Discontinuation of Lumacaftor-Ivacaftor May Lead to Deterioration in Cystic Fibrosis


Lumacaftor-ivacaftor (Orkambi) improves lung health in patients with cystic fibrosis who tolerate the treatment, but discontinuation rates may pose a risk of deterioration.

A new study finds that although lumacaftor-ivacaftor (Orkambi) is associated with improvements in patients with cystic fibrosis (CF) who tolerated treatment, those who discontinued the therapy were at a higher risk of clinical deterioration.

Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination approved for patients with CF homozygous for the Phe508del mutation.

The study, which was published in the American Journal of Respiratory and Critical Care Medicine, evaluated the safety and efficacy of the lumacaftor-ivacaftor combination in adolescents and adults in a real-life post-approval setting.

Lumacaftor-ivacaftor was approved by the FDA in 2015; however, the authors wrote that “the magnitude of effect on 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.”

According to the authors, phase 3 studies have demonstrated an acceptable safety profile for the combination therapy, but small real-life studies have suggested that respiratory adverse events (AEs) may lead to increased discontinuation.

For the study, patients with CF were evaluated for lumacaftor-ivacaftor safety and efficacy over the first year of treatment. Overall, of the 845 patients who initiated the treatment, 18.2% discontinued therapy, often due to respiratory (48.1%) or non-respiratory (27.9%) AEs, according to the results. The authors noted that the discontinuation rate was “markedly” higher than in pivotal clinical trials, in which less than 5% of patients discontinued combination therapy.

However, patients who remained on treatment showed an absolute increase in percent predicted forced expiratory volume in 1 sec (ppFEV1) (+3.67%), an increase in body mass index (BMI) (+0.73 kg/m2), and a decrease in intravenous (IV) antibiotic courses by 35%.

In addition to confirming previous efficacy data, the findings also showed that approximately 40% and 20% of patients treated with lumacaftor-ivacaftor as an add-on to standard therapy showed an absolute increase in ppFEV1 by 5% and 10%, respectively.

“These data suggest that lumacaftor-ivacaftor is associated with clinically significant benefits in patients with CF who were able to tolerate this treatment regimen,” the authors wrote.

Patients who discontinued treatment had a significant decrease in ppFEV1, without improvement in BMI or a decrease in intravenous antibiotic courses. The authors noted that factors associated with increased rates of discontinuation included adult age group, ppFEV1 <40%, and numbers of intravenous antibiotic courses during the year prior to lumacaftor-ivacaftor initiation.

Additionally, the study found that starting lumacaftor-ivacaftor at a reduced dose may be associated with higher risk of discontinuation.

Other key findings included:

  • Patients who discontinued treatment were more likely to have experienced an exacerbation after IV antibiotics in the year before taking the combination drug.
  • Adults were more likely than adolescents to discontinue treatment.
  • Adults, but not adolescents, who discontinued therapy were at high risk of rapid FEV1 decline, BMI decrease, and multiple respiratory exacerbations.
  • Lumacaftor-ivacaftor was associated with a reduction in frequent exacerbations per year.

Overall, the authors concluded that the study highlights the importance of large real-life studies to assess the safety and efficacy profile of novel therapies.

“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,” the authors wrote.


Burgel PR, Munck A, Durieu I, et al. Real-life safety and effectiveness of lumacaftor-ivacaftor in patients with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2019. https://www.thoracic.org/about/newsroom/press-releases/resources/pdf-releases/lumacaftor-ivacaftor-cf.pdf

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