Challenges and opportunities for the treatment of Chagas’ disease – DNDi perspectives

Carolina Batista¹, Marina Certo¹, Julia Alapenha¹, Andrea Marchiol¹

¹ DNDi – Drugs for Neglected Diseases initiative

Contacts: mcerto@dndi.org, jalapenha@dndi.org

Introduction

In February 1909, the first patient with Chagas’ disease was diagnosed. Two-year-old girl Berenice had her case identified by physician Carlos Chagas, who brilliantly uncovered both the disease transmission cycle, parasite behavior, and the evolution of infection and disease. However, despite more than a century since its discovery, Chagas’ disease has remained distant from the Research and Development (R&D) priorities of the pharmaceutical market. The first drugs with demonstrated efficacy for the disease were only developed and made available more than half a century after their discovery, in the 1960s: benznidazole, developed by Roche, and nifurtimox, developed by Bayer. More than four decades after their development, these two drugs remain the only therapeutic options for the disease, which alerts and highlights the need for more collaborative efforts in favor of innovation and access to Chagas’ disease.

Current treatments

Benznidazole and nifurtimox are currently recommended in both the chronic and acute phases of the disease, with lower cure rates during the chronic phase, acting on the parasite without reversing established cardiac damage. Important findings regarding the efficacy of benznidazole have already been documented, such as the one just published with the results of the study with the compound E1224. This study carried out by the group of professor and researcher at the Universidad de San Simon, Dr. Faustino Torrico, was a proof of concept to treat adult patients infected with T. cruzi and was carried out in Bolivia with the support of DNDi (Drugs for Neglected Diseases initiative). The study demonstrated that 82% of patients treated with benznidazole had a rapid and sustained effect on parasite clearance, including follow-up after 12 months. Despite the growing evidence in favor of the etiological treatment, there is still resistance to the prescription of treatments by the medical community. Despite its life-saving potential, less than 1% of patients with Chagas’ disease receive etiologic treatment. A major concern is the occurrence of side effects, which are more frequent and severe as patients age. Thus, there is great urgency to improve the tolerability profile of current treatments and identify optimal dosage and duration of regimen, as well as develop safer and more effective alternatives. This will facilitate the uptake of drugs for Chagas’ disease in the public health systems of affected countries.

In 2011, a significant innovation for the pediatric population affected by Chagas was achieved. Benznidazole was developed and launched at a dosage of 12.5mg, included in the WHO List of Essential Medicines. Although treatment with benznidazole was recommended for children, the tablets were only available in a dosage of 100mg for adults. In this formulation, it is necessary to break the tablet into up to 12 pieces for the treatment of young children, which often results in inadequate and inaccurate dosing. DNDi’s partnership with Lafepe (Pharmaceutical Laboratory of the State of Pernambuco) enabled the development of the first formulation in pediatric dosage, adapted to age and easy to use. Considering the effectiveness of the etiological treatment in the pediatric population and the greater chances of curing the infection in this group, it is considered of great importance to ensure the adoption and expansion of access to treatment for this population.

Current scenario of studies for Chagas

While we observed a decline in clinical studies for Chagas in the 1990s, the beginning of the 2000s was distinguished by new projects. Three studies with very similar designs that evaluated triazoles compared to benznidazole stand out: CHAGAZOL, STOP-CHAGAS, and the E1224 Proof of Concept. However, although the three compounds had good repercussion in the preclinical phase, their efficacy results in the clinical phase were not good enough. Currently, the pipeline of R&D projects focused on the disease continues to expand, with pre-clinical initiatives to search for new compounds and therapeutic vaccines, while some clinical phases of investigation are being conducted, in which the clinical studies ATTACH, BENDITA, BERENICE, CHICAMOCHA 2 and CHICAMOCHA 3, CHICO, and FEXINIDAZOL. Even so, several challenges and knowledge gaps remain in the search for new solutions for Chagas’ disease, and collaborative alliances and integration are crucial to overcome obstacles.

The BENEFIT study (Benznidazole Evaluation for Interrupting Trypanosomiasis), whose results were published in 2015, is considered the most relevant study in recent years, being the first randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy of benznidazole in the clinical course of chronic Chagas’ disease in patients with advanced cardiac involvement. Its primary objective was to evaluate the use of benznidazole in reducing mortality and progression of chagasic cardiomyopathy in this group, also seeking to determine the effects of the drug in conventional detection of the parasite by PCR and evaluating its safety and tolerability. The multicenter study included 2,854 patients in its evaluation, being the largest clinical trial ever performed for Chagas’ disease. However, the negative results of the intervention for specific groups of infected people with cardiac complications pointed to the urgency of treating patients early, while the high level of mortality among volunteer patients pointed to the severity of the disease for infected people. The BENEFIT study highlighted serious and relevant complexities in the ability of the scientific community to evaluate new drugs and therapies for Chagas’ disease, raising several questions regarding future clinical studies and serving as an alert for the need to seek new tools for patients affected by the disease.

Current DNDi projects

As a non-profit R&D and access organization driven by patient needs, DNDi seeks to develop safe, effective, and affordable treatments for neglected patients around the world. In terms of R&D for Chagas’ disease, the initiative aims to seek an effective, accessible and safe oral treatment for the chronic and acute forms of Chagas’ disease, including new therapeutic regimens and combined treatments with benznidazole, in addition to seeking new chemical entities. Thus, we can divide its strategy into two distinct approaches: the search for new compounds, while simultaneously testing different approaches and therapeutic regimens from existing compounds. While the first approach requires more research time and long-term investment, the second seeks to refine existing tools for a more comprehensive picture of effective and safe treatments.

For the initial research, DNDi began, in 2013, the activities in Latin America of the Lead Optimization Latin America (LOLA) consortium, establishing a research network in medicinal chemistry, which employs a collaborative and multidisciplinary approach for the identification and optimization of new compounds against T. cruzi and Leishmania. Through this network of partners, DNDi carries out multidisciplinary activities associated with the identification (initial screening) and optimization of leading compounds (lead optimization), thus increasing its ability to generate pre-clinical candidates with the potential to fill the target product profile.

In DNDi’s portfolio in the clinical phase, two studies for Chagas are currently under development: BENDITA, conducted in Bolivia, which aims to evaluate new therapeutic regimens for benznidazole, in monotherapy and in combination with fosravuconazole (E1224), for the treatment of adult patients in the indeterminate chronic phase of Chagas’ disease; and the FEXINIDAZOL study, which evaluates the new compound fexinidazole for the treatment of chronic Chagas’ disease, which is underway in Spain.

Another important knowledge gap is the difficulty in predicting the course of the disease and measuring the benefits of treatment. DNDi seeks to identify and evaluate new biological markers of therapeutic efficacy for chronic Chagas’ disease – biomarkers that allow understanding the evolution of the disease and serve as a parameter for evaluating the response to treatment, in order to support the development of drugs. Other groups also seek advances in the field of biomarkers, supported and encouraged by DNDi through the Ibero-American network NHEPACHA.

Conclusion:

The new knowledge acquired, the increase in the number of research projects and initiatives are reasons to renew optimism and emphasize the need for open collaborations, such as the model supported by the Clinical Research Platform in Chagas’ disease, a network of more than 400 researchers, academics, activists, and public health officials united in an effort to improve the lives of patients with Chagas’ disease. Although new treatment options are not on the horizon in the short term, new research with promising innovations can change the scenario of the disease in the medium term. Thus, with a critical and collaborative spirit, we search for new tools that improve the lives of patients affected by Chagas, expanding horizons and partnerships in search of effective actions and the best science for the most neglected.