Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.

Humans Cystic Fibrosis / drug therapy Cystic Fibrosis Transmembrane Conductance Regulator / genetics Mutation Benzodioxoles / therapeutic use Aminophenols / therapeutic use Chloride Channel Agonists / therapeutic use

Journal

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
ISSN: 1873-5010
Titre abrégé: J Cyst Fibros
Pays: Netherlands
ID NLM: 101128966

Informations de publication

Date de publication:
Nov 2023
Historique:
received: 06 01 2023
revised: 30 05 2023
accepted: 02 06 2023
medline: 4 12 2023
pubmed: 19 6 2023
entrez: 18 6 2023
Statut: ppublish

Résumé

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA. Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment. Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.

Sections du résumé

BACKGROUND BACKGROUND
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA.
METHODS METHODS
Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment.
RESULTS RESULTS
Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m
CONCLUSIONS CONCLUSIONS
This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.

Identifiants

DOI: 10.1016/j.jcf.2023.06.001 PMID: 37331863
pubmed: 37331863
pii: S1569-1993(23)00178-9
doi: 10.1016/j.jcf.2023.06.001
pii:
doi:

Substances chimiques

elexacaftor RRN67GMB0V
ivacaftor 1Y740ILL1Z
tezacaftor 0
Cystic Fibrosis Transmembrane Conductance Regulator 126880-72-6
Benzodioxoles 0
Aminophenols 0
Chloride Channel Agonists 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1062-1069

Informations de copyright

Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Ido Sadras (I)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Eitan Kerem (E)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel. Electronic address: eitank@hadassah.org.il.

Galit Livnat (G)

Cystic Fibrosis Center, Carmel Medical center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Israel.

Ifat Sarouk (I)

Pediatric Pulmonology Unit, The National Center for Cystic Fibrosis, Sheba Medical Center, Tel Hashomer and the Sackler Faculty of Medicine, Safra Children's Hospital, Tel Aviv University, Israel.

Oded Breuer (O)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Joel Reiter (J)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Alex Gileles-Hillel (A)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Ori Inbar (O)

The Cystic Fibrosis Foundation of Israel, Israel.

Michael Cohen (M)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Ayelet Gamliel (A)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Noemie Stanleigh (N)

Department of Genetics, The Life Sciences Institute, Hebrew University, Jerusalem Israel.

Tarini Gunawardena (T)

Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada.

Claire Bartlett (C)

Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada.

Tanja Gonska (T)

Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Division of Gastroenterology, Hepatology & Nutrition, Division of Respiratory Medicine, SickKids Hospital, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.

Theo Moraes (T)

Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Division of Gastroenterology, Hepatology & Nutrition, Division of Respiratory Medicine, SickKids Hospital, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.

Paul D W Eckford (PDW)

Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada.

Christine E Bear (CE)

Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.

Felix Ratjen (F)

Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Division of Gastroenterology, Hepatology & Nutrition, Division of Respiratory Medicine, SickKids Hospital, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.

Batsheva Kerem (B)

Department of Genetics, The Life Sciences Institute, Hebrew University, Jerusalem Israel.

Michael Wilschanski (M)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Michal Shteinberg (M)

Cystic Fibrosis Center, Carmel Medical center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Israel.

Malena Cohen-Cymberknoh (M)

Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Clinical and functional efficacy of...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies néonatales › Mucoviscidose › Clinical and functional efficacy of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Pompes ioniques › Transporteurs d'anions › Transporteurs d'anions organiques › Transporteurs d'anions organiques ATP-dépendants › Protéines associées à la multirésistance aux médicaments › Protéine CFTR › Clinical and functional efficacy of...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Clinical and functional efficacy of...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzodioxoles › Clinical and functional efficacy of...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Phénols › Aminophénols › Clinical and functional efficacy of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Modulateurs du transport transmembranaire › Agonistes de canaux chlorure › Clinical and functional efficacy of...