Targeted therapy for chronic respiratory disease: a new paradigm

Peter G Gibson, Matthew J Peters and Claire E Wainwright
Med J Aust 2017; 206 (3): . || doi: 10.5694/mja16.00731
Published online: 20 February 2017


  • Targeted therapy has emerged as a highly effective treatment approach for chronic respiratory diseases. Many of these conditions have dismal outcomes; however, targeted therapy shows great results for the subgroup who respond. This represents a new way to approach these conditions and offers great promise as a future treatment direction.
  • In severe eosinophilic asthma, therapy that targets the interleukin-5 pathway with monoclonal antibodies leads to a 50% reduction in asthma exacerbations in previously refractory disease.
  • In cystic fibrosis, lung function improves with therapy that targets specific molecular abnormalities in the cystic fibrosis transmembrane conductance regulator to increase the probability that this chloride channel is open.
  • In lung cancer, specifically adenocarcinoma with epidermal growth factor receptor (EGFR) mutation and overexpression of EGFR tyrosine kinase, therapy that inhibits EGFR tyrosine kinase gives better outcomes than conventional chemotherapy.

  • 1 John Hunter Hospital, Newcastle, NSW
  • 2 Concord Repatriation General Hospital, Sydney, NSW
  • 3 Lady Cilento Children's Hospital, Brisbane, QLD
  • 4 Child Health Research Centre, University of Queensland, Brisbane, QLD

Competing interests:

Peter Gibson has received honoraria for the delivery of independent medical education and grants from GlaxoSmithKline, AstraZeneca and Novartis. Matthew Peters has received honoraria from several companies that manufacture asthma medications for membership of committees and the provision of independent medical education. Claire Wainwright has received consulting fees from Medscape and Vertex, lecture fees and travel support from Vertex and Novartis, grant support from Vertex, GlaxoSmithKline and Novo Nordisk, and fees on a per patient basis from Boehringer Ingelheim as principal investigator of a clinical study.

  • 1. Jameson JL, Longo DL. Precision medicine–personalized, problematic, and promising. N Engl J Med 2015; 372: 2229-2234.
  • 2. Valent P, Groner B, Schumacher U, et al. Paul Ehrlich(1854-1915) and his contributions to the foundation and birth of translational medicine. J Innate Immunity 2016; 8: 111-120.
  • 3. Gibson PG, Marks GB, Sly PD, et al. Case for action proposal: targeted therapy for asthma. 11 May 2015. Submitted by the NHMRC Research Translation Faculty Asthma Steering Group; Feb 2015. (accessed Nov 2016).
  • 4. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343-373.
  • 5. Hekking PP, Wener RR, Amelink M, et al. The prevalence of severe refractory asthma. J Allergy Clin Immunol 2015; 135: 896-902.
  • 6. Vol Bulow A, Kreigbaum M, Backer V, Porsbjerg C. The prevalence of severe asthma and low asthma control among Danish adults. J Allergy Clin Immunol 2014; 2: 759-767.
  • 7. O’Neill S, Sweeney J, Patterson CC, et al, British Thoracic Society Difficult Asthma Network. The cost of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma Network. Thorax 2015; 70: 376-378.
  • 8. Sweeney J, Patterson CC, Menzies-Gow A, et al, British Thoracic Society Difficult Asthma Network. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry. Thorax 2016; 71: 339-346.
  • 9. Menzies-Gow A, Flood-Page P, Sehmi R, et al. Anti-IL5(mepolizumab) therapy indices bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol 2003; 111: 714-719.
  • 10. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380: 651-659.
  • 11. Ortega HG, Liu MC, Pavord ID, et al; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371: 1198-1207.
  • 12. Bel EH, Wenzel SE, Thompson PJ, et al; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371: 1189-1197.
  • 13. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715-1721
  • 14. Felarca AB, Lowell FC. The total eosinophil count in a nonatopic population. J Allergy 1967; 40: 16-20.
  • 15. Zhang XY, Simpson JL, Powell H, et al. Full blood count parameters for the detection of asthma inflammatory phenotypes. Clin Exp Allergy 2014; 44: 1137-1145.
  • 16. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1073-1080.
  • 17. 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: 1160-1167.
  • 18. Cystic Fibrosis Foundation. CFTR2 [website]. (accessed Jan 2017).
  • 19. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663-1672.
  • 20. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Resp Crit Care Med 2013; 187: 1219-1225.
  • 21. McKone EF, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014; 2: 902-910.
  • 22. De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cystic Fibrosis 2014; 13: 674-680.
  • 23. Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 2015; 3: 524-533.
  • 24. Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Aacd Sci U S A 2011; 108: 18843-18848.
  • 25. 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 Aacd Sci U S A 2009; 106: 18825-18830.
  • 26. Clancy JP, Rowe SM, Accurso FJ, et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012; 67: 12-18.
  • 27. Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142: 718-724.
  • 28. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; 373: 220-231.
  • 29. Kerem E, Konstan MW, De Boeck K, et al. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2014; 2: 539-547.
  • 30. Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175-184.
  • 31. Australian Institute of Health and Welfare. Australian Cancer Incidence and Mortality (ACIM) books: pancreatic cancer. (accessed Nov 2016).
  • 32. Gazdar AF. Personalized medicine and inhibition of EGFR signaling in lung cancer. N Engl J Med 2009; 361: 1018-1020.
  • 33. Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 2015; 4: 36-54.
  • 34. Peters MJ, Bowden JJ, Carpenter P, et al. Outcomes of an Australian testing programme for epidermal growth factor receptor mutations in non-small cell lung cancer. Int Med J 2014; 44: 575-580.
  • 35. Turner NC, Reis-Filho JS. Genetic heterogeneity and cancer drug resistance. Lancet Oncol 2012: 13: e178-e185.
  • 36. Flood-Page P, Swenson C, Faiferman I, et al, International Mepolizumab Study Group. Am J Respir Crit Care Med 2007; 176: 1062-1071.
  • 37. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290: 2149-2158.
  • 38. Lewis JRR, Lipworth WL, Kerridge IH, Day RO. The economic evaluation of personalised oncology medicines: ethical challenges. Med J Aust 2013; 199: 471-473. <MJA full text>
  • 39. Siracusa CM, Ryan J, Burns L, et al. Electronic monitoring reveals highly variable adherence patterns in patients prescribed ivacaftor. J Cystic Fibrosis 2015; 14: 621-626.
  • 40. Merlin T, Farah C, Schubert C, et al. Assessing personalized medicines in Australia: a national framework for reviewing codependent technologies. Med Decis Making 2013; 33: 333-342.
  • 41. Schork NJ. Personalized medicine: time for one-person trials. Nature 2015; 520: 609-611.


remove_circle_outline Delete Author
add_circle_outline Add Author

Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Online responses are no longer available. Please refer to our instructions for authors page for more information.