Characterizing CFTR modulated sweat chloride response across the cf population: Initial results from the CHEC-SC study.

Background: CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy.
Methods: Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses.
Results: 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response.
Conclusions: CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response.
Competing Interests: Conflict of Interest Statement NMH serves as a consultant through her institution in her role as Executive Director of the CF Therapeutics Development Network Coordinating Center (CF TDNCC) and has received personal consulting fees from Vertex Pharmaceuticals. She has received grant funding from the Cystic Fibrosis Foundation (CFF) and National Institutes of Health (NIH). DRV has received personal consulting fees from AbbVie, Albumedix, AN2, Aradigm, Armata, Arrevus, Calithera, Chiesi USA, Cipla, Corbus, CFF, Eloxx, Enbiotix, Eveo, Galephar, Horizon, IBF, ICON clinical sciences, Ionis, Kala, Merck, Microbion, NDA, Protalix, PTC, Pulmocide, Recida, Savara, Vast, and VRTX. MWK has received personal consulting fees for advisory board participation, grant support to his institution for clinical trial participation, and non-financial support from VRTX, Savara, Laurent, Corbus Pharmaceuticals, PTC, and AzurRx. He has received personal consulting fees and non-financial support from Chiesi, Celtaxsys, Merck, and Kala. Personal consulting fees were received from Albumedix, Paranta, Protalix, Santhera, pH Pharma, Novartis, Ionis, the Italian Cystic Fibrosis Foundation, and the Food and Drug Administration. SMR reports grants and personal fees from Vertex Pharmaceuticals Inc, during the conduct of the study; grants and personal fees from Novartis, grants and personal fees from Bayer, grants from Translate Bio, grants and non-financial support from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants, personal fees and non-financial support from Synedgen/Synspira, grants from Eloxx, grants from Celtaxsys, grants, personal fees and non-financial support from Vertex Pharmaceuticals Inc, personal fees and non-financial support from Renovion, grants and personal fees from Arrowhead, grants, personal fees and non-financial support from Ionis, grants from Astra Zenica, personal fees from Cystetic Medicines, outside the submitted work. ETZ reports grants and personal consulting fees from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation during the conduct of the study.
(Copyright © 2022. Published by Elsevier B.V.)