ABCMdb

PMID: 26403534

Brodlie M, Haq IJ, Roberts K, Elborn JS
Targeted therapies to improve CFTR function in cystic fibrosis.
Genome Med. 2015 Sep 24;7(1):101. doi: 10.1186/s13073-015-0223-6., [PubMed]

Sentences

No. Mutations Sentence Comment

29 ABCC7 p.Gly551Asp For example, Gly551Asp, the most common class III mutation, eliminates the ability of ATP to increase the opening rate of CFTR [11]. Login to comment 33 ABCC7 p.Gly551Asp Potentiators increase the function of CFTR channels expressed at the apical surface of epithelial cells; for example, ivacaftor increases the probability of Gly551Asp-CFTR channel opening. Login to comment 36 ABCC7 p.Arg117His Class IV mutations, such as Arg117His, often result in a milder phenotype owing to partial CFTR function. Login to comment 58 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Table 1 Summary of different classes of CFTR mutations Mutation class Nature of defect Functional consequence Example Therapeutic strategy I CFTR protein synthesis Reduced CFTR protein expression Gly542X Production correctors (ataluren) II CFTR protein processing Misfolded CFTR not transported to cell surface Phe508del Corrector plus potentiator (lumacaftor plus ivacaftor, VX-661 plus ivacaftor) III CFTR channel gating Reduced/lack of CFTR channel opening Gly551Asp Potentiator (ivacaftor) IV CFTR channel conductance Misshaped CFTR pore restricts Cl- movement Arg117His Potentiator (ivacaftor) V Reduced CFTR protein production Very low levels of CFTR protein 3849 + 10 kb C ࢐ T No data available VI High CFTR protein turnover at cell surface Functional but unstable CFTR protein at cell surface 120del23 No data available kb kilobases CFTR dysfunction as the underlying defect and potential therapeutic target The relationship between the severity of disease in an individual and sweat chloride concentration as a readout of the level of CFTR function is complex. Login to comment 74 ABCC7 p.Gly551Asp The most frequently occurring class III mutation is Gly551Asp, which accounts for around 5 % of all mutant CFTR alleles in the population [11]. Login to comment 75 ABCC7 p.Gly551Asp Gly551Asp is a missense mutation, in which the amino acid glycine is substituted for aspartate at position 551 in the nucleotide-binding domain-1 of the gene. Login to comment 81 ABCC7 p.Gly551Asp Once expressed at the membrane, Phe508del-CFTR then behaves as a gating (class III) mutation whose function could be potentiated in a similar fashion to Gly551Asp-CFTR [15, 16, 40]. Login to comment 84 ABCC7 p.Gly551Asp Further in vitro evaluation demonstrated that ivacaftor significantly augmented chloride transport and increased ASL height and cilia beat frequency in airway epithelial cells expressing Gly551Asp-CFTR mutation (Fig. 2) [36]. Login to comment 85 ABCC7 p.Gly551Asp This watershed moment in cystic fibrosis therapeutics then led to fast-tracked clinical trials to investigate the efficacy of ivacaftor as an orally bioavailable drug in patients who had at least one Gly551Asp allele. Login to comment 86 ABCC7 p.Gly551Asp Clinical trials of ivacaftor in patients with the Gly551Asp CFTR mutation A phase II double-blinded placebo-controlled trial was performed to determine the safety, efficacy and adverse outcomes of different doses of ivacaftor and to ascertain any clinical improvements with treatment versus placebo (Table 2) [42]. Login to comment 91 ABCC7 p.Gly551Asp Patients aged 18 years or older who had at least one Gly551Asp allele and a predicted FEV1 of at least 40 % were included in the study. Login to comment 96 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The study found a partial improvement in nasal potential difference and significant improvements in sweat Table 2 Summary of clinical studies investigating the efficacy of ivacaftor in patients with cystic fibrosis and the Gly551Asp mutation Study name and reference Accurso et al. 2010 [42] STRIVE: Ramsey et al. 2011 [6] ENVISION: Davies et al. 2013 [43] Davies et al. 2013 [44] Barry et al. 2014 [45] Type of study Phase II RCT Phase III RCT Phase III RCT Phase III RCT Case-control study Number of participants n = 39 n = 161 n = 52 n = 21 n = 56 Ivacaftor: 31; placebo: 8 Ivacaftor: 83; placebo: 78 Ivacaftor: 26; placebo: 22 Ivacaftor: 21; placebo: 35 Duration 28 days 48 weeks 48 weeks 29 days 9 months Inclusion criteria ࣙ18 years ࣙ12 years 6-11 years ࣙ6 years ࣙ18 years ࣙ1 Gly551Asp allele ࣙ1 Gly551Asp allele ࣙ1 Gly551AspP allele ࣙ1 Gly551Asp allele ࣙ1 Gly551Asp allele FEV1 > 40 % FEV1 40-90 % FEV1 40-105 % FEV1 > 90 % FEV1 < 40 % Weight ࣙ15 kg LCI >7.4 and/or actively listed for lung transplant Weight ࣙ15 kg Outcome measure Median change from baseline with 150 mg Treatment effect Treatment effect Treatment effect Changes within treated patients Treated patients versus controls Mean FEV1 (percentage predicted) +8.7 (P = 0.008) 24 weeks: +10.6 (P < 0.001) 24 weeks: +12.5 (P < 0.001) - +4.2 (P = 0.0068) +3.8 versus 0.6 (P = 0.009; median) 48 weeks: +10.5 (P < 0.001) 48 weeks: +10 (P < 0.0006) Sweat chloride levels (mmol/L) -59.5 (P = 0.008) -47.9 (P < 0.001) -54.3 (P < 0.001) - - - CFQ-R score (points) +8.3 (P = 0.06) +8.6 (P < 0.001) +6.1 (P = 0.109) - - - Nasal potential difference (mV) -3.5 (P = 0.02) - - - - - Weight (kg) - +2.7 (P < 0.001) +2.8 (P < 0.001) - +1.8 (P = 0.0058; median) +2.3 versus 0.6 (P = 0.25; median) BMI - - BMI-for-age z-score: 0.45 (P < 0.001) - +1.1 kg/m2 (P = 0.010; median) +0.84 versus 0.2 kg/m2 (P = 0.234; median) Time on intravenous antibiotics (days per year) - - - - -36 (P = 0.0016; median) -36 versus +10 (P = 0.0003; median) Pulmonary exacerbations - 55 % risk reduction No significant difference - - - (0.455 hazard ratio: P = 0.001) LCI - - - -2.16 (P < 0.0001) - - BMI body mass index (the weight in kilograms divided by the square of the height in meters), CFQ-R revised Cystic Fibrosis Questionnaire, FEV1 percentage predicted forced expiratory volume in 1 second for age, sex and height, LCI lung clearance index, RCT randomized controlled trial chloride concentrations in individuals who received ivacaftor. Login to comment 103 ABCC7 p.Gly551Asp Two larger phase III double-blinded randomized controlled trials (RCTs) were then performed to evaluate the efficacy of ivacaftor in patients with the Gly551Asp CFTR mutation (Table 2) [6, 43]. Login to comment 113 ABCC7 p.Gly551Asp This effect was not seen in the ENVISION study, which was not powered to detect such a change; the number of pulmonary Fig. 2 Summary of initial in vitro data on effects of ivacaftor (VX-770) on human bronchial epithelial cells (HBEs) expressing the Gly551Asp CFTR mutation. Login to comment 117 ABCC7 p.Gly551Asp The concentration-response curve for ivacaftor in the presence of FSK is shown for Gly551Asp/Phe508del HBEs isolated from the bronchi of a single individual (filled circles; n = 16) and Phe508del HBEs isolated from the bronchi of the three individuals who responded to ivacaftor (open circles; n = 7-24). Login to comment 121 ABCC7 p.Gly551Asp c Increased ciliary beat frequency (CBF) following treatment with ivacaftor. Mean (&#b1; standard error of the mean; n = 6) CBF for wild-type HBEs (filled bars) or Gly551Asp/Phe508del HBEs (open bars) after a 5-day treatment with DMSO, 30 nM VIP, 10 bc;M ivacaftor, or 30 nM VIP with 10 bc;M ivacaftor. Login to comment 122 ABCC7 p.Gly551Asp Single asterisk indicates significantly different (P < 0.05) from vehicle control in Gly551Asp/Phe508del HBEs; double asterisk indicates significantly different (P < 0.05) from vehicle control and ivacaftor alone. Login to comment 152 ABCC7 p.Gly551Asp In summary, the studies described above have clearly shown that ivacaftor is associated with significant health improvements in patients with the Gly551Asp CFTR mutation, who account for 5 % of people with cystic fibrosis, and have highlighted the beneficial role of this drug as a targeted therapy [46]. Login to comment 153 ABCC7 p.Gly551Asp Clinical trials of ivacaftor in patients with other CFTR mutations Gating mutations other than Gly551Asp account for around 1 % of all CFTR mutations; individually, many of these mutations are rare. Login to comment 154 ABCC7 p.Gly551Asp In addition to Gly551Asp, there is also in vitro evidence that ivacaftor potentiates CFTR function in other class III CFTR mutations [36, 47]. Login to comment 156 ABCC7 p.Arg117His These mutations include the Arg117His CFTR missense mutation that causes mixed conductance (class IV) and gating (class III) abnormalities, which is responsible for around 2 % of CFTR mutations in northern European populations [49]. Login to comment 162 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Non-Gly551Asp CFTR gating mutations The KONNECTION study was a two-part randomized international multicenter study designed to investigate the safety and efficacy of ivacaftor in patients with cystic fibrosis over the age of 6 years with a non-Gly551Asp CFTR gating mutation (Table 3) [51]. Login to comment 167 ABCC7 p.Gly970Arg Subgroup analysis confirmed these findings for individual genotypes, with the exception of patients with the Gly970Arg mutation, in which there was a substantially less pronounced reduction in sweat chloride levels. Login to comment 168 ABCC7 p.Gly551Asp As in the Gly551Asp studies, ivacaftor was generally well tolerated, with similar adverse events in the placebo and treatment groups [51]. Login to comment 169 ABCC7 p.Arg117His ABCC7 p.Arg117His Arg117His CFTR mutation The phenotype associated with the Arg117His mutation is variable, depending on the other CFTR mutation present and the presence of a polypyrimidine variant in the intron 8 acceptor splice site; the mutation is often associated with less severe clinical problems [52]. Login to comment 170 ABCC7 p.Arg117His The KONDUCT study was a phase III randomized controlled 24-week trial of ivacaftor versus placebo in people aged ࣙ6 years with an Arg117His CFTR mutation (Table 3) [53]. Login to comment 171 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His The primary outcome was change in percentage predicted FEV1, with secondary outcomes including changes in BMI, sweat chloride levels and the Table 3 Summary of clinical studies investigating the efficacy of ivacaftor in patients with cystic fibrosis mutations other than Gly551Asp Study name and reference Flume et al. 2012 [54] KONNECTION: De Boeck et al. 2014 [51] KONDUCT: Moss et al. 2015 [53] Type of study Phase II RCT with open label extension Phase III randomized crossover trial with open label extension Phase III RCT Number of participants n = 104 n = 39 n = 69 Ivacaftor 34; placebo 35 Duration 16 weeks (96-week extension) 24 weeks (total) 24 weeks 8 weeks placebo/ivacaftor 8 weeks ivacaftor/placebo 12 weeks ivacaftor Inclusion criteria ࣙ12 years ࣙ6 years ࣙ6 years Phe508del homozygous >1 non-Gly551Asp gating mutation >1 Arg117His mutation FEV1 > 40 % FEV1 > 40 % FEV1 > 40-90 % (>12 years) FEV1 > 40-105 % (6-11 years) Weight >15 kg Outcome measure Treatment effect Treatment effect after 8 weeks Treatment effect Mean FEV1 (percentage predicted) +1.7 (P = 0.15) +10.7 (P < 0.0001) All ages: +2.1 (P = 0.2) >18 years: +5 (P = 0.01) 6-11 years: -6.3 (P = 0.03) Sweat chloride levels (mmol/L) -2.9 (P = 0.04) -49.2 (P < 0.0001) -24 (P < 0.0001) CFQ-R score (points) No significant differences +9.6 (P = 0.0004) +8.4 (P = 0.009) Weight (kg) No significant differences - - BMI No significant differences BMI-for-age z-score 0.28 (P = 0.001) - BMI body mass index (the weight in kilograms divided by the square of the height in meters), CFQ-R revised Cystic Fibrosis Questionnaire, FEV1 percentage predicted forced expiratory volume in 1 second for age, sex and height, RCT randomized controlled trial respiratory domain of CFQ-R, as well as safety. Login to comment 181 ABCC7 p.Arg117His Overall, these results suggest a potential benefit of ivacaftor in patients with the Arg117His CFTR mutation and more advanced lung disease. Login to comment 190 ABCC7 p.Gly551Asp Clinical use of ivacaftor in the post-approval setting Ivacaftor was designated as an orphan medicine by the European Union in 2008, and since 2012 has been commissioned for use in the United Kingdom in patients aged 6 years or older with at least one Gly551Asp allele. Login to comment 193 ABCC7 p.Gly551Asp Although such mutations are individually rare, in 2014 the European Union granted approval to ivacaftor for the treatment of people with one of eight other non-Gly551Asp gating CFTR mutations. Login to comment 194 ABCC7 p.Arg117His In December 2014 the US FDA also approved the use of ivacaftor in patients with the Arg117His CFTR mutation. Login to comment 265 ABCC7 p.Gly551Asp The Table 5 Summary of clinical studies investigating the efficacy of lumacaftor and ivacaftor in patients with Phe508del mutations Study name and reference Boyle et al. 2014 [70] TRAFFIC and TRANSPORT: Wainwright et al. 2015 [8] Type of study Phase II RCT Phase III RCT Number of participants and study design Cohort 1: Cohort 1: 64 homozygotes n = 368 Lumacaftor 200 mg/day for 14 days Lumacaftor 600 mg/day plus ivacaftor 250 mg every 12 h Followed by: Cohort 2: Ivacaftor 150 mg/250 mg every 12 h for 7 days n = 369 OR Lumacaftor 400 mg every 12 h plus ivacaftor 250 mg every 12 h Placebo for 21 days Cohort 3: Cohorts 2 and 3: n = 371 96 homozygotes Placabo plus placebo 28 compound heterozygotes Cohort 2: Lumacaftor 200 mg, 400 mg, 600 mg/day for 56 days Cohort 3: Lumacaftor 400 mg every 12 h for 56 days Followed by: Ivacaftor 250 mg every 12 h after 28 days OR Placebo for 56 days Duration Cohort 1: 21 days 24 weeks Cohorts 2 and 3: 56 days Inclusion criteria ࣙ18 years ࣙ12 years >1 Phe508del allele Phe508del homozygous FEV1 > 40 % FEV1 40-90 % Outcome measure Treatment effect Pooled analysis of treatment effect in TRAFFIC and TRANSORT Mean FEV1 (percentage predicted) Cohort 2 with lumacaftor 600 mg/day: +5.6 (P = 0.013) Cohort 1: +3.3 (P < 0.001) Cohort 3: no significant differences Cohort 2: +2.8 (P < 0.001) Sweat chloride levels (mmol/L) Cohort 1 with 250 mg ivacaftor: -9.1 mmol/L (P < 0.001)Cohorts 2 and 3: no significant differences - CFQ-R score (points) - Cohort 1: 3.1 (P = 0.007) Cohort 2: 2.2 (P = 0.05) BMI - Cohort 1: 0.28 (P < 0.001) Table 5 Summary of clinical studies investigating the efficacy of lumacaftor and ivacaftor in patients with Phe508del mutations (Continued) Cohort 2: 0.24 (P < 0.001) Pulmonary exacerbations - Cohort 1: rate ratio 0.7 (P = 0.001) Cohort 2: rate ratio 0.61 (P < 0.001) BMI body mass index (the weight in kilograms divided by the square of the height in meters), CFQ-R revised Cystic Fibrosis Questionnaire, FEV1 percentage predicted forced expiratory volume in 1 second for age, sex and height, RCT randomized controlled trial magnitude of improvement in FEV1 was less substantial in these studies than in the large Gly551Asp ivacaftor trial, but is comparable to the improvements demonstrated with other interventions in cystic fibrosis [6, 25, 71]. Login to comment 269 ABCC7 p.Gly551Asp In vitro, VX-661 has been reported to improve trafficking and processing of Phe508del-CFTR and to have an additive effect when administered with ivacaftor on chloride transport compared with ivacaftor alone in cells heterozygous for Phe508del/Gly551Asp CFTR mutations [75]. Login to comment 270 ABCC7 p.Gly551Asp The preliminary results of a complex phase II study investigating the safety and tolerability of VX-661 monotherapy and in combination with ivacaftor in patients who are homozygous for Phe508del and heterozygous for Phe508del/Gly551Asp CFTR mutations were presented at the 2014 North American Cystic Fibrosis Conference [75]. Login to comment 274 ABCC7 p.Gly551Asp In Phe508del/Gly551Asp heterozygote participants, combination treatment was associated with non-statistically significant numerical decreases in sweat chloride levels, along with a statistically significant increase in FEV1 (+4.6 percentage points, P = 0.012). Login to comment 284 ABCC7 p.Gly551Asp There may also be the potential to use combination therapy in patients who are heterozygous for Phe508del/ Gly551Asp CFTR mutations to build further on the benefits associated with ivacaftor monotherapy. Login to comment 285 ABCC7 p.Gly551Asp Impact of targeted therapies on care The introduction of ivacaftor as a mutation-specific treatment that addresses the fundamental defect in people with the Gly551Asp mutation has been hugely exciting for patients with cystic fibrosis and clinicians alike. Login to comment