Cystic fibrosis triple therapy improves clinical outcomes in N1303K mutation

Key takeaways:

• Sweat chloride did not significantly differ between baseline and day 28 of triple therapy in this patient population.
• Lung function, respiratory-related quality of life, BMI and weight significantly improved.

Percent-predicted FEV₁ and respiratory-related quality of life improved with 28-day triple therapy in individuals with the N1303K cystic fibrosis transmembrane conductance defect, according to data published in Lancet Respiratory Medicine.

“CFTR modulators are approved for approximately 90% of people with cystic fibrosis in the [United States] and provide substantial clinical benefit,” George M. Solomon, MD, associate professor of pulmonary, allergy and critical care medicine at the University of Alabama at Birmingham, and colleagues wrote. “N1303K (Asn1303Lys), one of the most common class 2 CFTR defects, has not been approved for these therapies by any regulatory agency.”

Solomon and colleagues analyzed 20 individuals (mean age, 25 years; 50% male; 90% white) aged 12 years or older with CF encoding N1303K (at least one variant plus one allele) in a prospective, open-label, single-arm trial to determine how 28-day triple therapy (elexacaftor/tezacaftor/ivacaftor [ETI]; Trikafta, Vertex Pharmaceuticals) impacts sweat chloride, percent-predicted FEV₁, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, BMI and weight.

The triple therapy regimen was taken via pill in the morning (100 mg elexacaftor, 50 mg tezacaftor and 75 mg ivacaftor) and evening (150 mg ivacaftor) for 28 days, according to the study. Notably, adherence was high (more than 99%).

Sweat chloride went down by an average of 1.1 mmol/L between baseline and day 28, and researchers wrote that this signaled no significant change. The study also highlighted that achievement of a change greater than –15 mmol/L in this period was reached by one individual.

In contrast to the nonsignificant sweat chloride finding, percent-predicted FEV₁ significantly rose by an average of 9.5 percentage points at day 28 (P < .0001). When assessed individually, a minimum rise in percent-predicted FEV₁ of 5% was found in 15 individuals (75%), according to the study.

With higher CFQ-R respiratory domain scores indicating respiratory-related quality of life improvement, this factor was also found to significantly improve between baseline and day 28 (mean, 20.8 points; P < .0001).

At day 28, researchers further noted that mean BMI significantly improved from baseline (0.4 kg/m²; P = .0017), as did mean weight (1 kg; P = .002).

Individuals did not continue to receive triple therapy after the 28 days because there was a 28-day washout period.

“At day 56 after the washout period, ppFEV, CFQ-R respiratory domain, BMI and weight endpoints showed regression to values similar to baseline for most participants,” Solomon and colleagues wrote.

In terms of safety, adverse events occurred in 14 individuals. For all but two individuals, the event was classified as mild rather than moderate (n = 1) or serious (n = 1). Notably, “hospitalization attributed to pneumonia” was the event deemed as serious, according to the study.

“Our report provides compelling and supportive prospective clinical trial evidence that patients with the prevalent CFTR^N1303K variant have substantial improvement after ETI therapy while also showing a conventional safety profile in this patient population,” Solomon and colleagues wrote.