Lumacaftor/ivacaftor, sold under the brand name Orkambi among others, is a

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are th ...

of lumacaftor and

ivacaftor Ivacaftor is a medication used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (primarily the G551D mutation), who account for 4–5% cases of cystic fibrosis. It ...

used to treat people with cystic fibrosis who have two copies of the F508del mutation. It is unclear if it is useful in cystic fibrosis due to other causes. It is taken by mouth. Common side effects include

shortness of breath Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

, nausea, diarrhea, feeling tired, hearing problems, and rash. Severe side effects may include

liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the s ...

and

cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...

. Ivacaftor increases the activity of the CFTR protein, while lumacaftor improves

protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduc ...

of the CFTR protein. It was approved for medical use in the United States in 2015, and in Canada in 2016. In the United States it costs more than $US 22,000 a month as of 2018. While its use was not recommended in the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...

as of 2018, pricing was agreed upon in 2019 and it is expected to be covered by November of that year.

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 Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wi ...

(CFTR), the defective protein that causes the disease. This genetic abnormality is present in about half of cystic fibrosis cases in Canada. Its use is not recommended for anyone with cystic fibrosis in the

as of 2018. 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. The medication also does not appear to change a person's

quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

or the number of times a year a person has a worsening of lung function. Effects on

life expectancy Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, current age, and other demographic factors like sex. The most commonly used measure is life expectancy at birth ...

are unclear.

Side effects

Some people taking the combination drug had

elevated transaminases In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, transaminitis, and elevated ...

; the combination drug should be used with caution for people with advanced

liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the si ...

and liver function should be measured for the first three months for all people starting the combination drug. People starting the combination have respiratory discomfort, and some children taking the combination drug developed

. Lumacaftor/ivacaftor may interfere with

hormonal contraceptives Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origina ...

. Dosage of the combination drug should be reduced if the person is taking a drug that inhibits

CYP3A Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus. A homologous locus is found in mice. The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes. These genes ...

, and inducers of

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

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.

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.

History

Lumacaftor/ivacaftor was approved by the FDA in July 2015 under

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...

status and under a

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

. Previously approved for adults and pre-teens, 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. 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 The euro ( symbol: €; code: EUR) is the official currency of 19 out of the member states of the European Union (EU). This group of states is known as the eurozone or, officially, the euro area, and includes about 340 million citizens . ...

) each year per person. 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

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 Vertex Pharmaceuticals is an American biopharmaceutical company based in Boston, Massachusetts. It was one of the first biotech firms to use an explicit strategy of rational drug design rather than combinatorial chemistry. It maintains headqu ...

, 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. 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. 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.

References

External links

* {{Portal bar , Medicine Combination drugs CYP3A4 inducers Cystic fibrosis Breakthrough therapy Wikipedia medicine articles ready to translate Orphan drugs