DNDi aims to deliver new, safer, more affordable and effective treatments for people affected by Chagas disease. DNDi is also focused on improving access to diagnosis and treatment using existing tools.

DNDi’s current Chagas disease portfolio includes:

Discovery

• Screening: To identify new hit series that could be progressed and become new drug candidates for Chagas disease, DNDi tests chemical compounds for activity against Trypanosoma cruzi. High-throughput screening of compounds from natural product and synthetic compound collections from partners or commercial suppliers have been conducted, and hits have been identified and are currently being progressed.

• Chagas hit-to-lead: DNDi has continued its efforts in screening chemically diverse libraries to replenish the discovery pipeline. Confirmed new hits are continuously feeding the hit-to-lead pipeline. In 2019, a new consortium was established in collaboration with University of Campinas and University of Sao Paulo in Brazil. Through a team of scientists working in a global network, PITE (Research Partnership for Technological Innovation) aims to deliver a high-quality pre-clinical candidate compound that could become a new treatment for Chagas disease.

• NTD Drug Discovery Booster hit-to-lead: Screening activities were placed on temporary hold in early 2019 to focus efforts on transitioning existing hit series into lead optimization projects. Two hit series are currently under further investigation with Takeda, and work is underway to transition additional series for potential lead optimization in 2020.

• Daiichi-Sankyo Chagas hit-to-lead: The frontrunning series that is the current focus of this hit-to-lead project has clear activity against the T. cruzi parasite and will be progressed for Chagas disease.

• Chagas C205 series: This series is part of a collaboration agreement made in 2018 with the Drug Discovery Unit of Dundee University in Scotland and GlaxoSmithKline’s Global Health Unit in Spain. With work on the series resulting in a drug candidate for leishmaniasis that will move into translational research, research for a candidate for Chagas from the C205 series is currently on hold.

Translation

• Biomarkers: As there is no single reliable test of cure that can be used to monitor treatment effectiveness in chronic Chagas disease patients, DNDi continued work to raise awareness among Chagas stakeholders about the need for biomarkers, with particular emphasis on regulatory aspects and the biomarker development process. DNDi is also supporting the development of a prototype assay for newly identified biomarkers – Apo A1 and Fbn fragments issued from a collaboration with McGill University – together with InfYnity Biomarkers. The analysis of a multi-centre study carried out by NHEPACHA, an Ibero-American network of researchers working on Chagas, is being finalized and will be published in 2020.

• Fexinidazole: DNDi is evaluating fexinidazole, which was registered to treat sleeping sickness in 2018, as a potential new drug for Chagas disease. This Phase II proof-of-concept study, carried out in five sites in Spain, has been evaluating different short-course regimens of fexinidazole for adults with chronic indeterminate Chagas. The follow-up phase of the study was completed in late 2019; results will be available in 2020.

Development

• New benznidazole regimens: Phase II trial results available in early 2019 showed that all treatment arms were effective compared to placebo and the new regimens presented good safety profiles. The two-week course of treatment with benznidazole monotherapy was particularly promising. While significantly shorter than the standard eight-week treatment, it showed 83% efficacy and none of the patients assigned to this arm had to discontinue treatment due to side effects. Based on these results, DNDi is planning to run an international, multi-site confirmatory Phase III study.

Implementation

• Chagas access project: The Chagas Treatment Access project continued to consolidate and expand its activities in the Latin American region in 2019, working with partners in Colombia, Guatemala, Brazil and, since late 2019, Mexico. In Colombia, after two years since the first pilot projects started, the number of people screened in the municipalities of Támara and Nunchía in Casanare state increased from 25 in 2017 to 400 per year in 2019. For those who had access to diagnostic testing, the wait time to receive their results was reduced on average from one year to less than one month. Approximately 20% of people who had access to diagnosis during the two-year period tested positive for the disease.

• Chagas Clinical Research Platform (CCRP): With around 450 members from over 150 institutions and 24 countries, the Chagas Platform continued work to catalyse the involvement of researchers from endemic countries in improving R&D for Chagas, from drug discovery to implementation.Celebrating the Platform’s 10^th anniversary in 2019, members supported the development of products to help decision-making around Chagas research, such as a target product profile (TPP) for immunocompromised patients, a TPP for paediatric Chagas disease, and an algorithm to assess treatment response in primary health care. Members also discussed priorities for research in pre-clinical, clinical, and implementation research needed to contribute to Chagas disease control over the next decade.The Platform also started working to catalyse a prospective cohort to unify the Chagas clinical and research community, an action suggested in the ‘Santa Cruz letter’ developed by the Platform and the Chagas Coalition in 2018 that asked governments to step up efforts to eliminate Chagas as a public health problem. The letter also supported the request for an official World Chagas Day, which was approved by the World Health Organization at its 72^nd World Health Assembly in 2019. The first World Chagas Day will be celebrated on 14 April 2020.

Photo credit: Ana Ferreira-DNDi