Kalydeco Reduced Lung Inflammation in CF Preschoolers

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with Kalydeco (ivacaftor) significantly reduces the levels of inflammatory molecules in the lungs of preschool-age children with cystic fibrosis (CF), according to a small study.

A reduction in lung inflammation was not observed in preschoolers with CF who were treated with Orkambi (lumacaftor/ivacaftor). These findings add to some prior studies in older patients suggesting that Kalydeco may have greater anti-inflammatory effects than Orkambi.

“These results, which may not be generalizable to older patients with established lung disease, suggest that a reduction in early life pulmonary inflammation may be one of the mechanisms by which [Kalydeco] improves lung disease outcomes,” the researchers wrote.

Still, larger studies are needed to confirm these findings.

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The study, “Ivacaftor, not ivacaftor/lumacaftor, associated with lower pulmonary inflammation in preschoolcystic fibrosis,” was published in Pediatric Pulmonology.

CF is caused by mutations in both copies of the CFTR gene, which provides instructions to produce a protein channel with the same name that controls the flow of chloride ions (salt) and water through cells.

Kalydeco, developed by Vertex Pharmaceuticals, was the first CFTR modulator approved for treating CF caused by certain mutations. CFTR modulators work by improving the functionality of the mutated CFTR protein in people with certain CF-causing mutations.

Also developed by Vertex, Orkambi — consisting of Kalydeco’s active ingredient, ivacaftor, and another CFTR modulator, lumacaftor — was the second CFTR modulator available for CF patients with specific mutations.

Clinical trials have demonstrated that these medications can improve lung function in children and adults with CF carrying eligible mutations.

However, the effects of CFTR modulator treatment in lung inflammation — a common feature of CF patients, even in the absence of any infection — has not been studied thoroughly. Lung inflammation also is thought to contribute to CF-related lung function decline.

Some studies in adolescents and adults with CF suggested that Kalydeco may have stronger anti-inflammatory and immunoregulatory effects relative to Orkambi. However, the only study analyzing lung fluid of patients younger than 6 years found no such effects with Kalydeco relative to no treatment.

Current research in Australia

Now, a trio of scientists in Australia measured the levels of inflammatory molecules in the lung fluid of 54 preschool-aged children with CF being treated with either Kalydeco (nine children), Orkambi (five children), or neither (40 children). Those who were not on modulator therapy either were not eligible or their parents chose not to start such treatment.

The analysis also included preschoolers without lung disease as the control group.

Compared with the healthy controls, untreated children with CF had significantly higher levels of several inflammatory molecules, namely TNF-alpha, CCL3, CXCL9, CCL2, IL-8, and IL-6.

Patients treated with Kalydeco had significantly lower levels of the inflammatory molecules CCL3, CXCL9, CCL2, IL-8, IL-1-beta, and IL-6 relative to untreated children. However, no differences in these molecules were noted between untreated children with CF and those on Orkambi.

Further analyses illustrated that the inflammatory profile of Kalydeco-treated children was generally similar to that of children without lung disease, whereas the profile of children on Orkambi was comparable to that of untreated children with CF.

Analyses of inflammatory immune cells in a subset of the participants generally followed the same trend, with data from children treated with Kalydeco being “more similar to healthy controls,” and those of Orkambi-treated children being “more similar to untreated CF children,” the researchers wrote.

These findings highlight that “children treated with [Kalydeco] show lower pulmonary concentrations of a range of inflammatory mediators when compared to untreated children, as well as [Orkambi-treated] children,” the team wrote.

“In particular, [Kalydeco] treatment was associated with lower concentrations of two key [molecules]: IL-8 and [IL-1-beta] which have previously been associated with the development of early life structural lung disease,” they added. In turn, Orkambi “did not induce reductions of any inflammatory [molecule] when compared to untreated children with CF.”

The researchers noted, however, that the average duration of treatment was markedly longer for patients on Kalydeco than Orkambi — 1.88 vs. 0.93 years, respectively.

While this may have influenced the results, “it is unlikely that a longer duration of therapy of [Orkambi] would result in an altered inflammatory profile,” the team wrote, as CFTR modulators generally have an observable effect on lung function within weeks.

In addition, all Orkambi-treated patients had lung infections compared with about half (55.5%) of those on Kalydeco, which also may have influenced the levels of inflammatory molecules.

A study first, authors say

“This is the first work to illustrate a difference in airway inflammation in early life” between Kalydeco and Orkambi treatments, the researchers wrote. “The altered inflammatory environment may be secondary to an altered infection, or a direct effect of modulator therapy on CFTR function given the previous evidence that aberrant inflammation can occur in the absence of infection.”

Moreover, while group-level differences were evident, “some children treated with [Kalydeco] still exhibited a proinflammatory … profile suggesting the anti-inflammatory effect of modulator therapy may vary between individuals,” the team wrote.

Larger studies, collecting samples before and after treatment to appropriately assess treatment effects, are needed to confirm these findings.