Drugs in preclinical and early clinical development for the treatment of Chagas´s disease: the current status

ABSTRACT

Introduction

Chagas disease is spreading faster than expected in different countries, and little progress has been reported in the discovery of new drugs to combat Trypanosoma cruzi infection in humans. Recent clinical trials have ended with small hope. The pathophysiology of this neglected disease and the genetic diversity of parasites are exceptionally complex. The only two drugs available to treat patients are far from being safe, and their efficacy in the chronic phase is still unsatisfactory.

Areas covered

This review offers a comprehensive examination and critical review of data reported in the last 10 years, and it is focused on findings of clinical trials and data acquired in vivo in preclinical studies.

Expert opinion

The in vivo investigations classically in mice and dog models are also challenging and time-consuming to attest cure for infection. Poorly standardized protocols, availability of diagnosis methods and disease progression markers, the use of different T. cruzi strains with variable benznidazole sensitivities, and animals in different acute and chronic phases of infection contribute to it. More synchronized efforts between research groups in this field are required to put in evidence new promising substances, drug combinations, repurposing strategies, and new pharmaceutical formulations to impact the therapy.

KEYWORDS:

• Chemotherapy
• clinical trial
• combination
• preclinical tests
• repositioning
• Trypanosoma cruzi

Article highlights

• The CD is a neglected parasitic disease with no efficacious drug for treating patients in all phases of the disease.

• Drug combination, benznidazole new dosing regimen, and drug-repurposing are now the most studied strategies in clinical trials.

• New drugs and markers of parasite elimination after treatment are urgently needed.

• In the preclinical phase, animal models are essential to test drug efficacy, and new in vivo harmonized and robust protocols are required.

• Drug testing in acute and chronic phases of the animal infection is also required to identify new drug leads.

• New strategies have been investigated with promising results, such as new drug delivery systems to modify body distribution and pharmacokinetics and also administration routes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, patents received, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors received support from the Brazilian Federal Agency for Support and Evaluation of Graduate Education – Internationalization Program (CAPES/PrInt – FKVST), the research productivity program of National Council for Scientific and Technological Development - Brazil (CNPq - VCFM), and from University of Minas Gerais State (Researcher Productivity Scholarship, PQ/UEMG 06/2023 - ALM).