Pulmonary flares seen as key sex difference in patients on Kalydeco

Study finds disparities persist with CFTR modulator, and reasons unclear

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Despite treatment with Kalydeco (ivacaftor), females with cystic fibrosis (CF) continue to experience more lung exacerbations — periods when CF respiratory symptoms suddenly worsen — than do males, for reasons that are not well understood, a large patient registry study reported.

“Our findings demonstrate that sex disparities in CF persist in those treated with [Kalydeco] because of differences in pulmonary exacerbations. More research is needed to determine the specific pathophysiologic drivers of this disparity,” its researchers wrote.

The study, “Sex differences persist after treatment with ivacaftor in people with cystic fibrosis,” was published in the journal Chest by a research team at the University of Texas Southwestern Medical Center.

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Differences in outcomes for CF patients by sex have been noted for decades

CF is caused by mutations that result in no or faulty CFTR protein channels. These channels control the flow of chloride ions in and out of cells and help to keep the right balance of water. When they fail, sticky mucus builds in the lungs and other organs.

Vertex Pharmaceuticals’ Kalydeco works by keeping the CFTR protein channels open for longer, allowing salts and water to flow through the cell membrane. This increases the amount of water on the surface of cells, making mucus less thick and easing disease symptoms.

Studies since the 1990s have show shown that female patients tend to experience poorer lung function and have a shorter life expectancy compared with males, the researchers noted.

However, it’s unclear whether CF sex differences persist since the introduction of more effective therapies, particularly CFTR modulators like Kalydeco, a treatment first approved for the U.S. in January 2012.

To know more, the scientists drew on the CF Foundation Patient Registry to review data from patients treated with Kalydeco between 2010 and 2017. Kalydeco’s long availability in the U.S., they noted, provided an opportunity to assess how it might influence this sex gap.

Data collected covered 1,900 patients with a mean age of 33.1 and similar demographics. Among them, 972 (51.2%) were female and 928 (48.8%) were male. Before starting with Kalydeco, no significant differences in measures of lung function or infections by Pseudomonas aeruginosa bacteria were evident. On average, female patients had more hospital visits than males (4.81 vs. 4.37 per year).

All had been followed, on average, for at least five years before and after starting on Kalydeco.

Significant drop in pulmonary flares seen only in treated males

After starting treatment, a significant decrease in lung exacerbations was seen in males — from 0.38 to 0.34 per year — corresponding to an adjusted rate ratio of 0.89. In females, the change from 0.48 to 0.45 was not significant.

“We found that male patients experienced fewer pulmonary exacerbations than female patients both before and after [Kalydeco] treatment and that rates of pulmonary exacerbations improved before vs after [Kalydeco] treatment in male patients,” the researchers wrote. “We did not see the same improvement in pulmonary exacerbations in female patients.”

Both females and males, however, experienced similar average reductions in a measure of lung health called percent predicted forced expiratory volume in one second (ppFEV1), the researchers noted. ppFEV1 measures the maximum amount of air that can be exhaled in one second, even after adjusting for potential confounding factors.

Reports of P. aeruginosa lung infections, in contrast, declined for both females (by 12%) and males (by 15%) with Kalydeco’s use, with no significant differences by sex evident.

The persistence of some differences between females and males despite treatment with Kalydeco, the researchers noted, suggests that their underlying causes are not be solely related to the faulty CFTR protein channels that the modulator targets.

However, “the exact mechanisms behind these differences remain unknown,” they wrote.

“Given the known consequences of pulmonary exacerbations, this suggests that females will likely continue to fair worse than males even in the era of [highly effective modulator therapy],” the researchers concluded, adding that more research is needed to close the sex gap in CF.