Chagas disease: new compound shows promise in treatment

In recent decades, drug candidates for treatments have gone straight from experimental infections in mice to clinical trials in humans, where they have failed to cure the infection causing Chagas disease. The compound, known as AN15368, in addition to not

Researchers have identified a new drug 100% effective in the treatment of mice and Non-Human Primates (NHP) infected with Trypanosoma cruzi, the parasite causing Chagas disease. The compound, known as AN15368, in addition to not causing significant side effects, is more effective than all of the existing medications. The discovery marks the first widely validated and safe drug in more than 50 years for trypanocidal treatment of infection by T. cruzi. Human clinical trials are expected to begin in the coming years.

According to the article published in the scientific journal Nature Microbiology entitled “Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates“, AN15368 was considered active in vitro and in vivo against several strains of T. cruzi genetically distinct and uniformly curative in NHP with naturally acquired long-term infections. Treatment in Non-Human Primates also revealed no detectable toxicity or long-term impact on health or reproduction. The work was led by Dr. Rick Tarleton, professor at the University of Georgia.

Dr. Alejandro Luquetti Ostermayer, from the Chagas Disease Research Laboratory Hospital das Clínicas and Professor Emeritus of the Federal University of Goiás (UFG), explains that this extensive study verified the effect of a new group of drugs (benzoxaboroles) on the specific treatment of Chagas disease, drugs that have already been successfully tested in Trypanosoma brucei infection,  Leishmania donovani and Plasmodim falciparum. “For the study, AN15368 was selected, a prodrug – a biologically inactive compound that is metabolically activated – that penetrates the host’s infected cell, and in the amastigote form, is activated by enzymes of T.cruzi itself (carboxypeptidases) to produce a compound that targets its mRNA processing pathway, leading to its destruction,” he adds. The assays were conducted with cells (in vitro), later in mice and finally in 19 naturally infected rhesus monkeys, from a colony of more than 1,000 kept in captivity in the United States.

After 60 days of oral administration, the researchers were no longer able to detect the parasites in the blood of any of the animals. “Cure was observed under serial PCR, PCR in the organs of ten sacrificed animals, hemoculture and serology (multiplex) were observed in the nine unsacrificed, in the 42 month follow-up and in this period, not only all monkeys were healed, but scientists did not detect adverse reactions or effects on reproduction, as there were the birth of 13 monkeys (uninfected) of the treated mothers”, he adds. Also according to Dr. Luquetti, this may be an excellent new approach in the treatment of T.cruzi infection, considering that currently there are only two effective drugs (benznidazole and nifurtimox) which presents side effects in 20-30% of adults treated, and that several other drugs have not been effective.

Jadel Kratz, research and development (R&D) manager of the Drugs for Neglected Diseases Initiative (DNDi), points out that the results are very promising. “Testing the drug in non-human primates and tracking animals for so long strengthens the findings,” he adds, noting that the compound needs to go through the “valley of death” of drug development, regulatory toxicity studies and initial clinical trials that will determine whether it is indeed safe.

This is the first widely validated and safe compound in more than 50 years of research for the treatment of Chagas disease. After the work is complete, the team hopes to license the compound to an undisclosed company to conduct clinical trials. Dr. Tarleton’s group has been conducting research in the Chagas area for decades.

A silent and silenced disease

Chagas disease is endemic in 21 countries in the Americas, especially Brazil, Argentina, Bolivia, Paraguay, Venezuela, Chile, Colombia and Mexico. In Brazil, it is the fourth leading cause of death among infectious-parasitic diseases. In the Americas, an estimated 6 to 8 million people are infected with Trypanosoma cruzi, however, the majority (7 out of ten) are unaware of their condition due to the absence of clinical symptoms. More than 10 thousand people die each year as a result of clinical complications from the disease and about 75 million people in the region are at risk of contracting it.

The disease continues to cause great suffering and killing thousands of people in Latin America, especially in the poorest countries and among the most vulnerable populations. Currently, there are only two treatments available: benznidazole or nifurtimox, both developed at least 40 years ago, with a long treatment period of 60 days (8 weeks), and frequent side effects, especially in adults. Early detection is essential to improve treatment and cure effectiveness. Unfortunately the diagnosis often occurs in the final stages of the disease.