Emerging agents for the treatment of Chagas disease: what is in the preclinical and clinical development pipeline?

ABSTRACT

Introduction

Chagas disease treatment relies on the lengthy administration of benznidazole and/or nifurtimox, which have frequent toxicity associated. The disease, caused by the parasite Trypanosoma cruzi, is mostly diagnosed at its chronic phase when life-threatening symptomatology manifest in approximately 30% of those infected. Considering that both available drugs have variable efficacy by then, and there are over 6 million people infected, there is a pressing need to find safer, more efficacious drugs.

Areas covered

We provide an updated view of the path to achieve the aforementioned goal. From state-of-the-art in vitro and in vivo assays based on genetically engineered parasites that have allowed high throughput screenings of large chemical collections, to the unfulfilled requirement of having treatment-response biomarkers for the clinical evaluation of drugs. In between, we describe the most promising pre-clinical hits and the landscape of clinical trials with new drugs or new regimens of existing ones. Moreover, the use of monkey models to reduce the pre-clinical to clinical attrition rate is discussed.

Expert opinion

In addition to the necessary research on new drugs and much awaited biomarkers of treatment efficacy, a key step will be to generalize access to diagnosis and treatment and maximize efforts to impede transmission.

KEYWORDS:

• Benznidazole
• Chagas disease
• clinical trials
• drug discovery
• fexinidazole
• monkeys
• nifurtimox
• posaconazole
• pre-clinical assays
• Trypanosoma cruzi

Article highlights

• Chagas disease, caused by the parasite Trypanosoma cruzi, can be treated with the drugs benznidazole and/or nifurtimox. Despite showing good efficacy when administered early in the acute phase of the disease, their efficacy is variable during the symptomatic chronic phase, and both have frequently associated toxicity. Thus, safer and more efficacious drugs are urgently needed.

• Major advancements have been made during the last decade in the field of anti-T. cruzi drug discovery. Genetically engineered parasites are the basis of in vitro assays for the high throughput screening of large chemical collections to find new drugs, and of in vivo models that allow longitudinal assessment of drugs´ efficacy.

• Several clinical trials have been performed recently, and several more are currently ongoing, either evaluating the anti-parasitic capacity of new drugs like fexinidazole or new regimens of already used ones.

• Moreover, highly translational monkey models of acute and chronic T. cruzi infection have been developed to minimize the attrition rate between pre-clinical and clinical evaluation of candidates.

• The lack of biomarkers for the timely assessment of treatment response greatly hampers the development of new drugs for Chagas disease, as well as the daily management of patients. Availability of these tools would be a breakthrough, revolutionizing both the design and performance of clinical trials and the follow-up of treated T. cruzi-infected subjects.

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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, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

Authors would like to thank the financial support by the Departament d’Universitats i Recerca de la Generalitat de Catalunya, Spain [AGAUR; 2017SGR00924], and funding by the Instituto de Salud Carlos III (ISCIII) RICET Network for Cooperative Research in Tropical Diseases [ISCIII; RD12/0018/0010] and FEDER. JG research is supported by the Spanish Ministry of Science and Innovation-ISCIII project PI18/01054. MJP research is supported by the Ministry of Health, Government of Catalunya [PERIS 2016-2010 SLT008/18/00132]. In addition we acknowledge support from the Spanish Ministry of Science and Innovation through the ‘Centro de Excelencia Severo Ochoa 2019–2023’ Program [CEX2018-000806-S], and support from the Generalitat de Catalunya through the CERCA Program. Authors declare no other financial or other relationships such as consultancies, expert testimony, honoraria, speakers bureaus, retainers, stock options or ownership than their corresponding affiliations indicated in the title page.