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

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder caused by variants in the CFTR gene. Although the F508del mutation is common globally, the Middle East exhibits a higher prevalence of rare, region-specific variants. The triple-combination therapy elexacaftor/tezacaftor/ivacaftor (ETI) has revolutionized CF management; however, its efficacy in individuals with rare variants, often underrepresented in clinical trials, remains less certain. This study is aimed at evaluating the real-world outcomes of ETI therapy in CF patients with rare CFTR variants predominantly found in the Middle East.

METHODS: This retrospective, single-center study included 12 patients with CF carrying rare Middle Eastern variants. Data on percent predicted Forced Expiratory Volume in 1 second (ppFEV1), body mass index (BMI), and annual exacerbation frequency were collected before and after 12 months of ETI treatment. Nine of these patients were previously on ivacaftor and were switched to ETI. Changes in clinical outcomes were analyzed using Wilcoxon signed-rank tests due to nonnormally distributed data.

RESULTS: Following 12 months of ETI therapy, significant improvements were observed. The median ppFEV1 increased by 9.5% (range: 2-15). The median annual frequency of exacerbations decreased by two events (range: 0-4). BMI showed a modest median improvement of 1.5 kg/m2, which was not statistically significant. The cohort comprised nine females (75%) and three males (25%), with a median age of 24.3 years (range: 18.5-35.2 years) at the time of ETI initiation or transition.

CONCLUSION: ETI therapy led to statistically significant improvements in lung function and a reduction in pulmonary exacerbations in CF patients with rare Middle Eastern variants. These findings, from the first report of its kind in this region, support the expansion of ETI access to individuals with rare CFTR variants, particularly in underserved populations, based on functional response. This underscores the benefit of ETI beyond the common F508del mutation.