In countries where three diseases are endemic, patients have very few reasons to take comfort. The current chemotherapies for trypanosomatidic infections are highly toxic and often lead to relapses. Drugs used to combat Leishmaniasis have many shortcomings and are also used in animals, raising concerns over potential resistances. Chagas drugs were introduced over 40 years ago with no improvement since. The NMTRYPI (New Medicines for Trypanosomatidic Infections) project developed new prototypes for the three infections. It aimed to find less toxic and more effective compounds suitable for oral use. The project investigated the potential of a drug candidate to cure more than one trypanosomatidic infection, and it tested various compound combinations against new drug targets. ‘We developed four main compound series and tested more than 11 000 extracts from natural sources,’ says project coordinator Prof. Maria Paola Costi, of the University of Modena and Reggio Emilia. ‘Using a range of systematic strategies, we selected suitable leads for advanced animal testing and developed treatment schedules specifically for use against trypanosomatidic parasites.’ Tackling black fever Perhaps one of the most impressive project outcomes was the discovery of a drug candidate for visceral leishmaniasis, also known as black fever. The latter was validated in three animal species — mice, hamsters and dogs. Results on dogs were so promising that the animals were kept alive, adopted and are still being monitored: Now, almost 9 months after treatment, all animals are still healthy and have not shown any sign of relapse. In fact, the results were so encouraging that the team decided to proceed with preliminary exploration in monkeys. ‘We had the opportunity to test the compound in a monkey trial through a synergic collaboration with KINDRED, another FP7-funded project,’ Prof. Costi explains. Conducting tests on monkeys before phase I clinical trials has several advantages: their anatomy and physiology is close to that of humans, Leishmania infection is associated with a similar profile of parasite dissemination, and their use enables deep tissues analysis. Moreover, monkeys present a clearance mechanism for drugs similar to that found in humans. ‘Because immune-suppression is associated with the re-emergence of visceral leishmaniasis, understanding the immune response related to drug therapy is of crucial interest. Evaluating surrogate markers of immunity in experimental models allowed us to consider the factors that confer protection. We can use a new drug with immune modulatory properties or formulated with the right components to help control the disease,’ says Prof Costi. In its present form, the new drug candidate has a balance of efficacy and toxicity superior to that of the currently available oral treatment, Miltefosine. It proved to be effective against phase II HAT as well. ‘It is the first time that a compound for oral treatment can pass the brain barrier and has the potential to be used in phase II of Sleeping Sickness. This potentially opens the door to the first-ever oral combination therapy in the anti-Trypanosoma brucei field. Moreover, we have a genuine opportunity to use the same compound for more than one parasitic disease,’ says Prof Costi. In addition to the new drug candidate, the project helped identify some 20 compounds acting against T.brucei and different Leishmania species in vitro, all with suitable properties for animal testing. Administration of a combination of compounds against new targets was proposed as a proof of concept. Prof Costi is hopeful that patients will soon benefit from the project’s outcomes. ‘Development of a new drug is a long, risky and costly process, but, if everything goes well, Phase I trials could start in a three-years time approximately’. In the meantime, the consortium will keep applying for follow-up grants, either under the EU’s research framework programmes or with other funding agencies. ‘Interested stakeholders such as pharma companies are at the top of our list,’ Prof Costi concludes.
NMTRYPI, Leishmania infection, black fever, chemotherapy, trypanosomatidic infections, visceral leishmaniasis, Chagas disease, drug candidate