One of the objectives of the Drugs for Neglected Diseases initiative (DNDi) is to develop improved and new treatments for Chagas disease. DNDi is currently building its Chagas portfolio, which includes projects that yield near-term benefit to paediatric patients as well as long-term projects that will potentially benefit a large population of chronic-phase patients.

Although the disease was discovered more than 100 years ago by the Brazilian Carlos Chagas, very little investment has been made in research and development for an effective treatment. Currently available treatments are not effective and poorly tolerated. To address this serious unmet medical need, DNDi has raised funds from public and private donors, and formed R&D partnerships with a number of key institutions to develop Chagas treatments.

Filling gaps in the pipeline
DNDi has adopted a balanced approach to build a Chagas disease portfolio and works to improve existing treatments through the development of new formulations that are better adapted to patients' needs. To address the short- and mid-term needs of patients, DNDi aims to find alternative drugs through therapeutic switching. In the long term, new chemical entities have to be developed that fit the target product profile. DNDi works with various investigators to overcome methodological constraints that limit the accurate diagnosis and clinical evaluation of responses to new treatments in the pipeline. Additionally, DNDi is involved in strengthening existing clinical research capacities through a regional platform of experts that supports high-standard clinical trials.

Drug discovery
Key elements in DNDi's drug discovery process include:

• Focused approach to compounds sourcing: DNDi has access to various chemical compounds, focused drug classes, and classes of inhibitors, as well as to data mining through a number of partnerships with various institutions and pharmaceutical companies.

• Screening of compounds: to ensure that screening results from different locations are comparable, reference screening centres with standard operating procedures in place are used for small set screening and hit confirmation. A key challenge to overcome has been the limited output of currently available screening methodologies and centres. In a partnership at the forefront of technology development, DNDi and Institute Pasteur Korea (IPK) have developed a visual-based high throughput screening (HTS) platform for wild-type T. Cruzi. This technology offers the possibility of more rapid identification of a hit and chemical series of interest to be progressed as drug candidates. The technology has already been successfully developed for the screening of compounds against the intracellular Leishmania parasite by DNDi at IPK.

• Series to optimise (from screening to drug candidate): at the end of 2008, a lead optimisation consortium was established to engage in a critical, interactive, and iterative process - Lead Optimisation - allowing a rapid turnaround and with the goal of optimising the antiparasitic efficacy of lead compounds while addressing their Distribution Metabolism Pharmacokinetics (DMPK) properties and improving their safety. This consortium consists of teams of analytical and medicinal chemists, pharmacologists, and parasitologists and includes institutions in Australia (Epichem, Murdoch, and Monash Universities) and in Brazil, the Universidade Federal de Ouro Preto (UFOP).

Answering urgent needs
To minimise the risks and length of R&D, compounds already registered or in clinical development for other indications are evaluated. These compounds have a previously demonstrated in vitro and/or in vivo activity for Chagas disease. For almost 20 years, ergosterol biosynthesis has been recognised as a potential target for anti-T. Cruzi treatment but there is limited information and initially mixed results. A new generation of antifungal triazoles has appeared as promising alternative treatments as anti-trypanosomal agents. An agreement with the Japanese pharmaceutical company, Eisai, allows DNDi to assume responsibility for clinical development of one such compound, a pro-drug of ravuconazole, named E1224.
Since the 1990s, there has been consensus on the diagnosis and treatment of children and adolescents in the early chronic phase of Chagas disease. Despite decreasing vectorial transmission, young children continue to be an important target population for treatment, because congenital infection as a mode of transmission will remain a high risk for at least another generation. Current drugs, however, are formulated as tablets for adults only, and are not adapted to children's bodyweights. To treat children, tablet fractionation and extemporaneous formulations are used, thus increasing the risk of improper dosages and raising safety concerns regarding efficacy and stability, particularly in very young and malnourished children.
A partnership agreement signed in 2008 between DNDi and the Pharmaceutical Laboratory of Pernambuco (Lafepe) will deliver at cost the first paediatric formulation of benznidazole, the most widely used drug for the treatment of Chagas disease.

Clinical research - tackling the challenges
Outside of specific drug development projects, DNDi is working to address a number of key issues regarding clinical research:

• Methodological issues for proof-of-concept evaluation in Chagas disease: the long period for seroconversion after the elimination of the parasite has presented a challenge in the evaluation of response to treatment. Over recent years, an increasing body of data has pointed to a strong biological rationale in favour of the use of parasitological outcomes as surrogate markers of the therapeutic response in Chagas. A TDR-sponsored study for standardisation and validation of qualitative polymerase chain reaction (PCR) testing for T. Cruzi has just been completed. This represents a valuable first step for implementation in future clinical trials. Further work is needed to validate quantitative PCR and to better define procedures for employment in drug studies.

• Clinical site identification: clinical trial sites must be identified to ensure adequate recruitment of patients who are suffering from different stages of the disease and who are infected with different strains of T. Cruzi to guarantee that clinical trials are implemented according to international standards.

• Strengthening clinical research: the Chagas Platform was launched in 2009 with various partners, with the aim of strengthening clinical research capacity and creating an environment conducive to clinical trials. It also provides a forum for technical discussions, review of the Target Product Profile, and consensus-building, thus creating the potential to streamline clinical development processes and to facilitate access to new therapies.