A clinical trial for the treatment of Chagas disease carried out in Spain with a mostly Latin American population showed that the drug fexinidazole was well tolerated by patients in low doses, although it was not effective in the sustained elimination of the parasite Trypanosoma cruzi, which causes the disease. The results of the study have been published in the prestigious scientific journal The Lancet Infectious Diseases.
Fexinidazole was developed as a broad-spectrum antimicrobial and showed antitrypanosomal potential in preclinical studies in the 1970s and 1980s, before its development was abandoned. It was subsequently rediscovered by the Drugs for Neglected Diseases initiative (DNDi) and found to be safe and effective for the treatment of sleeping sickness in a Phase 2/3 study, besides showing an acceptable safety profile. The European Medicines Agency recommended fexinidazole as the first all-oral treatment for sleeping sickness in 2018.
The study of fexinidazole for Chagas, known as FEXI-12, was a multicentre, double-blind, randomized Phase 2 trial for the treatment of indeterminate chronic Chagas disease. It took place in five hospitals in Spain with extensive experience in caring for patients with Chagas disease. The study was sponsored by DNDi, having the Barcelona Institute for Global Health (ISGlobal), supported by ‘la Caixa’ Foundation, as its national coordinating centre.
FEXI-12 evaluated three fexinidazole regimens with different durations and doses. Even though the volunteer patients tolerated all the regimens and the parasite load decreased markedly after treatment, a rebound effect was observed ten weeks later. Therefore, researchers decided to stop the development of fexinidazole as a monotherapy for the treatment of Chagas disease.
More than six million people are infected by Trypanosoma cruzi worldwide, and it has a particularly high impact on vulnerable communities in Latin America. Only a small proportion of those affected has access to diagnosis and treatment with benznidazole or nifurtimox. Both drugs, used for the antiparasitic treatment of this chronic infection, were developed more than fifty years ago. Frequent adverse reactions during their use pose a significant barrier, leading one in five patients to stop the treatment.
Fexinidazole was shown to be effective for the treatment of Chagas disease in a previous clinical trial, but the study was interrupted because the evaluated doses were not well tolerated. The new study assessed lower fexinidazole doses and a shorter treatment cycle.
‘Despite its good tolerance, fexinidazole did not show an adequate efficacy against the T. cruzi parasite and therefore is not a viable alternative for the treatment of Chagas disease,’ said Julio A. Padilla, director of the Chagas Initiative at ISGlobal. ‘The search for alternatives [new products and the repurposing of compounds used for other illnesses] is a priority.’ To this end, ISGlobal is participating in the TESEO study with the goal of optimizing the drug regimens currently in use (benznidazole and nifurtimox), while it investigates potential biomarkers of therapeutic response.
Chagas is still a neglected disease, with less than 1% of patients estimated to have access to treatment. The development of new drugs that are safer and more effective than the current treatments will likely take many more years. Different clinical trials have shown that the standard treatment with benznidazole is effective against the infection (with efficacy measured by negative PCR results), with a sustained effect for at least 12 months of post-administration follow-up in approximately 80% of the treated patients. Currently, the optimization of existing treatments using alternative regimens is still a promising line of research.
‘DNDi is working with its partners on the NuestroBen study, which aims to assess whether a shorter regimen of benznidazole has the potential to become the standard for the treatment of Chagas disease. Our hope is that a shorter treatment will improve the risk-benefit ratio of using the drug and help increase adherence to the therapy. Making current therapies easier and safer to use is potentially a faster way to improve the quality of life of those affected by Chagas, while in parallel we pursue the longer process of researching molecules to find a completely new treatment for the disease,’ said María-Jesús Pinazo, Head of Chagas disease at DNDi.
After the completion of the BENDITA trial, which suggested that a shorter duration treatment with benznidazole could maintain a high antiparasitic efficacy, new clinical trials were developed and are ongoing. They aim to provide clearer evidence of the feasibility of alternative regimens for existing drugs, and whether they can improve tolerability and adherence to treatment by reducing the incidence of adverse effects. Meanwhile, efforts to discover new drugs continue, and promising new chemical entities are advancing to Phase 1 and 2 trials.
Pinazo MJ, Forsyth C, Losada I, Esteban ET, García-Rodríguez M, Villegas ML, Molina I, Crespillo-Andújar C, Gállego M, Ballart C, Ramirez JC, Aden T, Hoerauf A, Pfarr K, Vaillant M, Marques T, Fernandes J, Blum B, Ribeiro I, Sosa-Estani S, Barreira F, Gascón J, on behalf of the FEXI-12 Study Team. Efficacy and Safety of Fexinidazole for Treatment of Chronic Indeterminate Chagas Disease (FEXI-12): A Multicentre, Randomised, Double-Blind, Phase 2 Trial.The Lancet Infectious Diseases 2024. doi: 10.1016/S1473-3099(23)00651-5
About Chagas disease
Caused by the parasite protozoan Trypanosoma cruzi and transmitted by insects known as ‘kissing bugs’, Chagas disease is endemic in 21 countries in the Americas and is present in Spain and other European countries, as well as in Japan and Australia. The infection affects around 6-7 million people, with 30,000 new cases and 14,000 deaths occurring every year. Because people can live for many years without experiencing any symptoms, most do not know they have the infection. Up to one third of people living with Chagas disease will suffer heart damage, which can lead to progressive heart failure or even sudden death. Chagas kills more people in Latin America per year than any other parasitic disease, including malaria.
The Barcelona Institute for Global Health (ISGlobal) is the result of an innovative alliance between the “la Caixa” Foundation and academic and government institutions with the goal of contributing to the efforts of the international community to address health challenges in a globalized world. ISGlobal constitutes a hub of research and medical care excellence with origins in the hospital (Hospital Clínic and Parc de Salut MAR) and academic (University of Barcelona and Universitat Pompeu Fabra) sectors. Its work model is based on the generation of scientific knowledge through Research Programs and Groups, and its translation through the areas of Training and Analysis and Global Development. ISGlobal is accredited as a “Severo Ochoa Centre of Excellence” and is a member of the CERCA system of the Generalitat de Catalunya. www.isglobal.org
The Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit medical research organization that discovers, develops, and provides safe, effective, and affordable treatments for neglected populations. DNDi is developing treatments for sleeping sickness, leishmaniasis, Chagas disease, river blindness, mycetoma, dengue, paediatric HIV, advanced HIV disease, cryptococcal meningitis, and hepatitis C. Its research priorities include children’s health, gender equity and R&D with a gender perspective, and diseases impacted by climate change. Since its inception in 2003, DNDi has collaborated with public and private partners around the world to provide 13 new treatments, saving millions of lives. dndi.org
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