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A7687 - Baseline Cystic Fibrosis Transmembrane Conductance Regulator Protein Expression Predicts Subject Response to Lumacaftor-Ivacaftor Treatment
Author Block: G. S. Gilmartin1, C. Cotton2, M. Singh1, P. E. Bialek1, P. Lee1, S. Wilson3, B. McLaughlin1, P. A. Flume4, F. A. Ratjen5, G. S. Sawicki6; 1Proteostasis Therapeutics, Inc, Cambridge, MA, United States, 2Binnacle Biosciences LLC, Cleveland, OH, United States, 3Proteostasis Therapeutics Inc, Cambridge, MA, United States, 4Med Univ of S Carolina, Charleston, SC, United States, 5Hospital for Sick Children, Toronto, ON, Canada, 6Boston Children's Hospital, Boston, MA, United States.
Background: Personalized medicine approaches are increasingly important in leveraging clinical trial results to inform individual treatment decisions for patients with cystic fibrosis (CF). CF transmembrane regulator conductance (CFTR) modulator therapies such as lumacaftor-ivacaftor address the underlying protein defect in CF for certain populations. While a modest improvement in lung function was observed in Phe508del homozygous CF patients with lumacaftor-ivacaftor treatment, for those CF patients with only one copy of Phe508del, lumacaftor-ivacaftor combination therapy was not clinically effective. Additionally, variability in treatment response is observed between individual Phe508del homozygous patients. Such variability may be explained by substrate limitation limiting efficacy for those with lower levels of CFTR protein expression.
Methods: To assess variability in response to lumacaftor-ivacaftor we used primary human nasal epithelial cells (HNE) derived from 13 CF individuals homozygous for the Phe508del mutation. We then evaluated the relationship between nasal CFTR protein levels with lung function changes in response to lumacaftor-ivacaftor treatment for Phe508del homozygous CF patients participating in an on-going interventional clinical study (NCT02718495). Baseline CFTR protein was assessed using a CFTR ELISA on nasal mucosal samples obtained prior to any intervention in the trial. Lung function response to lumacaftor-ivacaftor was determined by a retrospective review documenting best lung function values within 6 months prior to lumacaftor-ivacaftor treatment and within 6 months after treatment initiation.
Results: In HNE cells basal expression of total CFTR protein positively correlated with lumacaftor‑ivacaftor induced changes in chloride current in an Ussing chamber assay (Pearson’s correlation coefficient r = 0.65, p = 0.0167). Similar to the in vitro data, higher baseline levels of CFTR protein in nasal mucosa was associated with greater improvement in FEV1 in response to lumacaftor-ivacaftor treatment (Pearson’s correlation coefficient r = 0.72, p = 0.0686).
Conclusion: Our results suggest the baseline levels of CFTR protein may be a clinically important predictor for responsiveness to CFTR modulator therapy.