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Rationale: Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). Objectives: We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods: SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run-in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY and a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth, and percent predicted forced expiratory volume in 1 second (ppFEV1) at study entry. Results: Forty-three participants discontinued both therapies by the end of SIMPLIFY, and 63 remained on both, with overall average ppFEV1 of 96.7% at study entry and 3.9 months as the average duration of follow-up from beginning of the first trial to completion of the second trial, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued and those who remained on both therapies (difference: 0.22% off-on; 95% confidence interval = −1.60, 2.03). Changes in lung clearance index at 2.5% starting concentration, patient-reported outcomes, and safety outcomes were also comparable. Patient-reported treatment burden, as measured by a Cystic Fibrosis Questionnaire–Revised subscale, significantly decreased in those who discontinued both therapies. Conclusions: SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared with those who remained on both therapies. These data continue to inform a new era of postmodulator care of people with cystic fibrosis. [ABSTRACT FROM AUTHOR]

Background: The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older., Methods: In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV 1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV 1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete., Findings: In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV 1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%])., Interpretation: Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV 1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators., Funding: Vertex Pharmaceuticals., Competing Interests: Declaration of interests TF, PM, PRS, NN, RZ, HM, NA, and AL are employees of Vertex Pharmaceuticals and own stock or stock options in that company. FV reports grants from HIT-CF Project, Research Foundation Flanders Strategic Basic Research, University KU Leuven Internal Funds, Cystic Fibrosis Foundation, and King Baudouin Foundation; a service agreement with Ziphius vaccines; a consulting agreement with Vertex Pharmaceuticals; and financial support from Viatris and Mylan. DP reports grants, consulting fees, and speaker fees from Vertex Pharmaceuticals. RWL reports grants from Vertex Pharmaceuticals and Cystic Fibrosis Foundation, and consulting fees and travel support from Vertex Pharmaceuticals. AT reports support from Vertex Pharmaceuticals and Cystic Fibrosis Foundation, travel support from Cystic Fibrosis Foundation, and is a board member of the local Cystic Fibrosis Foundation chapter. TK reports speaker fees and travel support from Vertex Pharmaceuticals. JM reports grants from Cystic Fibrosis Foundation, 4D Molecular Therapeutics, Boehringer Ingelheim, Clarametyx Biosciences, and Spirovant Pharmaceuticals. ATB reports grants from Vertex Pharmaceuticals and Cystic Fibrosis Foundation. MO reports speaker fees and travel support from Arrowhead Pharmaceuticals, and speaker fees from Vertex Pharmaceuticals. SS reports grants, consulting fees, and speaker fees from Vertex Pharmaceuticals, Boehringer Ingelheim, and Insmed; and grants and speaker fees from AstraZeneca. BR reports grants from the US National Institutes of Health (NIH) and the Cystic Fibrosis Foundation, consulting fees from Vertex Pharmaceuticals, Cystetic Medicines, and Sionna Therapeutics; and participation on a data safety monitoring or advisory board for the NIH. MAM reports grants from the German Research Foundation, German Ministry for Education and Research, German Innovation Fund, Vertex Pharmaceuticals, and Boehringer Ingelheim; consulting fees from AbbVie, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Splisense, and Vertex Pharmaceuticals; speaker fees from Vertex Pharmaceuticals; travel support from Boehringer Ingelheim and Vertex Pharmaceuticals; participation on a data safety monitoring board or advisory board for AbbVie, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari, and Vertex Pharmaceuticals; and is a Fellow of the European Respiratory Society. JLT-C reports grants and consulting fees from Vertex Pharmaceuticals and 4D Molecular Therapeutics; a grant from Eloxx; participation on a data safety monitoring board or advisory board for AbbVie; and serving as the adult patient care representative for the Cystic Fibrosis Foundation Board of Trustees, on the Cystic Fibrosis Foundation Clinical Research Executive Committee, as immediate past Chair of the Cystic Fibrosis TDN's Sexual Health, Reproduction and Gender Research Working Group, as Co-chair of the Health Equity Team Science Awards study section and on the Racial Justice Working Group, on the scientific advisory board for Emily's Entourage, on the American Thoracic Society Respiratory Health Awards and Scientific Grant Review Committees, as Chair-elect of the International Conference Committee, as Associate Editor for the Journal of Cystic Fibrosis, as a member of the International Advisory Board for The Lancet Respiratory Medicine, and on the Clinical Trials Review study section for the NIH. EFM reports grants and speaker fees from Vertex Pharmaceuticals, travel support from Menarini, and participation on a data safety monitoring board or advisory board for Cystic Fibrosis Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, AbbVie, Insmed, and Enterprise Therapeutics. ET reports grants from St Michael's Hospital and consulting fees, speaker fees, and travel support from Vertex Pharmaceuticals. AH reports grants from Cystic Fibrosis Trust, Cystic Fibrosis Foundation, and Vertex Pharmaceuticals; consulting and speaker fees from Vertex Pharmaceuticals; and serves as the Chair of the Cystic Fibrosis Trust Clinical Trials Accelerator Platform and Chair of the National Institute for Health and Care Research (NIHR) Respiratory Translational Research Collaboration. LMY and CK declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same CFTR genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for HFE p.H63D. He also has a very rare PLG p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis., (© 2020 Wilk et al.; Published by Cold Spring Harbor Laboratory Press.)