Cystic Fibrosis
ATS 2016. A5585 – Characterization of Ivacaftor and Lumacaftor Using BioMAP® Profiling – Implications for Cystic Fibrosis
S. Velichko et al.
Results: Using the DiscoveRx® PathHunter®Pharmacotrafficking assay specific for the delta-F508 mutation, we demonstrated that lumacaftor restored trafficking of CFTR to the cell surface, consistent with its mechanism of action. However, using our BioMAP Diversity PLUS phenotypic screening platform, we show that both ivacaftor and lumacaftor decrease several anti-inflammatory activities consistent with their clinical efficacy in CF. BioMAP systems are constructed using one or more human primary cell types pooled from healthy donors, and stimulated to recapitulate the complexity of disease biology. In a system modeling infection-mediated vascular inflammation, both ivacaftor and lumacaftor decreased prostaglandin E2 (PGE2) production, while IL-17 was decreased in a system modeling T cell activation and IL-8 production was decreased in a model of airway inflammation. Elevated IL-17 levels has been reported to be highly increased in the bronchoalveolar lavage (BAL) of CF patients; IL- 17 drives IL-8 production, an important mediator of neutrophil recruitment, as well as PGE2 production, which mediates inflammatory responses via interaction with its various receptors.
Conclusions: This data suggests that the anti-inflammatory effects of compounds targeting CFTR in the BioMAP Diversity PLUS panel correlate with clinical outcomes. Although it remains to be determined whether these shared activities are due to direct effects on wild-type CFTR, this evidence points to an additional anti-inflammatory component of these agents that may be beneficial for the treatment of cystic fibrosis.
CARE™ FACULTY PERSPECTIVE: Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and infection. Whether CFTR-targeting drugs that lead to increased CFTR expression and function will also have effects on airway infection and/or inflammation in treated patients is an interesting question with clinical relevance. An antibacterial effect of Ivacaftor (Kalydeco®) treatment has repeatedly been observed. A study by Hoffman et al now illustrates that Ivacaftor resulted in decreased abundance of total bacteria and specifically P. aeruginosa in sputum of treated patients. P. aeruginosa is a CF pathogen that is often resistant to antibiotics and frequently results in chronic infections of CF airways. Velichko et al report in their study that both the CFTR potentiator Ivacaftor and the corrector Lumicaftor deploy anti-inflammatory effects in-vitro. Whether combination therapy of Ivacaftor and Lumicaftor will have anti-inflammatory or antibiotic effects in treated patients has yet to be demonstrated. Ivacaftor and Lumicaftor (Orkambi®) therapy has recently been approved by FDA and Health Canada for CF patients homozygous for the most common CFTR mutation (F508del/F508del).
