New benznidazole regimens

Objective: Evaluate new therapeutic regimens of benznidazole as monotherapy, or in combination with fosravuconazole, for the treatment of adult patients with chronic Chagas disease.

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.

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 this new evidence, the NuestroBen study was redesigned, with the primary objective 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, the scientific community, and lead statisticians, DNDi reviewed the current clinical research landscape for Chagas and the suitability of short regimens of benznidazole and developed an agenda 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. The NuestroBen study was reinitiated in the second quarter of 2023 following ethical and regulatory approvals and preparation of study sites.

Photo credit: Ana Ferreira-DNDi