Evaluate new therapeutic regimens of benznidazole as monotherapy, or in combination with fosravuconazole, for the treatment of adult patients with chronic Chagas disease.
current phase of drug development
updated 15 Feb 2023
Benznidazole, currently the standard treatment for Chagas disease, is effective but has limitations: the treatment lasts 60 days, and some 20% of patients stop treatment due to side effects, which can include gastric intolerance, skin rashes, and neuromuscular problems. To explore whether the side effects were related to dose or treatment duration, DNDi decided to test the efficacy of new regimens where exposure to benznidazole would be reduced, either due to shorter treatment, lower doses, or both.
In 2013, a proof-of-concept trial showed that fosravuconazole, an azole-class antifungal drug discovered by Eisai Ltd (Japan), had good safety and was effective at clearing the parasite, but efficacy was not sustained. A Phase I drug-drug interaction study 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.
The BENDITA (Benznidazole New Doses Improved Treatment & Therapeutic Associations) study looked for regimens at least as effective as the standard treatment, with fewer side effects. From 2016 to 2018, a Phase II, randomized, placebo-controlled study was carried out in three sites in Bolivia to test six benznidazole treatments of differing lengths and dosages, both as a monotherapy and in combination with fosravuconazole, against a placebo. The aim was to improve efficacy, safety, and tolerability of treatment of adults with chronic indeterminate Chagas disease, thereby improving patients’ adherence and making the treatment more acceptable to physicians.
Results showed that the new regimens’ main benefits were related to an improved safety profile, but further assessment was required to confirm non-inferiority compared to standard regimens. DNDi continues to work with national programmes, partners, and health ministries of endemic countries to confirm these results and encourage the necessary steps to register the new regimen. In 2021, DNDi started a Phase III clinical trial in Argentina to validate a two-week regimen with benznidazole for adults in the chronic phase of the disease. In late 2021, recruitment was put on hold based on scientific evidence and new findings, including post-hoc analyses of the BENDITA study.
Based on new evidence from post-hoc analyses of the BENDITA study, the NuestroBen study was redesigned. The primary objective will be to compare the safety and efficacy of 2-week and 4-week regimens, versus the 8-week standard regimen, in adults in the chronic phase of Chagas disease of indeterminate form or with mild cardiac progression.
Together with partners Mundo Sano Foundation and Laboratorio Elea Phoenix in Argentina, DNDi reviewed the current clinical research landscape for Chagas and the suitability of short regimens of benznidazole. An agenda was developed in collaboration with the scientific community and lead statisticians to evaluate potential options for the study design of the Phase III clinical trial in Argentina. The updated study design was developed through a technical-scientific collaboration with Fiocruz – which leads a Phase III trial in Colombia and Bolivia with a similar approach – with the aim of harmonizing efficacy results across the Phase III trials. Ethical/regulatory submissions are expected by end of the first quarter 2023.
In conjunction with partners Mundo Sano Foundation and Laboratorio Elea Phoenix in Argentina, DNDi embarked on Phase III study to compare the safety and efficacy of a two-week treatment regimen of benznidazole to the current standard eight-week treatment. After obtaining all ethical and regulatory approvals, the study was initiated in July 2021. DNDi also began contributing as a key collaborator in a Fiocruz-led Phase III study of a short-course benznidazole treatment regimen in Colombia, Bolivia, and Brazil, as part of a Unitaid-funded project to interrupt congenital transmission of Chagas disease. This study is currently being reviewed by the relevant ethical committees.
In April 2021, a manuscript on the earlier BENDITA study was published in The Lancet Infectious Diseases.
BENDITA, the first Phase II study of new treatment regimens of benznidazole, was finalized and a manuscript describing the results was accepted for publication in Lancet Infectious Diseases. The results, indicating good efficacy and safety in shorter regimens of benznidazole and combination therapies with fosravuconazole, supported a strategy to validate a shortened treatment regimen in a Phase III clinical trial.
DNDi began leading, in conjunction with partners Mundo Sano Foundation and ELEA, a Phase III study to compare the efficacy and safety of a 2-week treatment of benznidazole compared to the current standard (an 8-week treatment). The study will take place in Argentina and begin recruitment in mid-2021.
The positive BENDITA results also provided the basis for a wider regional initiative with funding support from Unitaid to interrupt congenital transmission of Chagas disease; DNDi actively participated in the construction, along with Fiocruz, FIND, and other partners. The initiative will include a Phase III study of a short treatment of benznidazole in Colombia, Bolivia, and Brazil, which will help answer the question of whether a shortened treatment can be effective in different areas with different T. cruzi strains. DNDi is a key collaborator in the Fiocruz-led initiative.
Phase II trial results available in early 2019 showed that all treatment arms were effective compared to placebo and the new regimens presented good safety profiles. The two-week course of treatment with benznidazole monotherapy was particularly promising. While significantly shorter than the standard eight-week treatment, it showed 83% efficacy and none of the patients assigned to this arm had to discontinue treatment due to side effects. Based on these results, DNDi is planning to run an international, multi-site confirmatory Phase III study.
This proof-of-concept trial was completed in the third quarter of 2018 and results will be available in early 2019. A total of 210 patients were recruited for this study, which was conducted in three sites in Bolivia and aims to improve efficacy, safety and tolerability of treatment of adults with chronic indeterminate Chagas. The trial assessed the efficacy of different doses of benznidazole in monotherapy and in combination with fosravuconazole. The primary measure of efficacy is a sustained parasitological response at six months follow-up with a final assessment at 12 months.
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.
Regulatory approvals were secured in Bolivia to start a Phase II Proof of Concept (PoC) study to determine if the safety (known as the “BENDITA” study) and tolerability issues of benznidazole could be managed by reduced doses and treatment duration, or by combining it with fosravuconazole. Benznidazole in monotherapy or in combination with fosravuconazole at selected doses and treatment durations will be assessed versus placebo in 210 patients with chronic Chagas disease. Recruitment started at the end of November; 10 patients had been enrolled by the end of 2016.
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