Lumacaftor/Ivacaftor: A Review in Cystic Fibrosis
- 2.2k Downloads
Lumacaftor/ivacaftor (Orkambi™) is a fixed-dose tablet containing a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel’s open probability and transport of chloride. In two 24-week trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with standard therapy, was associated with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory volume in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clinically meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clinical benefit over a further 72 weeks of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clinical practice remains to be determined.
KeywordsCystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Improve Lung Function Pulmonary Exacerbation Lung Function Decline
During the peer review process, the manufacturer of lumacaftor/ivacaftor was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
Compliance with Ethical Standards
The preparation of this review was not supported by any external funding.
Conflict of interest
Emma Deeks is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
- 1.Cystic Fibrosis Foundation. About cystic fibrosis—what is cystic fibrosis? 2016. https://www.cff.org. Accessed 11 Mar 2016.
- 6.CFTR.info. Classification of CFTR mutations. 2016. http://www.cftr.info. Accessed 19 May 2016.
- 7.Mayo Clinic. Disease and conditions: cystic fibrosis. 2016. http://www.mayoclinic.org. Accessed 11 Mar 2016.
- 11.Cytsic Fibrosis News Today. Cystic fibrosis statistics. 2016. http://cysticfibrosisnewstoday.com/cystic-fibrosis-statistics/. Accessed 11 Mar 2016.
- 14.CFTR Science. Clinician’s guide to CFTR. CFTR mutations: 127 are known to be CF-causing. 2015. http://www.cftrscience.com/?q=cftr-mutations. Accessed 14 Mar 2016.
- 18.Vertex Pharmaceuticals Incorporated. Orkambi™ (lumacaftor/ivacaftor) tablets, for oral use: US prescribing information. 2016. http://www.fda.gov/. Accessed 1 Jul 2016.
- 19.Vertex Pharmaceuticals (Europe) Limited. Orkambi 200 mg/125 mg film-coated tablets: EU summary of product characteristics. 2016. http://www.ema.europa.eu/. Accessed 1 Jul 2016.
- 26.European Medicines Agency. Assessment report: Kalydeco (ivacaftor). 2012. http://www.ema.europa.eu. Accessed 17 Mar 2016.
- 27.Eckford PD, Li C, Ramjeesingh M, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem. 2012;287(44):36639–49.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Marigowda G, Liu F, Waltz D. Effect of bronchodilators in healthy individuals receiving lumacaftor in combination with ivacaftor [abstract no. 256 plus poster]. Pediatr Pulmonol. 2014;49(S38):S307.Google Scholar
- 38.Konstan MW, Ramsey B, Elborn S, et al. Safety and efficacy of treatment with lumacaftor in combination with ivacaftor in patients with CF homozygous for F508del-CFTR [abstract no. 211]. Pediatr Pulmonol. 2015;50(Suppl 41):269–70.Google Scholar
- 39.Konstan MW, McKone EF, Moss RB, et al. Evidence for reduced rate of lung function decline and sustained benefit with combination lumacaftor and ivacaftor (LUM/IVA) therapy in patients (pts) 12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation [poster no. 108]. In: 8th European Conference on Rare Diseases & Orphan Products; 2016.Google Scholar
- 40.McColley SA, Konstan MW, Ramsey BW, et al. Association between changes in percent predicted FEV1 and incidence of pulmonary exacerbations, including those requiring hospitalization and/or IV antibiotics, in patients with CF treated with lumacaftor in combination with ivacaftor [abstract no. 241]. Pediatr Pulmonol. 2015;50(Suppl 41):282.Google Scholar
- 41.De Boeck K, Elborn JS, Ramsey BW, et al. Efficacy and safety of lumacaftor + ivacaftor combination therapy in patients with CF homozygous for F508del-CFTR by FEV1 subgroups [abstract no. 245]. Pediatr Pulmonol. 2015;50(Suppl 41):283–4.Google Scholar
- 48.Sawicki GS, McKone EF, Millar S, et al. Similar rates of lung function decline in patients with cystic fibrosis and the G551D or hmozygous F508DEL CFTR gene mutation [abstract no. 487]. In: North American Cystic Fibrosis Conference; 2015.Google Scholar
- 49.Rubin JL, Pelligra CG, Ward AJ, et al. Modeling the intermediate health outcomes of patients with CF who are homozygous for the F508DEL CFTR mutation treated with lumacaftor and ivacaftor combination therapy [abstract no. 236]. Pediatr Pulmonol. 2015;50(Suppl 41):280.Google Scholar
- 52.Vertex. FDA approves Orkambi™ (lumacaftor/ivacaftor)—the first medicine to treat the underlying cause of cystic fibrosis for people ages 12 and older with two copies of the F508del mutation [media release]. 2015. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=920512. Accessed 2 July 2015.
- 53.European Medicines Agency. Report of the workshop on endpoints for cystic fibrosis clinical trials. 2012. http://www.ema.europa.eu. Accessed 16 Mar 2016.