Table 5. Main features of the narrative and systematic reviews accepted for the review.

A total of two narrative reviews and four systematic reviews were included in this review. The details of the included studies are summarized in this table.

Not reported (NR); Cystic fibrosis (CF); Phenylalanine 508 deletion mutation and an unknown genotype (Phe508del/unknown genotype); Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA); Phenylalanine 508 deletion mutation and a minimal function CFTR mutation (Phe508del/MF); Homozygous for phenylalanine 508 deletion mutation (Phe508del/Phe508del); Forced expiratory volume in one second (FEV1); Cystic fibrosis transmembrane conductance regulator (CFTR); Chloride channel agonist currently only used in clinical trials (VX-659); Elexacaftor (VX-445); Phenylalanine 508 deletion mutation-cystic fibrosis transmembrane conductance regulator (Phe508del-CFTR); Percent predicted forced expiratory volume in one second (ppFEV1); Phenylalanine 508 gene mutation (Phe508); Ivacaftor (IVA); Lumacaftor/Ivacaftor (LUM/IVA); Tezacaftor/Ivacaftor (TEZ/IVA).

First Author, Year	Study Type	Inclusion Criteria	Key points
Tewkesbury, 2021 [4]	Narrative Review	NR	Modulator therapies are likely to improve the course of the CF disease and its management
Marika, 2021 [8]		CF patients with Phe508del/unknown genotype	Treatment of ex vivo models of nasal epithelial cells with ELZ/TEZ/IVA showed excellent responsiveness
Jennifer, 2019 [2]	Systematic Review	Patients aged 12 and above with genotype Phe508del/MF or Phe508del/Phe508del, stable CF disease, and FEV1 % between 40 and 90	Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR function in vitro and have shown improvements in phase 2 studies in patients with CF with one or two Phe508del-CFTR alleles.
Andrea, 2020 [11]		Patients aged six years and above, phase 2 and phase 3 trials published from 2005 to 2020	Most studies assessed ppFEV1, safety, and tolerability of ELX/TEZ/IVA as their primary outcome, and all showed clinical improvement
Anielo, 2021 [12]		NR	CFTR modulators have been shown to change the clinical course of the CF in patients heterozygous for Phe508, especially if started at a young age
Dagenais, 2021 [13]		Full manuscripts or conference abstracts of observational studies, case series, and case reports from 2012 to 2020, participants that had a diagnosis of CF that received at least one dose of a CFTR modulator (i.e., IVA, LUM/IVA, TEZ/IVA, or ELX/TEZ/IVA) in the real-world setting, and reported adverse events that occurred while participants were receiving the CFTR modulator.	The types of adverse events reported generally aligned with what has been observed in clinical trials. It is necessary to monitor these effects in people with CF on CFTR modulators in the real-world setting to help better understand potential adverse events and patient characteristics that may be associated with a higher risk of specific adverse events.