Introduction and Background of the Project

1.Introduction

Over 6 million people are estimated by the World Health Organization (WHO) to have Chagas disease. It is an important public health issue in 21 endemic countries of Latin America but also increasingly in non-endemic developed countries because of globalization and population flows. Chagas disease is a potentially life-threatening illness with very limited and largely suboptimal therapeutic options. The standard-of-care drugs for the treatment of Chagas disease, benznidazole and nifurtimox, have substantial limitations including variable levels of efficacy in the chronic stage of the disease, severe adverse effects (occurring in up to 40% of treated patients), contraindications and compliance issues (the duration of treatment with benznidazole is 60 days).
This project is a continuation from the Hit-To-Lead development project funded by the GHIT Fund, aiming to add a new optimized lead candidate meeting the DNDi Target Candidate Profile (TCP) to the Chagas disease preclinical pipeline.

2.Project objective

The main objective of this two-year project is to deliver optimized lead candidate(s) meeting the efficacy and in vitro safety requirements described in the DNDi TCP. Fulfilling the TCP efficacy criteria compound(s) would be ready to enter preclinical development enabling studies addressing the complementary safety, DMPK (Drug Metabolism and Pharmacokinetics) and CMC (Chemistry, Manufacturing, and Controls) criteria of the TCP. The lead optimization efforts will focus on a novel spirocyclic series (Spiro 5) active against T. cruzi infection. In addition, this project aims at identifying the mechanism of action of this new series.

3.Project design

DNDi and Mitsubishi Tanabe Pharma Co. (MTPC) aim at developing through a two-year lead optimization collaboration a novel and very promising T. cruzi active series identified from a high throughput screening of a 51,200 MTPC proprietary library and progressed to date to lead stage. The project partners plan to chemically derivatize the lead series using a well-defined and diversified medicinal chemistry strategy to improve its in vitro T. cruzi potency, maintain its favorable DMPK properties while mitigating any safety liabilities. In parallel DNDi and MTPC plan to elucidate the mechanism of action of the series notably with the expert support of University of Dundee and make use of this information to guide the lead optimization program.

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

As Chagas disease usually remains asymptomatic for years after infection, most people with the disease are unaware of their condition as detection rates based on serological tests are lower than 10% and sometimes even lower than 1%. Estimates indeed suggest that only 7% of those infected have been diagnosed and that a much smaller percentage receives treatment.^1,2 If untreated, Chagas disease may cause irreversible, life-threatening damage to the heart and other vital organs. For 30-40% of people infected, the disease progresses to a late chronic stage.³ Of these, most will suffer cardiac damage, often leading to sudden death or progressive heart failure. The disease can also cause enlargement of the gastrointestinal tract and organs and gastrointestinal motor disorders.

Current available treatment are more than 40 years old, and while they show good efficacy in the acute phase, they need to be used in long regimens and cause significant side effects. This project aims to deliver a safe and efficacious new oral treatment for chronic Chagas patients, ideally efficacious also for acute Chagas patients and safe to use during pregnancy.

What sort of innovation are you bringing in your project?

It is essential to add to the preclinical pipeline new drug candidates from novel chemical classes that act via novel and pertinent mechanisms of action to maximise the chance of successfully completing the development of a safe and efficacious new drug to provide a short course, oral treatment, efficacious against the chronic stage of the disease.

A novel very promising spirocyclic scaffold (Spiro 5) has been identified and progressed within the frame of the GHIT funded screening and Hit-to-Lead collaboration between MTPC and DNDi. The Spiro 5 series fulfills the lead stage criteria set by DNDi and notably achieved proof of concept of in vivo efficacy in acutely and chronically infected mouse model. Additionally, all known, suboptimal mechanisms of action related to Chagas disease preclinical development (i.e. CYP51, cytochrome bc1, tRNA transferase, and proteasome inhibitions) have also been excluded. 

Role and Responsibility of Each Partner

The specific roles and responsibilities of each partner are as follows:
・Project management and coordination: DNDi with MTPC
・Compound design and synthesis: DNDi and MTPC with TCG Lifesciences
・DMPK in vitro and in vivo, drug safety and toxicology: DNDi and MTPC with TCG Lifesciences
・PK/PD (Pharmacokinetics/Pharmacodynamics) modelling: DNDi with Mahidol-Oxford Tropical Medicine Research Unit
・in vitro and in vivo parasitology: DNDi with Institut Pasteur Korea, Swiss Tropical and Public Health Institute, University of Dundee (in vitro) and London School of Hygiene & Tropical Medicine (in vivo)
・Elucidation of mechanism of action: DNDi with University of Dundee

DNDi and MTPC will contribute equally to the overall intellectual evaluation of the project, including in the triaging of compounds through the late-stage screening cascade and the eventual nomination of a preclinical candidate. DNDi and MTPC will also contribute equally to compound design of target compounds to be synthesized.

Others (including references if necessary)

1. World Health Organization. Chagas Disease in Latin America: an epidemiological update based on 2010 estimates. WHO 2005.

2. Pan American Health Organization. Diagnosis and Treatment of Chagas Disease in 21 Endemic Countries: the Americas, 2010-2016. 2018.

3. Rassi AJr, Rassi A, Marin-Neto JA. Chagas disease. The Lancet. 2010; 375(9723): 1388–402.