Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription - Archive ouverte HAL Access content directly
Journal Articles European Respiratory Journal Year : 2023

Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription

Pierre Régis Burgel
Aurelie Hatton
Naim Bouazza
  • Function : Author
Julie Macey
  • Function : Author
Sylvie Leroy
  • Function : Author
Isabelle Durieu
  • Function : Author
Laurence Weiss
  • Function : Author
Dominique Grenet
  • Function : Author
Nathalie Stremler
  • Function : Author
Camille Ohlmann
  • Function : Author
Philippe Reix
Michele Porzio
  • Function : Author
Pauline Roux Claude
  • Function : Author
Natacha Rémus
  • Function : Author
Benoit Douvry
  • Function : Author
Sylvie Montcouquiol
  • Function : Author
Laure Cosson
  • Function : Author
Julie Mankikian
  • Function : Author
Jeanne Languepin
  • Function : Author
Veronique Houdouin
  • Function : Author
Laurence Le Clainche
  • Function : Author
Anne Guillaumot
Delphine Pouradier
  • Function : Author
Adrien Tissot
Pascaline Priou
  • Function : Author
Laurent Mély
  • Function : Author
Frederique Chedevergne
  • Function : Author
Muriel Lebourgeois
Jean Lebihan
  • Function : Author
Clémence Martin
Jennifer da Silva
  • Function : Author
Lydie Lemonnier
  • Function : Author
Pierre Foucaud
  • Function : Author
Christophe Marguet
  • Function : Author
Alexandre Hinzpeter
Paola de Carli
  • Function : Author
Emmanuelle Girodon
Isabelle Sermet-Gaudelus

Abstract

Background Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator ( CFTR ) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. Methods CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (Δ I ETI/DMSO %WT). Results 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). Δ I ETI/DMSO %WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. Conclusions Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.
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Dates and versions

hal-04470518 , version 1 (21-02-2024)

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Elise Dreano, Pierre Régis Burgel, Aurelie Hatton, Naim Bouazza, Benoit Chevalier, et al.. Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription. European Respiratory Journal, 2023, 62 (4), pp.2300110. ⟨10.1183/13993003.00110-2023⟩. ⟨hal-04470518⟩

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