*3.1.3 Chronic determinate disease (CDD)*

In patients with chronic determinate disease (CDD), an antiparasitic drug might not be expected to improve established organ dysfunction, but intervention might still stop further tissue damage, worsening of cardiomyopathy and frequency of adverse cardiovascular outcomes. To address this hypothesis, a large, prospective, multicenter, controlled trial was conducted across five endemic countries. The BENEFIT study randomized over 2800 patients with Chagas cardiomyopathy to benznidazole or placebo [46]. The primary endpoint was a composite of cardiovascular mortality and morbidity events. The mean follow-up was over 5 years at the time of reporting with excellent patient retention rates. Over a 7-year period, some 60% of patients were PCR positive as baseline. and importantly these assays were standardized across reference laboratories. There was no significant difference in the clinical

outcomes with primary endpoint events seen in just under 30% of patients in both arms. In PCR-positive patients, BZN causes seroreversion in two-thirds of patients compared with one-third of placebo patients. No correlation between seroreversion and clinical outcomes was seen. Additionally, the PCR seroreversion rates were much higher in Brazil than in the other countries.

While BZN therapy in CDD significantly reduces parasite load, this has not translated into significant clinical benefit. For this reason, the PAHO guidelines do not recommend antitrypanosomal therapy in this population. This trial result, however, may only hold true for benznidazole (or the same drug class) and may not predict for a new drug class with a novel mechanism of action or combination approaches.

Specific drug development challenges associated with the different populations in Chagas disease are summarized in **Table 4**.

Once the primary indication has been chosen, a cohesive set of clinical trials must be designed to generate the scientific and medical evidence to support drug registration. The foundation of the development plan will be significantly shaped by the drugs' pharmacology and its anticipated effect in humans.

#### **3.2 Pharmacology and dose determination**

Determining the correct dosing schedule and dosage form for a new drug is driven by basic principles of drug pharmacology. For a drug to be effective, enough biologically active substance must traverse the body's natural physiological barriers and metabolic pathways to reach the target site of action to cause the desired effect, without undesirable "off target" effects. Establishing effective and safe therapeutic doses in infectious diseases has been well served historically by pharmacokinetic and pharmacodynamic (PK/PD) modeling. This process integrates *in vitro*, *in vivo*, and human data to predict clinical efficacy and provide a rational basis for clinical regimens and trial design. The PK/PD drivers of efficacy are well recognized for many classes of antibacterials [47] and for some antiparasitics [48].

A specific drug exposure response model is assembled from preclinical data for each new compound class and validated during clinical development. All models have limitations and in the case of Chagas disease, they may be limited by the complex parasite-host relationship including differential tissue distribution, mixed infections, variable drug susceptibility, and parasite dormancy [49, 50]. Exploration of drug effects in different parasite stages, especially the intracellular amastigote form and clinical isolates from endemic regions, is recommended to support selection of a clinically effective dose. In addition, essential elements of a development program will be assessing the potential for inducing drug resistance and monitoring for resistance emergence as a cause of therapeutic failure during clinical trials. The effect on host immune response (serology) in animal models and under immunocompromised conditions provides further useful information to support clinical dosing decisions.

Sustainable duration of response is a critical success factor and the shortest possible duration of drug exposure required to obtain cure, while limiting emergence of resistance is desirable. To achieve these goals, special attention must be paid to the therapeutic index (TI), which is the quantitative relationship between drug exposure causing the desired therapeutic effect and that at which toxic develops. Animal models and PK/PD modeling simulations can provide guidance. Monitoring for recurrence in clinical trials is indispensable, and molecular


### **Table 4.**

*Drug development challenges associated with different Chagas disease populations.*

testing may distinguish between recurrence and new infection in hyperendemic areas. Pharmacokinetic sampling during phase II and III clinical trial is required to support dose-regimen selection, explain variability of response, and help interpret reasons of treatment failure.
