R&D Status February 2017: DNDi Chagas disease programme

 

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:

 

Research

Research

Two projects in the research phase:

 

  • Chagas hit-to-lead: The project evaluates hits identified from screening and begins the process of optimizing new chemical series. If promising activity can be demonstrated in in vivo models of Chagas disease, the series will be advanced into full lead optimization programmes. This process of hit-to-lead optimization is ongoing with multiple series identified following DNDi screening efforts and coming from several pharmaceutical companies.
  • Chagas lead optimization: In 2016, two new compounds issued from two new chemical classes showed curative activities against chronic infection in the bioluminescence imaging mouse model. It was the first time that non-nitroimidazoles compounds have been found to be curative in this model.

 

Translation

Translation

Three projects in the translation phase:

 

  • New benz regimens +/- fosravuconazole: Although benznidazole, today’s standard treatment for Chagas, has sustained efficacy until 12 months post-therapy, the drug is associated with side effects that can result in treatment discontinuation. A proof-of-concept (PoC) trial carried out in 2013 showed that fosravuconazole (previously known as E1224) had good safety and was effective at clearing the parasite, but efficacy was not sustained. A Phase I drug-drug interaction study, undertaken in 2014 in 28 healthy human volunteers in Buenos Aires, Argentina, assessed the safety and pharmacokinetic interactions of fosravuconazole and benznidazole administered separately and in combination. No major clinically relevant safety or tolerability issues were identified. A PoC study (known as the “BENDITA” study) to determine if the safety and tolerability issues of benznidazole can be managed by reduced doses and treatment duration, or by combining it with fosravuconazole, was designed in 2016. Benznidazole in monotherapy or in combination with fosravuconazole at selected doses and treatment durations will be assessed versus placebo in approximately 210 patients with chronic Chagas disease. Recruitment started in Bolivia at the end of November, and by the end of 2016, 10 patients had been enrolled. Enrolment in Argentina, with two sites planned, awaits regulatory approval.
  • Fexinidazole: A Phase II PoC study of fexinidazole was initiated in 2014 in Cochabamba and Tarija, Bolivia. A total of 47 patients were included, but the study was interrupted due to safety and tolerability issues. Interim data efficacy and safety analysis suggested high efficacy rates of fexinidazole and decision was made to extend clinical study follow-up to 12 months. Analyses of key efficacy outcomes and safety demonstrated high efficacy findings at the lowest dose tested and for all treatment durations, with safety concerns with treatment with high doses tested for more than 14 days. In addition, acceptable safety and tolerability was found at low doses and short treatment durations – taken together, these results warrant further investigation of fexinidazole for Chagas disease. A new PoC study has been designed and will be run in four sites in Spain. Recruitment of patients is planned for 2017.
  • Biomarkers: 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.

 

ImplementationImplementation

Implementation and access to treatments:

 
  • Benznidazole paediatric dosage form: Following the registration in 2011 in Brazil of the paediatric dosage form of benznidazole that was developed by DNDi and LAFEPE to address babies and children up to two years of age’s needs, and the inclusion in 2013 of the treatment on the WHO Essential List for Children, the main objective has been to broaden availability of the product. To this end, DNDi and the Mundo Sano Foundation entered into collaboration with ELEA to deliver and register a second source of the treatment (Abarax© 12.5mg tablets). The submission process for regulatory approval in Argentina was still ongoing in 2016.
  • Access to Chagas to existing treatments and diagnosis: Together with the Global Chagas Coalition and other key stakeholders, DNDi continues to support endemic countries to develop and change existing policies and mechanisms to scale up access to diagnosis and treatment to existing therapies for Chagas disease. In 2016, together with the national control programme, health authorities and research networks in Colombia, DNDi developed a comprehensive patient-centred roadmap which defines operational interventions such as the implementation of pilot projects in four regions, registration of benznidazole and the design of a new diagnostic algorithm allowing for Chagas disease diagnosis at the primary health care level. Other access projects are ongoing in the US, aiming at generating evidence about the burden of disease and the different barriers that impede access, as well as in Central American countries.
 

 

Photo credit: Fabio Nascimento-DNDi