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 2024 includes:
Discovery
Screening: Continuing 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 yielded promising results. Four new collections of compounds from both synthetic and natural product origins have been identified, and two new GHIT awards allowed for the initiation of new screening collaborations with Shionogi and the Kitasato Institute. High-throughput screening of compounds in the 60K BINDS/University of Osaka collection and the Fraunhofer IME 5K natural product collection have been completed. Evaluation of the MMV HGL2 compound library was completed, with ten promising new chemical series identified.
Hit-to-lead: Several chemical scaffolds continue to be profiled and optimized mainly via phenotypic hit-to-lead campaigns. One series from the early-stage portfolio achieved lead criteria and was progressed to the lead optimization stage (Series-5824) in collaboration with Mitsubishi Tanabe, and several others were stopped due to difficulties in optimization.
Meanwhile, together with our discovery partners, we continued exploring new technologies, such as AI and machine learning, and alternative approaches such as target-based drug discovery to speed up compound progression and unlock new opportunities to identify novel candidates.
UW series: The project remains one of the most advanced drug discovery projects in DNDi’s kinetoplastid portfolio. DNDi and partners University of Dundee Drug Discovery Unit, GSK, and the University of Washington continued to identify optimized leads from the UW series – a scaffold that shows good efficacy (no relapse after immunosuppression) in the Chagas bioluminescence chronic model – as well as multiple other chemical series that act through the same promising mode of action.
Open Synthesis Network: Optimization of compounds from project P7 is currently underway. Completion of projects P5 and P1Tc are currently under review. Three scientific manuscripts resulting from OSN projects have been published. The team at the University of Munster, led by Prof. Bernhard Wünsch, authored two publications focused on medicinal chemistry and compound optimization for leishmaniasis. The team at the University of Washington at Tacoma, led by Prof. Kelly Kim, authored a paper investigating the regioselectivity of certain reactions employed in project P6.
Translation
Biomarkers: Published in Nature Communications, results from tests of the MultiCruzi assay for the first time demonstrate a decline in antibodies in treatment compared to placebo after 6 and 12 months of follow-up in adult Chagas patients in the BENDITA clinical trial. Analysis of the same samples, conducted at CONICET in Argentina for both the BENDITA and E1224 clinical trials, was completed, confirming the robustness and reproducibility of the MultiCruzi assay results. Additional studies are underway to further assess the potential of the MultiCruzi assay as a surrogate marker for parasitological cure in adult Chagas patients treated with antiparasitic drugs.
A collaborative research project with Novartis to identify potential host biomarkers using proteomics and MultiCruzi platforms has also been launched. At the same time, a review of the current biomarkers landscape for Chagas disease is ongoing.
DNDI-6148: Activities related to the clinical development of DNDI-6148 remain on hold.
Development
New benznidazole regimens: The NuestroBen study continued recruitment at six sites in Argentina (four in Buenos Aires and two in the north of the country), and recruitment of a total of 300 participants is expected by the end of 2025. At least one study site in Bolivia is expected to open in the first quarter of 2025.
The reanalysis of the BENDITA study based on individual patient data was completed, and the results and findings on healthcare provider acceptability of the shorter regimens will be published in early 2025.
Implementation
Chagas Access Project: DNDi teams and partners made significant progress in evaluating the performance of the rapid diagnostic test in Colombia, Guatemala, and Argentina, with pilot use and implementation of the test beginning in the three countries.
In Colombia and Guatemala, monitoring and evaluation efforts continued and activities to promote access to treatment were strengthened. In Colombia, our teams and partners conducted comparative analyses of Chagas treatment gaps and continued training programmes on clinical management of Chagas.
A study to assess the acceptability of contraception among women receiving treatment for Chagas in clinical trials – and in standard treatment settings – was initiated in Brazil and Colombia. In Guatemala and Colombia, the project advanced in its work to incorporate intercultural care routes into standard Chagas treatment, with a specific focus on the worldviews of indigenous peoples.
Photo credit: Neil Brandvold-DNDi
