(683) Characteristics of CFTR Modulator Response in Nasal Cell Models Derived from Patients with Rare CFTR Variants

Background: Although modulator therapy is available to the majority of North Americans with CF, additional approaches are necessary to treat all patients. One approach to expand drug access is the use of patient-specific laboratory models of therapeutic response, such as human nasal epithelial (HNE) cells. We sought to apply these models to expand real-world drug access for patients with rare CFTR variants, and to identify patient characteristics that are predictive of modulator response.

Methods: All studies were approved by the CCHMC IRB. Subjects with no modulator access at the time of sampling and ≥1 rare CFTR variant were enrolled and HNEs were collected. Cells were shipped to a central site for processing and expansion. Cells were then differentiated into air-liquid interface and spheroid cultures as previously described [1], and baseline and modulated CFTR function were quantified. Subjects were classified as responder or non-responder by functional improvement of >5% of wild-type CFTR (wtCFTR) function, with an absolute modulated function of >10% of wtCFTR. For responders, data were shared by letter to support insurance approval.

Results: Through 2021, a total of 149 subjects completed nasal cell testing. Average age was 23.8 years (SD 15.2), with 51% female. Fifty-nine subjects (39.6%) were classified as responders to at least one modulator, of which 40 (67.8% of responders) were successfully started on off-label therapy. The responder cohort included more F508del heterozygotes (22.0%) than non-responders (10.0%, p=0.043), however, all F508del heterozygotes were tested prior to the availability of elexacaftor/tezacaftor/ivacaftor (ETI). Compared to non-responders, responders trended less likely to harbor unidentified (8.5% vs 18.8%, p=0.055) or nonsense CFTR variants (47.5% vs 53.3%, p=0.096). Intronic variants were equally distributed among both groups (45.7% vs 40.0%, p=0.977). Baseline (unmodulated) CFTR function was higher among non-responders (mean 45.0% of wtCFTR) compared to responders (mean 17.4% of wtCFTR, p=0.013).



Among responders, all available modulator drugs were represented, including ivacaftor (I; n=23 individuals), lumacaftor/ivacaftor (LI; n=7), tezacaftor/ivacaftor (TI; n=7), and ETI (n=22). ETI was the predominant responding drug since it became available. There was a trend towards higher baseline CFTR function among those responsive to I (27.2% of wtCFTR) compared to LI (6.8%), TI (9.8%), or ETI (12.9%; p=0.059). Select variants within this cohort were universally responsive in 1 or 2 copies (e.g., L927P and TI, n=3 subjects), while other mutations vary in response from patient to patient (e.g., W1282X, 8 responders to I or ETI, and 12 non-responders).

Conclusions: Real-world nasal cell-based testing is able to consistently quantify CFTR function, to provide a pathway towards modulator access for those with rare CFTR variants, and to generate insights into subject characteristics that predict modulator response.

Acknowledgements: This work was supported by the CFF (grant numbers BREWIN20Y2-OUT and NAREN19R0) and the NIH/NHLBI (grant number HL144825-01A1).

References: [1] Brewington JJ, et al. Detection of CFTR Function and Modulation in Primary Human Nasal Cell Spheroids. J Cyst Fibros. 2018 Jan;17(1): 26-33. PMID 28712885.