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Improved Clinical and Radiographic Outcomes After Treatment With Ivacaftor in a Young Adult With Cystic Fibrosis With the P67L CFTR MutationImproved Outcome With Ivacaftor in P67L Cystic Fibrosis FREE TO VIEW

Shatha Yousef, MD; George M. Solomon, MD; Alan Brody, MD; Steven M. Rowe, MD, MSPH; Andrew A. Colin, MD
Author and Funding Information

From the Division of Pediatric Pulmonology (Drs Yousef and Colin), Miller School of Medicine, University of Miami, Miami, FL; the Department of Medicine (Drs Solomon and Rowe), University of Alabama at Birmingham, Birmingham, AL; and the Departments of Radiology and Pediatrics (Dr Brody), Cincinnati Children’s Hospital and the University of Cincinnati College of Medicine, Cincinnati, OH.

CORRESPONDENCE TO: Steven M. Rowe, MD, MSPH, 1918 University Blvd, MCLM 706, Birmingham, AL 35294-0006; e-mail: smrowe@uab.edu


Drs Yousef and Solomon contributed equally to this manuscript.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):e79-e82. doi:10.1378/chest.14-1198
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The underlying cause of cystic fibrosis (CF) is the loss of epithelial chloride and bicarbonate transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein. Ivacaftor is a gene-specific CFTR potentiator that augments in vivo chloride transport in CFTR mutations affecting channel gating. Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating. P67L is a class 4 conductance (nongating) mutation exhibiting residual CFTR function. We report marked clinical improvement, normalization of spirometry, and dramatic reduction in radiographic structural airway changes after > 1 year of treatment with ivacaftor in a young adult with the compound heterozygous genotype P67L/F508del CFTR. The case suggests that ivacaftor may have a potential benefit for patients with CF with nongating mutations.

Figures in this Article

Despite major advances in management, cystic fibrosis (CF) remains an illness with high morbidity and mortality.1,2 The underlying cause of CF is the loss of epithelial chloride and bicarbonate transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein.3 A new therapeutic approach involves improving the function of mutant CFTR.4 Ivacaftor (formerly VX-770) is a gene-specific CFTR potentiator that augments in vivo chloride transport in CFTR mutations affecting channel gating, such as G551D.5 Although marked improvements in spirometry, clinical outcome, and sweat chloride were observed in patients with G551D-CF treated with ivacaftor,4,6 its effect on structural lung disease has not been studied. Moreover, although ivacaftor alone has minimal effect on F508del homozygous individuals,7 it has demonstrated in vitro efficacy for conductance mutations other than G551D by augmenting gating to supernormal levels8 but has not yet been studied clinically. This includes P67L, a class 4 conductance mutation that exhibits residual CFTR function and relatively preserved CFTR expression, has a worldwide prevalence of 0.2%, and is the sixth most common mutation in Scotland.9 We report a case of a patient with CF who is a complex heterozygote for P67L/F508del with severe CF lung disease who improved significantly shortly after starting treatment with ivacaftor, including evidence of resolving structural lung disease.

The patient is an 18-year-old woman of Scottish descent with genotype F508del/P67L. Newborn screening for CF revealed an elevated immunoreactive trypsinogen and abnormal genotype. Until adolescence, multiple sweat tests revealed intermediate results (40-60 mmol/L), and she was managed for asthma, with occasional systemic antibiotics for sinopulmonary infections. Repeat sweat test at age 11 years demonstrated a sweat chloride level of 51 mmol/L. Chest and sinus CT scans revealed bronchiectasis and pansinusitis, respectively. At age 18 years, FEV1 and forced expiratory flow midexpiratory phase were 88% and 75% predicted, respectively. Sputum cultures demonstrated chronic mucoid Pseudomonas aeruginosa infection. Despite the use of dornase alfa, inhaled antibiotics, azithromycin, and IV antibiotics for pulmonary exacerbations, she experienced several incidents of pulmonary exacerbations associated with FEV1 decline (Fig 1) accompanied by worsening bronchiectasis (Fig 2) and increasing pulmonary exacerbations (three to four episodes per year). She also developed pancreatic insufficiency requiring pancreatic replacement therapy.

Figure Jump LinkFigure 1 –  Comparison of the average FEV1 of all available measurements obtained during the years prior to ivacaftor and after the start of ivacaftor treatment. Following initiation of ivacaftor, improved spirometry reaching 100% predicted at peak benefit was noted, with a mean improvement rate of 8.1 FEV1% predicted per y (P = .06 vs rate of change in FEV1% predicted prior to ivacaftor).Grahic Jump Location
Figure Jump LinkFigure 2 –  A-F, Axial, coronal, and three-dimensional reconstructions from CT scans obtained before (A-C) and after (D-F) ivacaftor treatment. There was a marked decrease in both large airway mucous plugging, seen as branching structures, and small airways mucous plugging, seen as centrilobular nodules (B [circled], E). Arrows identify airways that decreased in diameter after treatment (C, F), indicating improvement in bronchiectasis. Arrowheads show airways that increased in size after treatment, corresponding to clearing of mucous plugging and decreased bronchial wall thickening.Grahic Jump Location

Given her clinical trajectory, a trial of ivacaftor 150 mg bid was initiated at age 19 years after a successful physician appeal to her prescription drug provider, which was based on in vitro data and clinical experience. Following initiation of ivacaftor, she experienced improved spirometry, reaching 100% predicted at peak benefit and a mean improvement rate of 8.1 FEV1% predicted per year (P = .06 vs rate of change in FEV1% predicted prior to ivacaftor) (Fig 1), a reduction of sweat chloride level from 51 mmol/L to 25 mmol/L (obtained 1 month after initiating ivacaftor therapy), reduced frequency of exacerbations (one over a 1-year follow-up period), and improved pulmonary symptoms. She also gained > 4 kg body weight (a 10% improvement in BMI from pre-ivacaftor baseline). Sputum microbiology significantly improved, in that a culture of Mycobacterium abscessus resolved without treatment (confirmed by two serial assessments); P aeruginosa mucoidy also resolved as determined by five sequential sputum cultures, which demonstrated nonmucoid P aeruginosa in two cultures and no Pseudomonas in the other three culture samples). Additionally, the C-reactive protein levels declined from 47.1 mg/L based on historical data to 2.52 mg/L posttherapy. Serial CT scans revealed marked improvement in air trapping and mucous plugging. Multiple ectatic airways decreased in size between the two studies (Fig 2). The Brody score, assessed by a radiologist blinded to CT scan date and treatment data, improved from 58.5 to 42, with improvement in the bronchiectasis component from 24.5 to 21.5, and the air trapping component improved from 16 to 4.5. A marked decrease in large and small airway mucous plugging was seen, with a decrease in the mucous plugging component of the score from 13 to 11.

This case expands our knowledge about potential benefits of ivacaftor for nongating CFTR mutations. In vitro, ivacaftor has been shown to potentiate the function of 10 gating mutations,8 with recent reports of clinical10 and radiographic improvement11 in such patients. P67L is generally considered a CFTR mutation with reduced conductance.12 Furthermore, Sosnay and colleagues13 reported lower levels of mature glycosylated protein compared with wild-type CFTR (low band C/B ratio), suggesting an additional abnormality caused by ineffective maturation of P67L. Van Goor et al12 studied the in vitro effect of ivacaftor on multiple mutant CFTR forms due to missense mutations, including mutations that cause abnormal protein processing and reduced CFTR activity at the plasma membrane, such as P67L. In vitro, ivacaftor caused a significant increase in chloride current in epithelial cells expressing these mutations.12 Combined with data illustrated by this case, results strongly indicate that P67L is among the mutations that can exhibit a robust clinical response to ivacaftor. Moreover, the observed course of this patient supports the notion that ivacaftor could exhibit a class effect on CFTR mutations with decreased conductance but residual function and expression, such as P67L.

The marked clinical improvement, normalization of spirometry, improved sweat chloride, and dramatic reduction in radiographic structural airway changes are strong indicators supporting further investigation of ivacaftor use in patients with such mutations. Improvements in structural lung disease detected by serial high-resolution CT scan and the change in sputum microbiology suggest that ivacaftor could potentially alter the natural history of the disease, as also recently observed among G551D patients in a post-approval study.14 These clinical measures may be suitable outcome measures for patients in future clinical trials evaluating the efficacy of CFTR modulators. Further studies are warranted to determine whether long-term changes in the extent and severity of bronchiectasis are altered by ivacaftor treatment.

The US Food and Drug Administration has approved ivacaftor for eight additional alleles exhibiting gating defects. Currently, evaluation of conductance mutations has been limited to the R117H mutation, which also exhibits abnormal gating.15 Although ivacaftor has been reported to reduce the stability of some CFTR forms in vitro, including P67L, any detrimental effect on cell surface levels was not apparent based on a robust and sustained clinical response in this individual.16,17 Our positive experience emphasizes the need for definitive studies to test the potential benefit of ivacaftor for patients with CF with nongating missense mutations.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Rowe serves as principle investigator for clinical trials related to cystic fibrosis that the University of Alabama at Birmingham is funded to conduct by Vertex Pharmaceuticals Incorporated. Drs Yousef, Solomon, Brody, and Colin have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

CF

cystic fibrosis

CFTR

cystic fibrosis transmembrane conductance regulator

Goss CH, Ratjen F. Update in cystic fibrosis 2012. Am J Respir Crit Care Med. 2013;187(9):915-919. [CrossRef] [PubMed]
 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-2001. [CrossRef] [PubMed]
 
Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-1073. [CrossRef] [PubMed]
 
Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. [CrossRef] [PubMed]
 
Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44):18825-18830. [CrossRef] [PubMed]
 
Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. [CrossRef] [PubMed]
 
Flume PA, Liou TG, Borowitz DS, et al; for the VX 08-770-104 Study Group. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012;142(3):718-724. [CrossRef] [PubMed]
 
Yu H, Burton B, Huang CJ, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11(3):237-245. [CrossRef] [PubMed]
 
Gilfillan A, Warner JP, Kirk JM, et al. P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population. J Med Genet. 1998;35(2):122-125. [CrossRef] [PubMed]
 
McGarry ME, Nielson DW. Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest. 2013;144(4):1376-1378. [CrossRef] [PubMed]
 
Hoare S, McEvoy S, McCarthy CJ, et al. Ivacaftor imaging response in cystic fibrosis. Am J Respir Crit Care Med. 2014;189(4):484. [CrossRef] [PubMed]
 
Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014;13(1):29-36. [CrossRef] [PubMed]
 
Sosnay PR, Siklosi KR, Van Goor F, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-1167. [CrossRef] [PubMed]
 
Rowe SM, Heltshe SL, Gonska T, et al; GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014;190(2):175-184. [CrossRef] [PubMed]
 
Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993;362(6416):160-164. [CrossRef] [PubMed]
 
Cholon DM, Quinney NL, Fulcher L, et al. Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med. 2014;6(246):246ra96. [CrossRef] [PubMed]
 
Veit G, Avramescu RG, Perdomo D, et al. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci Transl Med. 2014;6(246):246ra97. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Comparison of the average FEV1 of all available measurements obtained during the years prior to ivacaftor and after the start of ivacaftor treatment. Following initiation of ivacaftor, improved spirometry reaching 100% predicted at peak benefit was noted, with a mean improvement rate of 8.1 FEV1% predicted per y (P = .06 vs rate of change in FEV1% predicted prior to ivacaftor).Grahic Jump Location
Figure Jump LinkFigure 2 –  A-F, Axial, coronal, and three-dimensional reconstructions from CT scans obtained before (A-C) and after (D-F) ivacaftor treatment. There was a marked decrease in both large airway mucous plugging, seen as branching structures, and small airways mucous plugging, seen as centrilobular nodules (B [circled], E). Arrows identify airways that decreased in diameter after treatment (C, F), indicating improvement in bronchiectasis. Arrowheads show airways that increased in size after treatment, corresponding to clearing of mucous plugging and decreased bronchial wall thickening.Grahic Jump Location

Tables

References

Goss CH, Ratjen F. Update in cystic fibrosis 2012. Am J Respir Crit Care Med. 2013;187(9):915-919. [CrossRef] [PubMed]
 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-2001. [CrossRef] [PubMed]
 
Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-1073. [CrossRef] [PubMed]
 
Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. [CrossRef] [PubMed]
 
Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44):18825-18830. [CrossRef] [PubMed]
 
Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. [CrossRef] [PubMed]
 
Flume PA, Liou TG, Borowitz DS, et al; for the VX 08-770-104 Study Group. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012;142(3):718-724. [CrossRef] [PubMed]
 
Yu H, Burton B, Huang CJ, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11(3):237-245. [CrossRef] [PubMed]
 
Gilfillan A, Warner JP, Kirk JM, et al. P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population. J Med Genet. 1998;35(2):122-125. [CrossRef] [PubMed]
 
McGarry ME, Nielson DW. Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest. 2013;144(4):1376-1378. [CrossRef] [PubMed]
 
Hoare S, McEvoy S, McCarthy CJ, et al. Ivacaftor imaging response in cystic fibrosis. Am J Respir Crit Care Med. 2014;189(4):484. [CrossRef] [PubMed]
 
Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014;13(1):29-36. [CrossRef] [PubMed]
 
Sosnay PR, Siklosi KR, Van Goor F, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-1167. [CrossRef] [PubMed]
 
Rowe SM, Heltshe SL, Gonska T, et al; GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014;190(2):175-184. [CrossRef] [PubMed]
 
Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993;362(6416):160-164. [CrossRef] [PubMed]
 
Cholon DM, Quinney NL, Fulcher L, et al. Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med. 2014;6(246):246ra96. [CrossRef] [PubMed]
 
Veit G, Avramescu RG, Perdomo D, et al. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci Transl Med. 2014;6(246):246ra97. [CrossRef] [PubMed]
 
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