Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR

Taylor‐Cousar, Jennifer L.; Jain, Manu; Barto, Tara Lynn; Haddad, Tarik; Atkinson, Jeffrey J.; Tian, Simon; Tang, Rui; Marigowda, Gautham; Waltz, David A.; Pilewski, Joseph M.

doi:10.1016/j.jcf.2017.09.012

Cited by 63 publications

(78 citation statements)

References 21 publications

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“…Improvements in sweat chloride, FEV1pp and CFQ‐R respiratory domain were seen in those receiving active drug, while the adverse event profile was similar to the placebo group . Subsequently, phase 3 studies, published in 2017, showed efficacy and safety, with absolute increase in FEV1pp of 4% in homozygous deltaF508 and 6.8%in those with one copy of deltaF508, leading to FDA approval. Phase 3 studies for tezacaftor/ivacaftor for ages 6 to 11 are underway .…”

Section: Cftr Modulatorsmentioning

confidence: 99%

“…Using the CF Foundation Patient Registry (CFFPR), the uptake for ivacaftor prescriptions in patients with G551D was 64% within 6 months and 80% within 1 year, while ivacaftor/lumacaftor was prescribed in only 40% and 54% at those time points . The newest modulator combination to be approved for use in F508del homozygous patients over age 12 in 2018 is tezacaftor/ivacaftor . Although regulatory submission dates cannot be predicted at the time of this review, research on “next generation compounds” VX‐445 and VX‐659 in combination with tezacaftor/ivacaftor are underway, with promising early results.…”

Section: Cftr Modulatorsmentioning

confidence: 99%

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Cystic fibrosis year in review 2018, part 1

Savant

McColley

2019

Pediatric Pulmonology

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Section: Cftr Modulatorsmentioning

confidence: 99%

Section: Cftr Modulatorsmentioning

confidence: 99%

Cystic fibrosis year in review 2018, part 1

Savant

McColley

2019

Pediatric Pulmonology

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“…Antimicrobial agents are frequently used in CF individuals after lung transplantation prophylactically, or to treat active infections in the respiratory tract or sinuses. In addition, some of the new CFTR modulators have been associated with liver test abnormalities . All patients with abnormal liver tests and diagnosed liver disease should be evaluated to exclude these common causes of liver disease (Table ).…”

Section: Cf‐associated Liver Diseasementioning

confidence: 99%

“…Lumacaftor is a CFTR corrector that showed no significant clinical effect in individuals with CF when used alone. The use in clinical trials of lumacaftor in combination with ivacaftor, however, improved pulmonary function and lowered rates of pulmonary exacerbations in patients with CF homozygous for Phe508del . Unfortunately, the effects of these agents in the gastrointestinal and biliary tracts are not well characterized .…”

Section: Cf‐associated Liver Diseasementioning

confidence: 99%

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Cystic Fibrosis–Associated Liver Disease in Lung Transplant Recipients

Mallea¹,

Bolan²,

Cortese

et al. 2019

Liver Transpl

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Cystic fibrosis (CF) is an autosomal recessive disease characterized by mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator protein (CFTR). CFTR gene mutations manifest as epithelial cell dysfunction in the airways, biliary tract, pancreas, gut, sweat glands, paranasal sinuses, and genitourinary tract. The clinical manifestations of this dysfunction include respiratory tract infections, bronchiectasis, pancreatic insufficiency, malabsorption, intestinal obstruction, liver disease, and male infertility. The liver disease manifestations of CF can include biliary disease, multilobular cirrhosis, and portal hypertension with and without cirrhosis. Pulmonary disease is the main cause for morbidity and mortality in individuals with CF, and according to the International Society for Heart and Lung Transplantation, CF is the third most common indication for lung transplantation in adults, accounting for 16% of procedures performed. The survival after lung transplantation in individuals with CF continues to improve and is now the highest among end‐stage lung diseases requiring transplant. The survival rate at 10 years is close to 50%. Given the potential presence of liver disease in CF patients undergoing an evaluation for lung transplantation and in lung transplant recipients, it is important to understand the manifestations of liver disease in CF patients and the recommended workup and follow‐up. This review aims to discuss the current literature and provide guidance in the management of these patients.

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

Ejiofor

Mathiesen

Jensen-Fangel

et al. 2020

Pediatric Pulmonology

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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.

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Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR

Cited by 63 publications

References 21 publications

Cystic fibrosis year in review 2018, part 1

Cystic fibrosis year in review 2018, part 1

Cystic Fibrosis–Associated Liver Disease in Lung Transplant Recipients

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

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