Real-Life Safety and Effectiveness of Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis

Burgel, Pierre‐Régis; Munck, À.; Durieu, I.; Chiron, R.; Mély, Laurent; Prévotat, A.; Murris-Espin, M.; Porzio, Michele; Reix, Philippe; Marguet, Christophe; Macey, Julie; Sermet‐Gaudelus, Isabelle; Corvol, Harriet; Bui, Stéphanie; Lemonnier, Lydie; Dehillotte, Clémence; Silva, Jennifer Da; Paillasseur, Jean-Louis; Hubert, D.; Mounard, Julie; Poulet, Claire; Rames, Cinthia; Person, Christine; Troussier, Françoise; Urban, T.; Dalphin, Marie‐Laure; Dalphin, Jean-Claude; Pernet, D.; Richaud-Thiriez, Bénédicte; Fayon, M.; Macey-Caro, Julie; Campbell, Karine; Laurans, M.; Borderon, Corinne; Héraud, M; Labbé, A.; Montcouquiol, Sylvie; Bassinet, L.; Remus, Natascha; Fanton, Annlyse; Houzel-Charavel, Anne; Huet, Frédéric; Perez-Martin, S.; Boldron-Ghaddar, Amale; Scalbert, Manuëla; Camara, B.; Llerena, C.; Pin, Isabelle; Quétant, S.; Cottereau, Aurélie; Deschildre, A.; Gicquello, Alice; Pérez, Thierry; Stervinou-Wémeau, L.; Thumerelle, C.; Wallaert, B.; Wizla, N.; Languepin, J.; Menetrey, Céline; Dupuy-Grasset, Magalie; Bazus, Lucie; Buchs, Clélia; Jubin, V.; Werck‐Gallois, Marie‐Christine; Mainguy, Catherine; Perrin, Thomas; Toutain-Rigolet, Agnès; Durupt, S.; Reynaud, Quitterie; Nové-Josserand, Raphaële; Baravalle‐Einaudi, M.; Coltey, Bérangère; Dufeu, Nadine; Dubus, Jean‐Christophe; Stremler, Nathalie; Caimmi, Davide; Billon, Y.; Derelle, J.; Kieffer, Sébastien; Pichon, Anne-Sophie; Schweitzer, Cyril; Tatopoulos, Aurélie; Abbes, Sarah; Bihouée, Tiphaine; Danner-Boucher, Isabelle; David, Valérie; Haloun, A.; Tissot, A. N.; Leroy, Sylvie; Bailly-Piccini, C.; Clément, Annick; Tamalet, Aline; Honoré, Isabelle; Kanaan, R.; Martin, Clémence; Bailly, Cécile; Chedevergne, F.; Blic, J. de; Fauroux, Brigitte; Bourgeois, Murielle Le; Delaisi, Bertrand; Gérardin, M.; Abély, M.; Ravoninjatovo, Bruno; Belleguic, Chantal; Desrues, B.; Brinchault, Graziella; Dagorne, M.; Deneuville, E.; Lefeuvre, Sylvaine; Dirou, Anne; Bihan, Jean Le; Ramel, Sophie; Dominique, S.; Payet, A.; Kessler, Romain; Rosner, V.; Weiss, Laurence; Miranda, S. De; Grenet, Dominique; Hamid, Abdoul; Picard, C.; Brémont, F.; Didier, A.; Labouret, Géraldine; Mittaine, M.; Têtu, L.; Cosson, Laure; Giraut, C.; Henriet, Anne-Cécile; Mankikian, Julie; Marchand, Sophie; Hüge, S.; Storni, V.; Coirier-Duet, Emmanuelle

doi:10.1164/rccm.201906-1227oc

Cited by 110 publications

(116 citation statements)

References 25 publications

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“…In line with the initial randomized study that assessed the lumacaftor-ivacaftor treatment effects on respiratory and nutritional status in CF [5] , along with a real-life study [19] , our data clearly revealed a positive lumacaftor-ivacaftor treatment impact on nutritional and pulmonary parameters. After one-year lumacaftor-ivacaftor treatment in 40 patients, we observed a significant increase in BMI and albuminemia levels, reflecting an improved nutritional status, as well as a decrease in percentage of patients who received at least one IV antibiotic course/year.…”

Section: Discussionsupporting

confidence: 86%

Effect of one-year lumacaftor–ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients

Misgault

Chatron

Reynaud

et al. 2020

Journal of Cystic Fibrosis

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Section: Discussionsupporting

confidence: 86%

Effect of one-year lumacaftor–ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients

Misgault

Chatron

Reynaud

et al. 2020

Journal of Cystic Fibrosis

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“…[24][25][26] p.F508del is the most frequent CFTR variant in Caucasians, accounting for approximately 70% of mutated alleles in general. 27 However, it is quite rare in Asian populations. p.F508del was observed only once in China (in heterozygosity), 26 and no cases have ever been reported in Japan, or Korea so far (except for mixed Asian-Caucasian parentage).…”

Section: Discussionmentioning

confidence: 99%

Pseudo‐Bartter syndrome in Chinese children with cystic fibrosis: Clinical features and genotypic findings

Shen

Tang

Liu

et al. 2020

Pediatric Pulmonology

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Objectives: To characterize the clinical and genotypic features of cystic fibrosisassociated pseudo-Bartter syndrome (CF-PBS) in Chinese children. Methods: We recruited and characterized the clinical manifestations of 12 Chinese children with CF-PBS. Sweat test, blood and urinary analysis, sputum culture, chest and sinus computed tomography, and abdominal ultrasonography were obtained. Whole-exome sequencing, bioinformatics analysis, and Sanger sequencing validation were performed to define the genotypes. Results: CF-PBS was accompanied by recurrent and/or persistent pneumonia (91.7%), pancreatitis (83.3%), vomiting and/or diarrhea (66.7%), failure to thrive and liver disease (58.3% respectively), among our patients. The predominant organisms found in the airways were Pseudomonas aeruginosa (83.3%) and Staphylococcus aureus (75.0%). The mean concentrations of blood gas and electrolytes were pH 7.58, bicarbonate 40.8 mmol/L, sodium 125.9 mmol/L, chloride 77.5 mmol/L, and potassium 2.6 mmol/L. A high recurrence rate (50.0%) of CF-PBS was observed despite continued electrolyte supplementation during follow-up. In all, 19 different variants of CFTR gene were identified, and 10 of these were found to be novel observations (c.262_266delTTATA [p.L88FfsX21], c.579+2insACAT, c.1210-3C>G, c.1733T>C[p.L578P], c.2236_2246del-GAGGCGATACTinsAAAAATC[p.E746KfsX8], c.3068T>G [p.I1023R], c.3635delT [p.V1212AfsX16], c.3859delG[p.G1287EfsX2], c.3964-7A>G and ΔE23 [c.3718-? _3873+?del]). The c.2909G>A[p.G970D] was the most common variant, with an allele frequency of 16.6%. A homozygous genotype of c.1521_1523delCTT[p.F508del] was discovered for the first time in patients of Chinese origin. Conclusions: In China, CF-PBS usually presents early and recurs frequently in infancy, accompanied by multiple comorbidities. Recurrence of CF-PBS in school-going patients does occur but is rare. The p.G970D is the most frequent variant, with a significant ethnic tendency of Chinese origin.

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“…Ivacaftor withdrawal resulted in accelerated deterioration of lung function consistent with a pulmonary exacerbation episode in a case series (Trimble and Donaldson, 2018). Patients who discontinued treatment with lumacaftor/ ivacaftor, mainly due to early adverse effects, also demonstrated a higher risk of worsening clinical manifestations compared to patients who continued treatment or those who restarted it after temporary discontinuation in a real-world study (Burgel et al, 2020). As patients have different lifestyles and socioeconomic conditions, the development of educational and motivational interventions at an individual level may help in ensuring optimal adherence to achieve the greatest clinical outcomes.…”

Section: Continuing the Optimization Of Therapeutic Regimens To Incrementioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Real-Life Safety and Effectiveness of Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis

Cited by 110 publications

References 25 publications

Effect of one-year lumacaftor–ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients

Effect of one-year lumacaftor–ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients

Pseudo‐Bartter syndrome in Chinese children with cystic fibrosis: Clinical features and genotypic findings

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

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