Investment

Details

Lead optimization of a candidate series active against Chagas Disease

Introduction and Background of the Project

Introduction

Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by Trypanosoma cruzi (T. cruzi). About 6 to 7 million people worldwide are estimated to be infected mainly in Latin American countries where the disease is endemic. Existing drugs for Chagas diseases are associated with serious side effects and suboptimal efficacy for chronic Chagas patients. Drugs for Neglected Diseases initiative (DNDi) and Daiichi Sankyo Co., Ltd. (DS) have been collaborating since early 2016 on the development of a totally new orally active drug with objective to deliver a safe and efficacious treatment for people affected by Chagas disease.

 

Project objective

This specific 2-year project aims at engineered out via Lead Optimization this promising class of compounds into one optimized lead candidate for Chagas Disease and at elucidating its mechanism of action by end Q1 2022. This optimized lead candidate shall meet the criteria of the Chagas Disease Target Candidate Profile (TCP) defined by DNDi.

 

Project design

The project team has developed a tailored-to-the needs assay cascade to address the development of this series. Basically, compounds with suitably balanced T. cruzi activity, selectivity and metabolic stability in vitro profiles will be considered as candidates for pharmacokinetic studies. Provided sufficient drug exposure is reached in animals used in those studies, compounds will then be tested in a Chagas acutely infected mouse assay model to assess its ability to clear an established T. cruzi infection targeting a non-detectable level of T. cruzi parasites at end of treatment. Compounds meeting this latter criterion as well as fulfilling a few additional safety-related requirements related to in vitro testing will be tested in the Chagas chronically infected assay model to assess their ability to clear an established T. cruzi chronic infection. Compounds able to sustainably clear out T. cruzi infection in this assay will be considered as curative and meet the Optimized Lead candidate stage criteria. Safety studies for those candidates will be completed in parallel or right after efficacy studies.

The relationship between drug dosing and efficacy will be deduced from PK and PD studies conducted on a few carefully selected candidates using adequate treatment regimens and modeling to identify the pharmacokinetic parameters driven efficacy in vivo. Safety and tolerability data will be considered to define the most appropriate dose regimen to be used in PK and PD studies. Various medicinal chemistry strategies will be applied to efficiently optimize the chemical series addressing the identified liabilities including metabolic stability. To manage and mitigate risks of lead molecules effectively, careful assessment of physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and excretion) properties, in vivo pharmacokinetics, in vitro and in vivo safety, and formulation will be performed in parallel with routine in vitro parasitological assay.

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

Chagas disease is caused by the parasite Trypanosoma cruzi. Nearly a century after its first description, Chagas disease remains endemic in 21 Latin American countries where PAHO now estimates around 6 million infected people and 70 million at risk for the disease. Around 12,000 deaths are estimated to occur annually from Chagas disease. According to PAHO, approximately 1.8 million of women of childbearing age (15-44 years) are infected, and 14,000 cases of congenital Chagas infection occur each year in the Americas region. Patient numbers are also growing in non-endemic, developed countries (e.g. Australia, Canada, Japan, Spain, and the United States), due to increased migration of Latin American immigrants unknowingly carrying the parasite in their blood.

One of the major challenges for Chagas disease control is that many individuals with the disease are not aware that they are infected. Fewer than 10% of people with Chagas disease in the Americas have been diagnosed and only about 1% of those with the disease have received antiparasitic treatment. Chagas Disease manifests in acute and chronic phases. A significant percentage (30-40%) of the untreated acute cases enter a chronic phase where patients can develop cardiac or intestinal complications, decades later, leading to sudden death. 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. None of the existing treatments are safe to use during pregnancy which is an important unmet medical need.

The project aims to address these challenges and deliver a safe and efficacious new oral treatment for chronic Chagas patients, ideally also efficacious for acute Chagas patients and safe to use during pregnancy.

What sort of innovation are you bringing in your project?

There are currently only two drugs available to treat Chagas disease (benznidazole and nifurtimox), which 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 can be up to 60 days).

It is essential to add new drug candidates from novel chemical classes acting via not yet explored mechanisms of action to the R&D pipeline to maximize the chance of successfully completing the development of a safe and efficacious new drug to provide a short course, oral treatment, efficacious also against the chronic stages of the disease. The current very thin preclinical R&D pipeline for Chagas Disease needs to be substantially strengthened in order to address the expected attrition rate preventing most drug candidate series from reaching the clinics and eventually to become approved drug treatments.

The project is expected to contribute to filling this gap by adding a new optimized drug candidate meeting the Chagas TCP defined by DNDi to the preclinical pipeline. This new drug candidate will be based on a very promising phthalazine scaffold identified and progressed in the frame of an early stage (screening and Hit to Lead) collaboration by Daiichi Sankyo and DNDi. In addition, this project also aims at identifying the mechanism of action of this optimized drug candidate, which will bring up a key piece of knowledge to the field of drug R&D for Chagas disease.

Role and Responsibility of Each Partner

The project will be implemented by a team comprising the project director and scientists from Daiichi-Sankyo and DNDi. The studies will be conducted in collaboration between Daiichi-Sankyo and DNDi, the principal investigators, and their partner test centers.

Ÿ Compound design, synthesis, physicochemical properties, DMPK (drug metabolism and pharmacokinetics), and safety: Daiichi Sankyo

Ÿ In vitro and in vivo parasitology: DNDi in collaboration with its mandated screening centers namely Institute Pasteur Korea (South Korea), University of Dundee (UK), Laboratory of Microbiology, Parasitology and Hygiene at University of Antwerp (Belgium), Griffith Institute for Drug Discovery at Griffith University (Australia), London School of Hygiene and Tropical Medicine (UK), and Swiss Tropical and Public Health Institute (Switzerland). All activities related to in vitro and in vivo efficacy studies will be managed by DNDi.

Ÿ Research studies related to the understanding of mechanism of action for Chagas Disease: DNDi in collaboration with University of Dundee (UK) and Swiss Tropical and Public Health Institute (Switzerland).