Correction: Dagenais et al. Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. J. Clin. Med. 2021, 10, 23

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and are generally well-tolerated; however, real-world studies indicate the frequency of discontinuation and adverse events (AEs) may be higher than what was observed in clinical trials. The objectives of this systematic review were to summarize real-world AEs reported for market-available CFTR modulators (i.e., ivacaftor (IVA), lumacaftor/ivacaftor (LUM/IVA), tezacaftor/ivacaftor (TEZ/IVA), and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA)), and to identify ways in which the pharmacist on CF healthcare teams may contribute to mitigating and managing these AEs. The MEDLINE, EMBASE, CINAHL, and Web of Science Core Collection online databases were searched from 2012 to 1 Aug 2020. Full manuscripts or conference abstracts of observational studies, case series, and case reports were eligible for inclusion. The included full manuscripts and conference abstracts comprised of 54 observational studies, 5 case series, and 9 case reports. The types of AEs reported generally aligned with what have been observed in clinical trials. LUM/IVA was associated with a higher frequency of respiratory-related AE and discontinuation in real-world studies. A signal for mental health and neurocognitive AEs was identified with all 4 CFTR modulators. A systematic approach to monitoring for AEs in people with CF on CFTR modulators in the real-world setting is necessary to help better understand potential AEs, as well as patient characteristics that may be associated with higher risk of certain AEs. Pharmacists play a key role in the safe initiation and monitoring of people with CF on CFTR modulator therapies.

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Real-World Outcomes of Ivacaftor Treatment in People with Cystic Fibrosis: A Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm10071527 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1527

Author(s):

Jamie Duckers ◽

Beth Lesher ◽

Teja Thorat ◽

Eleanor Lucas ◽

Lisa J. McGarry ◽

...

Keyword(s):

Systematic Review ◽

Cystic Fibrosis ◽

Real World ◽

Safety Profile ◽

Clinical Trial Data ◽

Patient Characteristics ◽

Healthcare Resource Utilization ◽

Patient Reported ◽

Clinical Benefits

Cystic fibrosis (CF) is a rare, progressive, multi-organ genetic disease. Ivacaftor, a small-molecule CF transmembrane conductance regulator modulator, was the first medication to treat the underlying cause of CF. Since its approval, real-world clinical experience on the use of ivacaftor has been documented in large registries and smaller studies. Here, we systematically review data from real-world observational studies of ivacaftor treatment in people with CF (pwCF). Searches of MEDLINE and Embase identified 368 publications reporting real-world studies that enrolled six or more pwCF treated with ivacaftor published between January 2012 and September 2019. Overall, 75 publications providing data from 57 unique studies met inclusion criteria and were reviewed. Studies reporting within-group change for pwCF treated with ivacaftor consistently showed improvements in lung function, nutritional parameters, and patient-reported respiratory and sino-nasal symptoms. Benefits were evident as early as 1 month following ivacaftor initiation and were sustained over long-term follow-up. Decreases in pulmonary exacerbations, Pseudomonas aeruginosa prevalence, and healthcare resource utilization also were reported for up to 66 months following ivacaftor initiation. In studies comparing ivacaftor treatment to modulator untreated comparator groups, clinical benefits similarly were reported as were decreases in mortality, organ-transplantation, and CF-related complications. The safety profile of ivacaftor observed in these real-world studies was consistent with the well-established safety profile based on clinical trial data. Our systematic review of real-world studies shows ivacaftor treatment in pwCF results in highly consistent and sustained clinical benefit in both pulmonary and non-pulmonary outcomes across various geographies, study designs, patient characteristics, and follow-up durations, confirming and expanding upon evidence from clinical trials.

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Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Breathe ◽

10.1183/20734735.0112-2021 ◽

2021 ◽

Vol 17 (4) ◽

pp. 210112

Author(s):

Daniel H. Tewkesbury ◽

Rebecca C. Robey ◽

Peter J. Barry

Keyword(s):

Cystic Fibrosis ◽

Precision Medicine ◽

Real World ◽

Chloride Ion ◽

Transmembrane Conductance Regulator ◽

Therapeutic Approaches ◽

Transmembrane Conductance ◽

Cftr Protein ◽

Cystic Fibrosis Transmembrane ◽

Cftr Modulators

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

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Effect of CFTR Modulators on Anthropometric Parameters in Individuals with Cystic Fibrosis: An Evidence Analysis Center Systematic Review

Journal of the Academy of Nutrition and Dietetics ◽

10.1016/j.jand.2020.03.014 ◽

2020 ◽

Cited By ~ 1

Author(s):

Julianna Bailey ◽

Mary Rozga ◽

Catherine M. McDonald ◽

Ellen K. Bowser ◽

Kristen Farnham ◽

...

Keyword(s):

Systematic Review ◽

Cystic Fibrosis ◽

Anthropometric Parameters ◽

Evidence Analysis ◽

Analysis Center ◽

Cftr Modulators

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A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis

Scientific Reports ◽

10.1038/s41598-019-43652-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 28

Author(s):

Al-Rahim R. Habib ◽

Majid Kajbafzadeh ◽

Sameer Desai ◽

Connie L. Yang ◽

Kate Skolnik ◽

...

Keyword(s):

Systematic Review ◽

Cystic Fibrosis ◽

Clinical Efficacy ◽

Efficacy And Safety ◽

Cftr Modulators

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PRO8 EFFICACY OF CFTR MODULATORS AGAINST PULMONARY EXACERBATION IN CYSTIC FIBROSIS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

Value in Health ◽

10.1016/j.jval.2019.09.2340 ◽

2019 ◽

Vol 22 ◽

pp. S842

Author(s):

J. Takyar ◽

K. Thapa ◽

A. Jain ◽

A. Sharma

Keyword(s):

Systematic Review ◽

Cystic Fibrosis ◽

Meta Analysis ◽

Pulmonary Exacerbation ◽

Cftr Modulators

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Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

Journal of Personalized Medicine ◽

10.3390/jpm11121376 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1376

Author(s):

Danya Muilwijk ◽

Marlou Bierlaagh ◽

Peter van Mourik ◽

Jasmijn Kraaijkamp ◽

Renske van der Meer ◽

...

Keyword(s):

Cystic Fibrosis ◽

Real World ◽

Target Therapy ◽

Chloride Concentration ◽

Sweat Chloride ◽

Limited Effectiveness ◽

Pulmonary Exacerbations ◽

Cftr Modulators

The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p < 0.001), with sex (males vs. females IRR: 0.36, 95%CI: 0.21–0.63, p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p < 0.001) and was associated with SwCl at baseline (−0.64, 95%CI: −0.90–−0.37, p < 0.001) and with sex (males vs. females 8.32, 95%CI: 1.82–14.82, p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation.

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From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms21165882 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5882 ◽

Cited By ~ 3

Author(s):

Andrea Gramegna ◽

Martina Contarini ◽

Stefano Aliberti ◽

Rosaria Casciaro ◽

Francesco Blasi ◽

...

Keyword(s):

Systematic Review ◽

Cystic Fibrosis ◽

Lung Function ◽

Real Life ◽

Scientific Data ◽

Current Evidence ◽

Symptom Improvement ◽

Efficacy And Safety ◽

Beneficial Effects ◽

Cftr Modulators

Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005–31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies.

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