Cystic fibrosis (CF) is characterised by repeated pulmonary infections and disordered innate immune-driven inflammation. The relationship between these two key drivers of disease progression remain poorly understood. We and others have recently provided evidence supporting the hypothesis that the NLRP3-inflammasome is a key regulator of inflammation in CF (McElvaney et al., 2019; Peckham et al., 2017; Scambler et al., 2019). We’ve demonstrated that both CF epithelia and monocytes/serum from patients with CF exhibit an enhanced pro-inflammatory signature when compared with healthy controls and patients with non-CF bronchiectasis. We observed CF-specific increases in IL-18, IL-1β, caspase-1 activity, in addition to ASC-speck release, that were all reversed by pre-treatment with epithelial sodium channel (ENaC) and NLRP3-inflammasome inhibitors (Peckham et al., 2017; Scambler et al., 2019). In this paper, we examine the therapeutic potential of controlling inflammation with CFTR modulators. These small molecules are known to correct CFTR dysfunction and partially restore CFTR-mediated ENaC inhibitory activity (Cholon et al., 2014; Pranke et al., 2017).

The NLRP3-inflammasome senses multiple damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Amongst the latter, lipopolysaccharide (LPS) is a major component of the outer membrane of two of the main pathogens found in CF airways, the gram-negative bacteriae such a Pseudomonas aeruginosa (P. aeruginosa) and members of the Burkholderia cepacia complex (B. cenocepacia). It has been reported that the latter organism can trigger the NLRP3-inflammasome and exacerbate the proinflammatory response, both through inflammasome activation and IL-1β/IL-18 processing (Rimessi et al., 2015; Gavrilin et al., 2012; Rosales-Reyes et al., 2012). In this regard, in both murine and human CF, NLRP3 activity contributes to IL-1β-dependent inflammation which can be negatively regulated by anakinra, an IL-1 receptor antagonist (IL-1Ra) (McElvaney et al., 2019; Iannitti et al., 2016). In mice, the NLRP3 inhibitor, MCC950, reduces IL-1β levels in the lungs, decreases airway inflammation and improves airway clearance of P. aeruginosa (McElvaney et al., 2019). Thus, defective CFTR expression and function appears to be driving inflammation, by lowering the threshold of innate immune defences and reducing the ability of myeloid cells, such as neutrophils and macrophages to resolve infection and inflammation (Barnaby et al., 2018; Bonfield et al., 2012). Conditional inactivation of Cftr in myeloid cells of mice resulted in a dysfunctional immune response, with Cftr-lacking mice taking longer to resolve inflammation and to rectify infection, when compared to wild-type (WT) mice (Bonfield et al., 2012). Finally, in young children with CF, inflammation can be detected in bronchoalveolar lavage (BAL) fluid, in the absence of infection, and this process is mainly driven via NLRP3-inflammasome activation (Rosenow et al., 2019; McElvaney et al., 2018).

The introduction of CFTR modulators into clinical practice has resulted in a paradigm shift in therapeutic options, whereby targeting the clinico-pathogenic origin of the defective CFTR rather than the secondary effects of CFTR dysfunction has become a reality (VX17-445-103 Trial Group et al., 2019; VX17-445-102 Study Group et al., 2019; VX08-770-102 Study Group et al., 2011; Taylor-Cousar et al., 2017; TRAFFIC Study Group et al., 2015). These drug regimens were primarily developed to improve cell-surface expression and function of the CFTR anion channel but there are limited data on whether they can directly modulate CF-related inflammation (Barnaby et al., 2018; Hisert et al., 2017). Treatment of primary bronchial epithelial cell cultures (BECs), bearing two Phe508del mutations, with the combination of ivacaftor/lumacaftor (IVA/LUM) depresses CXCL8 transcription, p38 MAPK phosphorylation and reduces serum levels of several proinflammatory cytokines, in response to P. aeruginosa (Barnaby et al., 2018; Ruffin et al., 2018). Treatment with the single agent, ivacaftor, currently approved for patients with gating mutations, such as G551D, has also been reported to reduce sputum levels of neutrophil elastase, IL-8, and IL-1β (VX08-770-102 Study Group et al., 2011; Hisert et al., 2017), and these changes may reflect improved clinical health rather than a direct anti-inflammatory consequence of increased CFTR function.

The aims of our study were firstly, to assess whether CFTR modulators could directly downregulate the increased serum and (innate-immune) cell-derived IL-1β and IL-18 cytokine signature in cells harvested from adults with CF, and secondly, to explore differences in response between drug regimens as a guide to inform future studies.

There is an ongoing debate as to whether correcting the primary ion transport defect, with CFTR modulators alone, can resolve both infection and inflammation, two key components driving CF lung pathology. As a result several novel anti-inflammatory agents are now being developed with the aim of slowing down disease progression (Cystic Fibrosis Foundation, 2020). As recurrent episodes of CF inflammation are the direct result of CFTR dysfunction, it follows that correcting CFTR itself should influence the aberrant changes in innate immunity present in CF, and downregulate the self-propagating inflammatory response (Mesureur et al., 2017).

The present study provides evidence of differential downstream regulation of inflammation, in vivo, following short term administration of IVA/LUM or IVA/TEZ. We observed a direct effect of CFTR modulators in both serum and NLRP3-stimulated PBMCs. Treatment with either IVA/LUM or IVA/TEZ significantly reduced serum and NLRP3-stimulated IL-18levels, TNF secretion and caspase-1 activity. There was also an increase in serum IL-10, which is a potent anti-inflammatory cytokine that downregulates the inflammatory response and ameliorates immunopathology (Asadullah et al., 2003). Only IVA/TEZ significantly reduced serum and NLRP3-stimulated IL-1β secretion and pro-IL-1β, mRNA transcripts. This difference is potentially important, as IL-1β is significantly elevated in CF and has a wide range of biological effects, associated with both infection and inflammation. Similar differences were also seen following the addition of IVA/TEZ drug to monocytes isolated from clinically stable ‘drug-naïve’ CF patients, homozygous for Phe508del.

Both LUM and TEZ exert their clinical effects by increasing the processing and trafficking of mature CFTR protein to the cell surface. When combined with the potentiator, IVA, they partially rectify CFTR function and alter CFTR-ENaC coupling, which results in the inhibition of the elevated amiloride-sensitive sodium transport that is characteristic of CF (Cholon et al., 2014; Pranke et al., 2017). Studies of nasal potential differences and rectal intestinal current measurements (ICM) studies suggest that dual combination therapy rescue Phe508del CFTR, by approximately 10% to 18% of normal, with both drugs having a similar effect on ion transport (Gentzsch and Mall, 2018; Graeber et al., 2018). The disparity in IL-1β secretion was, therefore, surprising and may result from off-target effects, which have been reported with CFTR modulators. For instance, IVA can influence various solute carriers in vitro and reduce the stability of LUM-rescued Phe508del-CFTR (Chin et al., 2018). Clinically, IVA/LUM has also been associated with unexplained increased respiratory adverse events, which can occur relatively acutely after starting treatment. Symptoms include dyspnoea and chest tightness, features which have not been reported with IVA/TEZ (Habib et al., 2019). It might also be the case that pharmacokinetics of LUM and TEZ may differ.

During this study, combination therapy was only available through a Vertex compassionate use program, with treatment inclusion criteria including lung transplant assessment and a ppFEV1 <40%, for at least two months. This is in contrast to reported phase three clinical trials which recruited stable patients with significantly higher lung function. In those studies, treatment over a 24 week period resulted in modest but significant improvements in lung function of around 3%, with reduced pulmonary exacerbations and a decrease in annual rate of ppFEV1 decline vs matched controls (Konstan et al., 2016). Furthermore, in adults with severe obstructive lung disease receiving IVA/LUM, significant improvements in FEV₁ can be absent in the first six months of treatment (Wark et al., 2019). While our study was not designed to investigate clinical efficacy, the absence of significant changes in clinical parameters, during our three month study period, was consistent with stable disease rather than a decline in health, as might be expected in a population with severe lung disease.

The association between CF and increased secretion of both IL-18 and IL-1β, as well as pro-IL-1β mRNA transcripts, may suggest that inhibiting IL-1β alone, with drugs such as anakinra, an IL-1 receptor antagonist, may prove less effective than drugs which target CFTR and, thereby, modify both IL-18 and IL-1β secretion. However baseline IL-1β levels remained elevated and additional targeting of the IL-1 receptor, could significantly enhance clinical effect, especially in patients on IVA/LUM where IL-1β was not significantly downregulated.

The effect of IVA/LUM and IVA/TEZ was lost at 36 hr post-oral therapy, but was regained following re-incubation with the corresponding drugs in vitro. This suggests that the anti-inflammatory properties of CFTR modulators can be prolonged, when drug levels are sustained through in vitro administration, but also highlights the additional effect of CFTR modulators on pro-inflammatory cytokine levels. This finding has potential implications for patients who struggle with compliance, as missing a single dose will influence inflammatory cytokine levels, and may lead to unwanted side-effects as well as influencing the effectiveness of the therapy (Abbott and Bilton, 2015).

From this study, it seems that IL-18 and IL-1β are the most reliable biomarkers to inform drug effectiveness at downregulating inflammation in CF. Although TNF is not elevated in serum or PBMCs from CF relative to HC (Figure 2—figure supplement 2, C), it has been shown by independent research groups, that the CFTR is actively involved in the regulation of TNF, via the NF- κB pathway in lung epithelial cells (Hunter et al., 2010; Vij et al., 2009). For example, transient-transfection of WT CFTR into CFTR-naive H441 lung epithelial cells, dose-dependently down-regulates both the basal and TNF evoked NF-κB activity (Hunter et al., 2010).

Some consideration should also be given to other biomarkers, such as IL-6, which did not change significantly with treatment and to the anti-inflammatory IL-10 cytokine which rose significantly and may help discriminate individual and drug specific responses in future studies.

In summary, systemic inflammation plays a major role in the pathogenesis of CF and, to our knowledge, this pilot study is the first to demonstrate that CFTR modulators have potent innate anti-inflammatory properties, that can be measured in the clinic, both ex vivo and in vitro. Differences in drug effects on regulation of the inflammatory response highlight the importance of optimising biomarkers of inflammation, when assessing their individual treatment efficacy, which can substantially vary between patients. The introduction of newer, and more effective, drug combinations may prove highly efficacious at normalising the inflammatory response in CF, with the prospect of controlling disease progression. We believe our approach creates a template for a candidate cytokine protocol for future evaluation in CF trials of dysregulated inflammation in CF.

All data generated or analysed during this study are included in the manuscript and supporting files.

1. 1. Abbott J
   2. Bilton D

   (2015) Adherence to ivacaftor is suboptimal

   Journal of Cystic Fibrosis 14:547–548.

   https://doi.org/10.1016/j.jcf.2015.08.001

   • PubMed
   • Google Scholar
2. 1. Asadullah K
   2. Sterry W
   3. Volk HD

   (2003) Interleukin-10 therapy--review of a new approach

   Pharmacological Reviews 55:241–269.

   https://doi.org/10.1124/pr.55.2.4

   • PubMed
   • Google Scholar
3. 1. Barnaby R
   2. Koeppen K
   3. Nymon A
   4. Hampton TH
   5. Berwin B
   6. Ashare A
   7. Stanton BA

   (2018) Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa

   American Journal of Physiology-Lung Cellular and Molecular Physiology 314:L432–L438.

   https://doi.org/10.1152/ajplung.00461.2017

   • PubMed
   • Google Scholar
4. 1. Bonfield TL
   2. Hodges CA
   3. Cotton CU
   4. Drumm ML

   (2012) Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection

   Journal of Leukocyte Biology 92:1111–1122.

   https://doi.org/10.1189/jlb.0412188

   • PubMed
   • Google Scholar
5. 1. Chin S
   2. Hung M
   3. Won A
   4. Wu YS
   5. Ahmadi S
   6. Yang D
   7. Elmallah S
   8. Toutah K
   9. Hamilton CM
   10. Young RN
   11. Viirre RD
   12. Yip CM
   13. Bear CE

   (2018) Lipophilicity of the cystic fibrosis drug, ivacaftor (VX-770), and its destabilizing effect on the major CF-causing mutation: f508del

   Molecular Pharmacology 94:917–925.

   https://doi.org/10.1124/mol.118.112177

   • PubMed
   • Google Scholar
6. 1. Cholon DM
   2. Quinney NL
   3. Fulcher ML
   4. Esther CR
   5. Das J
   6. Dokholyan NV
   7. Randell SH
   8. Boucher RC
   9. Gentzsch M

   (2014) Potentiator ivacaftor abrogates pharmacological correction of F508 CFTR in cystic fibrosis

   Science Translational Medicine 6:246ra96.

   https://doi.org/10.1126/scitranslmed.3008680

   • Google Scholar
7. Website

   1. Cystic Fibrosis Foundation

   (2020) Drug development pipeline

   Accessed February 8, 2008.

   https://www.cff.org/Trials/Pipeline
8. 1. Gavrilin MA
   2. Abdelaziz DH
   3. Mostafa M
   4. Abdulrahman BA
   5. Grandhi J
   6. Akhter A
   7. Abu Khweek A
   8. Aubert DF
   9. Valvano MA
   10. Wewers MD
   11. Amer AO

   (2012) Activation of the pyrin inflammasome by intracellular Burkholderia cenocepacia

   The Journal of Immunology 188:3469–3477.

   https://doi.org/10.4049/jimmunol.1102272

   • PubMed
   • Google Scholar
9. 1. Gentzsch M
   2. Mall MA

   (2018) Ion channel modulators in cystic fibrosis

   Chest 154:383–393.

   https://doi.org/10.1016/j.chest.2018.04.036

   • PubMed
   • Google Scholar
10. 1. Graeber SY
    2. Dopfer C
    3. Naehrlich L
    4. Gyulumyan L
    5. Scheuermann H
    6. Hirtz S
    7. Wege S
    8. Mairbäurl H
    9. Dorda M
    10. Hyde R
    11. Bagheri-Hanson A
    12. Rueckes-Nilges C
    13. Fischer S
    14. Mall MA
    15. Tümmler B

    (2018) Effects of Lumacaftor-Ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in Phe508del homozygous patients with cystic fibrosis

    American Journal of Respiratory and Critical Care Medicine 197:1433–1442.

    https://doi.org/10.1164/rccm.201710-1983OC

    • PubMed
    • Google Scholar
11. 1. Habib AR
    2. Kajbafzadeh M
    3. Desai S
    4. Yang CL
    5. Skolnik K
    6. Quon BS

    (2019) A systematic review of the clinical efficacy and safety of CFTR modulators in cystic fibrosis

    Scientific Reports 9:7234.

    https://doi.org/10.1038/s41598-019-43652-2

    • PubMed
    • Google Scholar
12. 1. Hisert KB
    2. Heltshe SL
    3. Pope C
    4. Jorth P
    5. Wu X
    6. Edwards RM
    7. Radey M
    8. Accurso FJ
    9. Wolter DJ
    10. Cooke G
    11. Adam RJ
    12. Carter S
    13. Grogan B
    14. Launspach JL
    15. Donnelly SC
    16. Gallagher CG
    17. Bruce JE
    18. Stoltz DA
    19. Welsh MJ
    20. Hoffman LR
    21. McKone EF
    22. Singh PK

    (2017) Restoring cystic fibrosis transmembrane conductance regulator function reduces airway Bacteria and inflammation in people with cystic fibrosis and chronic lung infections

    American Journal of Respiratory and Critical Care Medicine 195:1617–1628.

    https://doi.org/10.1164/rccm.201609-1954OC

    • PubMed
    • Google Scholar
13. 1. Hunter MJ
    2. Treharne KJ
    3. Winter AK
    4. Cassidy DM
    5. Land S
    6. Mehta A

    (2010) Expression of wild-type CFTR suppresses NF-kappaB-driven inflammatory signalling

    PLOS ONE 5:e11598.

    https://doi.org/10.1371/journal.pone.0011598

    • PubMed
    • Google Scholar
14. 1. Iannitti RG
    2. Napolioni V
    3. Oikonomou V
    4. De Luca A
    5. Galosi C
    6. Pariano M
    7. Massi-Benedetti C
    8. Borghi M
    9. Puccetti M
    10. Lucidi V
    11. Colombo C
    12. Fiscarelli E
    13. Lass-Flörl C
    14. Majo F
    15. Cariani L
    16. Russo M
    17. Porcaro L
    18. Ricciotti G
    19. Ellemunter H
    20. Ratclif L
    21. De Benedictis FM
    22. Talesa VN
    23. Dinarello CA
    24. van de Veerdonk FL
    25. Romani L

    (2016) IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

    Nature Communications 7:10791.

    https://doi.org/10.1038/ncomms10791

    • PubMed
    • Google Scholar
15. 1. Konstan M
    2. McKone E
    3. Moss R
    4. Marigowda G
    5. Cooke J
    6. Lubarsky B

    (2016) Evidence of reduction in annual rate of Fev1 decline and sustained benefits with lumacaftor and ivacaftor (Lum/Iva) in patients (Pts) with cf homozygous for F508del-Cftr

    Pediatric Pulmonology 51:260.

    https://doi.org/10.1002/ppul.23576

    • Google Scholar
16. 1. McElvaney OJ
    2. Gunaratnam C
    3. O'Neill L
    4. Reeves EP
    5. McElvaney G

    (2018) Metabolic reprogramming of the cystic fibrosis neutrophil drives Interleukin-1 beta via the NLRP3 inflammasome

    Pediatric Pulmonology 53:176.

    https://doi.org/10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A6188

    • Google Scholar
17. 1. McElvaney OJ
    2. Zaslona Z
    3. Becker-Flegler K
    4. Palsson-McDermott EM
    5. Boland F
    6. Gunaratnam C
    7. Gulbins E
    8. O'Neill LA
    9. Reeves EP
    10. McElvaney NG

    (2019) Specific inhibition of the NLRP3 inflammasome as an antiinflammatory strategy in cystic fibrosis

    American Journal of Respiratory and Critical Care Medicine 200:1381–1391.

    https://doi.org/10.1164/rccm.201905-1013OC

    • PubMed
    • Google Scholar
18. 1. Mesureur J
    2. Feliciano JR
    3. Wagner N
    4. Gomes MC
    5. Zhang L
    6. Blanco-Gonzalez M
    7. van der Vaart M
    8. O'Callaghan D
    9. Meijer AH
    10. Vergunst AC

    (2017) Macrophages, but not neutrophils, are critical for proliferation of Burkholderia cenocepacia and ensuing host-damaging inflammation

    PLOS Pathogens 13:e1006437.

    https://doi.org/10.1371/journal.ppat.1006437

    • PubMed
    • Google Scholar
19. 1. Peckham D
    2. Scambler T
    3. Savic S
    4. McDermott MF

    (2017) The burgeoning field of innate immune-mediated disease and autoinflammation

    The Journal of Pathology 241:123–139.

    https://doi.org/10.1002/path.4812

    • PubMed
    • Google Scholar
20. 1. Pranke IM
    2. Hatton A
    3. Simonin J
    4. Jais JP
    5. Le Pimpec-Barthes F
    6. Carsin A
    7. Bonnette P
    8. Fayon M
    9. Stremler-Le Bel N
    10. Grenet D
    11. Thumerel M
    12. Mazenq J
    13. Urbach V
    14. Mesbahi M
    15. Girodon-Boulandet E
    16. Hinzpeter A
    17. Edelman A
    18. Sermet-Gaudelus I

    (2017) Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

    Scientific Reports 7:7375.

    https://doi.org/10.1038/s41598-017-07504-1

    • PubMed
    • Google Scholar
21. 1. Rimessi A
    2. Bezzerri V
    3. Patergnani S
    4. Marchi S
    5. Cabrini G
    6. Pinton P

    (2015) Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

    Nature Communications 6:6201.

    https://doi.org/10.1038/ncomms7201

    • PubMed
    • Google Scholar
22. 1. Rosales-Reyes R
    2. Aubert DF
    3. Tolman JS
    4. Amer AO
    5. Valvano MA

    (2012) Burkholderia cenocepacia type VI secretion system mediates escape of type II secreted proteins into the cytoplasm of infected macrophages

    PLOS ONE 7:e41726.

    https://doi.org/10.1371/journal.pone.0041726

    • PubMed
    • Google Scholar
23. 1. Rosenow T
    2. Mok LC
    3. Turkovic L
    4. Berry LJ
    5. Sly PD
    6. Ranganathan S
    7. Tiddens H
    8. Stick SM

    (2019) The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis

    European Respiratory Journal 54:1801771.

    https://doi.org/10.1183/13993003.01771-2018

    • PubMed
    • Google Scholar
24. 1. Ruffin M
    2. Roussel L
    3. Maillé É
    4. Rousseau S
    5. Brochiero E

    (2018) Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells

    American Journal of Physiology-Lung Cellular and Molecular Physiology 314:L635–L641.

    https://doi.org/10.1152/ajplung.00198.2017

    • PubMed
    • Google Scholar
25. 1. Scambler T
    2. Jarosz-Griffiths HH
    3. Lara-Reyna S
    4. Pathak S
    5. Wong C
    6. Holbrook J
    7. Martinon F
    8. Savic S
    9. Peckham D
    10. McDermott MF

    (2019) ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis

    eLife 8:e49248.

    https://doi.org/10.7554/eLife.49248

    • PubMed
    • Google Scholar
26. 1. Taylor-Cousar JL
    2. Munck A
    3. McKone EF
    4. van der Ent CK
    5. Moeller A
    6. Simard C
    7. Wang LT
    8. Ingenito EP
    9. McKee C
    10. Lu Y
    11. Lekstrom-Himes J
    12. Elborn JS

    (2017) Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del

    New England Journal of Medicine 377:2013–2023.

    https://doi.org/10.1056/NEJMoa1709846

    • PubMed
    • Google Scholar
27. 1. TRAFFIC Study Group
    2. TRANSPORT Study Group
    3. Wainwright CE
    4. Elborn JS
    5. Ramsey BW
    6. Marigowda G
    7. Huang X
    8. Cipolli M
    9. Colombo C
    10. Davies JC
    11. De Boeck K
    12. Flume PA
    13. Konstan MW
    14. McColley SA
    15. McCoy K
    16. McKone EF
    17. Munck A
    18. Ratjen F
    19. Rowe SM
    20. Waltz D
    21. Boyle MP

    (2015) Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR

    New England Journal of Medicine 373:220–231.

    https://doi.org/10.1056/NEJMoa1409547

    • PubMed
    • Google Scholar
28. 1. Vij N
    2. Mazur S
    3. Zeitlin PL

    (2009) CFTR is a negative regulator of NFkappaB mediated innate immune response

    PLOS ONE 4:e4664.

    https://doi.org/10.1371/journal.pone.0004664

    • PubMed
    • Google Scholar
29. 1. VX08-770-102 Study Group
    2. Ramsey BW
    3. Davies J
    4. McElvaney NG
    5. Tullis E
    6. Bell SC
    7. Dřevínek P
    8. Griese M
    9. McKone EF
    10. Wainwright CE
    11. Konstan MW
    12. Moss R
    13. Ratjen F
    14. Sermet-Gaudelus I
    15. Rowe SM
    16. Dong Q
    17. Rodriguez S
    18. Yen K
    19. Ordoñez C
    20. Elborn JS

    (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation

    The New England Journal of Medicine 365:1663–1672.

    https://doi.org/10.1056/NEJMoa1105185

    • PubMed
    • Google Scholar
30. 1. VX17-445-102 Study Group
    2. Middleton PG
    3. Mall MA
    4. Dřevínek P
    5. Lands LC
    6. McKone EF
    7. Polineni D
    8. Ramsey BW
    9. Taylor-Cousar JL
    10. Tullis E
    11. Vermeulen F
    12. Marigowda G
    13. McKee CM
    14. Moskowitz SM
    15. Nair N
    16. Savage J
    17. Simard C
    18. Tian S
    19. Waltz D
    20. Xuan F
    21. Rowe SM
    22. Jain R

    (2019) Elexacaftor-Tezacaftor-Ivacaftor for cystic fibrosis with a single Phe508del allele

    New England Journal of Medicine 381:1809–1819.

    https://doi.org/10.1056/NEJMoa1908639

    • PubMed
    • Google Scholar
31. 1. VX17-445-103 Trial Group
    2. Heijerman HGM
    3. McKone EF
    4. Downey DG
    5. Van Braeckel E
    6. Rowe SM
    7. Tullis E
    8. Mall MA
    9. Welter JJ
    10. Ramsey BW
    11. McKee CM
    12. Marigowda G
    13. Moskowitz SM
    14. Waltz D
    15. Sosnay PR
    16. Simard C
    17. Ahluwalia N
    18. Xuan F
    19. Zhang Y
    20. Taylor-Cousar JL
    21. McCoy KS

    (2019) Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

    The Lancet 394:1940–1948.

    https://doi.org/10.1016/S0140-6736(19)32597-8

    • PubMed
    • Google Scholar
32. 1. Wark PAB
    2. Cookson K
    3. Thiruchelvam T
    4. Brannan J
    5. Dorahy DJ

    (2019) Lumacaftor/ Ivacaftor improves exercise tolerance in patients with cystic fibrosis and severe airflow obstruction

    BMC Pulmonary Medicine 19:106.

    https://doi.org/10.1186/s12890-019-0866-y

    • PubMed
    • Google Scholar

Author details

1. Heledd H Jarosz-Griffiths

   1. Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
   2. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Thomas Scambler

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5154-4815

2. Thomas Scambler

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft

   Contributed equally with

   Heledd H Jarosz-Griffiths

   Competing interests

   No competing interests declared

3. Chi H Wong

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2108-1615

4. Samuel Lara-Reyna

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9986-5279

5. Jonathan Holbrook

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

6. Fabio Martinon

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

   Contribution

   Resources, Funding acquisition

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6969-822X

7. Sinisa Savic

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
   3. Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds, United Kingdom

   Contribution

   Supervision, Funding acquisition, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7910-0554

8. Paul Whitaker

   Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

   Contribution

   Resources

   Competing interests

   No competing interests declared

9. Christine Etherington

   Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

   Contribution

   Resources

   Competing interests

   No competing interests declared

10. Giulia Spoletini

    Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

    Contribution

    Resources

    Competing interests

    No competing interests declared

11. Ian Clifton

    Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

    Contribution

    Resources

    Competing interests

    No competing interests declared

12. Anil Mehta

    Division of Medical Sciences, University of Dundee, Dundee, United Kingdom

    Contribution

    Formal analysis, Supervision, Validation, Visualization, Writing - original draft, Writing - review and editing

    Competing interests

    No competing interests declared

13. Michael F McDermott

    1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
    2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

    Contribution

    Conceptualization, Supervision, Funding acquisition, Validation, Visualization, Project administration, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-1015-0745

14. Daniel Peckham

    1. Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
    2. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
    3. Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Project administration, Writing - review and editing

    For correspondence

    D.G.Peckham@leeds.ac.uk

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7723-1868

• 2,552

  views

• 394

  downloads

• 82

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.