Introduction and Background of the Project

Introduction

Over 6 million people in the world are estimated to have Chagas disease, a potentially life-threatening disease caused by the parasite Trypanosoma cruzi, while an estimated 75 million people are at risk worldwide. An estimated number of 30,000 new infections occur every year causing around 10,000 deaths (9,490 in 2019). As people typically show no symptoms for many years, most are unaware they have Chagas disease. Up to a third of people with Chagas disease will suffer heart damage that becomes evident only many years later and can lead to progressive heart failure or sudden death.

Visceral Leishmaniasis is a life-threatening disease caused by Leishmania parasites and causes fever, weight loss, spleen and liver enlargement, and, if not treated, death. Over 600 million people are at risk of visceral leishmaniasis across the globe. An estimated 50,000-90,000 new cases are reported yearly causing around 10,000 deaths (5,710 in 2019). The 95% of new cases occur 10 countries: Brazil, China, Ethiopia, India, Iraq, Kenya, Nepal, Somalia, South Sudan and Sudan. 

Mitsubishi Tanabe and Drugs for Neglected Diseases initiative (DNDi) have been closely collaborating since September 2019 for a screening project funded by the GHIT Fund and have successfully identified nine active series mainly active against T. cruzi though a couple of them display dual T. cruzi and Leishmania donovani activities. Three T. cruzi active series have been prioritized. All series are novel to DNDi discovery programs and satisfy all criteria set by the GHIT Fund and DNDi, resulting in successful progression into hit to lead stage.

Project objective

The objective of this project is to identify at least one series meeting DNDi lead stage criteria for Chagas disease and/or visceral leishmaniasis in line with DNDi published Target Product Profiles (TPPs) for new chemical entities. Medicinal chemistry efforts will be carried out in priority on the three most promising series.

Project design

Screening cascade defined by DNDi for both diseases will be used to assess and progress T. cruzi and Leishmania active series. Compounds will be designed to address the identified liabilities of the series and explore the most promising chemical subset of activity based on structure activity relationship (SAR) identified to date. Any new compound qualifying as a hit in line with the in vitro activity and selectivity criteria will be considered for further profiling and progression in ADME in vitro assays and eventually PK studies assuming favorable ADME profile in vitro is confirmed. Plasma and culture medium protein binding measurements will be performed on promising compounds to evaluate the levels of drug available as free fraction and eventually correlate in vitro activity with drug plasmatic concentration in vivo. Compounds associated with sufficient drug exposure levels will be submitted to secondary assays as well as submitted in parallel to PD studies in acutely infected Chagas disease or leishmaniasis animal models to establish a PoC of in vivo efficacy. Compounds meeting the DNDi lead stage criteria are set as the final milestone of this 2-year project.

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

There are currently only two drugs available to treat Chagas disease - nifurtimox and benznidazole - both discovered half a century ago. They are effective against the disease if given soon after infection and appear to be effective in the chronic asymptomatic phase of the disease. However, the side effects and treatment duration are among the main barriers to treating more people with Chagas disease. They have not been proven effective in people with severe chronic symptoms. We need a new drug for chronic stages of the disease that is safe, efficacious, more affordable and adapted to the field.

Existing drugs for visceral leishmaniasis have serious drawbacks in terms of safety, resistance, stability, and cost. They have low tolerability, long treatment duration when used individually, and are difficult to administer. The ultimate goal is to develop an entirely new generation of all-oral drugs.

This project will strengthen the early pipeline for Chagas disease and/or visceral leishmaniasis by providing new promising series and increase the chance of success in addressing unmet medical needs in both diseases.

What sort of innovation are you bringing in your project?

Drug discovery and development at the early hit to lead stage for Chagas disease and visceral leishmaniasis is prone to a relatively high chance of failure. A critical mass of novel chemical series therefore needs to be identified and progressed through hit to lead and beyond to build up a solid portfolio of preclinical candidates aligned with the DNDi TPPs for Chagas disease and visceral leishmaniasis. Mitsubishi Tanabe and DNDi identified promising T. cruzi and Leishmania active series through the previous screening collaboration. Those series are all novel to our knowledge and expected to have a positive impact on the discovery portfolio related to both diseases. Additionally, most selected series are active against T. cruzi that are currently highly sought to feed the early-stage Chagas disease portfolio.  

Role and Responsibility of Each Partner

The project will be carried out by a team comprising the project leaders and scientists from Mitsubishi Tanabe and DNDi. The studies will be conducted in collaboration between Mitsubishi Tanabe and DNDi, the principal investigators and partner test centers.

・Compound design: Mitsubishi Tanabe and DNDi

・Synthesis of compounds: DNDi

・in vitro and in vivo parasitology: DNDi in collaboration with its mandated screening centers - Institute Pasteur Korea (South Korea), University of Dundee (UK), Laboratory of Microbiology, Parasitology and Hygiene at University of Antwerp (Belgium), The Griffith Institute for Drug Discovery, Griffith University (Australia), London School of Hygiene and Tropical Medicine (UK), Swiss Tropical and Public Health Institute (Switzerland).

・Physicochemical properties, in vitro ADMET and DMPK: Mitsubishi Tanabe and DNDi

・Project and data management: DNDi