Chagas disease, which is transmitted to humans by a blood-sucking insect known as an Assassin bug, is the most
devastating parasitic infection in Central and South America and Mexico. The protozoan parasite that causes the disease,
Trypanosoma cruzi, infects 16 to 18 million people, causing severe chronic illness and tens of thousands of deaths per year.

Until now, there has been no effective treatment for the long-term, chronic form of Chagas disease, which kills up to
one-third of those infected, usually by heart failure. However, two Howard Hughes Medical Institute (HHMI) international
research scholars have now found that in mice, a compound called TAK-187 is significantly more effective than the current
standard of care – the drug benznidazole – in preventing T. cruzi-induced cardiac damage. Julio Urbina from the Venezuelan
Institute for Scientific Research, Miguel Angel Basombrio from the National University of Salta, and colleagues report their
findings in an early online publication of the April issue of the journal Antimicrobial Agents and Chemotherapy.

Benznidazole, a drug used to treat acute, recent Chagas infections, often has toxic side effects and does not work once the
disease has entered its chronic phase. As an alternative, Urbina, Basombrio, and colleagues tested TAK-187, a compound that
prevents T.cruzi from producing a member of the steroid family called ergosterol, which is essential to the parasite’s life
cycle. The compound is currently in development as a systemic antifungal agent, but the results of the current study suggest
that drugs of this type, which inhibit ergosterol synthesis, could be a “superior alternative to currently available therapy
in the management of chronic Chagas disease,” Urbina and Basombrio write in their report.

The scientists infected a group of mice with T.cruzi, then treated those mice with either TAK-187, benznidazole, or nothing
at all. While both drugs eliminated T.cruzi from the blood of infected animals, the researchers found that TAK-187 was more
effective at preventing cardiac and skeletal inflammation and tissue damage, with no toxic side effects. Cardiac and skeletal
damage occur in chronic Chagas infection, causing crippling and death.

Importantly, TAK-187 was effective at a dose that was both 10 times lower and administered less frequently than that of
benznidazole. The researchers think this may be because the new compound is eliminated more slowly than benznidazole from the
treated animals and is also more resistant to metabolism by the mammalian host.

The latest study confirms results published in 2003 by Urbina and colleagues in the International Journal of Antimicrobial
Agents, when they found TAK-187 effective against drug-resistant strains of T.cruzi.

“These results, together with the previous publication, are very promising,” said Roberto Docampo, a professor at the Center
for Tropical and Emerging Global Diseases at University of Georgia. “The results strongly support the view that a more
efficient treatment for Chagas disease could be available.” But Louis Kirchhoff, a professor at University of Iowa, questions
whether the drug is effective enough. “TAK-187 suppresses T-cruzi,” he said. “What we are looking for is a compound that
wipes out the parasite.”

Urbina and colleagues now plan clinical trials to determine the safety and efficacy of TAK-187 in patients with Chagas
disease. “We must now examine the safety and effectiveness of therapeutic doses of this drug and determine the optimal
administration schedule, the treatment duration, and its possible combination with other drugs,” said Basombrio, who started
studying the disease 28 years ago because it is so prevalent in his homeland of Argentina.

Takeda Chemical Company, the largest pharmaceutical manufacturer in Japan, has patented TAK-187 as a systemic antifungal
agent. “The clinical development of this compound as an anti-T-cruzi agent in humans will depend on legal and economic
agreements with Takeda, which are being sought through the World Health Organization,” said Urbina.

The Venezuelan started doing basic research on Chagas disease 25 years ago, concerned by the neglect of this tropical disease
by the pharmaceutical industry and most academic research centers in Latin America and throughout the world. “Only one
percent of the new drugs introduced to the market in the last 25 years were developed to treat tropical diseases, despite the
enormous unmet need for such compounds,” he said. “Only 10 percent of current global health research is directed to address
the medical needs of 90 percent of the human population.”

Contact: Jennifer Donovan
donovanjhhmi
240-401-5783
Howard Hughes Medical Institute
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