Orkambi Eases Flares Even in CF Patients Slow to Show Improvement in Lung Health, Trial Data Show

Cystic fibrosis patients who failed to show early improvements in lung function while being treated with Orkambi (lumacaftor/ivacaftor) still experienced fewer pulmonary exacerbations than those given a placebo in Phase 3 studies, a pooled analysis of those trials reports.

Clinicians should consider the totality of outcomes when examining the benefits of CFTR modulators like Orkambi, researchers suggest.

The study, “Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV₁,” was published in the Journal of Cystic Fibrosis.

Orkambi, by Vertex Pharmaceuticals, is approved for cystic fibrosis (CF) patients who have two copies of the F508del mutation in the CFTR gene, the most common disease-causing mutation. It is made of a combination of lumacaftor and ivacaftor.

A combination treatment, it uses lumacaftor to increase the amount of CFTR channels at the surface of cells, and ivacaftor to help defective channels work better. Together, they maintain the balance between salt and water, keeping mucus from clogging the ducts of organs like the lungs and pancreas.

Orkambi’s approval was based on data from two placebo-controlled Phase 3 trial, called TRAFFIC (NCT01807923) and TRANSPORT (NCT01807949). These 24-week trials were similar in design, and together tested Orkambi in 1,108 CF patients, ages 12 years or older, with two copies of the F508del mutation.

Treatment was shown to significantly improve patients’ lung function, compared to placebo, as assessed using the percent predicted forced expiratory volume in 1 second (ppFEV1). It also lead to fewer hospital admissions and lower use of antibiotics.

Patients given Orkambi also experienced 30-39% fewer pulmonary exacerbations, or acute worsening of lung health and function.

But some trial patients given Orkambi failed to show an improvement in lung function in the first two weeks of treatment. Researchers wanted to determine if  these patients still experienced fewer pulmonary flares, and if their age, sex, or characteristics influenced the therapy’s efficacy.

Researchers at Vertex and academic institutions re-examined TRAFFIC and TRANSPORT data (five of this study’s 11 authors are Vertex employees). In their analysis, patients were categorized according to changes in lung function at week two.

Data showed that patients who were not early responders to treatment (measured by ppFEV1) had more pulmonary exacerbations than those who were. But all patients treated with Orkambi, regardless of change in ppFEV1 at two weeks, had significantly fewer flares than those on placebo.

This reduction was independent of patients’ characteristics at baseline, including ppFEV1, age, sex, medication use, and Pseudomonas aeruginosa status – the most common infection affecting CF patients.

The rate of pulmonary exacerbations requiring hospitalization was also significantly lower among Orkambi-treated than placebo-treated patients.

Overall, “this post hoc analysis showed that PEx [pulmonary exacerbations] were reduced even among patients who did not experience early increases in ppFEV1 in these phase 3 studies. Furthermore, these reductions were observed irrespective of patient baseline characteristics,” the study concluded.

Researchers added that “while measurements of ppFEV₁ are critical to assess lung function, these findings also underscore that CFTR modulators confer additional important benefits to treated patients.”

Orkambi is currently approved in the U.S. for CF patients ages 2 or older with two copies of the F508del mutation, and for those ages 6 and older in Europe.