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A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators

Stefano Ponzano, Giulia Nigrelli, Laura Fregonese, Irmgard Eichler, Fabio Bertozzi, Tiziano Bandiera, Luis J.V. Galietta, Marisa Papaluca
European Respiratory Review 2018 27: 170124; DOI: 10.1183/16000617.0124-2017
Stefano Ponzano
1European Medicines Agency, London, UK
2D3 PharmaChemistry, Istituto Italiano di Tecnologia, Genova, Italy
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Giulia Nigrelli
1European Medicines Agency, London, UK
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Laura Fregonese
1European Medicines Agency, London, UK
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Irmgard Eichler
1European Medicines Agency, London, UK
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Fabio Bertozzi
2D3 PharmaChemistry, Istituto Italiano di Tecnologia, Genova, Italy
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Tiziano Bandiera
2D3 PharmaChemistry, Istituto Italiano di Tecnologia, Genova, Italy
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Luis J.V. Galietta
3Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
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Marisa Papaluca
1European Medicines Agency, London, UK
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    FIGURE 1

    Classification by type of cystic fibrosis (CF) products that received orphan designation during the period 2001–2016. CFTR: CF transmembrane conductance regulator. 4,4′,6-trimethylangelicin was counted twice in the histogram, being both a CFTR modulator and an anti-inflammatory agent.

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  • TABLE 1

    Classification of gene mutations that cause cystic fibrosis (CF)

    ClassMutation examplesMutation mechanism
    IG542X, W1282XNo functional CFTR protein is synthesised due to the presence of premature termination codons
    IIF508delCFTR protein is synthesised but misfolded, keeping it from reaching the apical cell surface
    IIIG551D, G1349DFull-length CFTR protein reaching the apical cell surface exhibits abnormal gating (channel persists in the closed state)
    IVR117H, R334W, R347PFull-length CFTR protein reaches the apical cell surface but transport of chloride ions is reduced due to channel pore defect
    V2789+5G>A, 3849+10kbC>TReduced number of CFTR transcripts due to promoter or splicing abnormalities
    VI4326delTC, 4279insADefective CFTR stability at the cell surface; C-terminus mutations result in accelerated turnover

    CFTR: CF transmembrane conductance regulator.

    • TABLE 2

      Cystic fibrosis (CF) products that received a marketing authorisation within the centralised procedure until 2016

      Medicinal productActive substanceDate of authorisationMarketing authorisation holderApproved indicationOrphan medicinal product#
      CaystonAztreonam lysineSept 21, 2009Gilead Sciences International Ltd, Cambridge, UKSuppressive therapy of chronic pulmonary infections due to P. aeruginosa in patients with CF aged ≥6 yearsYes
      TOBI PodhalerTobramycinJuly 20, 2011Novartis Europharm Ltd, Camberley, UKSuppressive therapy of chronic pulmonary infection due to P. aeruginosa in adults and children with CF aged ≥6 yearsYes
      ColobreatheColistimethate sodiumFeb 13, 2012Teva BV, Haarlem, The NetherlandsManagement of chronic pulmonary infections due to P. aeruginosa in patients with CF aged ≥6 yearsNo
      BronchitolMannitolApril 13, 2012Pharmaxis Pharmaceuticals Ltd, London, UKTreatment of CF in adults aged ≥18 years as an add-on therapy to best standard of careYes
      KalydecoIvacaftorJuly 23, 2012Vertex Pharmaceuticals (Europe) Ltd, London, UKTreatment of CF in patients aged ≥2 years who have the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R; it is also indicated for the treatment of adult CF patients who have an R117H mutation in the CFTR geneYes
      VantobraTobramycinMarch 18, 2015PARI Pharma GmbH, Starnberg, GermanyManagement of chronic pulmonary infection due to P. aeruginosa in patients with CF aged ≥6 yearsNo
      QuinsairLevofloxacinMarch 26, 2015Chiesi Orphan BV, Schiphol, The NetherlandsManagement of chronic pulmonary infections due to P. aeruginosa in adult patients with CFNo
      OrkambiLumacaftor/ivacaftorNov 19, 2015Vertex Pharmaceuticals (Europe) Ltd, London, UKTreatment of CF in patients aged ≥12 years who are homozygous for the F508del mutation in the CFTR geneNo
      Enzepi¶Pancreas powderJune 29, 2016Allergan Pharmaceuticals International Ltd, Dublin, IrelandPancreatic enzyme replacement treatment in exocrine pancreatic insufficiency due to CF or other conditions (e.g. chronic pancreatitis, post-pancreatectomy or pancreatic cancer); indicated in adults, infants, children and adolescentsNo

      P. aeruginosa: Pseudomonas aeruginosa. #: for more details about the definition of orphan designation, see section “Trends in CF drug development”; ¶: Enzepi was withdrawn from the market in July 2017 for commercial reasons.

      • TABLE 3

        Nonclinical end-points used in different cell lines to demonstrate efficacy of ivacaftor, lumacaftor and orkambi

        Nonclinical end-pointCell mutationIvacaftorLumacaftorOrkambi
        Total ionic current (IT) (FRT cells)G551D✓
        F508del✓✓
        Total ionic current (IT) (HBE cells)F508del✓✓✓
        G551D/F508del✓
        Open probability (PO) (NIH-3T3 cells)G551D✓
        F508del✓✓✓#
        CFTR maturation (FRT cells)F508del✓
        CFTR maturation (HBE cells)F508del✓

        IT: total ionic current; FRT: Fischer rat thyroid; HBE: human bronchial epithelial; PO: open channel probability; CFTR: cystic fibrosis transmembrane conductance regulator. #: type of cells not reported.

        • TABLE 4

          Recovery of cystic fibrosis transmembrane conductance regulator (CFTR) functionality from nonclinical studies, and forced expiratory volume in 1 s (FEV1) and sweat chloride results from clinical trials for ivacaftor, lumacaftor and orkambi

          ProductCFTR mutation in HBE cells in nonclinical studiesRecovery of CFTR functionality compared with wild-type %CFTR mutation in patients for clinical trialsFEV1 % pred changeSweat chloride change mmol·L−1
          IvacaftorHomozygous F508del<10Homozygous F508del1.7¶−2.9+
          G551D/F508del48G551D/x mutation#10.5§−48.1ƒ
          LumacaftorHomozygous F508del14Homozygous F508del0.47##−8.2¶¶
          OrkambiHomozygous F508del25.1Homozygous F508del3.3++−9.5§§

          HBE: human bronchial epithelial. #: patients that have the G551D mutation on at least one allele (the “x” stands for the G551D mutation or any other class I–V mutation [23]); ¶: absolute change in FEV1 % pred from baseline through week 16 between ivacaftor and placebo groups (the observed change was not statistically significant) [60]; +: sweat chloride reduction in the ivacaftor versus placebo groups from baseline through week 16 [60]; §: increase from baseline in FEV1 % pred through week 48 in the ivacaftor group compared with placebo [23]; ƒ: sweat chloride reduction in the ivacaftor versus placebo groups from baseline through week 48 [23]; ##: mean percentage change from baseline in FEV1 % pred at day 28 for a 200 mg dose [61]; ¶¶: mean treatment difference in sweat chloride from baseline (−placebo) at day 28 for a 200 mg dose [61]; ++: treatment difference obtained from the pooled data of two phase 3 pivotal studies for the average absolute change from baseline in FEV1 % pred at week 16 and 24 (dose: lumacaftor 600 mg/ivacaftor 250 mg) [58]; §§: treatment difference in sweat chloride from a phase 2 trial for the lumacaftor 600 mg once daily/ivacaftor 250 mg once every 12 h homozygous group compared with the pooled combination placebo group in the mean absolute change from baseline at day 56 [58].

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          A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators
          Stefano Ponzano, Giulia Nigrelli, Laura Fregonese, Irmgard Eichler, Fabio Bertozzi, Tiziano Bandiera, Luis J.V. Galietta, Marisa Papaluca
          European Respiratory Review Jun 2018, 27 (148) 170124; DOI: 10.1183/16000617.0124-2017

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          A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators
          Stefano Ponzano, Giulia Nigrelli, Laura Fregonese, Irmgard Eichler, Fabio Bertozzi, Tiziano Bandiera, Luis J.V. Galietta, Marisa Papaluca
          European Respiratory Review Jun 2018, 27 (148) 170124; DOI: 10.1183/16000617.0124-2017
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          • Article
            • Abstract
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            • Current therapies for CF
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