Elexacaftor/tezacaftor/ivacaftor (ETI), which improves lung function and symptoms in people with cystic fibrosis (CF), accelerates mucociliary clearance (MCC) and improves the hydration of respiratory secretions in CF, according to study findings reported in the Journal of Cystic Fibrosis.

A substudy of the PROMISE trial (ClinicalTrials.gov Identifier: NCT04038047) evaluated whether the effects of ETI on CF transmembrane conductance regulator (CFTR) activity were associated with improved mucociliary clearance (MCC). The study was conducted at 4 specialized sites from the core PROMISE study.

Participants were at least 12 years of age, had at least 1 copy of the F508del-CFTR mutation, and were prescribed ETI. They had a baseline visit before initiating ETI and a post-treatment visit about 30 days afterward. The prespecified primary MCC endpoint was the average rate of whole right lung MCC for 60 minutes (WLAveClr60), and the primary respiratory biospecimen endpoint was the percentage of solids content.

A total of 45 patients initiated ETI therapy. Their mean age was 27.7 years (range, 12-54) and 63% were female. The median time between initiation of ETI and the post-treatment visit was 32.5 days (interquartile range [IQR], 27-50.8), and the median duration from baseline to post-treatment visit was 38.0 days (IQR, 31-53.8).

These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.

Large improvements in MCC were observed in all lung compartments, including whole lung (WL), central lung (CL), and peripheral lung (PL), after treatment with ETI. The WLAveClr60 after ETI was not significantly associated with the change in forced expiratory volume in 1 second (FEV1) percentage predicated (% pred), Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R), or sweat chloride, or with changes in sputum or exhaled breath condensate (EBC) endpoints.

Patients who were unable to produce sputum after ETI had significantly superior baseline lung function compared with persistent sputum producers (FEV1 % pred 89.0% vs 67.5%; P =.0015).

After initiation of ETI treatment, the percent solids content of sputum collected was significantly decreased (modeled mean 3.4 vs 2.2 %; P <.0001). Participants who were unable to produce sputum after ETI initiation had a lower baseline hydration of respiratory secretions (% solids) level (3.6% vs 4.7%; P =.18).

Sputum rheology endpoints (G’, G”, dynamic viscosity) varied, with no significant differences occurring. A significant association between % solids and each rheology endpoint was observed (Spearman ρ=0.37-0.60; each P ≤.0022).

Sialic acid:urea at baseline varied widely, and within subject correlation was poor (Spearman ρ = − 0.10; P =.56), although no difference was found between baseline and post-ETI measurements.

EBC pH values varied greatly at baseline, and within subject values were poorly correlated (Spearman ρ = 0.07; P = .68). After ETI treatment, no change was observed.

A moderate baseline correlation between baseline % solids and CFQ-R respiratory domain score (r = − 0.53, P =.001) was observed, although the correlation between changes in % solids and CFQ-R was not statistically significant (r = − 0.42; P =.13). Other associations between biospecimen endpoints and clinical variables were weak (r < 0.4) or were not observed.

“E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF,” the investigators concluded.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Source link