Personalized CFTR Modulator Therapy for G85E and N1303K Homozygous Patients with Cystic Fibrosis.

CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare CFTR mutations responsive in Fischer rat thyroid cells, including G85E, but not N1303K. However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a G85E homozygous patient and an N1303K homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in G85E/G85E and N1303K/N1303K pHNECs. In the G85E/G85E and the N1303K/N1303K patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare CFTR mutations.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis.

BACKGROUND: Recent studies demonstrated that the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in cystic fibrosis (CF) patients with at least one F508del allele. However, effects of ETI on downstream consequences of CFTR dysfunction, i.e. abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged ≥12 years throughout the first 12 months of therapy. METHODS: In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI. RESULTS: In total, 79 patients with CF and at least one F508del allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12 months after initiation (all p<0.01). Furthermore, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all time points. In addition, ETI reduced interleukin-8 at 3 months (p<0.05) and free neutrophil elastase activity at all time points (all p<0.001), and shifted the CF sputum proteome towards healthy. CONCLUSIONS: Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele over the first 12 months of therapy; however, levels close to healthy were not reached.

Effects of elexacaftor/tezacaftor/ivacaftor therapy on mental health of patients with cystic fibrosis.

Introduction: The CFTR modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) was shown to improve CFTR function and clinical symptoms in patients with cystic fibrosis (CF) with at least one F508del allele. Recently, some case reports suggested potential side effects of ETI on mental health with an increase in depressive symptoms and even suicide attempts in patients with CF. However, the general effects of this triple combination therapy on the mental health status of patients with CF remain largely unknown. Methods: We, therefore, performed a prospective, observational study in a real-life setting and investigated the relationship between initiation of ETI therapy and changes in mental health in adult patients with CF. We assessed Cystic Fibrosis Questionnaire-Revised (CFQ-R), Patient Health Questionnaire-9 (PHQ-9), Beck's Depression Inventory - Fast Screen (BDI-FS) and Generalized Anxiety Disorder 7-item Scale (GAD-7) at baseline and 8-16 weeks after initiation of ETI. Results: In total, 70 adult patients with CF with at least one F508del allele and a median age of 27.9 years were recruited. After initiation of ETI, the CFQ-R respiratory domain score improved by 27.9 (IQR 5.6 to 47.2; p < 0.001). The PHQ-9 score of depressive symptoms decreased by 1.0 (IQR -3.0 to 0.3; p < 0.05) with an increase of 16.9% in the group with a minimal score after initiation of ETI and a decrease in the groups of mild (-11.3%) or moderate (-5.7%) scores compared to baseline. The BDI-FS score of depressive symptoms decreased from 1.0 (IQR 0.0-2.0) at baseline to 0.0 (IQR 0.0 to 2.0; p < 0.05) after initiation of ETI. The group with a minimal BDI-FS score increased by 8.0% after initiation of ETI, whereas the groups with mild (-4.9%), moderate (-1.6%) or severe (-1.6%) scores decreased compared to baseline. The GAD-7 score of anxiety symptoms did not change after initiation of ETI compared to baseline (0.0; IQR -2.0. to 0.0; p = 0.112). Conclusion: Initiation of ETI improves symptoms of depression in adult patients with CF with at least one F508del allele. However, symptoms of anxiety do not change after short-term therapy with ETI.