Anti-trypanosomatid Drugs/Candidates in Clinical Trials: What's New and What's Missing?

Parasites and infectious agents are responsible for neglected tropical diseases (NTDs) that affect many countries worldwide. At least one NTD is found 149 countries, mostly in low-income countries with poor sanitation, and it impacts over a billion people. According to the World Health Organization, trypanosomiasis is a group of protozoan infections that cause Chagas disease (Trypanosoma cruzi), Human African Trypanosomiasis (sleeping sickness - Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense), and Leishmaniasis (Leishmania spp. - Trypanosomatidae family), which are all considered NTDs. It is estimated that approximately 500,000 deaths from NTD infections occur annually worldwide. Despite the many cases associated with NTDs, treatments for most of these diseases are available. However, they are associated with significant adverse effects and a growing number of drug-resistant microorganisms and require parenteral administration. Besides that, many trypanosomatid diseases are zoonotic, making eradication extremely difficult. In this way, despite scientific progress over the years, some drug discovery goals remain unmet, such as the development of new therapeutic classes, reduced toxicity, improved administration regimens, or the development of combination therapies. Therefore, this chapter intends to present the six categories of drugs, i.e., the currently used therapeutic agents, nitroaromatic compounds, azole antifungal, benzoxaboroles, nitrogen heterocycles, and miscellaneous agents in clinical trials for NTDs, focusing on infections caused by trypanosomatids. In addition, the review approach presents the development process of the new drugs or treatment regimens in Phase I, II, III, and IV studies of the clinical trials based on the Drugs for Neglected Diseases initiative (DNDi) portfolio published in December 2020.