ENsuring ACcess to optimal Therapy in CF: ENACT study

Cystic fibrosis (CF) is an autosomal recessive disorder caused by dysfunction of the CF Transmembrane Conductance Regulator (CFTR) channel. The care of patients with CF has rapidly evolved with the development of CFTR modulators, novel pharmaceuticals that address the basic CF defect and restore CFTR function. Most recently, a triple combination therapy, TC, has revolutionized the care of most patients (~90% of the population in the U.S.). However, as TC has been expanded in use, about a quarter of people with CF don’t have the robust response that were seen in the clinical trials, and others have neuropsychological side effects that limit tolerability. The compounds of TC are metabolized by cytochrome P450 (CYP3A enzymes). Genetic variation in these enzymes cause altered activity, resulting in variation in efficacy in many drugs and side effect profiles. Our preliminary data demonstrate considerable variation in TC concentrations in patients during real-world use, which is a concern given the dose-dependence of TC effect in the lung and other tissues. This study will provide innovative data on concentration variability among the largest observational study of TC use in people with CF, as well as novel data on pharmacogenetic variation in this population, and prospective data on the utility of concentration data and dose titration to optimize the clinical response of TC in the lungs, as well as throughout the body. Our prospective study is also designed to evaluate a balance between lung function response from TC and side effect profiles, particularly of an increasingly observed effect causing neuropsychological deterioration (i.e., worsening anxiety, depression, and cognition). The Specific Aims are: 1) Analyze population pharmacokinetics of the three TC compounds in plasma to determine pharmacokinetic parameters during real-world use and correlate drug exposure with drug response; 2) to determine novel genetic variants in relevant pharmacogenes associated with concentration or response to TC including pulmonary measures; 3) conduct a prospective study to ascertain the TC concentration relationship with neuropsychological side effects and assess the utility of dose titration to balance side effects with optimal pulmonary (and other organ system) responses to TC. To accomplish the goals of this research, the principal investigator has assembled a unique mentoring team with decades of experience in clinical trials, pharmacology, genetics, statistics, pharmacogenetics, psychology and drug metabolism. Together, we will shift the paradigm of care for CF by better understanding of the optimal concentration and dosing for individual’s lung function and tolerance of therapy, and transition to a truly personalized and patient-centered approach to modulator therapy.