(601) Effects of different combinations of CFTR targeted drugs on CFTR dependent sweating in Cystic Fibrosis (CF) patients.

Background: As novel personalized therapies become prevalent in the clinical practice, methods to assess the effects of such treatments are needed. We applied the Optical Sweat Beta Adrenergic test (1) to assess CFTR function in CF patients before and during treatment with different CFTR modulators. According to our previous prediction based on multilinear regression analysis and effects of lumacaftor/ivacaftor in CF patients (2) we compared two different outcomes: the single sweat droplets number (SDN) induced by a beta-adrenergic cocktail with the ratio of sweat rate induced by this cocktail versus sweat rate induced by methacholine as cholinergic stimulus (C/M ratio).

Methods: Two intradermal microinjections (100ul) were performed in order to induce first CFTR-independent sweat secretion by methacholine and then CFTR-dependent sweat secretion by a beta-adrenergic cocktail (aminophylline and isoprenaline) with atropine for inhibiting the cholinergic pathway. 32 CF patients were tested before and during treatment with lumacaftor/ivacaftor or tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor for a period up to one year. Images of single sweat droplets formed on the forearm in an oil layer containing a water-soluble dye (erioglaucine disodium, Sigma) were acquired by a camera; droplets were counted and measured at the end of both C and M phases lasting 30 and 10 min, respectively. SDN and C/M ratio were determined and then compared. Clinically relevant data available were considered such as the Body Mass Index (BMI), sweat chloride, Forced Expiratory Volume 1 (FEV1) and Nasal Potential Difference (NPD) measurements.

Results: In these 32 CF patients a statistically significant increase of SDN was observed with median value 13.5 (min-max -52.0 - 80.7; p-value = 0.006). We calculated a statistically significant C/M ratio median difference = 0.008 (min-max -0.58 – 0.83; p=0.02). Similar results were obtained in the subgroup of patients F508del +/+ (p=0.04 for SDN and C/M ratio, n=11). In the other 21patients carrying only one copy of F508del variant we calculated after six months of treatment a median increase of 12 SDN (min-max - 35 – 91, p=0.035), whilst no significant difference of C/M ratio (p=0.3) was detected (difference =0, min-max -0.5 – 0.4). Increases of CFTR function measured by SDN, C/M ratio, sweat Cl were higher during treatment with elexacaftor/tezacaftor/ivacaftor in comparison with tezacaftor/ivacaftor or lumacaftor/ivacaftor in single CF patients, consistently with lung function and/or BMI and/or NPD changes.

Conclusions: We show a significant improvement in CFTR function during treatment with different combinations of CFTR modulators with improved ability to monitor this effect by the simplified outcome SDN.

Acknowledgements: Supported by Lega Italiana Fibrosi Cistica-Associazione Veneta Onlus grant 2022, CFF Award# ASSAEL08A0.

References: < ! 1) Ratiometric sweat secretion optical test in cystic fibrosis, carriers and healthy subjects. Bergamini G, Tridello G, Calcaterra E, Ceri S, Tagliasacchi M, Bianchi F, Monti F, Masciadri A, Laudanna E, Peserico D, Sorio E, Esposito V, Leal T, Assael BM, Sorio C, Melotti P.J Cyst Fibros. 2018 Mar;17(2):186-189. doi: 10.1016/j.jcf.2017.12.003.

< 2) Optical Measurements of Sweat for in Vivo Quantification of CFTR Function in Individual Sweat Glands.Treggiari D, Kleinfelder K, Bertini M, Tridello G, Fedrigo A, Pintani E, Iansa P, Casiraghi A, Minghetti P, Cipolli M, Sorio C, Melotti P.J Cyst Fibros. 2021 Sep;20(5):824-827. doi: 10.1016/j.jcf.2021.03.003.