Figures
- 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.
Tables
- TABLE 1
Classification of gene mutations that cause cystic fibrosis (CF)
Class Mutation examples Mutation mechanism I G542X, W1282X No functional CFTR protein is synthesised due to the presence of premature termination codons II F508del CFTR protein is synthesised but misfolded, keeping it from reaching the apical cell surface III G551D, G1349D Full-length CFTR protein reaching the apical cell surface exhibits abnormal gating (channel persists in the closed state) IV R117H, R334W, R347P Full-length CFTR protein reaches the apical cell surface but transport of chloride ions is reduced due to channel pore defect V 2789+5G>A, 3849+10kbC>T Reduced number of CFTR transcripts due to promoter or splicing abnormalities VI 4326delTC, 4279insA Defective 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 product Active substance Date of authorisation Marketing authorisation holder Approved indication Orphan medicinal product# Cayston Aztreonam lysine Sept 21, 2009 Gilead Sciences International Ltd, Cambridge, UK Suppressive therapy of chronic pulmonary infections due to P. aeruginosa in patients with CF aged ≥6 years Yes TOBI Podhaler Tobramycin July 20, 2011 Novartis Europharm Ltd, Camberley, UK Suppressive therapy of chronic pulmonary infection due to P. aeruginosa in adults and children with CF aged ≥6 years Yes Colobreathe Colistimethate sodium Feb 13, 2012 Teva BV, Haarlem, The Netherlands Management of chronic pulmonary infections due to P. aeruginosa in patients with CF aged ≥6 years No Bronchitol Mannitol April 13, 2012 Pharmaxis Pharmaceuticals Ltd, London, UK Treatment of CF in adults aged ≥18 years as an add-on therapy to best standard of care Yes Kalydeco Ivacaftor July 23, 2012 Vertex Pharmaceuticals (Europe) Ltd, London, UK Treatment 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 gene Yes Vantobra Tobramycin March 18, 2015 PARI Pharma GmbH, Starnberg, Germany Management of chronic pulmonary infection due to P. aeruginosa in patients with CF aged ≥6 years No Quinsair Levofloxacin March 26, 2015 Chiesi Orphan BV, Schiphol, The Netherlands Management of chronic pulmonary infections due to P. aeruginosa in adult patients with CF No Orkambi Lumacaftor/ivacaftor Nov 19, 2015 Vertex Pharmaceuticals (Europe) Ltd, London, UK Treatment of CF in patients aged ≥12 years who are homozygous for the F508del mutation in the CFTR gene No Enzepi¶ Pancreas powder June 29, 2016 Allergan Pharmaceuticals International Ltd, Dublin, Ireland Pancreatic 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 adolescents No 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-point Cell mutation Ivacaftor Lumacaftor Orkambi 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
Product CFTR mutation in HBE cells in nonclinical studies Recovery of CFTR functionality compared with wild-type % CFTR mutation in patients for clinical trials FEV1 % pred change Sweat chloride change mmol·L−1 Ivacaftor Homozygous F508del <10 Homozygous F508del 1.7¶ −2.9+ G551D/F508del 48 G551D/x mutation# 10.5§ −48.1ƒ Lumacaftor Homozygous F508del 14 Homozygous F508del 0.47## −8.2¶¶ Orkambi Homozygous F508del 25.1 Homozygous F508del 3.3++ −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].
Supplementary Material
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Supplementary information ERR-0124-2017_Supplementary_information
