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Treatment effects of Elexacaftor/Tezacaftor/Ivacaftor in people with CF carrying non-F508del mutations

  • Author Footnotes
    1 The two first authors made an equal contribution
    Galit Livnat
    Footnotes
    1 The two first authors made an equal contribution
    Affiliations
    Pediatric Pulmonology Unit and CF Center, Carmel Medical Center, Haifa, Israel

    Technion- Israel institute of technology and the B. Rappaport Faculty of Medicine, Haifa, Israel
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  • Author Footnotes
    1 The two first authors made an equal contribution
    Adi Dagan
    Footnotes
    1 The two first authors made an equal contribution
    Affiliations
    Pediatric Pulmonology Unit and CF Center, Sheba Medical Center-, Tel Aviv, Israel
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  • Moshe Heching
    Affiliations
    Pulmonology Institute and CF center, Rabin Medical Center, Petach Tiqva, Israel
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  • Einat Shmueli
    Affiliations
    Pediatric Pulmonology Institute and CF center, Schneider Children's Medical Center, Petach Tiqva, Israel
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  • Dario Prais
    Affiliations
    Pediatric Pulmonology Institute and CF center, Schneider Children's Medical Center, Petach Tiqva, Israel

    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Karin Yaacoby-Bianu
    Affiliations
    Pediatric Pulmonology Unit and CF Center, Carmel Medical Center, Haifa, Israel

    Technion- Israel institute of technology and the B. Rappaport Faculty of Medicine, Haifa, Israel
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  • Nili Stein
    Affiliations
    Dept of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel
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  • Meir Mei-Zahav
    Affiliations
    Pediatric Pulmonology Institute and CF center, Schneider Children's Medical Center, Petach Tiqva, Israel

    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Michal Gur
    Affiliations
    Technion- Israel institute of technology and the B. Rappaport Faculty of Medicine, Haifa, Israel

    Pediatric Pulmonology Institute and CF Center, Rambam Medical Center, Haifa, Israel
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  • Author Footnotes
    2 The two last authors made an equal contribution
    Malena Cohen-Cymberknoh
    Footnotes
    2 The two last authors made an equal contribution
    Affiliations
    Pediatric Pulmonology Unit and CF Center, Hadassah Medical Center and Faculty of Medicine, The Hebrew University, Jerusalem, Israel
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  • Author Footnotes
    2 The two last authors made an equal contribution
    Michal Shteinberg
    Correspondence
    Corresponding author at: Pulmonology Institute, Carmel Medical Center, 7 Michal St. Haifa 34362, Israel.
    Footnotes
    2 The two last authors made an equal contribution
    Affiliations
    Technion- Israel institute of technology and the B. Rappaport Faculty of Medicine, Haifa, Israel

    Pulmonology Institute and CF Center, Carmel Medical Center, Haifa, Israel
    Search for articles by this author
  • Author Footnotes
    1 The two first authors made an equal contribution
    2 The two last authors made an equal contribution
Published:November 10, 2022DOI:https://doi.org/10.1016/j.jcf.2022.10.011

      Highlights

      • Patients carrying CFTR mutations other than F508del were treated with ETI.
      • In eight naïve patients, sweat chloride, FEV1, and exacerbations improved.
      • Patients transitioned from other modulators did not improve further with ETI.

      Abstract

      Background

      In vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations.

      Methods

      We retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI.

      Results

      We included 16 pwCF, including eight without previous use of CFTR modulators. Median time on treatment was 5.3 (range, 1.8-7.7) months. Compared to baseline, in the “naïve” group sweat chloride concentration was reduced from 113.0 (98-129) to 64.0 (32-97) mEq/L (n=7; median (IQR), p=0.018), and rate of pulmonary exacerbations declined from a median of 1.5 (IQR 1, 2.75) in the previous year to 0 (0,0) (p= 0.019) with a significant decline in annualized days with antibiotics (oral + parenteral) per year: 36 (17.5; 42) in the year before to 0 (0,0) (median (IQR), p= 0.027). Mean FEV1% changed from 66.3±25 to 72.4±29 % (mean ± SD, p=0.058). In the group of patients previously treated with Ivacaftor or Tezacaftor/Ivacaftor, we didn't observe significant improvements in any of the parameters.

      Conclusions

      We demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group.

      Graphical abstract

      Keywords

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