Clinical efficacy of CFTR modulator therapy in people with cystic fibrosis carrying the I1234V mutation.

BACKGROUND

The cystic fibrosis transmembrane conductance regulator (CFTR) mutation I1234V (I1234V, p.Ile1234Val, c.3700A>G), is a missense-mutation that creates a cryptic splice site, with the formation of a protein lacking 6 amino acids, that is misfolded and misprocessed. The in vitro effects of CFTR modulator (CFTRm) therapies on human bronchial cell models and intestinal organoids carrying this mutation are conflicting. The aim of this study was therefore to explore the clinical efficacy of CFTRm in people with cystic fibrosis (pwCF) carrying this mutation.

METHODS

This was a retrospective descriptive study of the clinical records of homozygous and compound heterozygous (none F508del) pwCF, for the I1234V mutation, that received CFTRm. Parameters explored were body mass index (BMI), forced expiratory volume in one second percent predicted (FEV1%), lung clearance index (LCI) and quantitative sweat chloride measurements.

RESULTS

Mean age was 38.6 ± 14 years (range 21-60). Two subjects were homozygous and five compound heterozygous, with minimal function mutations. Four were pancreatic insufficient and three pancreatic sufficient. The two homozygous subjects received Tezacaftor/Ivacaftor, the remaining Elexacaftor/Tezacaftor/Ivacaftor (ETI); treatment ranged from 6 to 12 months. Mean BMI score increased from 21.7 ± 1.3 to 23.6 ± 2.1 kg/m2 (p = 0.04); FEV1(%pred) increased by 20.14±10.2while mean change in FEV1 in the year prior to CFTRm initiation was -0.14±1.18 (p = 0.0001). Additionally, LCI 2.5% decreased from 18.7 to 14.5 (p = 0.07); sweat chloride decreased from 116±10 to 90±17 mEq/L (p = 0.017) and chronic pseudomonas airway infection was eradicated in one subject.

CONCLUSIONS

This study supports a clinical benefit for CFTRm therapy in pwCF carrying the I1234V mutation.