(155) Longitudinal Improvements in Clinical and Functional Outcomes following Initiation of Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis

Background: The advent of highly effective modulator therapies (HEMT), including elexacaftor/tezacaftor/ivacaftor (ETI) for treatment of cystic fibrosis (CF) has resulted in remarkable clinical improvements for both modulator naïve patients and for those who have been treated with prior modulator therapies. Intranasal micro-optical coherence tomography (µOCT) has previously detected functional abnormalities in the mucociliary apparatus of patients with CF.

Objective: To characterize the effects of ETI on nasal mucociliary clearance by µOCT and monitor the clinical changes conferred as a means to understand its effects.

Methods: 26 subjects, 12 years and older, with at least 1 F508del mutation were recruited. 24 subjects were enrolled and followed over 3 visits: baseline, +1 month (visit 2) and +6 months (visit 4) following initiation of ETI therapy, noting visit windows were affected by the COVID-19 pandemic. Intranasal µOCT imaging was conducted at baseline, and at visit 2 as previously described; additional imaging for +18 months (visit 5) is also in progress. Clinical outcomes including percent predicted forced expiratory volume in one second (ppFEV1) and sweat chloride levels were computed as part of the parent PROMISE study. In vivo µOCT parameters including mucociliary transport rate (MCT), ciliary beat frequency (CBF), and periciliary liquid depth (PCL) were analyzed by a blinded investigator team after devising an improved stabilization algorithm. Analysis of airway surface liquid layer (ASL) depths was excluded due to the limited number of cases in which the necessary condition for measurement, which is preservation of a clear air layer between the mucus layer and the probe, was satisfied.

Results: 23 subjects completed visits 1 and 2, and 18 subjects completed visits 1, 2 and 4. The average age at baseline was 27± 8.7 years; 69% were female and 43% were on prior 2-drug modulator therapy. No significant change in BMI was found between the visits. ppFEV₁ showed a significant change with an absolute increase of +10.9% (95%CI 76.1, 98.4) at visit 2, which persisted at visit 4 (+10.6%; 95%CI 87.7, 107.0; p=0.0006). Sweat chloride levels significantly decreased by -36.6mmol/L (95%CI 40.9, 54.9) and -41.3mmol/L (95%CI 34.9, 51.8) at visits 2 and 4, respectively (p< 0.0001). Analysis of µOCT images revealed significant improvement in MCT rate (2.8 ± 1.5mm/min at baseline vs 4.0 ± 1.5mm/min at visit 2, p=0.048), while no discernable changes were noted in CBF or PCL. When stratified on the basis of use of prior modulator therapy, no significant differences were found for any µOCT metric. No significant correlations between change in MCT rates and change in ppFEV1 or sweat chloride at visit 2 from baseline were found.

Conclusions: Treatment with ETI in people with CF, including those that were treatment naïve and on prior modulator therapy, resulted in significant and sustained improvements of lung function, and decreased sweat chloride levels at ~10 months, consistent with recently published reports. Functional improvements in MCT rate were evident after initiation of ETI therapy, which may partially explain the findings of better whole lung mucus clearance and reduction in chronic infections reported previously. µOCT imaging in patients with CF is sensitive to the treatment effect of HEMT and suggests improved mucociliary transport as a mechanism of action underlying the clinical benefits to lung health.

Acknowledgements: On behalf of the PROMISE Investigators

References: