Transformative mutation specific pharmacotherapy for cystic fibrosis

BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e79 (Published 09 January 2012) Cite this as: BMJ 2012;344:e79
  1. Don B Sanders, assistant professor1,
  2. Philip M Farrell, emeritus dean and professor2
  1. 1Department of Pediatrics, University of Wisconsin, Madison, WI 53792, USA
  2. 2Departments of Pediatrics and Population Health Sciences, University of Wisconsin
  1. dbsanders{at}pediatrics.wisc.edu

Has shown remarkable promise in clinical trials, and could revolutionise treatment

Ever since the discovery of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in 1989 explained the genetics and pathophysiology of cystic fibrosis,1 healthcare providers, patients, and parents have hoped that a CFTR based treatment would be discovered. The study by Ramsey and colleagues published in November 2011 is a crucial step towards fulfilling that hope.2

In conjunction with Vertex Pharmaceuticals, the Therapeutic Drug Network (TDN) of the US Cystic Fibrosis Foundation (CFF), and the European Cystic Fibrosis Society Clinical Trials Network, 63 cystic fibrosis centres conducted a phase III randomised double blind placebo controlled trial to evaluate the CFTR potentiator developed as VX-770 and then named ivacaftor.3 4 Over 48 weeks, the study assessed 161 patients with cystic fibrosis and at least one specific CFTR mutation (G551D) that decreases CFTR channel function at the cell surface. Ivacaftor is a small molecule that increases the time that activated CFTR channels are open to transmit chloride ions.3 Patients who received ivacaftor had no adverse effects but had a 10.6% absolute increase from baseline in pulmonary function (forced expiratory volume in one second; FEV1)—the study’s primary end point, were 55% less likely to have a pulmonary exacerbation, scored better on the respiratory symptoms domain of the quality of life instrument, gained 2.7 kg more weight, and had a 48.1 mmol/L improvement in the concentration of sweat chloride compared with those who received placebo (all P<0.001).2

Ramsey and colleagues note that the improvements in FEV1 and the frequency of pulmonary exacerbations compare favourably with other new treatments for cystic fibrosis.5 6 FEV1 is the most well studied and validated surrogate end point for patients with cystic fibrosis and reflects airways obstruction, but it would have been useful to have other pulmonary outcome data and respiratory microbiology results. Given that quantitative chest imaging and the lung clearance index are more sensitive than FEV1 as measures of lung disease in cystic fibrosis,7 8 it would have been interesting to know how ivacaftor affected those measures. Another interesting question is why most improvements in FEV1 occurred in the first two weeks of the study. Is this an immediate effect from better hydration of the airway surface liquid? Although the average rise of about 10% FEV1 is modest, individual patients have reported that this correlates with a marked reduction in symptoms and dramatic improvement in their lives.9

The most quantitatively impressive finding in this study, however, is the unique lowering of chloride concentrations in sweat. This observation provides direct evidence that CFTR linked chloride channel activity improved, confirming the systemic effect of ivacaftor. In fact, many treated subjects had normal sweat chloride concentrations, as was also seen in a smaller study.4

The story behind the study is just as interesting. About a decade ago, the Cystic Fibrosis Foundation decided to invest in the development of small molecule drugs on the basis of a convergence of several promising concepts and technologies, a vision to treat cystic fibrosis as a multisystem disorder, and the willingness to catalyse and partially finance targeted research.3 9 10 In contrast, the UK Cystic Fibrosis Trust elected to concentrate efforts and funding on gene therapy, targeting the lung disease exclusively.11 In 2000, the Cystic Fibrosis Foundation established a drug development programme and invested start-up money in a small company that began using high throughput screening with cystic fibrosis cell lines and identification of halide transfer by fluorescence resonance energy transfer to evaluate thousands of chemicals daily for restoration of chloride channel function. With the guidance of a multidisciplinary scientific advisory council, success came when VX-770 emerged from the evaluation of 228 000 compounds and was shown to increase the probability of CFTR channel opening in both the F508del processing mutation and the G551D gating mutation.3 Subsequent translational efforts for clinical trials via the Therapeutic Drug Network have culminated in Ramsey and colleagues’ remarkable achievement.2 In contrast, the UK CF Gene Therapy Consortium has had limited success, and questions remain about safety and efficacy.11

Studies of ivacaftor beyond 48 weeks’ duration are needed to monitor potential safety problems and to clarify whether additional gains in FEV1 may occur. Ongoing evaluations of the drug’s effects on the lung clearance index and chest imaging may shed light on its potential effect on structural lung disease. Perhaps the most important information that we do not yet have is whether ivacaftor causes a one time increase in FEV1, or whether continued treatment can slow the long term decline in FEV1 and improve survival. Until these additional questions are answered, the cystic fibrosis community should proceed with a combination of hope and caution, while recognising that the improvements promised 23 years ago with the discovery of CFTR seem to be on the horizon.1

For the 2-5% of patients with the G551D mutation, this drug has already been described as miraculous.12 The decreased cough and sputum production, combined with less burden from conventional treatment, has greatly enhanced their lifestyle. Rather than awaiting the progression of lung disease and premature death they can look forward to the future with hopeful expectations.12 Nevertheless, discussing the implications of this study with anxious patients and their parents can be challenging, and clinicians need to be careful.

Although ivacaftor may only potentiate CFTR channels on epithelial cells in patients with surface mutations, there are reasons to believe that combining CFTR rescue drugs for the greater number of patients with F508del mutations may also improve chloride channel function.3 Moreover, the high throughput screening strategy will probably lead to the discovery of other CFTR modulators for mutations that reduce the synthesis of CFTR and intracellular processing.

In any event, developments in the past decade have transformed the care of patients with cystic fibrosis and created a new era, especially for future generations of children. They can now be routinely diagnosed as newborns through screening programmes, at a time when their lungs are unaffected, and may soon be treated routinely with a CFTR modulator such as ivacaftor to potentially avoid severe lung disease. Such innovative multisystem treatment of the underlying defect transcends the previous strategies of treating the secondary pathophysiological effects of the CFTR mutation and truly is a “game changer.”


Cite this as: BMJ 2012;344:e79


  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; not externally peer reviewed.