Orkambi eased airway inflammation, boosted bacterial diversity

However, the treatment worked only if taken before chronic P. aeruginosa infection

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Treatment with Orkambi (lumacaftor/ivacaftor) for six months lessened airway inflammation and enhanced airway bacterial diversity in people with cystic fibrosis (CF), but only when administered before patients were chronically infected with the bacterium Pseudomonas aeruginosa, a study has found.

The findings suggest that “CFTR modulators [such as Orkambi] should be started as soon as possible, ideally before the patient is chronically colonized with P. aeruginosa,” researchers wrote.

The study, “Effects of Lumacaftor-Ivacaftor on Airway Microbiota-Mycobiota and Inflammation in Patients with Cystic Fibrosis Appear To Be Linked to Pseudomonas aeruginosa Chronic Colonization,” was published in the journal Microbiology Spectrum

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Study delves into how CFTR changes its shape to be effective

Mutations in the CFTR gene are the underlying cause of CF and result in a faulty CFTR protein, or no protein at all, being produced. This protein is present in cellular membranes and acts like a gate that regulates the movement of certain salt molecules and water in and out of the cell. Defects in CFTR result in the production of thick mucus that builds up and causes damage to several organs, particularly the lungs.

CFTR modulators are a class of therapies that can improve the protein’s function in people with specific CF-causing mutationsVertex Pharmaceuticals’ Orkambi, a combination of two compounds – lumacaftor and ivacaftor – is an approved oral treatment for CF patients with two copies of the F508del mutation, one inherited from each biological parent.

In clinical trials, Orkambi was shown to significantly improve lung function of CF patients when compared to a placebo, and lowered sweat chloride levels, elevations of which are a hallmark feature of CF.

Since bacterial infections commonly occur in the lungs of those with CF, the benefits of Orkambi also may be linked with changes in the airways’ microbiota, the community of microorganisms living in the lungs, and a reduction in inflammation.

Phase 4 study in France

To further understand this relation, a team led by researchers at the Bordeaux University, France, conducted the Lum-Iva-biota Phase 4 observational study (NCT03565692) that enrolled 75 CF patients (median age 21 years) across six centers in France.

They analyzed the airway microbiota collected at the start of the study, before any treatment (baseline) and after six months of treatment with Orkambi. Only 41 patients (median age 22.5 years) had enough sputum collected to perform the analysis again at the end of the study.

When compared to patients analyzed at baseline only (34 patients), the group with 41 patients had significantly worse lung function at baseline, as shown by a lower median predicted percentage of forced expiratory volume in one second (ppFEV1). That is a measure of how much air can be exhaled in one second after a deep inhaled breath (73% vs. 58%).

The burden of P. aeruginosa, a bacterium commonly found in CF airways,  also was higher in this patient population (66% vs. 41%).

At baseline, the airway microbiota was dominated by P. aeruginosa (21%), followed by the bacterium Streptococcus (13%) and Prevotella (12%). The bacteria Veillonella and Staphylococcus also were present and accounted for 10%.

The microbiota of CF adults (ages 18 and older) was distinct from that of adolescents (ages 12–17).

Importantly, a correlation between diversity of the microbiota and lung function was found, with patients who had worse lung function (ppFEV1 below 80%) showing significant increases in the relative abundances of the bacteria Pseudomonas and Lautropia.

Those with a ppFEV1 of 80% or higher, showed an abundance of the bacterium Streptococcus, Porphyromonas, Actinomyces, TM7x, and Peptostreptococcus.

In terms of fungi (mycobiota) diversity, no differences were seen regarding age or lung function.

Calprotectin levels

At baseline, the mean sputum levels of calprotectin — a measure of airway inflammation — in the overall patient population was 3,941 micrograms per milliliter (mcg/ml). The levels significantly increased with age and were negatively correlated with lung function and bacterial diversity, meaning higher levels of calprotectin associated with lower lung function and less bacterial diversity. Calprotectin levels were significantly higher — indicative of enhanced inflammation — in patients with chronic P. aeruginosa infection when compared to those without it (4,278 mcg/ml vs. 3,168 mcg/ml).

Analysis of the overall population showed that after six months of Orkambi treatment, patients had a significant increase in weight when compared to baseline, as measured by the body mass index (BMI, a measure of body fat).

The number of patients with the need for more than one administration of into-the-vein antibiotics also was significantly reduced (56% vs. 40%). However, no significant changes in lung function were seen.

To assess changes in the airway microbiota and mycobiota, the researchers focused on the 41 patients with sputum samples collected at baseline and after a median of 183 days of Orkambi treatment. No changes were seen in bacterial or fungi diversity in sputum samples after treatment, including in the P. aeruginosa load and levels of calprotectin, even after discriminating for age and lung function.

However, in patients not chronically infected with P. aeruginosa at baseline, the levels of calprotectin were lower and the bacterial diversity significantly increased after Orkambi treatment. No differences were seen in fungi diversity.

Overall, these findings show that “evolution of the airway microbiota-mycobiota in CF patients depends on the patient’s characteristics at lumacaftor-ivacaftor treatment initiation, notably chronic colonization with P. aeruginosa,” the researchers concluded.