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{{Short description|Cystic fibrosis treatment drug}}
{{Drugbox
{{Use British English|date=March 2020}}
{{Use dmy dates|date=November 2019}}
{{Infobox drug
| Verifiedfields = changed | Verifiedfields = changed
| verifiedrevid = 669804571
| Watchedfields = changed
| verifiedrevid = 477495886| drug_name = | drug_name =
| INN =
| IUPAC_name = ''N''-(2,4-Di-''tert''-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
| type = <!-- empty -->
| image = Ivacaftor.svg
| image = Ivacaftor.svg
| alt =
| width =
| caption =
| alt =
<!--Clinical data-->
| caption =
| tradename = Kalydeco

| licence_US = Ivacaftor
<!-- Clinical data -->
| Drugs.com =
| pronounce = {{IPAc-en|ˌ|aɪ|v|ə|ˈ|k|æ|f|t|ər}}<br />{{respell|EYE|və|KAF|tər}}
| MedlinePlus =
| tradename = Kalydeco
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| Drugs.com = {{drugs.com|monograph|ivacaftor}}
| pregnancy_US = B
| MedlinePlus = a612012
| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU = yes
| DailyMedID = Ivacaftor
| licence_US = Ivacaftor
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name= "Drugs.com pregnancy">{{cite web | title=Ivacaftor (Kalydeco) Use During Pregnancy | website=Drugs.com | date=9 November 2019 | url=https://www.drugs.com/pregnancy/ivacaftor.html | access-date=26 June 2020}}</ref>
| pregnancy_category= | pregnancy_category=
| routes_of_administration = ]
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| class =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| ATCvet =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
| ATC_prefix = R07
| ATC_suffix = AX02
| ATC_supplemental = {{ATC|R07|AX30}}, {{ATC|R07|AX31}}, {{ATC|R07|AX32}},

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Kalydeco Product information | website=] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=88237 | access-date=31 May 2022}}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only | legal_US = Rx-only
| legal_US_comment = <ref name="Kalydeco label" />
| legal_status =
| legal_EU = Rx-only
| routes_of_administration = Oral
| legal_EU_comment = <ref name="Kalydeco EPAR" />
<!--Pharmacokinetic data-->
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| bioavailability =
| legal_UN_comment =
| protein_bound = 99%
| legal_status = Rx-only
| metabolism = CYP3A

<!-- Pharmacokinetic data -->
| bioavailability =
| protein_bound = 99%
| metabolism = CYP3A
| metabolites =
| onset =
| elimination_half-life = 12 hrs (single dose) | elimination_half-life = 12 hrs (single dose)
| duration_of_action =
| excretion = 88% faeces
| excretion = 88% faeces
<!--Identifiers-->

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 873054-44-5
| CAS_supplemental =
| PubChem = 16220172
| IUPHAR_ligand = 4342 | IUPHAR_ligand = 4342
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 873054-44-5
| ATCvet =
| ATC_prefix = R07
| ATC_suffix = AX02
| PubChem = 16220172
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 66901
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = | DrugBank = DB08820
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 17347474 | ChemSpiderID = 17347474
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1Y740ILL1Z | UNII = 1Y740ILL1Z
| KEGG_Ref = {{keggcite|changed|kegg}}
| synonyms = VX-770
| KEGG = D09916
<!--Chemical data-->
| ChEBI_Ref = {{ebicite|correct|EBI}}
| chemical_formula =
| ChEBI = 66901
| C=24 | H=28 | N=2 | O=3
| ChEMBL = 2010601
| molecular_weight = 392.490 g/mol
| NIAID_ChemDB =
| smiles = O=C\2c1c(cccc1)N/C=C/2C(=O)Nc3cc(O)c(cc3C(C)(C)C)C(C)(C)C
| PDB_ligand =
| InChI = InChI=1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)
| synonyms = VX-770

<!-- Chemical and physical data -->
| IUPAC_name = ''N''-(2,4-Di-''tert''-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
| C= 24 | H= 28 | N= 2 | O= 3
| SMILES = O=C\2c1c(cccc1)N/C=C/2C(=O)Nc3cc(O)c(cc3C(C)(C)C)C(C)(C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29) | StdInChI = 1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PURKAOJPTOLRMP-UHFFFAOYSA-N | StdInChIKey = PURKAOJPTOLRMP-UHFFFAOYSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}
'''Ivacaftor''' (trade name '''Kalydeco''', developed as '''VX-770''') is a ] approved for patients with a certain mutation of ], which accounts for 4–5% cases of cystic fibrosis.<ref name="pmid19747007">{{cite journal | author = Jones AM, Helm JM | title = Emerging treatments in cystic fibrosis | journal = Drugs | volume = 69 | issue = 14 | pages = 1903–10 |date=October 2009 | pmid = 19747007 | doi = 10.2165/11318500-000000000-00000 }}</ref><ref name="pmid23616952">{{cite journal | author = McPhail GL, Clancy JP | title = Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis | journal = Drugs Today | volume = 49 | issue = 4 | pages = 253–60 |date=April 2013 | pmid = 23616952 | doi = 10.1358/dot.2013.49.4.1940984 }}</ref> Ivacaftor was developed by ] in conjunction with the ] and is the first drug that treats the underlying cause rather than the symptoms of the disease.<ref name="prnewswire">{{cite web | url = http://www.prnewswire.com/news-releases/phase-3-study-of-vx-770-shows-marked-improvement-in-lung-function-among-people-with-cystic-fibrosis-with-g551d-mutation-116725199.html | title = Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation | date = 2011-02-23 | publisher = Cystic Fibrosis Foundation | work = Press Release }}</ref> Called "the most important new drug of 2012",<ref>{{cite web |url=http://www.forbes.com/sites/matthewherper/2012/12/27/the-most-important-new-drug-of-2012/ |title=The Most Important New Drug Of 2012 - Forbes |format= |work= |accessdate=}}</ref> and "a wonder drug"<ref>{{cite web |url=http://www.nytimes.com/2014/07/19/opinion/joe-nocera-cystic-fibrosis-drug-price.html?_r=0 |title=The $300,000 Drug - NYTimes.com |format= |work= |accessdate=}}</ref> it is one of the most expensive drugs, costing over ]300,000 per year, which has led to criticism of Vertex for the high cost.


'''Ivacaftor''' is a ] used to treat ] in people with certain mutations in the ] (CFTR) gene (primarily the G551D mutation), who account for 4–5% cases of cystic fibrosis.<ref name="pmid19747007">{{cite journal | vauthors = Jones AM, Helm JM | title = Emerging treatments in cystic fibrosis | journal = Drugs | volume = 69 | issue = 14 | pages = 1903–1910 | date = October 2009 | pmid = 19747007 | doi = 10.2165/11318500-000000000-00000 | s2cid = 23344660 }}</ref><ref name="pmid23616952">{{cite journal | vauthors = McPhail GL, Clancy JP | title = Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis | journal = Drugs of Today | volume = 49 | issue = 4 | pages = 253–260 | date = April 2013 | pmid = 23616952 | doi = 10.1358/dot.2013.49.4.1940984 }}</ref> It is also included in ]s, ], ], and ] which are used to treat people with cystic fibrosis.<ref name="Orkambi Label" /><ref name="Symdeko label" /><ref name="Symkevi EPAR" />
Cystic fibrosis is caused by any one of several defects in a protein, ] (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 ]&nbsp;(G) in position 551 is replaced with ]&nbsp;(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 ], 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.<ref name="pmid22942289">{{cite journal | author = Eckford PD, Li C, Ramjeesingh M, Bear CE | title = 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 | journal = J. Biol. Chem. | volume = 287 | issue = 44 | pages = 36639–49 |date=October 2012 | pmid = 22942289 | doi = 10.1074/jbc.M112.393637 }}</ref><ref name="pmid19846789">{{cite journal | author = 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 | title = Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 44 | pages = 18825–30 |date=November 2009 | pmid = 19846789 | pmc = 2773991 | doi = 10.1073/pnas.0904709106 }}</ref><ref name="pmid20829696">{{cite journal | author = Sloane PA, Rowe SM | title = Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis | journal = Curr Opin Pulm Med | volume = 16 | issue = 6 | pages = 591–7 |date=November 2010 | pmid = 20829696 | doi = 10.1097/MCP.0b013e32833f1d00 }}</ref>

Ivacaftor was developed by ] in conjunction with the ] and is the first medication that treats the underlying cause rather than the symptoms of the disease. It was approved by the U.S. ] (FDA) in January 2012. It is one of the most expensive drugs, costing over {{US$|300,000}} per year, which has led to criticism of the high cost. The combination drug lumacaftor/ivacaftor was approved by the FDA in July 2015.

Cystic fibrosis is caused by any one of several defects in the CFTR protein, 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 ]&nbsp;(G) in position 551 is replaced with ]&nbsp;(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 ], 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.<ref name="pmid22942289">{{cite journal | vauthors = Eckford PD, Li C, Ramjeesingh M, Bear CE | title = 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 | journal = The Journal of Biological Chemistry | volume = 287 | issue = 44 | pages = 36639–36649 | date = October 2012 | pmid = 22942289 | pmc = 3481266 | doi = 10.1074/jbc.M112.393637 | doi-access = free }}</ref><ref name="pmid19846789">{{cite journal | vauthors = 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 | display-authors = 6 | title = Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 44 | pages = 18825–18830 | date = November 2009 | pmid = 19846789 | pmc = 2773991 | doi = 10.1073/pnas.0904709106 | doi-access = free | bibcode = 2009PNAS..10618825V }}</ref><ref name="pmid20829696">{{cite journal | vauthors = Sloane PA, Rowe SM | title = Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis | journal = Current Opinion in Pulmonary Medicine | volume = 16 | issue = 6 | pages = 591–597 | date = November 2010 | pmid = 20829696 | pmc = 3733473 | doi = 10.1097/MCP.0b013e32833f1d00 }}</ref>
{{TOC limit|3}}


== Medical uses == == Medical uses ==
Ivacaftor is used for the treatment of ] in people having one of several specific mutations in the ] (CFTR) protein: E56K, G178R, S549R, K1060T, G1244E, P67L, E193K, G551D, A1067T, S1251N, R74W, L206W, G551S, G1069R, S1255P, D110E, R347H, D579G, R1070Q, D1270N, D110H, R352Q, S945L, R1070W, G1349D, R117C, A455E, S977F, F1074L, R117H, S549N, F1052V, D1152H.<ref>Cystic Fibrosis Foundation: FDA Approves Ivacaftor for 23 Additional CFTR Mutations </ref><ref name="Kalydeco label">{{cite web | title=Kalydeco- ivacaftor tablet, film coated Kalydeco- ivacaftor granule prescribing information | website=] | date=25 April 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ab0c9f8-3eee-4e0f-9f3f-c1e16aaffe25 | access-date=20 November 2019}}</ref><ref>{{cite press release | title=FDA expands approved use of Kalydeco to treat additional mutations of cystic fibrosis | website=U.S. ] (FDA) | date=17 May 2017 | url=https://www.fda.gov/news-events/press-announcements/fda-expands-approved-use-kalydeco-treat-additional-mutations-cystic-fibrosis | archive-url=https://web.archive.org/web/20191121042502/https://www.fda.gov/news-events/press-announcements/fda-expands-approved-use-kalydeco-treat-additional-mutations-cystic-fibrosis | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}{{PD-notice}}</ref>
Ivacaftor is used for the treatment of cystic fibrosis in persons having one of several specifics mutations in the CFTR protein including G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P,
S549N,or S549R.<ref>{{cite web |url=http://pi.vrtx.com/files/uspi_ivacaftor.pdf |title=pi.vrtx.com |format= |work= |accessdate=}}</ref>


Ivacaftor is also included in a combination product, ], in a single pill, which is used to treat people with ] who have the ] mutation in CFTR.<ref name=2015revKuk/><ref name=CW>{{cite web|title=Orkambi (lumacaftor and ivacaftor)|url=http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100082/orkambi-lumacaftor-and-ivacaftor|publisher=CenterWatch|access-date=24 March 2016|archive-date=19 March 2016|archive-url=https://web.archive.org/web/20160319043353/http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100082/orkambi-lumacaftor-and-ivacaftor|url-status=dead}}</ref><ref name="Orkambi Label">{{cite web | title=Orkambi- lumacaftor and ivacaftor tablet, film coated Orkambi- lumacaftor and ivacaftor granule prescribing information | website=] | publisher = U.S. National Library of Medicine | date=15 July 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3fc1c40e-cfac-47a1-9e1a-61ead3570600 | access-date=20 November 2019}}</ref><ref name="Orkambi Snapshot">{{cite web | title=Drug Trials Snapshots: Orkambi | website=U.S. ] (FDA) | date=30 July 2015 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-orkambi | archive-url=https://web.archive.org/web/20191121051727/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-orkambi | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}} {{PD-notice}}</ref>
===G551D mutation===
Of the approximately 70,000 cases of cystic fibrosis worldwide, 4% (~3,000) are due to a mutation called G551D.<ref>{{cite web |url=http://www.cff.org/AboutCF/Faqs/ |title=FAQs about the Cause, Diagnosis, Treatment of Cystic Fibrosis & More &#124; CF Foundation |format= |work= |accessdate=}}</ref><ref>{{cite journal |author=Bobadilla JL, Macek M, Fine JP, Farrell PM |title=Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening |journal=Hum. Mutat. |volume=19 |issue=6 |pages=575–606 | date=June 2002 |pmid=12007216 |doi=10.1002/humu.10041 |url=}}</ref> The safety and efficacy of ivacaftor for the treatment of cystic fibrosis in patients with this mutation was examined in 2 clinical trials.


Ivacaftor is also included in the combination product ]/ivacaftor with ivacaftor sold as Symdeko and as Symkevi.<ref name="Symdeko label">{{cite web | title=Symdeko- tezacaftor and ivacaftor kit prescribing information | website=] | date=11 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=302ae804-37db-44fd-ac2f-3dbdeda9aa4b | access-date=20 November 2019}}</ref><ref name="Symdeko Snapshot">{{cite web | title=Drug Trials Snapshots: Symdeko | website=U.S. ] (FDA) | date=7 March 2018 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-symdeko | archive-url=https://web.archive.org/web/20191121051752/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-symdeko | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}} {{PD-notice}}</ref><ref>{{cite web | title=Symdeko (tezacaftor/ivacaftor) Tablets | website=U.S. ] (FDA) | date=13 March 2018 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210491Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20191211224240/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210491Orig1s000TOC.cfm | archive-date=11 December 2019 | url-status=live | access-date=11 December 2019}}</ref><ref>{{cite web | title=Summary Basis of Decision - Symdeko | date=2019-04-15 | website=Health Canada | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00402 | archive-url=https://web.archive.org/web/20191121053458/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00402 | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}</ref><ref name="Symkevi EPAR" />
The first trial was performed in adults having baseline respiratory function (FEV1) between 32% and 98% of normal for persons of similar age, height, and weight. The baseline average was 64%. Improvement in FEV1 was rapid and sustained. At the end of 48 weeks, people treated with ivacaftor had on average an absolute increase in FEV1 of 10.4%, vs. a decline of 0.2% in the placebo group. Pulmonary exacerbations were reduced by about half in the ivacaftor group relative to the placebo group.<ref>{{cite web |url=http://pi.vrtx.com/files/uspi_ivacaftor.pdf |title=pi.vrtx.com |format= |work= |accessdate=}}</ref>


Symdeko is indicated to treat people aged six and older who have two copies of the F508del mutation in CFTR.<ref name="Symdeko label" /><ref name="Symdeko Snapshot" /><ref name="FDA Symdeko PR">{{cite press release | title=FDA expands approval of treatment for cystic fibrosis to include patients ages 6 and older | website=U.S. ] (FDA) | date=21 June 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-expands-approval-treatment-cystic-fibrosis-include-patients-ages-6-and-older | archive-url=https://web.archive.org/web/20191211223605/https://www.fda.gov/news-events/press-announcements/fda-expands-approval-treatment-cystic-fibrosis-include-patients-ages-6-and-older | archive-date=11 December 2019 | url-status=live | access-date=11 December 2019}} {{PD-notice}}</ref>
In a second trial conducted in children age 6 to 11, the average improvement in FEV1 was an absolute increase of 12.5% in the ivacaftor group at 48 weeks, compared to a very slight decline in the placebo group.<ref>{{cite web |url=http://pi.vrtx.com/files/uspi_ivacaftor.pdf |title=pi.vrtx.com |format= |work= |accessdate=}}</ref>


Symkevi is indicated in a combination regimen with ivacaftor 150&nbsp;mg tablets for the treatment of people with cystic fibrosis (CF) aged twelve years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T.<ref name="Symkevi EPAR">{{cite web | title=Symkevi EPAR | website=] (EMA) | date=22 November 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/symkevi | access-date=26 June 2020}} {{PD-notice}}</ref>
Ivacaftor is approved for use in cystic fibrosis patients in the US, Canada<ref>http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_kalydeco_155318-eng.php</ref> and across some European countries. The US ] approved ivacaftor in January 2012 and the European Medicines Agency (EMA) followed soon after.<ref name="pmid21083385">{{cite journal | author = 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 | title = Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation | journal = N. Engl. J. Med. | volume = 363 | issue = 21 | pages = 1991–2003 |date=November 2010 | pmid = 21083385 | pmc = 3148255 | doi = 10.1056/NEJMoa0909825 }}</ref><ref name="url_EMA_Kalydeco">{{cite web | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002494/WC500130696.pdf | title = Kalydeco: Annex I: Summary of product characteristics | author = | format = PDF | work = | publisher = European Medicines Agency }}</ref>


Ivacaftor is available in a combination product with ] and ] called ] for the treatment of people with cystic fibrosis who have the ] mutation or other mutations.<ref name="Trikafta FDA label">{{cite web|date=29 January 2020|title=Trikafta- elexacaftor, tezacaftor, and ivacaftor kit|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f354423a-85c2-41c3-a9db-0f3aee135d8d|access-date=22 August 2020|website=DailyMed}}</ref>
===G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R mutations ===
A third clinical trial examined the effiacy of ivacaftor in people with cystic fibrosis due to G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations. This trial, which included 39 people of age greater than 6 years, used a crossover design. The people in the trial had FEV1 averaging 78% of normal at basline. The people in the trial were randomized to receive either ivacaftor or placebo for 8 weeks. This was followed by a 4 to 8 week washout period, then each group received the opposite treatment from what it received in the first part of the trial. At Week 8, the people on treatment with ivacaftor experienced an average absolute improvement in FEV1 of 13.8%, but there was a strong dependence of the efficacy on the exact mutation that a patient had. The detailed data for different mutation types is shown in the U.S package insert.<ref>{{cite web |url=http://pi.vrtx.com/files/uspi_ivacaftor.pdf |title=pi.vrtx.com |format= |work= |accessdate=}}</ref>


== Adverse effects == == Adverse effects ==


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.<ref name="url_EMA_Kalydeco"/> The most common adverse reactions experienced by patients who received ivacaftor in the pooled placebo-controlled Phase III studies were abdominal pain (15.6% versus 12.5% on placebo), ] (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.<ref name="url_EMA_Kalydeco"/><ref name="Kalydeco EPAR" />


==Pharmacology== ==Pharmacology==
Line 83: Line 132:
=== Pharmacodynamics === === Pharmacodynamics ===


Ivacaftor is a "potentiator" of CFTR, meaning it increases the probability that the defective channel will be open and allow chloride ions pass through the channel pore.<ref name=2015revKuk>{{cite journal | vauthors = Kuk K, Taylor-Cousar JL | title = Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects | journal = Therapeutic Advances in Respiratory Disease | volume = 9 | issue = 6 | pages = 313–326 | date = December 2015 | pmid = 26416827 | doi = 10.1177/1753465815601934 | doi-access = free }}</ref>
Ivacaftor acts a chaperone for the CFTR protein and helps it reach the membrane when it otherwise would not.


===Pharmacokinetics=== ===Pharmacokinetics===
Line 89: Line 138:
==== Distribution ==== ==== Distribution ====


Ivacaftor is approximately 99% bound to plasma proteins, primarily to ] and ]. Ivacaftor does not bind to human red blood cells.<ref name="url_EMA_Kalydeco"/> Ivacaftor is approximately 99% bound to plasma proteins, primarily to ] and ]. Ivacaftor does not bind to human red blood cells.<ref name="url_EMA_Kalydeco"/><ref name="Kalydeco EPAR" />


==== Biotransformation ==== ==== Biotransformation ====


Ivacaftor is extensively metabolised in humans. ] and ] 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.<ref name="url_EMA_Kalydeco"/> Ivacaftor is extensively metabolised in humans. ] and ] 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.<ref name="url_EMA_Kalydeco"/><ref name="Kalydeco EPAR" />


==== Elimination ==== ==== Elimination ====


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&nbsp;mg dose was 17.3 (8.4)&nbsp;L/h in healthy subjects at steady state.<ref name="url_EMA_Kalydeco"/> 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&nbsp;mg dose was 17.3 (8.4)&nbsp;L/h in healthy subjects at steady state.<ref name="url_EMA_Kalydeco"/><ref name="Kalydeco EPAR" />


== Economics == ==History==
Ivacaftor was developed by ] in conjunction with the ] and is the first medication that treats the underlying cause rather than the symptoms of the disease.<ref name="prnewswire">{{cite press release | url = http://www.prnewswire.com/news-releases/phase-3-study-of-vx-770-shows-marked-improvement-in-lung-function-among-people-with-cystic-fibrosis-with-g551d-mutation-116725199.html | title = Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation | date = 2011-02-23 | publisher = Cystic Fibrosis Foundation | via = PR Newswire }}</ref>
The cost of ivacaftor is $311,000 per year, roughly similar to the price of other drugs for extremely rare diseases.<ref>{{cite news |url=http://www.nytimes.com/2012/02/01/business/fda-approves-cystic-fibrosis-drug.html |title=F.D.A. Approves New Cystic Fibrosis Drug |work=New York Times |date=January 31, 2012 |accessdate=2015-02-10 }}</ref> In the first 9 months of its second year on the market (2014), ivacaftor sales were $339M, representing 54% of Vertex's product sales revenue. During the same period, drug development expenses were $458M, most of which was spent on cystic fibrosis-related research.<ref>{{cite web |url=http://www.sec.gov/Archives/edgar/data/875320/000087532014000063/a2014q310-q.htm |title=Vertex Pharmaceuticals 10-Q, Quarter ending September 30, 2014 |accessdate=2015-02-10 }}</ref>


== Society and culture ==
An editorial in JAMA called the price of ivacaftor "exorbitant", citing the support by the ] in its development and the contribution made by fundamental scientific research performed by the ] and relied upon by Vertex in its cystic fibrosis drug discovery programs.<ref name="exorbitant">{{cite journal| title =Viewpoint: Pricing for Orphan Drugs: Will the Market Bear What Society Cannot?| journal =JAMA. | date =October 2, 2013| author1 =Brian P. O’Sullivan| author2 = David M. Orenstein| author3 = Carlos E. Milla| volume =310| issue =13| pages =1343–1344| url =http://jama.jamanetwork.com/article.aspx?articleID=1745685| doi =10.1001/jama.2013.278129| pmid =| pmc =}}</ref> The company responded in an email that "while publicly funded academic research provided important early understanding of the cause of cystic fibrosis, it took Vertex scientists 14 years of their own research, funded mostly by the company, before the drug won approval."<ref>{{cite web |url=http://www.medpagetoday.com/Pulmonology/CysticFibrosis/39217 |title=Cystic Fibrosis: Charity and Industry Partner for Profit |publisher=MedPage Today |date=May 19, 2013 |accessdate=2015-02-10 }}</ref>
=== Legal status ===
The U.S. ] (FDA) approved ivacaftor in January 2012,<ref>{{cite press release | title=FDA approves Kalydeco to treat rare form of cystic fibrosis | website=U.S. ] (FDA) | date=31 January 2012 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm | archive-url=https://web.archive.org/web/20160318062836/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm | archive-date=18 March 2016 | url-status=dead | access-date=20 November 2019}}{{PD-notice}}</ref>
<ref>{{cite web | title=Drug Approval Package: Kalydeco (ivacaftor) | website=U.S. ] (FDA) | date=13 March 2012 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188s000TOC.cfm | archive-url=https://web.archive.org/web/20191121044013/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188s000TOC.cfm | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}{{PD-notice}}</ref><ref>{{cite web | vauthors = Herper M |url=https://www.forbes.com/sites/matthewherper/2012/12/27/the-most-important-new-drug-of-2012/ |title=The Most Important New Drug Of 2012 |website=] }}</ref><ref>{{cite news |url=https://www.nytimes.com/2014/07/19/opinion/joe-nocera-cystic-fibrosis-drug-price.html|title=The $300,000 Drug | vauthors = Nocera J |website=] |date=18 July 2014 |access-date=20 November 2019 }}</ref>


Soon afterwards so too did the ] (EMA)<ref name="url_EMA_Kalydeco">{{cite web | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002494/WC500130696.pdf | title = Kalydeco: Annex I: Summary of product characteristics | publisher = European Medicines Agency | access-date = 24 July 2013 | archive-date = 20 September 2018 | archive-url = https://web.archive.org/web/20180920153601/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002494/WC500130696.pdf | url-status = dead }}</ref><ref name="Kalydeco EPAR">{{cite web | title=Kalydeco EPAR | website=] (EMA) | date=6 August 2012 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/kalydeco | archive-url=https://web.archive.org/web/20191121052623/https://www.ema.europa.eu/en/medicines/human/EPAR/kalydeco | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}</ref> and Canada<ref>{{Cite web |url=http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_kalydeco_155318-eng.php |title=Summary Basis of Decision (SBD): Kalydeco - 2012 - Health Canada |access-date=19 August 2014 |archive-url=https://web.archive.org/web/20140806003330/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_kalydeco_155318-eng.php |archive-date=6 August 2014 |url-status=dead }}</ref> and across some European countries.<ref>{{cite web | title=Kalydeco 50mg granules sachets - Summary of Product Characteristics (SmPC) | website=(emc) | date=30 August 2019 | url=https://www.medicines.org.uk/emc/product/1954/smpc | archive-url=https://web.archive.org/web/20191121053025/https://www.medicines.org.uk/emc/product/1954/smpc | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}</ref><ref>{{cite web | title=Kalydeco 75mg granules sachets - Summary of Product Characteristics (SmPC) | website=(emc) | date=30 August 2019 | url=https://www.medicines.org.uk/emc/product/10150/smpc | archive-url=https://web.archive.org/web/20191121053132/https://www.medicines.org.uk/emc/product/10150/smpc | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}</ref><ref>{{cite web | title=Kalydeco 150 mg film-coated tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=30 August 2019 | url=https://www.medicines.org.uk/emc/product/3040/smpc | archive-url=https://web.archive.org/web/20191121053223/https://www.medicines.org.uk/emc/product/3040/smpc | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}</ref>
The Cystic Fibrosis Foundation, a non-profit organization dedicated to improving healthcare for people with cystic fibrosis, provided $150 million of the funding for the development for ivacaftor in exchange for royalty rights in the event that the drug was successfully developed and commercialized. In 2014, the Foundation sold these royalty rights for $3.3 billion. The Foundation has stated that it intends to spend these funds in support of further research.<ref>{{cite web |url=http://www.xconomy.com/boston/2014/11/19/cf-foundation-cashes-out-on-kalydeco-in-3-3b-sale-to-royalty-pharma/ |title=CF Foundation Cashes Out on Kalydeco in $3.3B Sale to Royalty Pharma &#124; Xconomy |format= |work= |accessdate=}}</ref><ref>{{cite web |url=http://www.cff.org/aboutCFFoundation/PressRoom/PressReleases/PressReleaseArchive/11-19-Transformational-Royalty-Sale.cfm |title=CF Foundation Royalty Sale Will Be Transformational for People with CF |format= |work= |accessdate=}}</ref>


Lumacaftor/ivacaftor was approved by the FDA in July 2015, under ] status and under a ].<ref>{{cite press release |title=FDA approves new treatment for cystic fibrosis|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453565.htm|publisher=U.S. ] (FDA) |date=2 July 2015|archive-url=https://wayback.archive-it.org/7993/20180126023456/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453565.htm | archive-date=2018-01-26 | url-status=dead }}{{PD-notice}}</ref><ref>{{cite web | title=Orkambi (lumacaftor/ivacaftor) Oral Tablet | website=U.S. ] (FDA) | date=21 November 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/0206038Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20191121060150/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/0206038Orig1s000TOC.cfm | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}{{PD-notice}}</ref>
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.<ref>{{cite press release |author=<!--Staff writer(s); no by-line.--> |title= FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis|url= http://investors.vrtx.com/releasedetail.cfm?ReleaseID=644257|location= Cambridge, Massachusetts|publisher= ]|date= 2012-01-31|accessdate=2014-02-01}}</ref> In 2012, 24 US doctors and researchers involved in the development of the drug wrote to Vertex to protest the price of the drug, which had been set at about $300,000 per year. 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 (]) at between £335,000 and £1,274,000 —well above the ] thresholds.<ref name="BMJ-2014">{{cite journal| title =Orphan Drugs: Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding| journal =BMJ | date =12 February 2014| author1 =Deborah Cohen| author2 = James Raftery| volume =348 | issue =| pages =g1445| url =http://www.bmj.com/content/348/bmj.g1445| doi =10.1136/bmj.g1445 | pmid =| pmc =}}</ref>


===Economics===
The drug was not covered under the ] plan until June 2014 when the ] and the manufacturer negotiated for what "Ontario Health Minister ] 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.<ref>{{cite news |last= Ferguson|first=Rob |date=June 20, 2014 |title=OHIP to cover cystic fibrosis drug Kalydeco |url=http://www.thestar.com/news/queenspark/2014/06/20/ohip_to_cover_cystic_fibrosis_drug_kalydeco.html |newspaper=The Toronto Star |location= |publisher= |accessdate= June 20, 2014}}</ref>
It is one of the most expensive drugs, costing over {{US$|300,000}} per year, which has led to criticism of the high cost. The cost of ivacaftor is {{US$|311,000}} per year, roughly similar to the price of other medications for extremely rare diseases.<ref>{{cite news | vauthors = Pollack A |url=https://www.nytimes.com/2012/02/01/business/fda-approves-cystic-fibrosis-drug.html |title=F.D.A. Approves New Cystic Fibrosis Drug |work=] |date=31 January 2012 |access-date=2015-02-10 }}</ref> In the first nine months of its second year on the market (2014), ivacaftor sales were $339M, representing 54% of Vertex's product sales revenue. During the same period, total drug development expenses were $458M, most of which was spent on cystic fibrosis-related research.<ref>{{cite web |url=https://www.sec.gov/Archives/edgar/data/875320/000087532014000063/a2014q310-q.htm |title=Vertex Pharmaceuticals 10-Q, Quarter ending September 30, 2014 |access-date=2015-02-10 }}</ref>


An editorial in JAMA called the price of ivacaftor "exorbitant", citing the support by the ] in its development and the contribution made by fundamental scientific research performed by the ] and relied upon by Vertex in its cystic fibrosis drug discovery programs.<ref name="exorbitant">{{cite journal | vauthors = O'Sullivan BP, Orenstein DM, Milla CE | title = Pricing for orphan drugs: will the market bear what society cannot? | journal = JAMA | volume = 310 | issue = 13 | pages = 1343–1344 | date = October 2013 | pmid = 24084916 | doi = 10.1001/jama.2013.278129 }}</ref> The company responded in an email that "while publicly funded academic research provided important early understanding of the cause of cystic fibrosis, it took Vertex scientists 14 years of their own research, funded mostly by the company, before the drug won approval."<ref>{{cite web | vauthors = Fauber J |url=http://www.medpagetoday.com/Pulmonology/CysticFibrosis/39217 |title=Cystic Fibrosis: Charity and Industry Partner for Profit | work = Milwauke Journal-Sentinel | via = MedPage Today |date=19 May 2013 |access-date=2015-02-10 }}</ref>
The province of ] began covering the drug in July 2014, and in September the province of ] became the third province to include it in its provincial drug plan.<ref>{{cite news

The Cystic Fibrosis Foundation, a non-profit organization dedicated to improving healthcare for people with cystic fibrosis, provided $150 million of the funding for the development for ivacaftor in exchange for royalty rights in the event that the medication was successfully developed and commercialized. In 2014, the Foundation sold these royalty rights for $3.3 billion. The Foundation has stated that it intends to spend these funds in support of further research.<ref>{{cite web | vauthors = Fidler B |url=http://www.xconomy.com/boston/2014/11/19/cf-foundation-cashes-out-on-kalydeco-in-3-3b-sale-to-royalty-pharma/ | archive-url = https://web.archive.org/web/20150204040909/http://www.xconomy.com/boston/2014/11/19/cf-foundation-cashes-out-on-kalydeco-in-3-3b-sale-to-royalty-pharma/ | archive-date = 4 February 2015 |title=CF Foundation Cashes Out on Kalydeco in $3.3B Sale to Royalty Pharma | work = Xconomy |date=19 November 2014 }}</ref><ref>{{cite web |url=http://www.cff.org/aboutCFFoundation/PressRoom/PressReleases/PressReleaseArchive/11-19-Transformational-Royalty-Sale.cfm |title=CF Foundation Royalty Sale Will Be Transformational for People with CF |archive-url=https://web.archive.org/web/20141227030211/http://www.cff.org/aboutCFFoundation/PressRoom/PressReleases/PressReleaseArchive/11-19-Transformational-Royalty-Sale.cfm |archive-date=27 December 2014 |url-status=dead }}</ref>

Vertex said it would make the medication available free to patients in the United States with no insurance and a household income of under $150,000.<ref>{{cite press release |author=<!--Staff writer(s); no by-line.--> |title= FDA Approves Kalydeco (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis|url= http://investors.vrtx.com/releasedetail.cfm?ReleaseID=644257|location= Cambridge, Massachusetts|publisher= ]|date= 2012-01-31|access-date=2014-02-01}}</ref> In 2012, 24 US doctors and researchers involved in the development of the medication wrote to Vertex to protest the price of the medication, which had been set at about $300,000 per year. In the UK, the company provided the medication 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 (]) at between £335,000 and £1,274,000 —well above the ] thresholds.<ref name="BMJ-2014">{{cite journal | vauthors = Cohen D, Raftery J | title = Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding | journal = BMJ | volume = 348 | pages = g1445 | date = February 2014 | pmid = 24523379 | doi = 10.1136/bmj.g1445 | s2cid = 8702814 }}</ref>

The medication was not covered under the ] plan until June 2014, when the ] and the manufacturer negotiated for what "Ontario Health Minister ] had called a "fair price" for taxpayers". The negotiations took 16 months and it was estimated that around 20 Ontarians required the medication at the time.<ref>{{cite news | vauthors = Ferguson R |date=20 June 2014 |title=OHIP to cover cystic fibrosis drug Kalydeco |url=https://www.thestar.com/news/queenspark/2014/06/20/ohip_to_cover_cystic_fibrosis_drug_kalydeco.html |newspaper=The Toronto Star |access-date= 20 June 2014 }}</ref>

The province of ] began covering the medication in July 2014, and in September the province of ] became the third province to include it in its provincial medication plan.<ref>{{cite news
| url = http://www.cbc.ca/news/canada/saskatchewan/saskatchewan-to-cover-300k-cystic-fibrosis-drug-kalydeco-1.2749525 | url = http://www.cbc.ca/news/canada/saskatchewan/saskatchewan-to-cover-300k-cystic-fibrosis-drug-kalydeco-1.2749525
| title = Saskatchewan to cover $300K cystic fibrosis drug Kalydeco | title = Saskatchewan to cover $300K cystic fibrosis drug Kalydeco
| publisher = ] | publisher = ]
| date = 2014-08-28 | date = 2014-08-28
| accessdate = 2014-08-28}}</ref> | access-date = 2014-08-28
}}</ref>


Government delays in agreeing to provide ivacaftor in national health plans led to patient group protests in Wales,<ref>{{cite web |url=http://www.itv.com/news/wales/update/2013-05-08/plea-for-kalydeco-drug-to-be-introduced/ |title=Plea for Kalydeco drug to be introduced &#124; Wales - ITV News |format= |work= |accessdate=}}</ref><ref>{{cite web |url=http://www.bbc.com/news/uk-wales-22440811 |title=BBC News - Cystic fibrosis: New drug Kalydeco refused for Welsh NHS |format= |work= |accessdate=}}</ref> England,<ref>{{cite web |url=http://www.birminghammail.co.uk/news/health/protests-at-birmingham-hospital-as-cystic-fibrosis-274099 |title=Protests at Birmingham Hospital as cystic fibrosis sufferer is denied life-saving drug - Birmingham Mail |format= |work= |accessdate=}}</ref> and Australia.<ref>{{cite web |url=http://www.manningrivertimes.com.au/story/1991040/kalydeco-breakthrough-plea-for-life-saving-medicine-proves-a-winner/ |title=Kalydeco breakthrough: Plea for life-saving medicine proves a winner &#124; Manning River Times |format= |work= |accessdate=}}</ref> Delay in agreement on a price for Vertex to charge national health plans led to patient group protests in Wales,<ref>{{cite web |url=http://www.itv.com/news/wales/update/2013-05-08/plea-for-kalydeco-drug-to-be-introduced/ |title=Plea for Kalydeco drug to be introduced | location = Wales | work = ITV News }}</ref><ref>{{cite web |url=https://www.bbc.com/news/uk-wales-22440811 |title=Cystic fibrosis: New drug Kalydeco refused for Welsh NHS |website=BBC News Online|date=8 May 2013 }}</ref> England,<ref>{{cite web | vauthors = Lockley M |url= http://www.birminghammail.co.uk/news/health/protests-at-birmingham-hospital-as-cystic-fibrosis-274099 |title=Protests at Birmingham Hospital as cystic fibrosis sufferer is denied life-saving drug |website=Birmingham Mail |date=29 October 2012 }}</ref> and Australia.<ref>{{cite web | vauthors = Swain E |url=http://www.manningrivertimes.com.au/story/1991040/kalydeco-breakthrough-plea-for-life-saving-medicine-proves-a-winner/ |title=Kalydeco breakthrough: Plea for life-saving medicine proves a winner |website=Manning River Times |date=23 December 2013 }}</ref>


{{As of|March 2016}}, {{clarify span|the combination medication Orkambi|which combination drug?|date=March 2024}} cost $259,000 a year in the United States.<ref name=FierceNICE>{{cite web| vauthors = Wasserman E |title=NICE gives initial thumbs-down to Vertex's CF combo med Orkambi, citing costs|url=http://www.fiercepharma.com/story/nice-gives-initial-thumbs-down-vertexs-cf-combo-med-orkambi-citing-costs/2016-03-23|publisher=FiercePharma|date=23 March 2016}}</ref>
== See also ==

* ], targeting premature stop codons
==Research==
* ], targeting the F508del mutation
The clinical trials used in the regulatory approval of ivacaftor are described here.

===G551D mutation===
Of the approximately 70,000 cases of cystic fibrosis worldwide, 4% (~3,000) are due to a mutation called G551D.<ref>{{cite web |url=http://www.cff.org/AboutCF/Faqs/ |title=FAQs about the Cause, Diagnosis, Treatment of Cystic Fibrosis & More | work = CF Foundation |access-date=27 December 2014 |archive-date=25 October 2006 |archive-url=https://web.archive.org/web/20061025192633/http://www.cff.org/AboutCF/Faqs/ |url-status=dead }}</ref><ref>{{cite journal | vauthors = Bobadilla JL, Macek M, Fine JP, Farrell PM | title = Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening | journal = Human Mutation | volume = 19 | issue = 6 | pages = 575–606 | date = June 2002 | pmid = 12007216 | doi = 10.1002/humu.10041 | s2cid = 35428054 | doi-access = }}</ref> The safety and efficacy of ivacaftor for the treatment of cystic fibrosis in patients with this mutation was examined in two clinical trials.{{citation needed|date=November 2019}}

The first trial was performed in adults having baseline respiratory function (FEV1) between 32% and 98% of normal for persons of similar age, height, and weight. The baseline average was 64%. Improvement in FEV1 was rapid and sustained. At the end of 48 weeks, people treated with ivacaftor had on average an absolute increase in FEV1 of 10.4%, vs. a decline of 0.2% in the placebo group. Pulmonary exacerbations were reduced by about half in the ivacaftor group relative to the placebo group.<ref name="Kalydeco label" />

In a second trial conducted in children age six to 11, the average improvement in FEV1 was an absolute increase of 12.5% in the ivacaftor group at 48 weeks, compared to a very slight decline in the placebo group.<ref name="Kalydeco label" />

===Other mutations ===
A third clinical trial examined the efficacy of ivacaftor in people with cystic fibrosis due to G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations. This trial, which included 39 people of age greater than six years, used a crossover design. The people in the trial had FEV1 averaging 78% of normal at baseline. The people in the trial were randomized to receive either ivacaftor or placebo for eight weeks. This was followed by a four to eight week washout period, then each group received the opposite treatment from what it received in the first part of the trial. At week 8, the people on treatment with ivacaftor experienced an average absolute improvement in FEV1 of 13.8%, but there was a strong dependence of the efficacy on the exact mutation that a patient had. The detailed data for different mutation types is shown in the U.S. package insert.<ref name="Kalydeco label" />


== References == == References ==
{{reflist|35em}} {{reflist}}


== External links == == External links ==
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/ivacaftor | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Ivacaftor }}
* from the Cystic Fibrosis Foundation
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/ivacaftor%20mixture%20with%20lumacaftor | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Ivacaftor mixture with lumacaftor }}
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/ivacaftor%20regimen%20with%20tezacaftor | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Ivacaftor regimen with Tezacaftor }}
* {{cite web | title=Lumacaftor and Ivacaftor | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a615037.html }}
* {{cite web | title=Tezacaftor and Ivacaftor | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a618022.html }}
* {{cite web | title=Elexacaftor, Tezacaftor, and Ivacaftor | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a619061.html }}


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