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:
Three projects in the research phase:
- Chagas H2L: A new discovery cascade has been implemented comprising new in vitro and in vivo models. If promising activity is demonstrated, the identified series would then be advanced into full lead optimization programmes.
- Booster H2L: Two new companies joined the booster in 2017, with Merck becoming the sixth consortium partner and AbbVie the seventh, and an eighth under negotiation to join. To date, 32 iterations of the booster have been launched around 16 distinct seed compounds. Ten hit series have been identified, four of which will enter into proof-of-concept in vivo efficacy studies by the first quarter of 2018.
- Daiichi-Sankyo CH2L (new project in 2017): The objective of this 18-month hit-to-lead collaboration project, which is supported by GHIT and was initiated in April 2017, is to identify at least one – possibly two – progressable lead series meeting DNDi lead stage criteria for visceral leishmaniasis and/or Chagas disease. Three T. cruzi active series (series 1-3) were identified from a high throughput screening of 40,000 members of the Daiichi Sankyo Pharma Space Library. Current medicinal chemistry efforts of this hit-to-lead collaboration focus on one series (series 1) that was confirmed as the most promising chemotype in terms of activity and selectivity profile. To date, over 100 analogs to series 1 have been synthetized and tested for T. cruzi activity at Institut Pasteur Korea, leading to the identification of four preferred molecules nominated to proceed with pharmacokinetics studies. A parallel screening of a representative compound set of the still-unscreened part of the Daiichi-Sankyo Pharma Space Library has enabled us to identify T. cruzi active chemotypes, of which two have been prioritized for resynthesis and follow-up activity.
Two projects in the translation phase:
- New benznidazole regimens (monotherapy or in combination with fosravuconazole): Benznidazole monotherapy is the standard treatment for Chagas disease worldwide. This proof-of-concept trial (known as the “BENDITA” study) aims to improve safety, tolerability and compliance whilst maintaining or increasing efficacy compared to current regimens for chronic indeterminate Chagas disease patients. The programme has integrated different doses, dosing frequency and treatment duration of the drug in monotherapy or in combination with fosravuconazole. The trial is being conducted in three sites in Bolivia, with recruitment completed in late 2017. The primary efficacy parameter is sustained parasitological response at six months. The final assessment will include 12 months of follow-up, with final results available in early 2019.The BENDITA study was developed based on results from two previous clinical trials conducted by DNDi. A proof-of-concept trial carried out in 2013 showed that fosravuconazole (previously known as E1224) was safe and effective at clearing the parasite. Efficacy, however, 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.
- Fexinidazole: DNDi is evaluating fexinidazole as a potential new drug candidate for Chagas disease. This phase II proof-of-concept study targets urgent unmet need for a new oral treatment of chronic Chagas patients. A previous phase II proof-of-concept study of fexinidazole was conducted in Bolivia with a total of 47 patients included before the study was interrupted due to safety and tolerability issues. Efficacy and safety analysis suggested the potential for shorter and lower-dose treatment regimens. Consequently, a new study was started in 2017 at four sites in Spain. The target conclusion date is in the second quarter of 2019.
Implementation and access to treatments:
- Benznidazole paediatric dosage form: DNDi and the Mundo Sano Foundation collaborated with ELEA to deliver and register a second source of the paediatric treatment against Chagas (Abarax© 12.5mg tablets). The registration process for regulatory approval in Argentina is ongoing. The first paediatric formulation was registered in Brazil in 2011, developed by DNDi and LAFEPE to address infants and children up to two years old. The treatment was included in the WHO Essential List for Children two years later.
- Access to Chagas to existing treatments and diagnosis: DNDi started its access to Chagas treatment initiative in 2015 and has prioritized the implementation of its activities in countries with high disease burdens, diverse epidemiology, and political/policy opportunities, with the objective of developing scalable approaches to be replicated in different epidemiological contexts.DNDi works with partners to develop pilot projects that can demonstrate the feasibility of a patient-centred approach to Chagas disease that includes diagnosis and treatment at the primary health care level. Projects foster collaboration with key partners, especially with in-country stakeholders from academia, health providers, patient groups and policy makers.
In Colombia, DNDi’s role has been to catalyse the public health response to Chagas disease by providing technical consultation and organizational support for the creation and implementation of a new, patient-centred roadmap. Now being piloted in five communities in areas endemic for Chagas disease, the roadmap has greatly simplified the diagnostic process and moved treatment into more accessible primary care facilities. Interim results in 2017 showed a substantial increase in access to diagnosis and treatment. Results after one year of the pilot projects will be shared in mid-2018.
This same methodology, as part of a Global Access Plan for Chagas disease, is the framework for a new project starting in 2018 in Guatemala. In collaboration with IDRC, Mundo Sano Foundation and local partners, the project will identify core barriers to diagnosis and treatment, and implement a roadmap for comprehensive care of Chagas patients living in areas with a high burden of the disease.
- Chagas Clinical Research Platform (CCRP): The CCRP offers a space for sharing information and coordinating efforts among researchers, and for discussing and refining an overall research strategy for the disease. The CCRP strengthens collaboration by forging an international network of researchers, healthcare providers, patient associations, academics, public health officials, pharmaceutical industry, non-profit organizations, and other key stakeholders. CCRP members identify priority topics and unmet needs to guide clinical research and to support effective and efficient clinical trials to deliver improved treatments. It also fosters collaboration between endemic country researchers and health providers to ensure that research findings are quickly translated into health policies, thus addressing patients’ needs more effectively.
Photo credit: Felipe Abondano-DNDi