ABCMdb

PMID: 25083129

Pettit RS, Fellner C
CFTR Modulators for the Treatment of Cystic Fibrosis.
P T. 2014 Jul;39(7):500-11., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC7 p.Gly551Asp Class II includes the most common mutation, which involves a deletion that codes for phenylalanine at position 508 in the CFTR protein; hence, this defect is known as F508del.12 In class III mutations (e.g., G551D), which affect about 4% of CF patients,13,15 full-length CFTR proteins reach the cell surface but exhibit abnormal channel "gating," meaning they do not open (gate) properly to allow a normal flow of chloride into and out of the cells.15 Alternatively, in class IV mutations a normal amount of CFTR reaches the epithelial membrane but has reduced chloride conductance. Login to comment 11 ABCC7 p.Gly542* Table 1 Classification of Gene Mutations That Cause Cystic Fibrosis1,12,14 Class Exemplar Mutation Description I G542X Presence of premature termination codons (PTCs) causes CFTR protein synthesis to be defective or absent. Login to comment 13 ABCC7 p.Gly551Asp ABCC7 p.Arg334Trp III G551D Disordered regulation: Full-length CFTR proteins reach apical cell surface but are not activated by ATP or cAMP; proteins exhibit abnormal chloride-channel "gating" (i.e., open time is reduced) IV R334W Impaired function: Full-length CFTR proteins reach apical cell surface, but transport of chloride ions is reduced. Login to comment 14 ABCC7 p.Arg117His V R117H Synthesis and surface expression of normal CFTR proteins are reduced because of promoter or splicing abnormalities. Login to comment 25 ABCC7 p.Gly551Asp A clinically significant change in the CFQ-R score is defined as a change of 4 points.15 IVACAFTOR On January 31, 2012, the FDA approved ivacaftor (Kalydeco, Vertex Pharmaceuticals), a CFTR potentiator, for the treatment of CF patients 6 years of age and older with the G551D mutation, which represents about 4% of patients with CF.13,26 As a CFTR potentiator, ivacaftor increases the time the CFTR channel is open, allowing chloride ions to flow through the CFTR proteins on the surface of epithelial cells.27,28 Ivacaftor is the first CFTR Modulators for the Treatment of Cystic Fibrosis FDA-approved treatment to target the basic defect in CF. Login to comment 26 ABCC7 p.Gly551Asp The approved dosage of ivacaftor is one 150-mg tablet taken orally every 12 hours (total daily dose, 300 mg) with fat-containing foods.27 Clinical Efficacy Data Ivacaftor (25, 75, 150, and 250 mg twice daily) was initially studied against placebo in 39 adult patients with CF who had at least one copy of G551D. Login to comment 36 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Ser1251Asn ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn ABCC7 p.Gly970Arg ABCC7 p.Gly178Arg At 48 weeks, 67% of patients in the ivacaftor group had not had a pulmonary exacerbation compared with 41% in the Table 2 Ivacaftor Clinical Trials Reference Design CFTR Mutation Population Treatment Duration Results Ramsey(2011)30 STRIVE: Randomized, double-blind, placebo-controlled G551D Age 12-53 years N = 161 FEV1 40-90% IVA 150 mg b.i.d. or PBO b.i.d. 48 wks ߦ Percent change in FEV1 from baseline to 24 wks (P < 0.001): IVA, 10.4%; PBO, -0.2% ߦ Percent change in FEV1 from baseline to 48 wks compared with PBO (P < 0.001): IVA, 10.5% ߦ Percent of patients pulmonary exacerbation-free at 48 wks: IVA, 67%; PBO, 41% ߦ Change in body weight from baseline to 48 wks: IVA, 3.1 kg; PBO, 0.4 kg ߦ Sweat chloride change from baseline to 48 wks compared with PBO (P < 0.001): IVA, -48.1 mmol/L ߦ Change in CFQ-R respiratory domain from baseline to 48 wks (P < 0.001): IVA, 5.9 pts; PBO, -2.7 pts Davies (2013)29 ENVISION: Randomized, double-blind, placebo-controlled G551D Age 6-11 years N = 52 FEV1 40-105% IVA 150 mg b.i.d. or PBO b.i.d. 48 wks ߦ Absolute change in FEV1 percentage from baseline at 48 wks compared with PBO (P < 0.001): IVA, 10% ߦ Absolute change in FEV1 percentage from baseline at 24 wks (P < 0.001): IVA, 12.6%; PBO, 0.1% ߦ Mean change in sweat chloride from baseline to 48 wks compared with PBO (P < 0.001): IVA, -54.3 mmol/L ߦ Body weight change from baseline to 48 wks compared with PBO (P < 0.001): IVA, 2.8 kg ߦ Absolute CFQ-R change from baseline to 24 wks compared with PBO (P = 0.109): IVA, 6.1 pts McKone (2013)31 PERSIST: Open-label extension G551D Age ࣙ 6 years Patients had completed 48 wks of either ENVISION or STRIVE IVA 150 mg b.i.d. 96 wks (patients received 96 wks or 144 wks of IVA depending on ENVISION or STRIVE randomization) ߦ Absolute change in percent predicted FEV1: &#b0; &#b0; STRIVE (IVA ࢐ IVA) Study start (48 wks of prior treatment): 9.4 &#b1; 8.3 &#b0; &#b0; STRIVE (IVA ࢐ IVA) 144 wks: 9.4 &#b1; 10.8 &#b0; &#b0; STRIVE (PBO ࢐ IVA) Study start: -1.2 &#b1; 7.8 &#b0; &#b0; STRIVE (PBO ࢐ IVA) 96 wks: 9.5 &#b1; 11.2 &#b0; &#b0; ENVISION (IVA ࢐ IVA) Study start (48 wks of prior treatment): 10.2 &#b1; 15.7 &#b0; &#b0; ENVISION (IVA ࢐ IVA) 144 wks: 10.3 &#b1; 12.4 &#b0; &#b0; ENVISION (PBO ࢐ IVA) Study start: -0.6 &#b1; 10.1 &#b0; &#b0; ENVISION (PBO ࢐ IVA) 96 wks: 10.5 &#b1; 11.5 ߦ Absolute change in weight (kg): &#b0; &#b0; STRIVE (IVA ࢐ IVA) Study start (48 wks of prior treatment): 3.4 &#b1; 4.9 &#b0; &#b0; STRIVE (IVA ࢐ IVA) 144 wks: 4.1 &#b1; 7.1 &#b0; &#b0; STRIVE (PBO ࢐ IVA) Study start: 0.3 &#b1; 2.2 &#b0; &#b0; STRIVE (PBO ࢐ IVA) 96 wks: 3 &#b1; 4.2 &#b0; &#b0; ENVISION (IVA ࢐ IVA) Study start (48 wks of prior treatment): 6.1 &#b1; 2.9 &#b0; &#b0; ENVISION (IVA ࢐ IVA) 144 wks: 14.8 &#b1; 5.7 &#b0; &#b0; ENVISION (PBO ࢐ IVA) Study start: 2.9 &#b1; 1.8 &#b0; &#b0; ENVISION (PBO ࢐ IVA) 96 wks: 10.1 &#b1; 4.1 ߦ Absolute change in CFQ-R respiratory domain: &#b0; &#b0; STRIVE (IVA ࢐ IVA) Study start (48 wks of prior treatment): 6.4 &#b1; 16.8 &#b0; &#b0; STRIVE (IVA ࢐ IVA) 144 wks: 6.8 &#b1; 19.6 &#b0; &#b0; STRIVE (PBO ࢐ IVA) Study start: -3.6 &#b1; 14.1 &#b0; &#b0; STRIVE (PBO ࢐ IVA) 96 wks: 9.8 &#b1; 16.2 &#b0; &#b0; ENVISION (IVA ࢐ IVA) Study start (48 wks of prior treatment): 7.4 &#b1; 17.4 &#b0; &#b0; ENVISION (IVA ࢐ IVA) 144 wks: 10.6 &#b1; 18.9 &#b0; &#b0; ENVISION (PBO ࢐ IVA) Study start: 0.8 &#b1; 18.4 &#b0; &#b0; ENVISION (PBO ࢐ IVA) 96 wks: 10.8 &#b1; 12.8 CFTR Modulators for the Treatment of Cystic Fibrosis Table 2 Ivacaftor Clinical Trials Reference Design CFTR Mutation Population Treatment Duration Results Davies (2013)32 Placebo-controlled, double-blind, crossover study G551D Age > 6 years N = 17 FEV1 > 90% LCI > 7.4 Sequence 1: PBO ࢐ WO ࢐ IVA 150 mg b.i.d. Sequence 2: IVA 150 mg b.i.d. ࢐ WO ࢐ PBO 28-day treatment and WO periods ߦ Average change in LCI from baseline compared with PBO (P < 0.0001): IVA, -2.16 (95% CI, -2.88 to -1.44) ߦ Average change in FEV1 from baseline compared with PBO (P = 0.0103): IVA, 8.67 (95% CI, 2.36 to 14.97) ߦ Average change in FEF25-75 from baseline compared with PBO (P = 0.0237): IVA, 16.56 (95% CI, 2.30 to 27.71) Barry (2013)34 Retrospective review G551D Age 20-31 in IVA group N = 21 FEV1 < 40% IVA 150 mg b.i.d. (n = 21); matched controls (n = 35) Median duration, 237 days ߦ Absolute FEV1 change from baseline (P = 0.0075): IVA, 0.125 L; CON, 0.01 L ߦ Percent predicted FEV1 change from baseline (P = 0.0092): IVA, 12.7%, CON, 2.2% ߦ Median weight increase from baseline: IVA, 1.8 kg; CON, 0.1 kg ߦ Median inpatient days per year decreased from 23 days to 0 days in the IVA group (P = 0.001) ߦ Median total intravenous antibiotic days per year decreased from 74 days to 38 days in the IVA group (P = 0.002) De Boeck (2013)37 KONNECTION: Randomized, double-blind, crossover, placebo-controlled Non-G551D gating mutations G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, G1349D Age ࣙ 6 years N = 39 FEV1 ࣙ 40% Treatment sequence 1: IVA 150 mg b.i.d. ࢐ WO ࢐ PBO ࢐ open-label Treatment sequence 2: PBO ࢐ WO ࢐ IVA 150 mg b.i.d. ࢐ open-label 8 wks of IVA or PBO; 4-8 wks WO period; 16 wks open label ߦ Absolute change from baseline percent predicted FEV1 (P < 0.0001): IVA, 7.49%; PBO, -3.19% ߦ Absolute change from baseline BMI (P < 0.0001): IVA, 0.68; PBO, 0.02 ߦ Absolute change from baseline in CFQ-R respiratory domain (P = 0.0004): IVA, 8.94 pts; PBO, -0.67 pts ߦ Absolute change from baseline in sweat chloride (mmol/L): IVA, -52.28; PBO, -3.11 Flume (2011)35 Randomized, double-blind, placebo-controlled, parallel group with open-label extension Homozygous F508del Age ࣙ 12 years Part 1: N = 140 Part 2: N = 33 42 patients were eligible for part 2 if change in FEV1 ࣙ 10% or sweat chloride decreased by at least 15 mmol/L at day 15 and week 8 Part 1: IVA 150 mg b.i.d. or PBO 16 wks Part 2: Open label IVA 150 mg b.i.d. Login to comment 53 ABCC7 p.Arg117His A phase 3 trial of ivacaftor monotherapy in CF patients with R117H showed a nonsignificant 2.1% increase in the mean absolute change from baseline in percent predicted FEV1 (P = 0.2).36 A subgroup analysis of patients at least 18 years old found a statistically significant 5% difference in the mean absolute change from baseline in percent predicted FEV1 (P = 0.01). Login to comment 54 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Although ivacaftor did not meet its primary endpoint in patients with R117H, Vertex planned to discuss the finding with the FDA to determine future direction.36 Ivacaftor has shown efficacy in patients with a G551D mutation, one of the class III "gating" mutations, and initially received FDA approval for patients with this mutation. Login to comment 55 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Ivacaftor use in non-G551D gating mutations was studied in patients older than 6 years of age in a randomized, placebo-controlled crossover study (Table 2).37 This study showed an absolute percent change in FEV1 of 10.68% at eight weeks (P < 0.0001).37 There was a significant increase in body mass index (P < 0.0001) and CFQ-R scores (P = 0.0004), with a decrease in sweat chloride similar to the trials in G551D patients (P < 0.0001). Login to comment 56 ABCC7 p.Gly551Asp ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Ser1251Asn ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn ABCC7 p.Gly178Arg These promising results led to an FDA label expansion to include CF patients with the following eight mutations in addition to G551D: G178R, S549R, S549N, G551S, G1244E, S1251N, S1255P, and G1349D.38 Clinical Considerations Ivacaftor was well tolerated in clinical trials. Login to comment 70 ABCC7 p.Gly551Asp In the phase 2 study, the benefit of ivacaftor therapy diminished shortly after therapy was withdrawn.15 A recent paper suggests that missing even a single dose of ivacaftor can decrease the medication`s effect on sweat chloride.41 Ivacaftor, the first drug in its class of CFTR potentiators, is an expensive medication with a yearly average wholesale price of $373,800.42 Patient assistance is available for those who qualify.43 Ivacaftor represents an important breakthrough in CF management, and has provided benefit for patients with CF who have a G551D mutation. Login to comment 74 ABCC7 p.Gly551Asp Studies of ivacaftor in patients ages 2 to 5 with a G551D or a CFTR gating mutation are ongoing. Login to comment 75 ABCC7 p.Gly551Asp These studies are evaluating dosing of 50 mg twice a day in patients who weigh less than 14 kg and 75 mg twice a day in patients who weigh 14 kg or more.46 Ivacaftor has successfully improved lung function and weight in patients with G551D and may soon benefit patients with other gating mutations and those younger than 6 years of age. Login to comment 147 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp 4PBA In vitro, sodium 4-phenylbutarate (4PBA), a short-chain fatty acid, restored chloride transport in CF epithelial cells containing the F508del mutation, although the compound`s mechanism of action was unclear.69 In a subsequent clinical study of 18 CF patients with the F508del mutation, oral 4PBA only partially restored CFTR activity in the nasal epithelium and had no effect on sweat chloride concentrations.70 Another study showed, however, that treatment with 20 mg of oral 4PBA could induce significant chloride transport in nasal epithelia compared with placebo in 19 adult CF patients with the F508del mutation.71 Additional evidence suggests that the combination of oral 4PBA with topical or aerosol flavonoids may restore CFTR function in CF airways.72,73 VRT-532 The pyrazole VRT-532 was found to be a CFTR potentiator in proteins bearing the F508del mutation in human CF airway cultures.74 Subsequent preclinical studies demonstrated that VRT-532 also functions as a CFTR corrector, rescuing the surface expression of proteins affected by F508del and G551D mutations.75-78 VRT-532 has shown an approximately fivefold greater affinity for F508del than for G551D.74 N6022 N6022 is a new injectable compound that has been shown to increase the amount of CFTR at the epithelial membrane and decrease the inflammation in the lungs.79 N6022 works by increasing the level of S-nitrosoglutathione (GSNO) by inhibiting GSNOR, an enzyme that breaks down GSNO.80 GSNO is a signaling molecule that decreases in people with CF. Login to comment 149 ABCC7 p.Gly551Asp Ivacaftor, the first CFTR potentiator to receive FDA approval, has overall been well tolerated and produced dramatic results in CF patients with a G551D mutation. Login to comment