DNDi and our partners are searching for shorter, safer, more effective treatments to stop a silent killer. In the short term, we are working to develop improved treatment regimens with the existing drug benznidazole, reduce mother-to-child transmission, and help roll out ‘test-and-treat’ strategies to reach people living with Chagas disease in remote areas of Latin America. Our longer-term goal is to discover and develop entirely new drug candidates, with the aim of launching at least one Phase III trial by 2028.
Our progress in 2023 includes:
Discovery
Screening: DNDi continued to work with the Institute Pasteur Korea, University of Dundee, and Nagasaki University to identify new T. cruzi active hit series using its well-established high-throughput screening platform. New collections of both synthetic and natural product origin compounds acquired from commercial suppliers were screened to identify compounds with promising characteristics.
Hit-to-lead: Discovery efforts prioritized the identification of high-quality compounds that show novelty in terms of both chemical structure and mode of action. Several new hit-to-lead projects started in 2023 after a systematic hit assessment following reanalysis of hits originating from commercial compound libraries.
In parallel, ongoing hit-to-lead campaigns continued to progress via partnerships around the globe. For at least two chemical series, advanced leads showed promising efficacy in in vivo models – an important milestone for go/no-go decisions on advancement to full lead optimization programmes – with in vitro data pointing to a novel mode of action.
UW series: DNDi continued work with the alliance to further optimize and de-risk a new generation of compounds related to the original UW series and chemically diverse backup series.
Translation
Biomarkers: Analysis of samples from the BENDITA and E1224 clinical trials using the MultiCruzi assay yielded promising outcomes. After relatively brief post-treatment monitoring periods as compared with conventional ELISA testing, the MultiCruzi assay allowed for quantification of the degree of seroreduction and thus predict future seroreversion as a surrogate marker of parasitological cure for patients with Chagas disease. Antibody decline in samples from the studies’ treatment arms was significantly faster than in the placebo arms, and a dynamic and sustained response to treatment was observed between 6 and 12 months’ follow-up. Results are pending an analysis of the same samples conducted by CONICET in Argentina to assess the inter-laboratory reproducibility of the technique.
DNDI-6148: The development of DNDI-6148 has been paused pending further studies to determine the potential for reproductive toxicity. Due to their potential teratogenic effects, current treatments for Chagas disease – benznidazole and nifurtimox – cannot be used by pregnant women or women who may become pregnant. Together with partners, DNDi is currently conducting pre-clinical assessments of a number of oxaboroles to select the best candidate for further development.
Development
New benznidazole regimens: Working together with partners Mundo Sano Foundation and Laboratorio ELEA-Phoenix in Argentina, the NuestroBen study was reinitiated in the second quarter of 2023 following receipt of ethical and regulatory approvals and preparation of study sites. The first participant entered the study in August in accordance with the revised study protocol. Four study sites were opened by the end of the year in Buenos Aires and northern Argentina. A total of 300 participants are expected to be recruited by the first quarter of 2025.
Implementation
Chagas Access Project: DNDi teams and partners continued work to support the decentralization of Chagas diagnosis and treatment in Latin America. In Colombia, support expanded to include projects in a total of seven departments of the country, covering 47 municipalities. The proportion of endemic municipalities implementing the care roadmap for Chagas disease rose to 54% by the end of the year, with 16,484 people tested for Chagas – 11,682 of whom were women of childbearing age.
In Guatemala, DNDi contributed to decentralizing diagnosis and treatment in 3 of 10 endemic areas of the country.
DNDi and partners also continued work to deliver evidence on the use of rapid diagnosis tests (RDRs) to detect T.cruzi infection, with several studies implemented to evaluate RDT performance. In Colombia, a study evaluating the performance of 11 RDTs under laboratory conditions was completed, and a prospective study to evaluate four RDTs under field conditions at five sites is ongoing. In Guatemala, a study was conducted to evaluate the performance of three RDTs under field conditions. In Argentina, DNDi supported the National Institute of Parasitology ‘Dr. Mario Fatala Chaben’ in the validation of commercial RDTs and development of recommendations for their use.
Photo credit: Diogo Galvão-DNDi
