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An end is in sight: a perspective on PCR as an endpoint for Chagas disease treatment trials
Natasha S Hochberg1,2, Srinivasa P S Rao1,2, Gerhild Angyalosi3
1Novartis Biomedical Research, Cambridge, MA, United States.
Abstract:
Novel therapies for chronic indeterminate Chagas disease (CICD) are needed, but trials are limited by the absence of tests to detect infection and early treatment efficacy. This perspective highlights the shortfalls and strengths of polymerase chain reaction (PCR) as a study endpoint for anti-parasitic drug development. Serologic reversion, the gold standard test of cure, may take decades to occur in adults and therefore is challenging as an endpoint for drug development. Use of PCR as a marker of infection and treatment response has notable limitations due to low parasitemia in CICD, fluctuations in circulating (versus tissue) parasite burden, strain differences, and assay performance. It is, however, rapidly responsive to therapy, and technological advances have improved detection of different strains and may allow for parasite quantification. Until we have more sensitive tests for parasitological clearance, PCR as a measure of treatment failure may be the best available efficacy endpoint to accelerate early development of much-needed novel therapies. Adequately designed clinical studies are needed to correlate PCR clearance with clinical outcomes and to identify novel biomarkers predictive of clinical outcomes in patients with CICD. Public-private partnerships and health authority engagement are paramount to identify feasible trial endpoints and deliver promising new drug candidates for Chagas disease.
Insights
Polymerase chain reaction (PCR) shows promise as a rapid endpoint for evaluating new chronic indeterminate Chagas disease therapies. Despite limitations, PCR offers a faster alternative to serologic reversion for assessing treatment efficacy in drug development.
Area of Science:
- Parasitology
- Infectious Diseases
- Drug Development
Background:
- Chronic indeterminate Chagas disease (CICD) lacks effective diagnostic and early treatment efficacy tests.
- Current gold standard for cure, serologic reversion, takes decades in adults, hindering drug development.
- Novel anti-parasitic therapies for CICD are urgently needed.
Purpose of the Study:
- To evaluate the utility of polymerase chain reaction (PCR) as a study endpoint for anti-parasitic drug development in CICD.
- To highlight the limitations and strengths of PCR compared to serologic reversion.
- To propose strategies for improving clinical trial endpoints in Chagas disease research.
Main Methods:
- This perspective analyzes the application of PCR as a surrogate marker for infection and treatment response in CICD clinical trials.
- It discusses limitations including low parasitemia, fluctuating parasite burden, strain variability, and assay performance.
- Technological advancements in PCR for strain detection and quantification are considered.
Main Results:
- PCR is rapidly responsive to anti-parasitic therapy, offering a faster assessment of treatment efficacy.
- Limitations of PCR in CICD include low parasite levels and variability in detection.
- Technological improvements enhance PCR's ability to detect diverse strains and potentially quantify parasites.
Conclusions:
- PCR, despite its limitations, may be the most feasible efficacy endpoint to accelerate the development of novel CICD therapies.
- Further research is needed to correlate PCR clearance with clinical outcomes and identify predictive biomarkers.
- Public-private partnerships and regulatory engagement are crucial for establishing viable trial endpoints and delivering new Chagas disease drugs.
