Reducing treatment burden in the era of CFTR modulators - Authors' reply.

Paul D Robinson and colleagues correctly point out that the non-inferiority of discontinuing hypertonic saline or dornase alfa was observed over a short period of time in the healthy SIMPLIFY cohort.1Mayer-Hamblett N Ratjen F Russell R et al.Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials.Lancet Respir Med. 2023; 11: 329-340Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar They highlight a minority of individuals who had more than 5% reduction in percent predicted FEV1 (ppFEV1) after discontinuing hypertonic saline (appendix pp 21–22) or dornase alfa (appendix pp 23–24). However, ppFEV1 was within 5% of baseline values in more than 80% of participants and even increased by more than 5% in some cases, irrespective of which group they were randomly assigned to. Adverse events were carefully collected and were distinctly uncommon in SIMPLIFY, but this might not predict what would occur over longer periods of time or in people with cystic fibrosis with more severe lung disease. Should greater clinical stability be expected from elexacaftor plus tezacaftor plus ivacaftor (ETI) than ivacaftor alone? Our colleagues cite several studies suggesting that the benefits of ivacaftor diminish over time, particularly in those with more advanced lung disease at initiation. Notwithstanding the effects of the COVID-19 pandemic on pulmonary exacerbation detection and reporting in cystic fibrosis, large post-approval studies of ETI identified rapid and durable improvements in lung function and substantially lowered pulmonary exacerbation rates.2Griese M Costa S Linnemann RW et al.Safety and efficacy of elexacaftor/tezacaftor/ivacaftor for 24 weeks or longer in people with cystic fibrosis and one or more F508del alleles: interim results of an open-label phase 3 clinical trial.Am J Respir Crit Care Med. 2021; 203: 381-385Crossref PubMed Scopus (76) Google Scholar, 3Nichols DP Paynter AC Heltshe SL et al.Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a clinical trial.Am J Respir Crit Care Med. 2022; 205: 529-539Crossref PubMed Scopus (68) Google Scholar, 4Bower JK Volkova N Ahluwalia N et al.Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: interim results of a long-term registry-based study.J Cyst Fibros. 2023; (published online March 22.)https://doi.org/10.1016/j.jcf.2023.03.002Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar Improvements in airway microbiology after starting ETI are broad without evidence of rebounding infection to date.5Nichols DP Morgan SJ Skalland M et al.Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist.J Clin Invest. 2023; 133e167957Crossref PubMed Scopus (1) Google Scholar Most convincingly, mean sweat chloride concentration among those who were heterozygous for F508del and switched from ivacaftor to ETI declined from the indeterminate to healthy range.3Nichols DP Paynter AC Heltshe SL et al.Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a clinical trial.Am J Respir Crit Care Med. 2022; 205: 529-539Crossref PubMed Scopus (68) Google Scholar SIMPLIFY was conducted to begin understanding the role of therapies directed at manifestations of CFTR impairment in those who might have improved CFTR function through drug therapy. More work is needed to address these questions, and we share our colleagues concerns that early findings, although encouraging, are inadequate to inform care decisions in many cases. Shared decision making will balance potential benefits, risks, and uncertainties.6Cameron RA Office D Matthews J et al.Treatment preference among people with cystic fibrosis: the importance of reducing treatment burden.Chest. 2022; 162: 1241-1254Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar We look forward to findings from other studies, some of which are already ongoing. AHG reports grants and contracts from the Cystic Fibrosis Foundation, Insmed, AbbVie, and 4D Molecular Therapeutics. NM-H reports grants from the Cystic Fibrosis Foundation, National Institutes for Health, and US Food and Drug Administration; consulting fees from Enterprise Therapeutics; and Data and Safety Monitoring Board membership for the National Institutes for Health. DPN reports grants from the Cystic Fibrosis Foundation and National Institutes for Health; consulting fees from BiomX, Clarametyx, Genentech, GlaxoSmithKline, Nabriva, Respirion, and Vertex Pharmaceuticals; and advisory board membership for the Cystic Fibrosis Foundation and Kither Biotechnology. Reducing treatment burden in the era of CFTR modulatorsWe read with interest the findings of Nicole Mayer-Hamblett and colleagues,1 which provide important initial evidence to inform the reduction of treatment burden in people using CFTR modulators. In people with cystic fibrosis with essentially normal or mild lung disease (mean percent predicted FEV1 [ppFEV1] 96·9%; 92·9% with ppFEV1 values of ≥70%; and 67·1% with ppFEV1 values of ≥90%) established on treatment with elexacaftor plus tezacaftor plus ivacaftor (ETI), the discontinuation of hypertonic saline (at a concentration of ≥3%) or dornase alfa was non-inferior to continuing treatment with regards to absolute change in ppFEV1 (or lung clearance index at 2·5% of the starting end-tidal concentration [LCI2·5] in the subgroup performing multiple breath washout). Full-Text PDF