Patients with cystic fibrosis and advanced lung disease benefit from lumacaftor/ivacaftor treatment

Abstract

Background Several studies have assessed safety and efficacy outcomes for lumacaftor/ivacaftor therapy. We report on lumacaftor/ivacaftor's impact on lung function, physical performance, and health‐related quality of life (HRQOL) in a subpopulation of Danish people with Cystic Fibrosis (CF; PWCF) with advanced pulmonary disease who would not fulfill inclusion criteria for these studies. Methods This follow‐up study examined lumacaftor/ivacaftor's effect in a highly selected CF population. Inclusion criteria included low percent predicted forced expiratory volume in one second (ppFEV1), fast deteriorating ppFEV1, low body mass index (BMI), and difficult‐to‐treat infections. Primary endpoints included change in ppFEV1 slope, cardiopulmonary exercise testing (CPET), and all domains of the Cystic Fibrosis Questionnaire‐Revised (CFQ‐R). Secondary outcomes included change in ppFEV1, BMI Z‐score, and sweat chloride concentration. Results A total of 21 patients homozygous for the F508del mutation and a median ppFEV1 of 38.7 were included. We found significant improvements in ppFEV1 (+4.2 p < .01, +5.8 p < .01, +4.8 p < .01 and +3.8 p = .03 ppFEV1 after 3, 6, 9, and 12 months of treatment compared to baseline), ppFEV1 slope (+6.84 ppFEV1/year between the year before and the year after treatment initiation; p = .02), and saturation at CPET initiation (+1.4%, p < .02) and termination (+2.6%, p < .01) after 6 months of treatment. Finally, HRQOL improved significantly in all CFQ‐R domains except Emotion and Treat. Conclusions Our findings suggest that lumacaftor/ivacaftor reduces lung function decline, improves lung function, physical performance, and HRQOL to a greater extent in PWCF with severe lung disease than previously recognized.

Toward the Establishment of New Clinical Endpoints for Cystic Fibrosis: The Role of Lung Clearance Index and Cardiopulmonary Exercise Testing

“…Exercise testing has shown additional benefits over spirometry in characterizing for example the efficacy of therapeutic interventions to treat pulmonary exacerbations (89,90). It has also been used as an outcome measure for assessing the effectiveness of CFTR modulators (87,91,92) and as an incentive for as well as measure of the effectiveness of pulmonary rehabilitation (93)(94)(95)(96). It has also been used for exercise prescription (97-100), pre-and post-transplantation assessment (101-103) and as a primary and secondary endpoint measure in clinical trials (95,104,105).…”

The clinical impact of Lumacaftor-Ivacaftor on structural lung disease and lung function in children aged 6-11 with Cystic Fibrosis in a real-world setting

“…In contrast to the clinical trials, they did not report improvement in ppFEV 1 , but did show an improvement of 0.55 units in LCI values at twelve months among 49 participants over six years of age [42]. Other real-world studies have reported improvements in ppFEV 1 in those with impaired lung function at baseline but not in those with preserved lung function [29] [43]. In the French real-world study of outcomes with LUM/IVA, adolescents with impaired pulmonary function and raised LCI values (mean 12.3) did not demonstrate improvements in LCI or ppFEV 1 over one year [44].…”

Review of CFTR modulators 2020

“…Initial phase 3 studies of CFTR modulators did not include PwCF with ALD, defined as FEV1pp < 40%. A Danish single‐center observational study was performed in 21 PwCF with severe lung disease ≥13 years old who were started on lum/iva as part of a compassionate use program and followed for 12 months 17 . Criteria for inclusion were FEV1pp < 30% for adults or FEV1pp < 40% for children, or demonstration of two criteria including FEV1pp < 40% in adults or <30% in children, FEV1pp slope less than −2.5% in past 12 months, chronic difficult to treat pulmonary infections, or body mass index (BMI) z‐score < −2.0 for children and BMI ≤ 18 for adults.…”

“…17 Criteria for inclusion were FEV1pp < 30% for adults or FEV1pp < 40% for children, or demonstration of two criteria including FEV1pp < 40% in adults or <30% in children, FEV1pp slope less than −2.5% in past 12 months, chronic difficult to treat pulmonary infections, or body mass index (BMI) z-score < −2.0 for children and BMI ≤ 18 for adults. The median slope for FEV1pp decline was -2.6 in the year before treatment, compared to −2.1 during the year of treatment.…”