Mucus thinner use high for modulator-ineligible CF patients
Study finds variety in CFTR modulator-ineligible population
Most people with cystic fibrosis (CF) who carry mutations that make them ineligible for CFTR modulators are prescribed medications that improve mucus thinning and clearance. Antibiotic use is also high, and because most patients had pancreatic insufficiency, treatment with pancreatic enzyme replacement therapy is also common.
That’s according to a study that analyzed data from the CF Foundation Patient Registry, which contains data for children, adolescents, and adults.
“With a growing pipeline of therapies aimed at improving CFTR function for those who cannot benefit from modulators … characterization of both the size and outcomes of these populations are critical to inform optimal clinical development plans and future clinical trials,” the scientists wrote.
The study, “Characteristics of individuals with cystic fibrosis in the United States ineligible for ivacaftor and elexacaftor/tezacaftor/ivacaftor”, was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the CFTR gene, which encodes a protein of the same name critical for the production of watery mucus in the airways and other organs. When the protein is faulty or missing, thick and sticky mucus builds up to cause respiratory and other disease symptoms.
Not all CF patients eligible for modulators
CFTR modulator therapies, which help increase CFTR protein function in people with certain disease-causing mutations, have greatly contributed to better clinical outcomes in the CF patient population. However, not all CF patients are eligible for these treatments.
The researchers intended to characterize patients in the U.S. who are not eligible for any CFTR modulator due to the type of mutation they carry. Data from 2017 and 2022 were analyzed.
A total of 2,790 patients with no history of lung transplant before 2017 were included in the analysis. Annual loss to follow-up, meaning patients who contributed to the study in one year but not the next, ranged from 4% to 7%. During the study period, 148 patients died, 116 underwent lung transplants, and 73 women became pregnant.
By 2022, 54% of the participants were adults. Median age at diagnosis was 1.2 months for children and 3.1 years for adults. Most patients were white. Hispanic or Black patients were more commonly children than adults.
The highest proportion of children ages 2 to 11 was reported in the Southeast, and the highest proportion of adults was in the Northeast.
The researchers also looked at outcomes, measuring lung function using percent predicted forced expiratory volume in one second (ppFEV1), pulmonary exacerbations (periods of sudden symptom worsening), and nutritional status. Children had generally better lung function than adults.
The majority of patients (77.8%) with ppFEV1 measurements had pancreatic insufficiency, a digestive problem that occurs when the pancreas doesn’t release enough digestive enzymes. The estimated mean annual decline in ppFEV1 among these patients ranged from 1.5 per year in children aged 6-11 and in adults, and 2.2 in adolescents. The largest ppFEV1 decline in the group with sufficient pancreatic function was 0.9 per year in adolescents.
The proportion of patients positive for Pseudomonas aeruginosa, a major contributor to lung disease in CF patients, was lowest in children ages 2 to 5 (17.1%) and highest in adolescents and adults (about 40%).
To assess nutritional status, the researchers analyzed body mass index (BMI), a measure of body fat based on height and weight, or, for children, BMI percentile, which evaluates BMI compared with children of the same age and sex. Adults had a median BMI of 22.9 kg/m2 which is close to the lowest BMI recommended by the CF Foundation.
Children of all age groups had BMI percentiles within the recommended range (50th percentile or higher): 59.5 in children ages 2 to 5, 55.6 in those ages 6 to 11, and 52.5 in adolescents.
A high proportion of adults and adolescents (ranging from 71.2% to 89.6%) were prescribed the mucus-thinning agent Pulmozyme (dornase alfa), while a smaller proportion of children younger than 2 (34.8%) received the therapy.
Other commonly prescribed medications included hypertonic saline to help with mucus clearance, antibiotics to treat bacterial infections, and pancreatic enzyme replacement therapy for patients with pancreatic insufficiency.
Off-label Trikafta (elexacaftor/tezacaftor/ ivacaftor) or Kalydeco (ivacaftor) were prescribed to about 10% of the adults in 2022; these patients were excluded from the analysis, as treatment with these CFTR modulators could be a confounding factor.
Children and adolescents participated in routine CF care more often than adults, with 78.5% of adolescents reporting at least four visits to outpatient centers.
“These results highlight the heterogeneity of the CFTR modulator ineligible population which has immediate implications for clinical trial planning, but also presents opportunities for future detailed research of this population,” the researchers wrote.
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