Lumacaftor/ivacaftor explained

Type:combo
Width:240
Component1:Lumacaftor
Class1:CFTR chaperone
Component2:Ivacaftor
Class2:CFTR potentiator
Tradename:Orkambi, Lucaftor
Dailymedid:Orkambi
Pregnancy Au:B3
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth
Atc Prefix:R07
Atc Suffix:AX30
Legal Au:S4
Legal Au Comment:[2]
Legal Ca:Rx-only
Legal Ca Comment:[3]
Legal Uk:POM
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[4]
Cas Number:1815566-23-4
Kegg:D10685

Lumacaftor/ivacaftor, sold under the brand name Orkambi among others, is a combination of lumacaftor and ivacaftor used to treat people with cystic fibrosis who have two copies of the F508del mutation.[5] It is unclear if it is useful in cystic fibrosis due to other causes.[5] It is taken by mouth.[5]

Common side effects include shortness of breath, nausea, diarrhea, feeling tired, hearing problems, and rash.[5] [6] Severe side effects may include liver problems and cataracts.[5] Ivacaftor increases the activity of the CFTR protein, while lumacaftor improves protein folding of the CFTR protein.[5]

It was approved for medical use in the United States in 2015, and in Canada in 2016.[5] [7] In the United States it costs more than a month as of 2018.[8] [9] While its use was not recommended in the United Kingdom as of 2018,[6] pricing was agreed upon in 2019 and it is expected to be covered by November of that year.[10]

Medical use

The combination of lumacaftor/ivacaftor is used to treat people with cystic fibrosis who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease.[11] This genetic abnormality is present in about half of cystic fibrosis cases in Canada.[7] Its use is not recommended for anyone with cystic fibrosis in the United Kingdom as of 2018.[6]

While the medication resulted in improvement in the amount of air a person can breathe out in one second, the improvement seen did not reach a clinically important amount.[7] The medication also does not appear to change a person's quality of life or the number of times a year a person has a worsening of lung function.[7] Effects on life expectancy are unclear.[7]

Side effects

Some people taking the combination drug had elevated transaminases; the combination drug should be used with caution for people with advanced liver disease and liver function should be measured for the first three months for all people starting the combination drug.[11]

People starting the combination have respiratory discomfort, and some children taking the combination drug developed cataracts.[11]

Lumacaftor/ivacaftor may interfere with hormonal contraceptives. Dosage of the combination drug should be reduced if the person is taking a drug that inhibits CYP3A, and inducers of CYP3A should not be used concomitantly.[11]

Mechanism of action

F508del is a mutation that causes the CFTR protein to misfold and cells destroy such proteins soon after they are made; lumacaftor acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface.[12] [13] Ivacaftor is a potentiator of CFTR that is already at the cell surface, increasing the probability that the defective channel will be open and allow chloride ions to pass through the channel pore.[14] The two drugs have synergistic effects.[14]

Physical properties

Each of lumacaftor and ivacaftor is a white to off-white powder that is practically insoluble in water. The combination drug is a single pill containing 200 mg of lumacaftor and 125 mg of ivacaftor.[11]

History

Lumacaftor/ivacaftor was approved by the FDA in July 2015, under breakthrough therapy status and under a priority review.[15] Previously approved for adults and pre-teens, approved in 2018 for children age 2–5.[16] In 2022 it was approved for children age 1–2.[17]

Society and culture

As of March 2016, the combination drug cost per year in the United States.[18]

In Denmark, it was estimated in August 2015, that if the drug were introduced, the cost would amount to 2 million Danish krones (approximately 270,000 euro) each year per person.[19]

The Dutch Minister of Health announced in October 2017 that the drug would not be admitted to the public health insurance package, making it impossible to have treatment with the drug covered by Dutch health insurance. The minister stated that the price for the drug, negotiated to 170,000 euro per patient per year, is "unacceptably high in relation to the relatively modest effect, as determined by the (Dutch) Healthcare Institute". Approximately 750 patients are affected by this decision.[20] On 25 October, the Dutch Minister of Health announced that an agreement had been brokered with Vertex Pharmaceuticals, the company that manufactures the drug, resulting in admittance to the Dutch public health insurance package. Part of the agreement is that the result of the negotiation about the price of the treatment will not be disclosed.[21]

NHS Scotland and NHS England both struck deals with Vertex in 2019. This followed discussions where Vertex wanted per person for Orkambi.[10]

Notes and References

  1. Web site: Ivacaftor / lumacaftor (Orkambi) Use During Pregnancy . Drugs.com . 10 September 2020 . 15 October 2020 . 26 October 2020 . https://web.archive.org/web/20201026170717/https://www.drugs.com/pregnancy/ivacaftor-lumacaftor.html . live .
  2. Web site: Prescription medicines: registration of new chemical entities in Australia, 2016 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 10 April 2023.
  3. Web site: Health Canada New Drug Authorizations: 2016 Highlights . . 14 March 2017 . 7 April 2024.
  4. Web site: Orkambi . European Medicines Agency . 19 November 2015 . 4 July 2024.
  5. Web site: Orkambi Monograph for Professionals . Drugs.com . AHFS . 8 January 2019 . 9 January 2019 . https://web.archive.org/web/20190109012007/https://www.drugs.com/monograph/orkambi.html . live .
  6. Book: British national formulary : BNF 76. 2018. Pharmaceutical Press. 9780857113382. 293–294. 76. 4 February 2019. 28 August 2021. https://web.archive.org/web/20210828151648/https://www.nice.org.uk/bnf-uk-only. live.
  7. Web site: [116] New drug for cystic fibrosis: Regulatory approval, clinical uncertainty? ]. Therapeutics Initiative . 8 January 2019 . 28 December 2018 . 9 January 2019 . https://web.archive.org/web/20190109062208/https://www.ti.ubc.ca/2018/12/27/116-new-drug-for-cystic-fibrosis-regulatory-approval-clinical-uncertainty/ . live .
  8. Ferkol T, Quinton P . Precision Medicine: At What Price? . American Journal of Respiratory and Critical Care Medicine . 192 . 6 . 658–9 . September 2015 . 26207804 . 10.1164/rccm.201507-1428ED .
  9. News: Thomas . Katie . A Drug Costs $272,000 a Year. Not So Fast, Says New York State. . 8 January 2019 . The New York Times . 24 June 2018 . 9 January 2019 . https://web.archive.org/web/20190109012133/https://www.nytimes.com/2018/06/24/health/drug-prices-orkambi-new-york.html . live .
  10. Kmietowicz Z . 204883523 . Cystic fibrosis drugs to be available on NHS in England within 30 days . BMJ . 367 . l6206 . October 2019 . 31649013 . 10.1136/bmj.l6206 . 25 October 2019 . 25 October 2019 . https://web.archive.org/web/20191025055904/https://www.bmj.com/content/367/bmj.l6206 . live .
  11. Web site: Orkambi- lumacaftor and ivacaftor tablet, film coated Orkambi- lumacaftor and ivacaftor granule . DailyMed . 11 May 2020 . 15 October 2020 . 3 August 2020 . https://web.archive.org/web/20200803141717/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3fc1c40e-cfac-47a1-9e1a-61ead3570600 . live .
  12. Web site: Orkambi (lumacaftor and ivacaftor). CenterWatch. 24 March 2016. 19 March 2016. https://web.archive.org/web/20160319043353/http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100082/orkambi-lumacaftor-and-ivacaftor. live.
  13. Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, Hoffman BJ, Cyr DM . VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1 . Molecular Biology of the Cell . 24 . 19 . 3016–24 . October 2013 . 23924900 . 3784376 . 10.1091/mbc.E13-05-0240 .
  14. Kuk K, Taylor-Cousar JL . Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects . Therapeutic Advances in Respiratory Disease . 9 . 6 . 313–26 . December 2015 . 26416827 . 10.1177/1753465815601934 . free .
  15. Web site: FDA approves new treatment for cystic fibrosis. United States Food and Drug Administration. 2 July 2015. 16 December 2019. 26 January 2018. https://wayback.archive-it.org/7993/20180126023456/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453565.htm. live.
  16. FDA Approves ORKAMBI (lumacaftor/ivacaftor) as First Medicine to Treat the Underlying Cause of Cystic Fibrosis for Children Ages 2-5 Years with Most Common Form of the Disease . Business Wire . 28 March 2024 . 7 August 2018.
  17. Vertex Announces U.S. FDA Approval for ORKAMBI (lumacaftor/ivacaftor) in Children With Cystic Fibrosis Ages 12 to . Business Wire . 28 March 2024 . 2 September 2022.
  18. Web site: Wasserman. Emily. NICE gives initial thumbs-down to Vertex's CF combo med Orkambi, citing costs. FiercePharma. 23 March 2016. 25 March 2016. 28 March 2016. https://web.archive.org/web/20160328152332/http://www.fiercepharma.com/story/nice-gives-initial-thumbs-down-vertexs-cf-combo-med-orkambi-citing-costs/2016-03-23. live.
  19. News: Sebastian Stryhn . Kjeldtoft . vanc . 10-årige Elisabeth spiser 33 piller om dagen . Information . 1 August 2015 . Danish . 1 August 2015 . 3 August 2015 . https://web.archive.org/web/20150803045054/http://www.information.dk/540825 . live .
  20. News: . Onderhandelingen over taaislijmziekte weer mislukt . Negotiations over throat gland disease failed again . NOS . 9 August 2017 . Dutch . Algemeen Nederlands Persbureau . 11 October 2017 . 10 October 2017 . https://web.archive.org/web/20171010194804/https://nos.nl/artikel/2197100-onderhandelingen-over-taaislijmziekte-weer-mislukt.html . live .
  21. News: Zenthis R . Medicijn tegen taaislijmziekte toch opgenomen in basispakket . Cystic Fibrosis medicine approved for basic insurance package . Nu.nl . 25 August 2017 . Dutch . Algemeen Nederlands Persbureau/Nu.nl . 25 October 2017 . 25 October 2017 . https://web.archive.org/web/20171025234119/https://www.nu.nl/gezondheid/4979288/medicijn-taaislijmziekte-toch-opgenomen-in-basispakket.html . live .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Lumacaftor/ivacaftor".

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