SIMPLIFYing cystic fibrosis treatment in a post-modulator era.

Abstract

The introduction of CFTR modulators, which are oral drugs that improve the function of the CFTR protein, has changed the treatment paradigm in cystic fibrosis from one that has been limited to treating the downstream consequences of CFTR dysfunction to one that, hopefully, prevents those complications from developing. The benefits of CFTR modulators in improving lung function, pulmonary exacerbations, nutrition, quality of life, and sweat chloride have been established in clinical trials for children aged 6 years or older, with studies in children aged 2–5 years underway. 1 Middleton PG Mall MA Dřevínek P et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019; 381: 1809-1819 Crossref PubMed Scopus (699) Google Scholar , 2 Zemanick ET Taylor-Cousar JL Davies J et al. A Phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis and at least one F508del allele. Am J Respir Crit Care Med. 2021; 203: 1522-1532 Crossref PubMed Scopus (61) Google Scholar The first modulator (ivacaftor) was only effective for patients with gating mutations; however, with the advent of effective triple therapy (elexacaftor plus tezacaftor plus ivacaftor [ETI]) for patients who are heterozygous for the most common genetic variant (F508del), more than 90% of patients are expected to benefit from CFTR modulators. 3 Bell SC Mall MA Gutierrez H et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020; 8: 65-124 Summary Full Text Full Text PDF PubMed Scopus (345) Google Scholar Many challenges, including timely diagnosis (particularly in low-income and middle-income countries), equitable access to these high-cost medications, and the absence of modulators for patients with less common genetic variants, cannot be disputed. However, highly effective CFTR modulators are arguably the biggest event in cystic fibrosis treatment since the introduction of pancreatic enzymes in the 1950s. 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 trialsIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment. Full-Text PDF