Highly Effective Modulator Therapy in Cystic Fibrosis: Addressing Unusual Variants in the Middle East

Area of Science:

• Medical Research
• Genetics
• Pulmonology

Background:

• Cystic fibrosis (CF) is an autosomal recessive genetic disorder.
• The Middle East has a high prevalence of rare CFTR gene variants, distinct from the common F508del mutation.
• Elexacaftor/tezacaftor/ivacaftor (ETI) is a triple-combination therapy transforming CF care, but its effectiveness in rare variants is less understood.

Purpose of the Study:

• To evaluate the real-world effectiveness of ETI therapy in Middle Eastern CF patients with rare CFTR variants.
• To assess changes in lung function, BMI, and exacerbation frequency.
• To provide evidence for expanding ETI access to underserved populations with rare CFTR variants.

Main Methods:

• Retrospective, single-center study of 12 CF patients with rare Middle Eastern CFTR variants.
• Collected data on percent predicted Forced Expiratory Volume in 1 second (ppFEV1), BMI, and annual exacerbation frequency over 12 months of ETI treatment.
• Analyzed outcome changes using Wilcoxon signed-rank tests.

Main Results:

• Median ppFEV1 increased by 9.5% (2-15%) after 12 months of ETI.
• Median annual exacerbation frequency decreased by two events (0-4).
• Median BMI showed a non-significant improvement of 1.5 kg/m².

Conclusions:

• ETI therapy demonstrated statistically significant improvements in lung function and reduced pulmonary exacerbations in CF patients with rare Middle Eastern CFTR variants.
• This study is the first in the region to report on ETI outcomes in this population.
• Findings support expanding ETI access to individuals with rare CFTR variants based on functional response, highlighting benefits beyond the F508del mutation.