In the past two years, Arkansas Children’s Research Institute (ACRI) has received more than $6 million from the National Institutes of Health (NIH) toward Cystic Fibrosis (CF) research, led by Principal Investigator Jennifer S. Guimbellot, M.D., Ph.D.
In the fall of 2024, ACRI received a $2.9 million grant for the ENACT (Ensuring Access to Optimal Therapy in Cystic Fibrosis) study, which focuses on ensuring optimal therapy for CF patients using triple-combination (TC) therapy. TC is now a primary approach to CF therapy using Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator drugs. It has been a life-changing discovery, improving lung function and overall health for nearly 90% of eligible people with CF. Some estimates suggest that about half of children who begin this therapy early will have a substantially longer life span.
“We have consistently seen wide variation in drug concentrations in multiple modulator therapies in several of our studies. When we measured drug levels in the blood, we found big differences from person to person — even though everyone was taking the same approved dose,” said Dr. Guimbellot, a pediatric pulmonologist and chief of pulmonology and sleep medicine at Arkansas Children’s and an associate professor of pediatrics at the University of Arkansas for Medical Sciences. “The connection between drug level and sweat chloride remained clear when we looked across all patients. Some patients aren’t getting enough of the medicine to see the full benefit, while others may be getting more than they need without any additional gain. This supports the idea that understanding drug levels to tailor therapy will help ensure everyone gets the best balance of benefit and safety.”
The ENACT study consists of two parts, with part one dedicated to better understanding the factors that influence concentration variability in a large population. The second part focuses on whether it is useful to use concentration-guided dosing titration, targeting feasibility and safety endpoints, as well as repeated measures of ppFEV1, sweat chloride and mental health outcomes.
“In one of our previous studies, some reduced-dose patients maintained concentrations near effect thresholds and reported side-effect mitigation, but not everyone did,” Dr. Guimbellot explained. “We need to understand if this is a viable and evidence-based strategy to manage side effects while also maintaining the positive effects of the drug.”
