Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®.

Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®. Pathway to Personalized Therapy in Cystic Fibrosis

The purpose of the study is to investigate whether the correction of CFTR function by Lumacaftor/Ivacaftor in a patient-derived primary nasal cell model is a surrogate biomarker for respiratory improvement in Orkambi® treated patients.

Orkambi® is a combination of Ivacaftor (a CFTR channel potentiator) and Lumacaftor (a corrector partially rescuing the traffic of mutated CFTR). This treatment is now marketed in France for patients homozygotes for the mutation p.Phe508del, aged 12 and above. Systematic use of this product is a concern due to the lack of predictive markers of efficacy, the highly variable respiratory improvement in patients and potential serious side effects.

The purpose of this study is to investigate the predictive value for improvement of the respiratory function after 24 weeks of Orkambi treatment of an in vitro test. This test quantifies the correction of CFTR activity as assessed by the change of cyclic AMP (cAMP) dependant chloride (Cl-) secretion in patient derived Human Nasal Epithelial (HNE) derived primary culture after Lumacaftor/Ivacaftor 48 hours incubation.

Inclusion Criteria:

• Homozygous F508del patient aged 5 years or older
• Patient with an indication for Orkambi® treatment according to the marketing authorization application
• Patient never received Orkambi® in the past
• Patient able to perform FEV1
• Signed Informed consent form by the patient (if aged ≥ 18 years), or by parents / legal guardian and patient's agreement (if aged < 18 years) Patient affiliated to the health insurance system

Exclusion Criteria:

• Homozygous F508del patients who do not meet the treatment indications according to the marketing authorization application
• Patients refusing Orkambi®
• CF patients not homozygous for the p.Phe508del mutation
• Active smoker
• Severe nasal mucosa disrepair
• Contraindications to xylocaine anesthesia,
• Participation with another interventional study with drug