(43) CFTR Modulator Induced Sweat Chloride Changes Across the Cystic Fibrosis Population from the CHEC-SC Study: 2022 Update

Background: We previously reported on the preliminary results from the CHEC-SC study (Characterizing CFTR Modulated Changes in Sweat Chloride)[1], a large population-based epidemiologic study characterizing the heterogeneity in sweat chloride (SC) response to CFTR modulators and evaluating the association between SC and long-term clinical outcomes. With the approval of elexacaftor/tezacaftor/ivacaftor (ELE/TEZ/IVA) in 2019, we now have SC, demographic and clinical outcome data for all 4 commercially available modulators in use in the U.S. In this report, we present an update on change in SC following initiation of ivacaftor (IVA), lumacaftor/ivacaftor (LUM/IVA), and tezacaftor/ivacaftor (TEZ/IVA), including new participants at younger ages, and new data on the association between change in SC following initiation of ELE/TEZ/IVA.

Methods: Eligible subjects who have been prescribed any of the 4 commercially approved CFTR modulators for ≥ 90 days were enrolled for a single visit to collect sweat to be analyzed for SC at their local laboratory. Diagnostic pre-modulator SC values were obtained from chart review. Clinical data obtained at this visit was augmented by data obtained from the CFF Patient Registry (CFFPR). Subjects who switch to an alternative prescribed commercially approved CFTR modulator for ≥ 90 days were eligible to re-enroll in the study.

Results: CHEC-SC began in 2018. As of February 2022, over 3500 subjects age 0.88-77 years were enrolled from 51 U.S. sites in the CF TDN. For all modulators, the majority of treated subjects were ≥ 12 years age, with 36% of 526 IVA subjects 0-11 years, 35% of 783 LUM/IVA subjects 2-11 years, 9.7% of 699 TEZ/IVA and 7.5% of 1532 ELE/TEZ/IVA subjects 6-11 years. Among the 4 modulators, the IVA group had the greatest percentage of Hispanic or Latino subjects (11%). Regarding CFTR genotype, 52% of the IVA group had gating mutations. 100% (LUM/IVA), 90% (TEZ/IVA) and 57% (ELE/TEZ/IVA) were homozygous for F508del. Median time (years) from start of prescribed modulator to post modulator SC collection was 2.48 (IVA), 1.76 (LUM/IVA), 0.57 (TEZ/IVA), and 1.14 (ELE/TEZ/IVA).

Pre- and post-modulator SC are presented in Figure 1. Average SC changes tracked consistently with those reported in clinical trials, with the greatest change observed with ELE/TEZ/IVA, -59.9 (standard deviation [SD] 23.6). This change resulted in the greatest proportion of SC values falling below the diagnostic value for CF of 60 mmol/L; 79% post- ELE/TEZ/IVA (pre 3.5%). The average SC change with IVA overall was -31.9 (30.5); for those with gating mutations -50.7 (25.8), and for R117H -20.3 (21.3). Average SC change associated with LUM/IVA was -20.8 (19.3) and TEZ/IVA -10.5 (17.6). Pre- and post-modulator SC < 60 with IVA was 19.9% and 64.4%, LUM/IVA 0.1% and 10.9%, and TEZ/IVA 3.9% and 6.8%. Heterogeneity in SC changes across key population factors and among rare genotype groups, as well as changes among patients changing modulator regimens are being evaluated. The first analysis spanning across all CFTR modulators evaluating the association between SC response and FEV1 change across the large CHEC-SC population when accounting for genotype and age group will be presented at NACFC.

Conclusions: CHEC-SC is the largest study characterizing changes in modulator induced SC and clinical outcome changes, and factors associated with these changes across the CF population.

Acknowledgements: Supported by the Cystic Fibrosis Foundation

References: [1] Mayer-Hamblett N, et al. Ped Pulmonol Suppl 54:229(202), 2019.