Abstract
Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy. A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years. We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA.
Highlights
Cystic fibrosis (CF) is a rare, autosomal recessive, life-shortening genetic disease that affects more than 90,000 people worldwide [1]
It is caused by variants in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells throughout the body
We found that lung response variability to ivacaftor was associated with variants in the Solute Carrier Family 26 Member 9 (SLC26A9) gene in a cohort of French people with CF (pwCF), confirming results observed in Canadians [12,13]
Summary
Cystic fibrosis (CF) is a rare, autosomal recessive, life-shortening genetic disease that affects more than 90,000 people worldwide [1]. It is caused by variants in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells throughout the body. Considerable efforts have led to the development of therapies that target the CFTR protein named CFTR modulators. Since 2012, pwCF carrying some CFTR gating variants can be treated with ivacaftor, a potentiator therapy which increases the probability of CFTRchannel opening. Lumacaftor, a CFTR corrector that improves the processing and trafficking of the Phe508del-CFTR protein, was combined with ivacaftor to treat pwCF homozygous for the Phe508del-CFTR variant.
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