Idrevloride in hypertonic saline improves lung function in primary ciliary dyskinesia

Key takeaways:

• Both percent-predicted FEV₁ and FVC in primary ciliary dyskinesia improved with the addition of idrevloride to hypertonic saline.
• Patient-reported adverse events were in line with manifestations of the disease.

Idrevloride in combination with hypertonic saline for 28 days resulted in better lung function vs. hypertonic saline alone in primary ciliary dyskinesia, according to a European Respiratory Society International Congress presentation.

Idrevloride (Parion Sciences), a nebulized epithelial sodium channel inhibitor, also appeared safe for this patient population, according to the study results, which were simultaneously published in The Lancet Respiratory Medicine.

“At current, there is no specific therapy for this disease,” Thomas W. Ferkol Jr., MD, pediatric pulmonologist at University of North Carolina (UNC) Health and chief of pulmonology in the UNC department of pediatrics, said during the presentation. “In fact, most of the therapies we use have been borrowed from other diseases, like cystic fibrosis and asthma.”

In a phase 2 randomized, double-blind, placebo-controlled crossover trial (CLEAN-PCD), Ferkol and colleagues analyzed 123 patients (mean age, 28 years; 63% female) aged 12 years or older with primary ciliary dyskinesia from 32 care centers/hospitals in several countries to determine the impact of idrevloride with or without hypertonic saline on lung function at 28 days.

“[In primary ciliary dyskinesia], there’s a ciliary sensing defect, which results in increased sodium channel activity and dehydration of the airway surface fluid and the mucus, which then impairs cough clearance,” Ferkol said. “You can’t clear this thick, more tenacious, more viscous mucus out of the lungs.

“The thought [behind using idrevloride with hypertonic saline] is that there’s two processes that are going on,” Ferkol added. “The hypertonic saline is drawing water into the airway lumen, and the sodium channel blocker inhibits sodium and water absorption from the airway and stimulates chloride secretion, which then results in a more liquefied, more hydrated mucus that is much easier to clear by cough.”

Researchers randomly assigned patients to one of four groups that consisted of two 28-day treatment periods with a 28-day washout period in between. The first group received nebulized idrevloride (85 µg twice a day) in hypertonic saline (4.2% NaCl) during the first period followed by hypertonic saline alone (n = 43); the second group received hypertonic saline alone first then with idrevloride (n = 41); the third group received idrevloride followed by placebo (n = 21); and the fourth group received placebo followed by idrevloride (n = 18).

Results

Of the total cohort, mean FEV₁ was 66.1% predicted and mean FVC was 83.7% predicted at baseline.

Excluding patients who did not complete the treatment or who did not have available data, in total across treatment groups 78 patients received idrevloride in hypertonic saline, 75 received hypertonic saline alone, 34 received idrevloride alone and 34 received placebo.

Compared with patients given only hypertonic saline for 28 days, those given idrevloride in hypertonic saline showed more improvement in percent predicted FEV₁ from baseline (absolute change, 1% vs. –0.5%; difference, 1.5 percentage points; 95% CI, < 0.1-3; P = .044).

However, researchers did not observe significant differences in percent predicted FEV₁ between patients who received idrevloride in hypertonic saline and those who received only idrevloride or placebo, nor was there a significant difference for the crossover comparisons of idrevloride alone vs. placebo or hypertonic saline alone vs. placebo.

Patients who received idrevloride in hypertonic saline also had significant improvement in percent predicted FVC compared with those who received hypertonic saline alone (absolute change, 1.3% vs. –0.1%; difference, 1.4 percentage points; 95% CI, 0.2-2.5; P = .026) and placebo (absolute change, 1.3% vs. –2.1%; difference, 3.4 percentage points; 95% CI, 0.8-6; P = .012).

Adding ivacaftor

In a second part of this study, researchers evaluated how measures of lung function and quality of life specific to PCD changed with the addition of 28 days of ivacaftor (Kalydeco, Vertex Pharmaceuticals) — a CFTR-modifying drug — to the patients’ treatment at the end of the second period. This analysis included 54 patients.

According to Ferkol, ivacaftor did not change patients’ lung function; however, those receiving idrevloride in hypertonic saline for 56 days demonstrated an increase of 4.7% percent predicted FEV₁ (95% CI, 0.8-6.6; P = .018), which was a significant change from baseline.

“The combination therapy was required for sustained improvement and pulmonary function, and the combination therapy had a greater effect in percent predicted FEV₁ after 56 days more than [after] 28 days,” Ferkol said during his presentation.

Those receiving idrevloride in hypertonic saline for 2 months also had a significant absolute change from baseline in quality-of-life scores that measured respiratory symptoms (16.7; 95% CI, 1.9-31.4; P =. 029).

Adverse events

All treatment groups had a comparable prevalence of patient-reported adverse events (idrevloride in hypertonic saline, 65%; hypertonic saline, 57%; idrevloride, 59%; placebo, 64%), including one serious adverse event each.

Frequent adverse events included cough, headache, oropharyngeal pain, nasal congestion and increased sputum, which Ferkol said are in line with manifestations of the disease.

Notably, those receiving placebo had fewer reports of cough compared with the other treatment groups, and oropharyngeal pain was observed the most among patients receiving the combination treatment.

According to the presentation, a 1-year phase 3 study of the combination of idrevloride and hypertonic saline is the next step in this research.

References:

• Researchers release results from clinical trial for treatment of primary ciliary dyskinesia. https://news.unchealthcare.org/2023/09/researchers-release-results-from-clinical-trial-for-treatment-of-primary-ciliary-dyskinesia/. Published Sept. 12, 2023. Accessed Sept. 14, 2023.
• Ringshausen FC, et al. Lancet Respir Med. 2023;doi:10.1016/S2213-2600(23)00226-6.