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.

In 2022, the main experimental focus was the further assessment of the multiplex assay, MultiCruzi, for use in clinical settings. Clinical samples (including one year follow-up samples) from DNDi-sponsored clinical trials of new benznidazole regimens and fosravuconazole were delivered to InfYnity Biomarkers and CONICET, respectively. Analysis of samples with the MultiCruzi assay is pending the finalization of ongoing manufacturing scale-up of the multiplex chips.

In 2021, the main experimental focus was the further assessment of the multiplex assay, MultiCruzi, for use in clinical and pre-clinical settings. In addition, two expert meetings on PCR testing and serology for Chagas disease biomarkers were held to further elucidate mechanisms for predicting treatment outcomes at an earlier stage.

Following more than a year’s consultation with experts in Chagas disease, a Target Product Profile (TPP) was published in April 2020 for a test to determine if a Chagas disease patient has been cured after treatment.  

The development of a prototype assay using a host marker (ApoA1 fragment) and a new T. cruzi parasite antibody (Ab3 from InfYnity Biomarkers) was put on hold while discrepancies between results from different platforms are being investigated.

DNDi began testing the diagnostic performance of a Multiplex assay, MultiCruzi, which appears to predict seroconversion earlier than conventional serology in children; further refinement of the algorithm continued.

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.

Presentation of the Chagas Clinical Data Sharing Platform project (IDDO/DNDi) in plenary at the 2018 Chagas Platform Meeting in Santa Cruz was well received by clinicians. In parallel, the development of a prototype assay is ongoing for newly identified biomarkers – Apo A1 and Fbn fragments issued from a collaboration with McGill University – with InfYnity Biomarkers.

The analysis of the NHEPACHA study data is pending and will be presented at the XV Chagas Disease Workshop organized by the Institute for Global Health Barcelona in March 2019.  

Pre-clinical studies started in 2016 and were ongoing in 2017 to identify and validate potential biological markers of therapeutic response in Chagas patients. In addition, through the Ibero-American network NHEPACHA, DNDi is fostering work on testing four biomarkers to assess the response to Chagas treatment.

Pre-clinical studies are ongoing to identify and validate potential biological markers of therapeutic response in Chagas disease patients to support clinical development.  In addition, DNDi is fostering and encouraging work for testing four biomarkers to assess response of treatment of Chagas through the Iberoamerican network NHEPACHA.

Analysis of sera from children treated with benznidazole was undertaken in order to evaluate a potential correlation between seroconversion and the presence or absence of biological markers. Early indications are that these can be used to classify patients as cured or not, and results of confirmatory experiments are expected in 2016.

DNDi is collaborating with the University of Georgia and the Texas Biomedical Research Institute in a Wellcome Trust funded, non-human primate study in naturally infected animals with chronic Chagas disease, to further determine PCR and other markers as sensitive tools to consistently differentiate parasitological cure from treatment failure. The dosing period of the non-human primate study in naturally infected animals with chronic Chagas disease ended in 2015, and a 12-month follow-up assessment was completed in August 2015. The study immunosuppression phase was initiated in October 2015 and will end in mid-2016, at which point blood and tissue sample PCR and assessment of other biomarkers will be undertaken to determine if they can differentiate parasitological cure from treatment failure.

DNDi is a member of the NHEPACHA network of investigators created for the long-term cohort evaluation of potential biomarkers.