No Way to Know If the Drug Worked

Approximately 6 million people are infected with Trypanosoma cruzi, the parasite causing Chagas disease, and only two drugs exist to treat it — benznidazole and nifurtimox, both developed over 50 years ago and both with significant toxicity profiles. No new drug has been approved because no drug development programme can generate the primary evidence regulators require: proof that treatment eliminated the parasite. The conventional test of cure for Chagas is serological — measuring antibody decline by ELISA — but antibody titers in treated patients decline over years to decades, making it impossible to run a clinical trial within a commercially or scientifically viable timeframe. The field is not blocked by the absence of candidate molecules; it is blocked by the absence of a validated, timely endpoint.

The consequence of the measurement gap is that Chagas drug development is structurally unable to complete. Any trial that requires conventional serological cure confirmation cannot produce a result in a timeframe that justifies the investment — a fundamental market failure that applies equally to academic and commercial developers. Fewer than 10% of infected individuals know their status, partly because testing is concentrated in formal healthcare systems that are inaccessible to most at-risk populations in Latin America. The disease causes progressive cardiomyopathy in 20–30% of chronic cases, producing heart failure that requires expensive tertiary care. The absence of treatment options means this trajectory is currently uninterruptible once established.

PCR can detect T. cruzi DNA directly, which should in principle provide a faster confirmation of parasite clearance than serology, but parasitemia in chronic Chagas is intermittent and low-level, making PCR sensitivity insufficient for reliable test-of-cure in chronic patients. Host biomarker programmes — searching for human biological markers that change predictably with treatment response — were pursued but suspended due to inter-platform discrepancies: the same samples analyzed on different platforms produced inconsistent results, preventing the validation needed for regulatory acceptance. DNDi developed the MultiCruzi serological assay, which measures antibody responses to multiple T. cruzi antigens simultaneously and showed antibody decline at 6–12 months post-treatment in the BENDITA trial — a significant acceleration over conventional ELISA. However, MultiCruzi itself requires clinical validation across diverse patient populations and regulatory acceptance before it can serve as a primary trial endpoint, meaning there is a validation gap between the promising assay and the validated tool the field needs.

MultiCruzi requires a dedicated validation programme: prospective studies across multiple endemic-country sites, diverse patient populations, and disease stages, with explicit regulatory engagement to define what validation evidence would support endpoint acceptance. This is regulatory science and clinical validation work, not drug discovery — a category of investment that does not fit neatly into pharmaceutical development pipelines or traditional academic grant structures. Parallel investment in understanding the biological basis of the years-to-decades antibody decline in conventional serology could clarify whether faster-declining markers exist that have been overlooked. WHO prequalification or regulatory agency engagement at the validation design stage — rather than after completion — would reduce the risk that a validated MultiCruzi assay still fails to achieve endpoint acceptance.

A regulatory science team could map what existing precedents exist for surrogate endpoint acceptance in neglected tropical disease trials, and what evidentiary standard MultiCruzi validation would need to meet for FDA, EMA, and ANVISA (Brazil) acceptance. A diagnostic validation design team could draft a study protocol for MultiCruzi validation that explicitly addresses the population diversity, platform consistency, and regulatory engagement requirements. A basic science team could investigate the immunological mechanism behind slow antibody decline in Chagas — understanding why conventional serology takes decades to turn negative might reveal faster-declining markers or suggest intervention points in the serological response.