Lumacaftor/ivacaftor (brand name Orkambi) is a combination drug available as a single pill that is used for the treatment of cystic fibrosis in people who have two copies of the F508del mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is a combination drug that consists of lumacaftor and ivacaftor. Ivacaftor increases the activity of the CFTR protein at the surface of epithelial cell, while lumacaftor acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. It was approved by the US FDA in July 2015.
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.
Precautions, side effects and interactions
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.
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.
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. 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. The two drugs have synergistic effects.
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.
Lumacaftor/ivacaftor was approved by the FDA in July 2015 under breakthrough therapy status and under a priority review. Previously approved for adults and pre-teens, recently Approved on 8-7-18 for children age 2-5
Society and culture
As of March 2016 the combination drug cost $259,000 a year in the United States.
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. 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 end result of the negotiation about the price of the treatment will not be disclosed. 
- Lumacaftor/ivacaftor label. Last updated July 2015. Check index page here for label updates
- Kuk, K; Taylor-Cousar, JL (2015). "Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects". Ther Adv Respir Dis. 9 (6): 313–26. doi:10.1177/1753465815601934. PMID 26416827.
- "Orkambi (lumacaftor and ivacaftor)". CenterWatch. Retrieved 24 March 2016.
- Ren, H. Y.; Grove, D. E.; De La Rosa, O.; Houck, S. A.; Sopha, P.; van Goor, F.; Hoffman, B. J.; Cyr, D. M. (7 August 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): 3016–3024. doi:10.1091/mbc.E13-05-0240. PMC . PMID 23924900.
- "FDA approves new treatment for cystic fibrosis". United States Food and Drug Administration. July 2, 2015.
- Wasserman, Emily (March 23, 2016). "NICE gives initial thumbs-down to Vertex's CF combo med Orkambi, citing costs". FiercePharma.
- Sebastian Stryhn Kjeldtoft (1 August 2015). "10-årige Elisabeth spiser 33 piller om dagen" (in Danish). Information.
- "Onderhandelingen over taaislijmziekte weer mislukt" [Negotiations over throat gland disease failed again] (in Dutch). NOS. Algemeen Nederlands Persbureau. 9 August 2017.
- R. Zenthis (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.