies will inevitably progress and the ingredients needed to meet the malaria eradication agenda (2). The project team is now working on three confirmed chemical hit series inhibiting the asexual blood stage of the parasite life cycle. The prioritized series is directly repurposed from Takeda portfolio, the other two series are from the GHIT Screening Platform with Takeda 20,000 compound library against the asexual blood, liver and sexual stages of malaria. The screening was performed at MMV testing centres in USA (Prof. Elizabeth Winzeler – University of California, San Diego) and in Australia (Prof. Vicky Avery – Griffith Institute for Drug Discovery, Griffith University) against the liver (3), blood asexual (4) and sexual (5) stages of the malaria parasite. 

Project objective

The objectives for the project are to transform these hits into Lead series with proven in vivo efficacy at the animal disease models so as to identify before March 2020 at least one compound series that meets the GHIT/MMV criteria for progression to Lead Optimization stage.

Project design

During the first phase of the project, frontrunner compounds from the three series selected for hit-to-lead progression will be profiled in the parasite life cycle assays to confirm their Target Candidate Profile (TCP). In parallel, medicinal chemistry will be carried out and analogues will be profiled in parasitology and cytotoxicity assays. The physicochemical properties, stability and ADMET characteristics will also be determined. Then the most promising compounds will be evaluated in rodents PK experiments and in the disease model of human malaria to demonstrate in vivo efficacy. After further optimization of their properties, the goal is to select a couple of lead molecules which will be the basis of a new proposal to GHIT for a Lead Optimization program. 

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

In the fight against malaria new medicines are essential weapons. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made. For example, there is a need for combination medicines allowing single dose regimens that are cheaper, safer and more effective and/or with improved stability under field conditions. In the absence of a highly effective vaccine, new drugs are needed to protect patient populations. Moreover, in the context of the malaria eradication agenda endorsed by the Bill and Melinda Gates Foundation and the WHO, new attributes to malaria medicines are required, such as the ability to block transmission between human and mosquitoes and to kill the dormant liver stages. 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. 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 (7). This collaborative project between Takeda, MMV and GHIT is focused on delivering compounds that meet at least one of the TCPs, such as i) rapid clearance of blood-stage parasites to relieve disease symptoms quickly, ii) long-acting profile that, in a combination regimen, is capable of providing a total cure and post-treatment prophylaxis, iii) anti-relapse medicine for patients infected with Plasmodium vivax and Plasmodium ovale, iv) transmission blocking medicine targeting the host gametocyte population and preventing infection to the mosquito and v) chemoprotective agent capable of protecting vulnerable populations from reinfection.

What sort of innovation are you bringing in your project?

The series which are currently investigated have been prioritised based on novelty of the chemotype (and, by inference, the mode of action) or of the drug target, life-cycle fingerprint (in particular dual asexual blood and liver stage activities) relevant for eradication potential, 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 GHIT-MMV criteria (8) and also offer differentiation compared to existing series in the MMV portfolio at the time of the proposal.

Role and Responsibility of Each Partner

The project team consists of medicinal chemistry and biology experts from Takeda and MMV. Takeda's role is to lead this project and to make scientific inputs for the medicinal chemistry plans, the selection of analogues for further studies and the profiling of the hit chemical series with scientists from MMV. Takeda is also planning to provide advices on DMPK, physicochemical profiles and safety pharmacology based on Takeda's experience and expertise in drug discovery and development. MMV's role is to provide drug discovery and malaria biology expertise as well as strategic input to the project.

Others (including references if necessary)

(1)       World Health Organization (WHO). WORLD MALARIA REPORT 2017. (2017). DOI:ISBN: 978 92 4 156552 3

(2)       Wells, T. N. C., Huijsduijnen, R. H. Van, Voorhis, W. C. Van, van Huijsduijnen, R. H. & Van Voorhis, W. C. Malaria medicines : a glass half full ? Nat. Rev. Drug Discov. 14, 424–442 (2016).

(3)       Meister, S. et al. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372–7 (2011).

(4)       Duffy, S. & Avery, V. M. Development and optimization of a novel 384-well anti-malarial imaging assay validated for high-throughput screening. Am. J. Trop. Med. Hyg. 86, 84–92 (2012).

(5)       Lucantoni, L. & Avery, V. Whole-cell in vitro screening for gametocytocidal compounds. Future Med. Chem. 4, 2337–2360 (2012).

(6)       Wassermann, A. M. et al. Dark chemical matter as a promising starting point for drug lead discovery. Nat. Chem. Biol. (2015). doi:10.1038/nchembio.1936

(7)         Burrows, J. N., Duparc, S., Gutteridge, W. E., van Huijsduijnen, R. H., Kaszubska, W., Macintyre, F., Mazzuri, S., Möhrle, J. J. & Wells, T. N. C. New developments in anti-malarial target candidate amd product profiles. Malar. J. 16:26 (2017). DOI: 10.1186/s12936-016-1675-x 

(8)         Katsuno, K. et al. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discov. 14, 751–8 (2015).

Final Report

1. Project objective

The objectives for the project were to transform hit chemical series into Lead series with proven in vivo efficacy in the animal disease models so as to identify before September 2020 at least one compound series that meets the GHIT/MMV criteria for progression to Lead Optimization stage.

2. Project design

During the first phase of the project, frontrunner compounds from three chemical series selected for hit-to-lead progression were profiled in the parasite life cycle assays to confirm their Target Candidate Profile (TCP). In parallel, medicinal chemistry was carried out and analogues were profiled in parasitology and cytotoxicity assays. The physicochemical properties, stability and ADMET characteristics were also determined for potent compounds. Then the most promising compounds were evaluated in rodents PK experiments and in the disease model of human malaria to demonstrate in vivo efficacy. The final goal was to select a couple of lead molecules which should be the basis of a new proposal to GHIT for a Lead Optimization program.

3. Results, lessons learned

The project team prioritized the most advanced chemical series and medicinal chemistry effort has been focused on it according to suggestion by GHIT. During the first phase of the project, the frontrunner compounds from the most advanced chemical series were profiled in the parasite life cycle assays and its Target Candidate Profile (TCP) was determined to blood stage killers (TCP1) and chemoprotection (TCP4). Since the physicochemical properties, stability and ADMET characteristics of the frontrunners were acceptable to go for in vivo experiment to confirm the antimalarial efficacy, those compounds were subjected to in vivo experiment using mouse infection model (50mg/kg, p.o, qd, 4-day treatment) and showed >99.8% activity compared to untreated control mice.

In the second phase of the project, the project team focused on improving safety risk of the most advanced chemical series. At first medicinal chemistry aimed at designing compounds showing inhibitory activities not against human orthologue but against malaria orthologue. Once the project team generated such kind of compounds, the physicochemical properties, stability and ADMET characteristics of the representatives were evaluated. In the final phase of the project, based on the profiling data, the project team made a decision that the Target Candidate Profile should be focused on chemoprotection (TCP4) and then started evaluation of the newly generated analogs in liver stage malaria parasite growth inhibition assays. This Hit-to-lead activity (H2018-101) has been completed in September 2020 but the successor project (H2020-101) has just started in October 2020. In the next project (H2020-101) the project team continue to focus on the most advanced chemical series identified in H2018-101 to generate candidate molecules that meet MMV/GHIT early lead criteria for TCP4 to go for lead optimization stage. 

This project was impacted by COVID-19 pandemic. Almost all labs involved in this project had to be closed during lock down in each country, however the project team re-started our own work as soon as possible and could start new phase (H2020-101) without fatal delays and funding gap thanks to support by GHIT.