Pierre-Régis Burgel MD, PhD Professor of Respiratory Medicine French National Reference Center for Cystic Fibrosis (coordinator) Cochin Hospital and Paris Descartes University Paris, France

Cystic Fibrosis: Lumacaftor-Ivacaftor Improved Lung and Nutritional Status, But May Be Better Tolerated by Adolescents than Adults

MedicalResearch.com Interview with:

Pierre-Régis Burgel MD, PhD Professor of Respiratory Medicine French National Reference Center for Cystic Fibrosis (coordinator) Cochin Hospital and Paris Descartes University Paris, France

Dr. Burgel

Pierre-Régis Burgel MD, PhD
Professor of Respiratory Medicine
French National Reference Center for Cystic Fibrosis (coordinator)
Cochin Hospital and Paris Descartes University
Paris, France

MedicalResearch.com: What is the background for this study? How does lumacaftor-ivacaftor differ from other treatments for CF? 

Response: Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which acts as a chloride and bicarbonate ion channel across many epithelia. Defective ion transport leads to multiple organ dysfunction, but airway involvement (related to mucus plugging and infection) and malnutrition are among the most important prognostic factors in patients with CF. Over the past decades, symptomatic treatment, including inhaled and systemic antibiotics, nutritional support, pancreatic enzyme replacement, and specialized center care organization have led to major prognostic improvement. More recently, mutation-specific small molecules targeting defective CFTR have been shown to partly restore ion transport in epithelia, which translated into clinical benefits.

Phe508del is the most common CFTR mutation with approximately 70% of patients with cystic fibrosis carrying one Phe508del mutation and 40-50% of patients being homozygous for this mutation. Safety and efficacy of lumacaftor-ivacaftor, which partially restores CFTR function, have been reported in phase 3 clinical trials in patients 12 years of age or older who had CF and were homozygous for the Phe508del. Improvement in lung function, reduction in pulmonary exacerbations and a trend towards an increase in body mass index (BMI) led to its approval by the Food and Drug Administration in February 2015 and by the European Medicines Agency in November 2015. However, the magnitude of effect on percent predicted forced expiratory volume in 1 sec (ppFEV1), the small improvement in nutritional status and the limited use of concomitant treatment for reducing exacerbations have cast doubt on the clinical benefits associated with lumacaftor-ivacaftor, which has not been approved in several countries.

The present study is a multicenter (n=47 centers) observational post-marketing study aimed at evaluating the effects of lumacaftor-ivacaftor treatment in a real-life setting in France. All patients who initiated lumacaftor-ivacaftor in 2016 in the French cystic fibrosis reference network, which comprises 47 pediatric and/or adult centers, was performed. Our goal was to examine its safety and effectiveness over the first year of treatment in a large, unselected, population of adolescents (≥12 years) and adults (≥18 years) with CF and Phe508del homozygous mutations. 

MedicalResearch.com: What are the main findings?

Response: Between January 1st and December 31st 2016, 845 patients (292 adolescents, 553 adults) initiated treatment with lumacaftor-ivacaftor in the 47 centers of the French CF Reference Network. Lumacaftor-ivacaftor was discontinued in 18.2% of patients, most due to respiratory AEs and, to a lesser extent, to non-respiratory AEs. The proportion of patients who discontinued lumacaftor-ivacaftor was more than 3 times higher in this study compared with pivotal clinical trials, where less than 5% of patients discontinued lumacaftor-ivacaftor. These findings were likely related to a higher proportion of patients with severe respiratory disease (i.e., ppFEV1<40% and/or several IV antibiotic courses in the previous year) compared with pivotal clinical trials. Significant improvements in ppFEV1 and in body weight and BMI, and reduction in the number of IV antibiotic courses were observed in the overall cohort.

These results were driven by patients who received prolonged (continuous or intermittent) exposure to lumacaftor-ivacaftor, whereas patients in whom lumacaftor-ivacaftor was discontinued had a significant decrease in ppFEV1, no increase in body weight or BMI and no decrease in the use of IV antibiotics. Importantly, treatment discontinuation was less prevalent in adolescents than in adults and the results suggest that the magnitude of lung function improvement could be greater in adolescents. 

MedicalResearch.com: What should readers take away from your report?

Response: The present study showed that 12 months of treatment with lumacaftor-ivacaftor was associated with clinically-significant benefits, including significant improvement in lung function and nutritional status, and a reduction in IV antibiotic courses in adolescents and adults with cystic fibrosis homozygous for Phe508del who tolerated the treatment. It highlighted the importance of large real-life studies to assess the safety and effectiveness profile of novel therapies because patients treated in post-marketing studies often show reduced lung function and less stable disease characterized by higher rates of exacerbations than those included in clinical trials. These data further indicate that the benefits and risks of new therapies cannot be extrapolated to patients who are excluded from clinical trials. Further, findings from the present study concur with the concept that starting CFTR modulators earlier in life could be an important strategy.  

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: The anticipated availability of novel combination of CFTR modulators and the extension of indications to younger age groups warrant further real-life study that should be launched as soon as the drugs become available in eligible populations. 

MedicalResearch.com: Is there anything else you would like to add?

Response: The study was funded by the French CF Patient Association “Vaincre la Mucoviscidose”, the French CF learning Society, and Legs Pascal Bonnet. It was conducted independently from the lumacaftor-ivacaftor manufacturer. 


Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Running title: Real-life study of lumacaftor-ivacaftor Pierre-Régis Burgel1,2,3, Anne Munck4 , Isabelle Durieu3,5,6, Raphaël Chiron7 , Laurent Mely8 , Anne Prevotat9 , Marlene Murris-Espin10, Michele Porzio11, Michel Abely12, Philippe Reix13 , Christophe Marguet14, Julie Macey15, Isabelle Sermet-Gaudelus3,16,17, Harriet Corvol18 , Stéphanie Bui19, Lydie Lemonnier20, Clémence Dehillotte20, Jennifer Da Silva1,3,21 Jean-Louis Paillasseur22, Dominique Hubert2,3 for the French Cystic Fibrosis Reference Network study group
American Thoracic Society October 2019


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Last Modified : Oct 13, 2019 @ 7:49 pm




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