The rapid development of medical science over the past decades has changed the approaches to cystic fibrosis therapy. With the appearance of targeted drugs in 2012, new possibilities of a personalized approach to the therapy of patients with cystic fibrosis were revealed. Currently, four targeted drugs are used in the world that modulate (correct) the CFTR protein:
Kalydeko, Orkambi, Symdeko, Trikafta (thanks to this drug, the therapeutic coverage of patients increased from 50% to 90%).
In January 2012, Vertex offered Kalydeco (Kalydeco, ivacaftor) – the first drug against cystic fibrosis – is a CFTR potentiator (stimulator), increases the probability of opening the ion channel of the CFTR protein (due to the extension of its opening time), so that chlorine ions can freely pass through it . Ivacaftor works only in certain CFTR mutations (4-5% of patients) and does not work in the case of F508del mutation of the CFTR gene.
On July 15, 2015, Vertex launched Orkambi (Orkambi, lumacaftor + ivacaftor) in patients homozygous for the F508del CFTR mutation (approximately 50%). The CFTR corrector (modulator) lumacaftor enhances the conformational stability of F508del mutant CFTR, ensuring the processing and migration of a large amount of mature CFTR protein to the cell surface. For ivacaftor to work successfully, it is necessary for the CFTR protein to be on the surface of the cell, which is exactly what lumacaftor contributes to.
In February 2018, Symdeko/Symkevi appeared (Symdeko/Symkevi, tezacaftor+ivacaftor, ivacaftor), which, being an improved version of Orkambi, expanded patient coverage and reduced the number of adverse reactions. The CFTR corrector tezacaftor is a further development of lumacaftor, similarly promotes the migration to the cell surface of normal and certain mutant forms of CFTR, including F508del. But approximately 30% of patients remain on the sidelines, because their disease is characterized by heterozygosity: one allele of the CFTR gene carries the F508del mutation, while the second is a mutation with minimal functionality, which leads to the absence or synthesis of a defective protein insensitive to CFTR correctors. Trikafta/Caftrio (Trikafta, elexacaftor + tezacaftor + ivacaftor, ivacaftor) is intended for such a population – the corrector elexacaftor included in its composition otherwise modulates CFTR, and therefore its mechanism of action enters into synergy with tezacaftor, providing an additional increase in the amount of F508del of the CFTR protein on cell surface.
The 24-week appointment of Trikafta shows a reliable improvement: the functionality of the lungs
There are also side effects, but it is worth noting that each patient is unique and the manifestations may differ significantly. But you need to monitor the condition of the eyes, because cataracts are possible. Also, before taking Trikafta, you need to tell your doctor about kidney and liver problems, as well as about pregnancy, if you have one, or if you plan to become pregnant.
The price trick: Vertex has set the cost for US patients at $311,500 per year. In Europe, patients take Caftrio, so treatment with it per year is 194,000 euros.
Trikaft, what’s next: In the future, patient coverage will expand due to lowering the age bar to (from 2-5 years). Also, Vertex is testing a new scheme of triple therapy, which will have to be taken 1 time a day, and not 2, as Trikafta is now. The regimen, which is expected to be more effective than Tricafta, consists of 3 drugs: the CFTR potentiator VX-561, and two CFTR correctors, tezacaftor and VX-121. VX-561, or deutivacaftor, is ivacaftor modified by deuterium chemistry. Vertex is also testing CRISPR-Casg gene editing technology, which will cover those patients who are not helped by Trikafta, and it is also suggested to create an approach that will allow inhalation to deliver drugs to the lungs.
Currently, targeted therapy is available to patients with cystic fibrosis in the following countries: USA, Italy, Germany, France, Bulgaria, Czech Republic, Hungary, Israel, Slovakia, Turkey, Canada, Denmark, Austria, Holland.