Predictive factors for lumacaftor/ivacaftor clinical response

https://doi.org/10.1016/j.jcf.2018.12.011Get rights and content
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Highlights

  • Clinical response to Lumacaftor/ivacaftor is variable

  • CFTR Biomarkers, do not correlate with the improvements in clinical status at 6 months of lumacaftor/ivacaftor treatment.

  • Serum drug levels do not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers.

  • Exonic variants may influence response to treatment

Abstract

Background

Ivacaftor-lumacaftor combination therapy corrects the F508 del-CFTR mutated protein which causes Cystic Fibrosis. The clinical response of the patients treated with the combination therapy is highly variable. This study aimed to determine factors involved in the individual's response to lumacaftor-ivacaftor therapy.

Methods

Sweat test was assessed at baseline and after 6 months of ivacaftor-lumacaftor treatment in 41 homozygous F508del children and young adults. β-adrenergic peak sweat secretion, nasal potential difference (NPD) and intestinal current measurements (ICM) were performed in patients accepting these tests. Seric level of lumacaftor and ivacaftor were determined and additional CFTR variant were searched.

Results

Sweat chloride concentration significantly decreased after treatment, whereas the β-adrenergic peak sweat response did not vary in 9 patients who underwent these tests. The average level of F508del-CFTR activity rescue reached up to 15% of the normal level in intestinal epithelium, as studied by ICM in 12 patients (p = .03) and 20% of normal in the nasal epithelium in NPD tests performed in 21 patients (NS). There was no significant correlation between these changes and improvements in FEV1 at 6 months. Serum drug levels did not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers. Additional exonic variants were identified in 4 patients. The F87L-I1027T-F508del-CFTR complex allele abolished the lumacaftor corrector effect.

Conclusion

This observational study investigates a number of potential factors linked to the clinical response of F508del homozygous patients treated with lumacaftor-ivacaftor combination therapy. Lumacaftor and ivacaftor blood levels are not associated with the clinical response. Additional exonic variants may influence protein correction.

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