**3. The clinical development a new therapeutic agent**

A rational starting point of a new drug development program is a thorough understanding of the "patient journey," i.e., the pathway of patient experiences from contracting infection to their end outcome which includes access to the healthcare systems, diagnosis, treatment, and follow-up. Inevitably, the perspectives of multiple stakeholders (e.g., patients, caregivers, regulators, payers, policymakers) in the Chagas disease ecosystem must be integrated into program design.

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

Drug developers aspire to design new medicines to match a preconceived set of criteria called a "target product profile" or "TPP." This is a statement of the desired characteristics of the drug candidate and serves multiple purposes. It is a framework for generating scientific and clinical evidence to support a final product label; it guides program decision-making and facilitates dialog with regulatory authorities. The TPP may be modified during the development process based on the generated scientific data or a shift in the external environment. Characteristics of an "ideal" drug for a Chagas disease therapeutic are given in **Table 3**, and examples of TPPs have been given by Rao et al. [19] and the Drugs for Neglected Diseases initiative (DNDi) [27].

The remainder of this chapter will focus on the clinical development stage of a new drug and assumes that discovery and preclinical development stages have been completed. Readers wishing to have deeper insights into design of preclinical programs for Chagas drug candidates are referred to the comprehensive reviews by Romanha [28] and Kratz [29].

#### **3.1 Target indications and choice of study populations**

As patient needs lie at the core of any new drug development program, a critical strategic decision is the choice of the patient population and the projected clinical benefit. This drives a more specific TPP, determines the associated development risks, and ultimately determines the approved drug label.

The unique and complex nature of Chagas disease, characterized by varying parasitological and clinical effects at different stages of disease, has substantial implications for clinical trial study populations and the indication chosen for approval. A schema showing the possible disease intervention points and associated challenges is given in **Figure 1**.


#### **Table 3.**

*Characteristics of an "ideal" antitrypanosomal drug for Chagas disease.*

#### **Figure 1.**

*Development challenges vary by disease stage. (Adapted from Lidani et al. The Complement System: A Prey of Trypanosoma cruzi. Front. Microbiol., 20 April 2017).*

We will focus our principal discussion on issues associated with development in a general population of acute and chronic Chagas disease including children and adults. A pediatric development plan would be expected by most regulatory authorities. From a drug development perspective, neonates, pregnant women, and immunocompromised patients are considered special study populations and will not be further discussed in any detail. They would seldom be chosen as the first indication as the benefit-risk profile of the drug has not been fully established, but they may be included later when the appropriate supportive data are available.

#### *3.1.1 Acute Chagas' disease (ACD)*

It stands to reason that early intervention in Chagas disease with an effective and safe drug, without the mutagenicity liabilities or drug interactions associated with BZN or NFX, would be beneficial. Symptomatic acute Chagas disease (ACD) is a potentially favorable setting for testing a new drug for both early efficacy and to seek an approved indication. Patients with acute disease typically have significant parasitemia and many exhibit severe clinical manifestations [30], which could serve as the basis for measurement of a treatment effect. Endpoints measures are further discussed in section 3.4.

Since BZN and NFX response rates in ACD are already high, clinical trials intended for a regulatory submission must be powered to show superiority or noninferiority and require a large sample size. In early phase II studies of a new drug, using historical BZN control data is feasible, but better is the inclusion of a concurrent BZN calibration arm to gauge assay sensitivity. A concurrent placebo control would be unacceptable in a trial of monotherapy with a new agent and rescue medication (BZN or NFX) should be offered.

The main operational challenge in ACD is the enrollment of patients for clinical trials. The number of documented ACD cases in endemic countries is low [31, 32], and even in larger countries such as Brazil, where acute Chagas disease due to oral ingestion of contaminated foodstuffs has become more common, the reported

incidence is less than 0.15 cases per 100,000 of the population [33]. Prospective studies in ACD are uncommon with most published studies being case series, longitudinal cohort, or observational studies [34–36].

A modest size early phase II trial in ACD may be feasible if focused on a region of high endemicity, and a few trial sites but restricting eligibility to adults may slow recruitment rates. Interpretation of study result may also be challenging in that geographical variability in measured drug effect varies for many reasons [37, 38], and results from a small study in one region may not be reproducible in another region nor representative of a broader study population.

### *3.1.2 Chronic indeterminate disease (CID)*

Chronic indeterminate disease (CID) is an alternative study population with both high medical need and greater prevalence than ACD. The number of studies published in chronic disease far exceed those in the acute setting and accounted for almost 80% of 109 studies in a recent review of trials in Chagas disease [36]. Patients with CID are usually asymptomatic, physically active, and have no or minimal evidence of functionally significant organ damage. As evidence for the benefit of using antiparasitic therapy in CID is not compelling, a case can be made for designing trials with concurrent placebo controls, and the CID population is becoming increasingly used for early placebo-controlled studies of experimental drugs.

Including this population in a development program is a key opportunity to prevent progression to end-organ damage and have a major public health impact. Parasite persistence is considered to play a key role in developing clinical sequelae including cardiomyopathy [39], but the pathogenesis of organ damage is not fully understood [40, 41]. Choosing cardiac-related events as study endpoints in this patient population has significant logistic challenges as event rates are low (1–2% per year), and multiyear follow-up is needed [42–44]. Even with 13 years of follow-up in patients at low risk of progression, the large randomized placebo-controlled TRAENA study of BZN (Clinicaltrials.gov-NCT02386358) failed to detect any benefit on cardiovascular outcomes despite clear evidence of an antiparasitic effect [45].

The main study methodology challenges in studying CID are choice of appropriate measures of treatment effect (parasitological, laboratory, and clinical endpoints); variability in response associated with geographical, parasitological, and immune factors; and the extended follow-up needed to establish a relationship between shortterm response and long-term outcomes.
