R&D MODEL & PORTFOLIO
The disease has two clinical phases, the acute phase (fatal for 2-8% of children), which is often asymptomatic or poorly symptomatic and unrecognized, and the chronic phase, which can be divided into two stages: • The chronic, asymptomatic (or indeterminate) stage, during which patients can transmit the parasite to others (mostly through blood, congenital transmission, or occasionally organ transplant) and which may last decades after infection. • The chronic, symptomatic stage, developing later in up to 30% of infected patients. Chagas disease causes abnormal dilation of the large intestine (megacolon), is the leading cause of infectious heart disease (cardiomyopathy) in the world, and the leading cause of death from a parasitic disease in Latin America.
IN LATIN AMERICA
people at risk
What are the current treatments and their limitations?
Current treatments, benznidazole and nifurtimox, are effective against the acute phase of infection, and while there is increasing evidence of their efficacy in the chronic indeterminate phase of the disease, broad use of these drugs has been limited due to lack of guidelines and policies supporting implementation. Drawbacks include long treatment periods (60-90 days), dose-dependent toxicity, and a high drop-out rate of patients due to side-effects. There is currently no approved treatment for the chronic form of the disease with target organ involvement (chronic symptomatic stage).
people infected, leading to approximately 7,000 deaths every year
WHAT IS DNDi DOING TO ADDRESS UNMET TREATMENT NEEDS?
DNDi’s short-term goal was to make better use of existing treatments, for example through the development of a paediatric dosage form of benznidazole – a goal which was achieved in 2011. The treatment is registered in Brazil by LAFEPE (2011), and was included on the WHO Essential Medicines List for children in 2013. An agreement signed in 2013 with the Mundo Sano Foundation ensures a second source of the paediatric dosage form to be produced by ELEA. Collaborative activities will continue to support country registration and adoption, and greater treatment availability to patients. As a medium-term strategy, DNDi has been assessing known families of compounds, such as nitroimidazoles and the new triazole antifungals, for activity against T. cruzi in adult chronic patients. A proof-of-concept trial showed fosravuconazole (E1224) monotherapy did not show sustained efficacy, as measured by sustained parasite clearance one year after end of treatment. In contrast, the current regimen of benznidazole was very efficacious over the period of 12 months of follow-up. Alternative benznidazole regimens, including reduced dosing and duration of treatment in monotherapy, and combination treatment with fosravuconazole, are now being explored. Fexinidazole, a non-genotoxic nitroimidazole currently in development for HAT and VL, is also being evaluated for treatment of adult indeterminate Chagas disease. Additionally, DNDi continues to search for potential biomarkers of treatment response to enhance clinical trial capabilities for evaluation of new compounds. As part of its long-term strategy, DNDi continues to identify and engage partners from private and public sectors in order to identify, characterize, and advance the development of promising compounds as well as to pursue discovery efforts for innovative therapies. In addition, DNDi supports clinical research capabilities and access through the Chagas Clinical Research Platform (see p. 60), which was launched in 2009. Ideally, a new treatment would target both acute and chronic phases of the disease, with activity against most parasite species in all endemic regions, with a better safety profile than existing drugs and noninferior efficacy to benznidazole, being easy-to-use (oral, once-a-day for less than 30 days, requiring no hospitalization, and little or no monitoring), affordable, and adapted to tropical climates.