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. 2023 Oct 19;62(4):2300110.
doi: 10.1183/13993003.00110-2023. Print 2023 Oct.

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

Elise Dreano  1   2 , Pierre Régis Burgel  2   3   4   5 , Aurelie Hatton  1   2 , Naim Bouazza  2   6 , Benoit Chevalier  1   2 , Julie Macey  7 , Sylvie Leroy  8 , Isabelle Durieu  9 , Laurence Weiss  10 , Dominique Grenet  11 , Nathalie Stremler  12 , Camille Ohlmann  13 , Philippe Reix  13 , Michele Porzio  14 , Pauline Roux Claude  15 , Natacha Rémus  16 , Benoit Douvry  16 , Sylvie Montcouquiol  17 , Laure Cosson  18 , Julie Mankikian  19 , Jeanne Languepin  20 , Veronique Houdouin  21 , Laurence Le Clainche  21 , Anne Guillaumot  22 , Delphine Pouradier  23 , Adrien Tissot  24 , Pascaline Priou  25 , Laurent Mély  26 , Frederique Chedevergne  27 , Muriel Lebourgeois  27 , Jean Lebihan  28 , Clémence Martin  2   3 , Flora Zavala  1   2 , Jennifer Da Silva  3 , Lydie Lemonnier  29 , Mairead Kelly-Aubert  1   2 , Anita Golec  1   2 , Pierre Foucaud  29 , Christophe Marguet  30 , Aleksander Edelman  1   2 , Alexandre Hinzpeter  1   2 , Paola de Carli  29 , Emmanuelle Girodon  1   2   31   32 , Isabelle Sermet-Gaudelus  33   2   5   23   32 , Iwona Pranke  1   2   32 ; French CF Reference Network study group
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Free article

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

Elise Dreano et al. Eur Respir J. .
Free article

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 (ΔI 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). ΔI 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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Conflict of interest statement

Conflict of interest: P.R. Burgel reports grants from Vertex and GSK, outside the submitted work. N. Stremler reports advisory board participation with Vertex, outside the submitted work. B. Douvry reports grants and advisory board participation with Vertex, outside the submitted work. L. Le Clainche reports payment for expert testimony from Zambon, Novartis and Viatris, outside the submitted work. C. Marguet reports consulting fees from Vertex and Mylan, and payment for expert testimony from Vertex and Zambon, outside the submitted work. P. de Carli reports grants from Vaincre la Mucoviscidose, outside the submitted work. I. Sermet-Gaudelus reports support for the present manuscript from Vaincre la Mucoviscidose and Mucoviscidose ABCF2. I. Sermet-Gaudelus also reports, outside the submitted work, grants from Agence Nationale pour la Recherche, Assistance Publique–Hôpitaux de Paris and Vertex Innovation Award, and consulting fees and travel support from Vertex therapeutics. All other authors have nothing to disclose.

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