First real-world study of fetal therapy with CFTR modulators in cystic fibrosis: Report from the MODUL-CF study.
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Bonnel Anne-Sophie, Bihouée Tiphaine, Ribault Mélanie, Driessen Marine, Grèvent David, Foissac Frantz, Truong Ngoc Hoa, Benhamida Myriam, Arnouat Baptiste, Borghese Roxana, Chedevergne Frédérique, Couderc-Kohen Laure, da Silva Jennifer, Grenet Dominique, Houdouin Véronique, Le Anais, Marchal Sarah, Deneuville Eric, Pouradier Delphine, Rousseau Véronique, Treluyer Jean-Marc, Francart Arnaud, Steffann Julie, Reix Philippe, Benaboud Sihem, Mamzer Marie France, Ville Yves, Martin Clémence, Burgel Pierre-Régis, Sermet-Gaudelus Isabelle, MODUL-CF study group
Аннотация
METHODS: Dyads were included if the foetus had a genetic diagnosis of CF and carried at least one variant responsive to VST. Standardized assessment included pre-VST Magnetic Resonance Imaging (MRI), repeated ultrasound (US), and VST drug concentrations in cord blood, maternal and infant plasma.
RESULTS: We enrolled 13 dyads. One withdrew from the study. VST therapies (Elexacaftor (ELX)/Tezacaftor (TEZ)/Ivacaftor(IVA) (ETI) n = 11, ivacaftor (IVA) n = 1) were administered to the pregnant women between 19 and 36 weeks' of gestation for a median[IQR] of 35[55] days, either as a curative indication of MI (n = 8) or as a tertiary prevention of fetal CF-related intestinal symptoms (n = 4). One foetus experienced increased bowel dilatation after ETI introduction. MRI revealed intestinal atresia. One dyad received only 2 doses. In the other 6 cases, resolution of MI was observed within 14[10] days of ETI. Fetal development and neonatal tolerance were excellent. Fecal elastase at birth was always below 200 ng/g even in the ETI breast-fed infant. Cord-to-maternal concentration yielded median ratios of 0.40 for ELX, 0.54 for IVA and 1.59 for TEZ.
CONCLUSION: ETI administration from the third trimester of pregnancy enables MI resolution. Trans-placental transfer is high. Fetal tolerance at ETI initiation needs to be monitored by a standardized assessment.