Investment

Details

New Hit-to-Lead Activity for New Anti-Malaria drugs between MMV and Sumitomo Dainippon Pharma
  • RFP Year
    2017
  • Awarded Amount
    $445,500
  • Disease
    Malaria
  • Intervention
    Drug
  • Development Stage
    Lead Identification
  • Collaboration Partners
    Sumitomo Dainippon Pharma Co., Ltd., Medicines for Malaria Venture (MMV)
  • Past Project

Introduction and Background of the Project

Introduction

Malaria is a mosquito-borne disease that infects more than 200 million people every year. In 2016, the disease caused an estimated 445,000 deaths worldwide. The vast majority of those who lost their lives were children under the age of 5 years (1). Novel classes of antimalarial medicines targeting different parasite stages are urgently needed to provide both effective alternatives to current therapies falling prey to resistance, and to provide pharmaceutical tools to meet the malaria eradication agenda (2).

This project originates from a GHIT-funded screening of a 28,810-compound library selected from Sumitomo’s library. The screening was performed at MMV testing centers in Australia (by Prof. Vicky Avery at Griffith Institute for Drug Discovery, Griffith University) and in USA (by Prof. Winzeler at the University of California, San Diego) against the blood-stage, (asexual (3) and sexual (4)) and the liver stage (5) of the malaria parasite. In parallel, the activity of the compounds was measured in cellular models of human toxicity. Several novel series were identified, and in 2017 further profiling as well as expansion of hit series was conducted to further understand their biological profile and structure activity. Pharmacokinetic and physicochemical measurements were also conducted. The project is now at the Hit-to-Lead phase with four series. All four series show good potency in whole cell blood-stage assays; in addition, two series show good activity in both liver-stage and gametocyte formation assays.

 

Project objective

The objective of this project is to transform at least one series identified through the high-throughput screening, into a Lead series with in vivo activity in an animal disease model before April 2019. The series will need to meet GHIT/MMV criteria for progression to Lead Optimization stage. Further work will be performed during the Hit-to-Lead phase to understand the activity of the series in the parasite lifecycle and alignment to Target Candidate Profiles (TCP).

 

Project design

During the first phase of the project, work to improve specific properties of each series to meet Lead Optimization criteria will be performed. Examples of such properties are potency in biological models of malaria parasite, pharmacokinetic properties, especially metabolic stability and physicochemical properties, such as solubility. Also, work will be undertaken to try to identify the mechanism of action for the series. Finally, frontrunner compounds from the four series selected for Hit-to-Lead progression will be profiled in the pharmacological models of the parasite lifecycle to confirm their alignment to Target Candidate Profiles (TCPs) (6). The most promising compounds will be evaluated in rodent PK experiments and in the disease model of human malaria to demonstrate in vivo efficacy. The goal is to select several lead molecules that will form the basis of a new proposal to GHIT for a Lead Optimization program.

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

Malaria remains a significant life-threating disease. The majority of the almost half million malaria-related deaths are of young children, mainly in African countries. The global community is jointly working towards a common goal, the eradication of malaria. In this fight new medicines are essential weapons. Significant improvements can still be made over the current gold standard, artemisinin combination therapies. For example, there is a need for combination medicines in single-dose regimens that are safer and more effective. In the context of malaria eradication, 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.

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 (6). This project 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)         anti-relapse for patients infected with Plasmodium vivax and Plasmodium ovale

iii)        transmission blocking by targeting the host gametocyte population and

preventing infection to the mosquito 

iv)        chemoprotection capable of protecting vulnerable populations from reinfection.

The profiles from pharmacological studies during hit evaluation indicate that series have the potential to meet one or several of these targets. Finally, the Hit-to-Lead phase aims to also develop compounds able to show a long-acting profile.

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 (in particular, activity on gametocytes 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 (7) and  offer differentiation compared to existing series in the MMV portfolio at the time of the LO proposal.

All series have novel drug-like chemotypes, different from current antimalarial drugs in use or compounds in the clinical pipeline. Their mode of action will also be studied in the Hit-to-Lead phase.

Role and Responsibility of Each Partner

The project team consists of drug discovery and medicinal chemistry experts from Sumitomo Dainippon Pharma and MMV as well as parasitology and DMPK specialists from within the MMV network. The role of project members from Sumitomo Dainippon Pharma, together with scientists from MMV, Griffith University and Monash University, is to provide scientific input into the medicinal chemistry plans, the selection of analogues for further studies and the profiling of the hit chemical series. MMV is leading the project, in close partnership with Sumitomo Dainippon Pharma, providing drug discovery and malaria expertise as well as strategic input to the project. MMV is also responsible for connecting the project team with partners from its network so that data on selected project compounds are available to aid decision making. MMV partners, Prof. Vicky Avery (Griffith University) and Prof. Susan Charman (Center for Drug Candidate Optimization, Monash University) are members of the project team, and are responsible for delivering in vitro blood stage parasitology data and in vitro / in vivo DMPK data, respectively, on compounds selected by the team.

Others (including references if necessary)

1. World Health Organization (WHO). WORLD MALARIA REPORT 2015. (2015). DOI:ISBN 978 92 4 156515 8

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. 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).

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

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

6. 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

7. 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).