R&D Portfolio Update February 2019: DNDi Chagas disease programme

21 Feb 2019

DNDi aims to deliver:

A new benznidazole monotherapy regimen.
A new benznidazole and fosravuconazole combination treatment regimen.
A new fexinidazole monotherapy regimen.
A new chemical entity to be tested in clinical trials for treatment of patients with chronic Chagas disease.

DNDi’s current Chagas disease portfolio includes:

Four projects in the discovery phase:

Chagas hit-to-lead (H2L): DNDi has continued its efforts in screening chemically diverse libraries for identification and confirmation of new hits that could progress and feed the H2L pipeline. In 2018, a new partnership was established with the Drug Discovery Unit from Dundee University in Scotland and GSK to jointly characterize and progress new promising hits.

Booster hit-to-lead (H2L): In 2018, the Japanese pharmaceutical company Astellas Pharma Inc. joined the NTD Drug Discovery Booster, becoming the eighth company in the consortium. The project conducts multilateral, simultaneous searches of millions of compounds based on an active seed supplied by DNDi and uses computational approaches to refine the search iteratively. Since its creation in 2015, the Booster project has launched 45 iterations around 22 seed compounds, with the result that 13 hit series have been released, of which six have progressed to in vivo proof-of-concept studies for Chagas and/or leishmaniasis.

Daiichi-Sankyo Chagas hit-to-lead: This project, which ended in September 2018, aimed to identify at least one progressable lead series meeting DNDi lead-stage criteria for Chagas disease and/or visceral leishmaniasis. The project milestone was reached with the identification of a progressable Chagas lead series with proven in vivo efficacy. Daiichi Sankyo and DNDi are now looking for funding to progress this promising series for Chagas disease in 2019.

Chagas C205 series: This series is part of the GSK/DDU/DNDi discovery collaboration portfolio, following a research agreement made in early 2018. Work on the series has concentrated on safety profiling and exploratory toxicology for the selected front-runners. Decision on if and how to proceed will be made once the complete BENDITA trial data are available.

Three projects in the translation phase:

Biomarkers: Current work is focusing on raising awareness among Chagas stakeholders about the need for biomarkers, with particular emphasis on regulatory aspects and the biomarker development process. 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.

Benznidazole new regimens (‘Bendita’ study): This proof-of-concept trial was completed in the third quarter of 2018 and results will be available in early 2019. A total of 210 patients were recruited for this study, which was conducted in three sites in Bolivia and aims to improve efficacy, safety and tolerability of treatment of adults with chronic indeterminate Chagas. The trial assessed the efficacy of different doses of benznidazole in monotherapy and in combination with fosravuconazole. The primary measure of efficacy is a sustained parasitological response at six months follow-up with a final assessment at 12 months.

Fexinidazole: DNDi is evaluating fexinidazole as a potential new drug for Chagas disease. By September 2018, 45 patients had been recruited for this Phase II proof-of-concept study carried out in five sites in Spain to test different short-course regimens of fexinidazole for adults with chronic indeterminate Chagas. The study is now in the follow-up phase and will be completed in late 2019 with results available in 2020. If the study shows fexinidazole is effective, this will be the first new drug to treat Chagas disease in more than 50 years.

Implementation and access to treatments:

Chagas Access Project: The Chagas Treatment Access project expanded its activities significantly in 2018. A new project was launched in Guatemala by DNDi with local and international partners, and a seminar held in Jutiapa to identify the main barriers and develop actions to strengthen disease control and treatment access. Another new project was launched in Brazil in partnership with the Oswaldo Cruz Foundation; seminars to address barriers were held in Rio de Janeiro and Recife. Meanwhile, the Colombian project expanded to new communities, and year 1 results showed a 997% increase in people tested and a 95% reduction in time to diagnosis in the pilot study areas.

Benznidazole paediatric dosage form: The paediatric formulation of benznidazole, the main drug of choice for treating Chagas disease, was registered in Argentina in 2018. This was the result of a partnership between Fundación Mundo Sano, DNDi and Laboratorio Elea Phoenix to enable registration in more disease-endemic countries and provide a second source of the drug. The paediatric formulation of benznidazole was developed through a collaboration between DNDi and Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE) of Brazil and was first registered in 2011, in Brazil. It improves accuracy, safety, and adherence to treatment for children under two years of age (or up to 20 kg).

Chagas Clinical Research Platform (CCRP): With nearly 400 members from 150 institutions and 24 countries, the CCRP works to catalyse the involvement of researchers from endemic countries in improving R&D for Chagas, from drug discovery to implementation. In 2018, in a meeting in Bolivia, 95 members of the platform defined research priorities for the coming years and signed the Santa Cruz Letter, calling on governments, organizations and donors to step up their efforts to control and eliminate Chagas as a public health problem.

Photo credit: Rodrigo Carvalho-DNDi