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Systematic (IUPAC) name
Clinical data
Trade names Kalydeco
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Protein binding 99%
Metabolism CYP3A
Half-life 12 hrs (single dose)
Excretion 88% faeces
CAS number 873054-44-5 N
ATC code R07AX02
PubChem CID 16220172
ChemSpider 17347474 YesY
Synonyms VX-770
Chemical data
Formula C24H28N2O3 
Mol. mass 392.490 g/mol
 N (what is this?)  (verify)

Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved for patients with a certain mutation of cystic fibrosis, which accounts for 4–5% cases of cystic fibrosis.[1][2] Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with the Cystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease.[3] It is one of the most expensive drugs, costing over $300,000 per year, and doctors who developed the drug have criticized Vertex for charging so much.

Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator (CFTR), which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. One such defect is the G551D mutation, in which the amino acid glycine (G) in position 551 is replaced with aspartic acid (D). G551D is characterized by a dysfunctional CFTR protein on the cell surface. In the case of G551D, the protein is trafficked to the correct area, the epithelial cell surface, but once there the protein cannot transport chloride through the channel. Ivacaftor, a CFTR potentiator, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.[4][5][6]


Ivacaftor is approved for use in cystic fibrosis patients in the US, Canada[7] and across some European countries. The US Food and Drug Administration approved Ivacaftor in January 2012 and the European Medicines Agency (EMA) followed soon after.[8][9]


The cost of ivacaftor is $311,000 per year, which an editorial in JAMA called "exorbitant", particularly because of the support by the National Institutes of Health and Cystic Fibrosis Foundation in its development.[10] Vertex said it would make the drug available free to patients in the United States with no insurance and a household income of under $150,000.[11] In 2012, 24 US doctors and researchers involved in the development of the drug wrote to Vertex, “We have invested our lives and careers toward the success of these inspiring therapeutic agents. We also write with feelings of dismay and disappointment that the triumph and honor that should be yours is diminished by the unconscionable price assigned to Kalydeco." In the UK, the company provided the drug free for a limited time for certain patients, then left the hospitals to decide whether to continue to pay for it for those patients. UK agencies estimated the cost per quality adjusted life year (QALY) at between £335,000 and £1,274,000 —way above the National Institute for Health and Care Excellence thresholds.[12]

The drug was not covered under the Ontario Drug Benefit plan due to the elevated price until June 2014 when the Province of Ontario and the manufacturer negotiated for what "Ontario Health Minister Deb Matthews had called a “fair price” for taxpayers". The negotiations took 16 months and it was estimated that around 20 Ontarians required the drug at the time.[13]

The province of Alberta began covering the drug in July 2014, and in September the province of Saskatchewan became the third province to include it in its provincial drug plan.[14]

Clinical trials[edit]

During Phase 3 clinical trials, the STRIVE study demonstrated a 10.6% mean absolute improvement in baseline lung function (FEV1) over a 24 week period and a 10.5% mean absolute improvement in lung function over 48 weeks among those who had the G551D mutation and were treated with Ivacaftor.[15]

Side effects[edit]

The most common adverse reactions experienced by patients who received ivacaftor in the pooled placebo-controlled Phase 3 studies were abdominal pain (15.6% versus 12.5% on placebo), diarrhoea (12.8% versus 9.6% on placebo), dizziness (9.2% versus 1.0% on placebo), rash (12.8% versus 6.7% on placebo), upper respiratory tract reactions (including upper respiratory tract infection, nasal congestion, pharyngeal erythema, oropharyngeal pain, rhinitis, sinus congestion, and nasopharyngitis) (63.3% versus 50.0% on placebo), headache (23.9% versus 16.3% on placebo) and bacteria in sputum (7.3% versus 3.8% on placebo). One patient in the ivacaftor group reported a serious adverse reaction: abdominal pain.[9]



Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells.[9]


Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.[9]


Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The mean (±SD) of CL/F for the 150 mg dose was 17.3 (8.4) L/h in healthy subjects at steady state.[9]

See also[edit]


  1. ^ Jones AM, Helm JM (October 2009). "Emerging treatments in cystic fibrosis". Drugs 69 (14): 1903–10. doi:10.2165/11318500-000000000-00000. PMID 19747007. 
  2. ^ McPhail GL, Clancy JP (April 2013). "Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis". Drugs Today 49 (4): 253–60. doi:10.1358/dot.2013.49.4.1940984. PMID 23616952. 
  3. ^ "Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation". Press Release. Cystic Fibrosis Foundation. 2011-02-23. 
  4. ^ Eckford PD, Li C, Ramjeesingh M, Bear CE (October 2012). "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. 287 (44): 36639–49. doi:10.1074/jbc.M112.393637. PMID 22942289. 
  5. ^ Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P (November 2009). "Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770". Proc. Natl. Acad. Sci. U.S.A. 106 (44): 18825–30. doi:10.1073/pnas.0904709106. PMC 2773991. PMID 19846789. 
  6. ^ Sloane PA, Rowe SM (November 2010). "Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis". Curr Opin Pulm Med 16 (6): 591–7. doi:10.1097/MCP.0b013e32833f1d00. PMID 20829696. 
  7. ^ http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_kalydeco_155318-eng.php
  8. ^ Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW (November 2010). "Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation". N. Engl. J. Med. 363 (21): 1991–2003. doi:10.1056/NEJMoa0909825. PMC 3148255. PMID 21083385. 
  9. ^ a b c d e "Kalydeco: Annex I: Summary of product characteristics" (PDF). European Medicines Agency. 
  10. ^ Brian P. O’Sullivan; David M. Orenstein; Carlos E. Milla (October 2, 2013). "Viewpoint: Pricing for Orphan Drugs: Will the Market Bear What Society Cannot?". JAMA. 310 (13): 1343–1344. doi:10.1001/jama.2013.278129. 
  11. ^ "FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis" (Press release). Cambridge, Massachusetts: Vertex Pharmaceuticals. 2012-01-31. Retrieved 2014-02-01. 
  12. ^ Deborah Cohen; James Raftery (12 February 2014). "Orphan Drugs: Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding". BMJ 348: g1445. doi:10.1136/bmj.g1445. 
  13. ^ Ferguson, Rob (June 20, 2014). "OHIP to cover cystic fibrosis drug Kalydeco". The Toronto Star. Retrieved June 20, 2014. 
  14. ^ "Saskatchewan to cover $300K cystic fibrosis drug Kalydeco". CBC News. 2014-08-28. Retrieved 2014-08-28. 
  15. ^ "Phase 3 STRIVE Study of VX-770 Showed Durable Improvements in Lung Function (FEV1) and Other Measures of Disease Among People With a Specific Type of Cystic Fibrosis (NASDAQ:VRTX)". Press Release. Vertex Pharmaceuticals Incorporated. 2011-06-11. 

External links[edit]