**2. Current drug therapy**

The two mainstays of drug therapy in adult and children with Chagas disease are benznidazole (BZN) and nifurtimox (NFX). These two nitroheterocyclic prodrugs have been in clinical use for over four decades, and their background, efficacy, and safety are well documented [8–12]. Both reduce parasitemia and cause seroreversion but with less effect as the infection becomes more established. Both drugs are genotoxic, clastogenic, and in animals, are carcinogenic. The main inconveniences associated with their use are treatment duration of several weeks, avoidance of alcohol, and the associated clinical side effects. Adverse effects commonly seen with benznidazole are hypersensitivity reactions, skin rashes, gastrointestinal intolerance, peripheral neuropathy, and bone marrow suppression [8–14]. Nifurtimox is less well tolerated and associated with more nervous system toxicity (anorexia, sleepiness) and gastrointestinal intolerance [10].

While two drugs differ in safety profile, there is little evidence to favor efficacy of one over the other although preliminary results of one small randomized study appeared to show a slight trend in favor of BZN [15]. Results from two ongoing randomized studies (NCT02369978, NCT03981523) comparing multiple BZN and NFX regimens in adults with chronic indeterminate disease may help clarify this situation.

A simplified summary of the essential strengths and weaknesses of these two pillars of Chagas disease treatment from a drug developers' perspective is give in **Table 1**.

While a 60d treatment regimen is approved for both drugs, shorter BZN regimens show encouraging data of improved tolerability without loss of short-term efficacy [16, 17]. The results of three ongoing trials are awaited with interest; the MULTIBENZ three-arm randomized phase II trial (NCT03191162) compares both low dose for 60d and high dose for 15 d against standard 60d treatment; the nonrandomized NuestroBen phase III study (NCT 04897516) compares 2 weeks to 8 weeks of BZN and uses historical controls; and the phase III BETTY trial (NCT03672487) compares 30d of low-dose BZN to 60d standard-dose BZN in women of reproductive age.

*New Therapeutics for Chagas Disease: Charting a Course to Drug Approval DOI: http://dx.doi.org/10.5772/intechopen.102891*


#### **Table 1.**

*Simplified summary of essential product characteristics of benznidazole and nifurtimox.*

The Pan American Health Organization (PAHO) has issued guidance on the treatment and management of Chagas disease with these drugs based on critical review of available scientific evidence [18]. These comprehensive guidelines consider the both drugs to be effective in reducing short-term parasitemia but evidence is much less convincing for improving long-term clinical outcomes. Hence, there is still much room for improvement in efficacy and safety for different patient populations. Salient points of interest in these guidelines from a drug development perspective are summarized in **Table 2**.

The preclinical and development pipeline of experimental antitrypanosomal drug candidates is covered by several reviews [12, 19–21]. Only a few new drugs have reached phase II trials, notably the azoles class represented by posaconazole and fosravuconazole (E1224). Unfortunately, both failed to produce sustained


*\* Adapted from [18]: Pan American Health Organization. Guidelines for the diagnosis and treatment of Chagas' disease. Washington, D.C.: PAHO; 2019. OR = Odds ratio; and RR = Relative risk.*

**Table 2.**

*Current treatment recommendations for antitrypanosomal therapy.*

parasite suppression compared with BZN [17, 22–24] and have not progressed further. Fexinidazole, a 5-nitroimidazole approved for treating Human African Trypanosomiasis (HAT), has been tested in two phase II trials of Chagas disease (NCT 02498782, NCT 03587766). Following poor tolerability in the first study [25], a second study with modified dose regimens was conducted but results have not been published. Other novel drug classes (oxaboroles, nitroimadazoles, proteosome inhibitors) being developed for other trypanosomal diseases such as leishmaniasis and HAT may also have potential to treat Chagas disease [26].
