Lumacaftor/ivacaftor

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Lumacaftor/ivacaftor
Ivacaftor and lumacaftor.svg
Combination of
Lumacaftor CFTR chaperone
Ivacaftor CFTR potentiator
Clinical data
Trade names Orkambi, Lucaftor
AHFS/Drugs.com Monograph
MedlinePlus a615037
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
KEGG

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. [4] It is unclear if it is useful in cystic fibrosis due to other causes. [4] It is taken by mouth. [4]

Contents

Common side effects include shortness of breath, nausea, diarrhea, feeling tired, hearing problems, and rash. [4] [5] Severe side effects may include liver problems and cataracts. [4] Ivacaftor increases the activity of the CFTR protein, while lumacaftor improves protein folding of the CFTR protein. [4] [6]

It was approved for medical use in the United States in 2015, and in Canada in 2016. [4] [6] In the United States it costs more than US$22,000 a month as of 2018. [7] [8] While its use was not recommended in the United Kingdom as of 2018, [5] pricing was agreed upon in 2019 and it is expected to be covered by November of that year. [9]

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. [3] [10] This genetic abnormality is present in about half of cystic fibrosis cases in Canada. [6] Its use is not recommended for anyone with cystic fibrosis in the United Kingdom as of 2018. [5]

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. [6] 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. [6] Effects on life expectancy are unclear. [6]

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. [3]

People starting the combination have respiratory discomfort, and some children taking the combination drug developed cataracts. [3]

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. [3]

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. [11] [12] 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. [10] The two drugs have synergistic effects. [10]

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. [3]

History

Lumacaftor/ivacaftor was approved by the FDA in July 2015 under breakthrough therapy status and under a priority review. [13] Previously approved for adults and pre-teens, approved in 2018 for children age 2–5. [14] In 2022 it was approved for children age 1–2. [15]

Society and culture

As of March 2016 the combination drug cost $259,000 a year in the United States. [16]

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. [17]

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. [18] 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. [19]

Protracted discussions within the United Kingdom were brought to a conclusion in September and October 2019 as NHS Scotland and NHS England both struck deals with Vertex respectively. This followed discussions where Vertex had wanted £105 000 per patient for Orkambi. [9]

The drug was not patented in Argentina, so can be made by other companies. Buyers' clubs in the UK have been buying the generic version from the Argentinian company Gador. [20]

Related Research Articles

<span class="mw-page-title-main">Cystic fibrosis</span> Autosomal recessive disease mostly affecting the lungs

Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. The hallmark feature of CF is the accumulation of thick mucus in different organs. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.

<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in humans

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

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<span class="mw-page-title-main">Cystic Fibrosis Foundation</span> American non-profit organisation

The Cystic Fibrosis Foundation (CFF) is a 501(c)(3) non-profit organization in the United States established to provide the means to cure cystic fibrosis (CF) and ensure that those living with CF live long and productive lives. The Foundation provides information about cystic fibrosis and finances CF research that aims to improve the quality of life for people with the disease. The Foundation also engages in legislative lobbying for cystic fibrosis.

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<span class="mw-page-title-main">Ivacaftor</span> Cystic fibrosis treatment drug

Ivacaftor is a medication used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, who account for 4–5% cases of cystic fibrosis. It is also included in combination medications, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor which are used to treat people with cystic fibrosis.

Lumacaftor (VX-809) is a pharmaceutical drug that acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. It is available in a single pill with ivacaftor; the combination, lumacaftor/ivacaftor, is used to treat people with cystic fibrosis who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the defective protein that causes the disease. It was developed by Vertex Pharmaceuticals and the combination was approved by the FDA in 2015. As of 2015, lumacaftor had no medical use on its own.

<span class="mw-page-title-main">Tezacaftor</span> Chemical compound

Tezacaftor is a drug used for the treatment of cystic fibrosis (CF) in people six years and older, who have a F508del mutation, the most common type of mutation in the CFTR gene. It is sold as a fixed-dose combination with ivacaftor under the brand name Symdeko. It was approved by the U.S. FDA in 2018. The combination of elexacaftor, tezacaftor, and ivacaftor is being sold as Trikafta.

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Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta and Kaftrio, is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.

<span class="mw-page-title-main">Elexacaftor</span> Chemical compound

Elexacaftor is a medication that acts as cystic fibrosis transmembrane conductance regulator (CFTR) corrector.

Peter Grootenhuis was a Dutch-American Medicinal Chemist. Grootenhuis was the Project Leader and Co-Inventor of Ivacaftor (VX-770), the first CFTR potentiator FDA approved drug to treat the underlying cause of Cystic Fibrosis (CF) in patients with certain mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, who account for 4-5% of CF cases. Grootenhuis also led the Vertex team to subsequent discovery of Orkambi, the combination of Ivacaftor and Lumacaftor(VX-809), approved to treat CF in people with two copies of the F508del mutation. Most recently, Grootenhuis's team discovered Tezacaftor (VX-661) and Elexacaftor (VX-445), which in combination with Ivacaftor are the components of Trikafta, a drug approved by the FDA in 2019 to treat CF in more than 90% of CF patients. For Grootenhuis’ contributions to the discovery of these compounds, he was awarded the 2018 IUPAC Richter Prize, the American Chemical Society’s 2013 Heroes of Chemistry Award, and inducted into the American Chemical Society Division of Medicinal Chemistry Hall of Fame. Grootenhuis has contributed to the discovery of over 11 clinical candidates, co-authored more than 100 peer reviewed papers and is inventor of 65 + U.S Patents, and more than 50 EU Patents.

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Paul Adrian Negulescu is an American–Romanian cell biologist. He is the Senior Vice President and Site Head of the San Diego Research Center of American pharmaceutical company Vertex Pharmaceuticals. He received the 2022 Shaw Prize in Life science and medicine, together with Michael J. Welsh, for their work that uncovered the etiology of cystic fibrosis and developed effective medications.

Michael James Welsh is an American pulmonologist. He is the current Roy J. Carver Chair in Biomedical Research, the Professor of Internal Medicine in Pulmonary, Critical Care and Occupational Medicine at the Department of Internal Medicine, and the Director of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa. He is also a professor at the Department of Neurosurgery, Department of Neurology, and Department of Molecular Physiology and Biophysics. He received the 2022 Shaw Prize in Life science and Medicine, together with Paul A. Negulescu, for their work that uncovered the etiology of cystic fibrosis and developed effective medications.

References

  1. ↑ "Ivacaftor / lumacaftor (Orkambi) Use During Pregnancy". Drugs.com. 10 September 2020. Archived from the original on 26 October 2020. Retrieved 15 October 2020.
  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  3. 1 2 3 4 5 6 "Orkambi- lumacaftor and ivacaftor tablet, film coated Orkambi- lumacaftor and ivacaftor granule". DailyMed. 11 May 2020. Archived from the original on 3 August 2020. Retrieved 15 October 2020.
  4. 1 2 3 4 5 6 7 "Orkambi Monograph for Professionals". Drugs.com. AHFS. Archived from the original on 9 January 2019. Retrieved 8 January 2019.
  5. 1 2 3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 293–294. ISBN   9780857113382. Archived from the original on 28 August 2021. Retrieved 4 February 2019.
  6. 1 2 3 4 5 6 "[116] New drug for cystic fibrosis: Regulatory approval, clinical uncertainty?". Therapeutics Initiative. 28 December 2018. Archived from the original on 9 January 2019. Retrieved 8 January 2019.
  7. ↑ Ferkol T, Quinton P (September 2015). "Precision Medicine: At What Price?". American Journal of Respiratory and Critical Care Medicine. 192 (6): 658–9. doi:10.1164/rccm.201507-1428ED. PMID   26207804.
  8. ↑ Thomas K (24 June 2018). "A Drug Costs $272,000 a Year. Not So Fast, Says New York State". The New York Times. Archived from the original on 9 January 2019. Retrieved 8 January 2019.
  9. 1 2 Kmietowicz Z (October 2019). "Cystic fibrosis drugs to be available on NHS in England within 30 days". BMJ. 367: l6206. doi:10.1136/bmj.l6206. PMID   31649013. S2CID   204883523. Archived from the original on 25 October 2019. Retrieved 25 October 2019.
  10. 1 2 3 Kuk K, Taylor-Cousar JL (December 2015). "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. doi: 10.1177/1753465815601934 . PMID   26416827.
  11. ↑ "Orkambi (lumacaftor and ivacaftor)". CenterWatch. Archived from the original on 19 March 2016. Retrieved 24 March 2016.
  12. ↑ Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, et al. (October 2013). "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. doi:10.1091/mbc.E13-05-0240. PMC   3784376 . PMID   23924900.
  13. ↑ "FDA approves new treatment for cystic fibrosis". United States Food and Drug Administration. 2 July 2015. Archived from the original on 26 January 2018. Retrieved 16 December 2019.
  14. ↑ "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". www.businesswire.com. 7 August 2018. Retrieved 28 March 2024.
  15. ↑ "Vertex Announces U.S. FDA Approval for ORKAMBI® (lumacaftor/ivacaftor) in Children With Cystic Fibrosis Ages 12 to". www.businesswire.com. 2 September 2022. Retrieved 28 March 2024.
  16. ↑ Wasserman E (23 March 2016). "NICE gives initial thumbs-down to Vertex's CF combo med Orkambi, citing costs". FiercePharma. Archived from the original on 28 March 2016. Retrieved 25 March 2016.
  17. ↑ Kjeldtoft SS (1 August 2015). "10-årige Elisabeth spiser 33 piller om dagen" (in Danish). Information. Archived from the original on 3 August 2015. Retrieved 1 August 2015.
  18. ↑ "Onderhandelingen over taaislijmziekte weer mislukt" [Negotiations over throat gland disease failed again] (in Dutch). NOS. Algemeen Nederlands Persbureau. 9 August 2017. Archived from the original on 10 October 2017. Retrieved 11 October 2017.
  19. ↑ Zenthis R (25 August 2017). "Medicijn tegen taaislijmziekte toch opgenomen in basispakket" [Cystic Fibrosis medicine approved for basic insurance package] (in Dutch). Nu.nl. Algemeen Nederlands Persbureau/Nu.nl. Archived from the original on 25 October 2017. Retrieved 25 October 2017.
  20. ↑ Boseley S (4 June 2019). "Families create buyers club for cut-price cystic fibrosis drug". The Guardian . Archived from the original on 18 May 2020. Retrieved 29 January 2020.
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