Elexacaftor/tezacaftor/ivacaftor

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Elexacaftor/tezacaftor/ivacaftor
Combination of
Elexacaftor Cystic fibrosis transmembrane conductance regulator (CFTR) corrector
Tezacaftor CFTR corrector
Ivacaftor Chloride channel opener
Clinical data
Trade names Trikafta, Kaftrio
AHFS/Drugs.com Monograph
MedlinePlus a619061
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
KEGG

Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta and Kaftrio, is a fixed-dose combination medication used to treat cystic fibrosis. [8] [9] Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators. [8]

Contents

It is approved for use in the United States for people aged two years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene. [8] It is also approved for use in Canada, the European Union, and Australia. [9] [11] [2]

Medical uses

The combination is indicated for the treatment of people aged two years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene. [8]

Side effects

The most common side effects affecting more than 5% of patients are headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increase, nasal congestion, blood creatine phosphokinase increase, aspartate aminotransferase increase, rhinorrhea, rhinitis, influenza, sinusitis, and blood bilirubin increase. [8]

Interactions

Concomitant use with CYP3A inducers is not recommended. [12] [8] Dosage must be adjusted with moderate or strong CYP3A inhibitors. [8] [12]

Other drugs with the potential for interaction include warfarin, digoxin, statins, glyburide, nateglinide, and repaglinide. [8] [12]

Pharmacology

Cystic fibrosis and CFTR

Cystic fibrosis is an autosomal recessive genetic disorder of the CFTR protein which reduces chloride and sodium ion transport through the cell membrane, causing thicker than normal mucus secretions. [13] [14] The CFTR protein is found in epithelial cells of the lung, liver, pancreas, digestive tract, and reproductive tracts. [15] [16] [17] CFTR has a role in the production of mucus, sweat, and digestive fluids. [18] The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts. [19] [20]

Mechanism of action

Elexacaftor/tezacaftor/ivacaftor is a tridrug treatment in which the medications work together to increase the transport of chloride and sodium ions and correct fluid shifts that are dysregulated in cystic fibrosis. [21] Its effectiveness is dependent on the type of CF mutations the patient has. [22]

Elexacaftor tezacaftor ivacaftor mechanism of action.png
Complex of ivacaftor with CFTR Complex of Ivacaftor bound to CFTR.png
Complex of ivacaftor with CFTR
Ivacaftor Ivacaftor.svg
Ivacaftor

CFTR channel potentiator

Ivacaftor is a selective small-molecule potentiator of the CFTR protein that increases the protein's ability to open chloride channels. [23] [24] Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein. [25] Ivacaftor's primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations. [24] In the crystalline figure is shown ivacaftor, displayed as a gray ball and stick model on the bottom-right, bound to CFTR docked in a cleft formed by transmembrane helices at the protein-lipid interface. [26]

CFTR correctors

Elexacaftor Elexacaftor.svg
Elexacaftor
Tezacaftor Tezacaftor.svg
Tezacaftor

Elexacaftor and tezacaftor act as CFTR correctors to repair F508del processing by binding to the CFTR protein to increase the availability of CFTR protein on the cell surface. [24] They work by modulating the position of the CFTR protein into the right position on the cell surface. [21] Elexacaftor binds at a different site than tezacaftor. [27]

The combination of increased CFTR protein in the correct position on the cell surface with ivacaftor's potentiation of chloride channel opening results in increased transport of chloride and thinned mucus secretions. [24]

Pharmacokinetics

Elexacaftor/tezacaftor/ivacaftor is primarily metabolized by CYP3A4 /5. This medication should be taken with a high fat meal to improve absorption through the gut. [23] It is excreted as metabolites or unchanged mainly through feces and to a smaller extent urine. The mean effective half-life of elexacaftor, tezacaftor, and ivacaftor is 27.4 hours, 25.1 hours, and 15 hours, respectively. [8]

History

A phase III trial published in 2019 showed people treated with elexacaftor/tezacaftor/ivacaftor improved in FEV1 at four weeks with sustained improvement at 24 weeks. Rate of pulmonary exacerbation was 63% lower and sweat chloride concentration was 41.8 mmol/L lower. [28] [29] [30]

Society and culture

United States

The combination was approved for use in the United States in 2019, for people twelve years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population. [31] In December 2020, after an additional clinical trial was completed, and FDA approval was expanded for 177 other cystic fibrosis mutations. [32] FDA approval for children aged 6–11 was added in January 2021, after a third clinical trial was completed. [33] In 2023, approval was extended to children 2–5. [34]

The US Food and Drug Administration (FDA) granted the application priority review, in addition to fast track, breakthrough therapy, and orphan drug designations. The drug's manufacturer Vertex Pharmaceuticals will receive a rare pediatric disease priority review voucher for having developed this therapy. [31]

Australia

In March 2021, health regulators in Australia approved the combination for people aged 12 years and older with at least one copy of the F508del mutation. [35] At the end of April 2022, it was placed on the Pharmaceutical Benefits Scheme, thus reducing the cost from tens of thousands of dollars a month, to tens of dollars a month. [36]

Canada

In June 2020, Health Canada approved the combination for people aged 12 years and older. [11] In September 2021, the provinces Alberta and Saskatchewan announced they will join Ontario in funding the medication. They will determine coverage on a case-by-case basis using criteria that have not yet been announced. [37]

European Union

In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended approval of the combination for the treatment of cystic fibrosis. [38] [39] It was approved for medical use in the European Union in August 2020. [9]

Norway

In April 2022, Beslutningsforum for nye metoder approved the combination for treatment of cystic fibrosis. [40]

New Zealand

In February 2022, Pharmac recommended, with medium priority, funding for people aged 12 years and over. [41] In December 2022, Pharmac announced it had reached a provisional agreement with Vertex funding Trikafta starting on 1 April 2023 for patients aged six or above. [42] [43]


Economics

United States

The list price of a year's treatment in the US is US$322,000 [44] (formerly US$311,000). [45] However, a 2020 report by Institute for Clinical and Economic Review found that the price has made the treatment not cost effective and that "an appropriate health-benefit price would range from $67,900–$85,500 per year". [46] [47]

Australia

Following the listing of the combination on the Pharmaceutical Benefits Scheme in 2022, the cost for people aged twelve years of age or older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator gene is $30.00 per month, or $7.30 for concession card holders. [48]

Germany

The initial list price in Germany for one year of therapy in 2020 was 295,000€, and in 2024 it was lowered to 207,000€. Vertex return on sales has been 36%. [49]

Ireland

In March 2023, Ireland's Health Service Executive approved funding for the provision of Kaftrio to people aged six and over with cystic fibrosis. [50] [51]

Spain

In November 2021, the Spanish government approved the reimbursement of the combination for people aged 12 years and older with at least one copy of the F508del mutation. [52]

Controversy

In addition to Trikafta's high list price, Vertex declines to make the combination available in developing countries and works to block generic alternatives. This has led to groups of patients in three countries, namely India, Ukraine and South Africa, to initiate legal and regulatory processes to compel their governments to allow the importation or local production of low-cost generic versions of Trikafta through compulsory licensing. [44] [53] In 2022, the estimated cost of manufacturing a year's supply of Trikafta was US$5,700. [44] [54]

Research

Human studies/trials
TrialTypePrimary endpointTarget ageTarget mutationsResultsReferences
Trial 1A placebo-controlled trial in patients heterozygous for the F508del mutation and another specific mutationAbsolute change in ppFEV1 from baseline at Week 4People aged 12 years and older
  • Heterozygous for the F508del mutation and one of ~200 other mutations in the CFTR gene that resulted in either:
    • No CFTR protein
    • A CFTR protein that lacks baseline activity and is not responsive to ivacaftor and tezacaftor/ivacaftor
  • ppFEV1 between 40% and 90% at screening
percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks [55] [56]
Trial 2A double-blind, active-controlled, phase 3 studyAbsolute change in ppFEV1 from baseline at Week 4People aged 12 years and olderHomozygous for the F508del mutationElexacaftor/tezacaftor/ivacaftor showed improvements in percent predicted forced expiratory volume (ppFEV1) over patients receiving tezacaftor/ivacaftor [57]
Trial 3Open label study with no placebo controlSafety, pharmacokinetics and efficacyChildren aged 6–11
  • Homozygous for the F508del mutation OR
  • Heterozygous for the F508del mutation and one of ~200 other mutations in the CFTR gene that resulted in either:
    • No CFTR protein
    • A CFTR protein that lacks baseline activity and is not responsive to ivacaftor and tezacaftor/ivacaftor
safety and pharmacokinetic profiles were generally consistent with those observed in older patients [58]

CFTR mutations that are responsive to elexacaftor/tezacaftor/ivacaftor were determined by an in-vitro study of Fischer Rat Thyroid (FRT) cells that expressed mutant CFTR. Elexacaftor/tezacaftor/ivacaftor showed effectiveness with mutations where the CFTR protein was being successfully delivered to the cell surface. [8]

Related Research Articles

<span class="mw-page-title-main">Cystic fibrosis</span> Medical condition

Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably Staphylococcus aureus. 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.

<span class="mw-page-title-main">Vertex Pharmaceuticals</span> American pharmaceutical company

Vertex Pharmaceuticals Incorporated 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 headquarters in South Boston, Massachusetts, and three research facilities, in San Diego, California, and Milton Park, Oxfordshire, England.

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

Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.

<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.

<span class="mw-page-title-main">Ataluren</span> Duchenne muscular dystrophy medication

Ataluren, sold under the brand name Translarna, is a medication for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics.

Orla Tinsley is an Irish journalist, campaigner and multimedia artist.

<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">Lumacaftor/ivacaftor</span> Cystic fibrosis drug

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

Chloride channel openers refer to a specific category of drugs designed to modulate chloride channels in the human body. Chloride channels are anion-selective channels which are involved in a wide variety of physiological functions and processes such as the regulation of neuroexcitation, transepithelial salt transport, and smooth muscle contraction. Due to their distribution throughout the body, diversity, functionality, and associated pathology, chloride channels represent an ideal target for the development of channel modulating drugs such as chloride channel openers.

<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.

<span class="mw-page-title-main">Elexacaftor</span> Cystic fibrosis medication

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.

Bonnie W. Ramsey is the Endowed Chair in Cystic Fibrosis at the University of Washington School of Medicine and the director of the Center for Clinical and Translational Research at Seattle Children's Research Institute. Her research focuses on treatments for cystic fibrosis.

Batsheva Kerem is an Israeli geneticist who was on the research team that identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later established the Israel National Center for CF Genetic Research. She discovered the most prevalent cystic fibrosis-causing mutations among the Israeli population, allowing for the establishment of nationwide genetic screening programs to identify carriers of these mutations and enabling prenatal diagnoses. She researches how some CF mutations prevent CFTR protein production by causing nonsense-mediated decay and abnormal mRNA splicing, and how therapies might be able to counteract those problems. She also studies the role of genetic instability in cancer. She is currently a professor at the Hebrew University.

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

Icenticaftor is a drug candidate for the treatment of chronic obstructive pulmonary disease (COPD) and cystic fibrosis. The drug is being developed by Novartis.

<span class="mw-page-title-main">Cystic fibrosis and race</span>

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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.

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