Until recently, the only drugs prescribed to patients with cystic fibrosis (CF) were aimed to alleviate some of the general symptoms of CF. However, true improvement requires functional CFTR proteins. As long as these proteins are not working, the thick mucus will keep forming. To address this, two main approaches are being used1. First, small molecules are being developed to help defective CFTR proteins to restore ion transport. The other approach focuses on gene therapy, introducing a correct CFTR template that can replace the dysfunctional CFTR protein. Some small molecules restoring CFTR function are already available to CF patients2 (see Available CFTR modulator drugs) and while gene therapy looks very promising, it is still in the future (see Blog).
Molecules designed to restore CFTR functions are called CFTR modulators. CFTR mutations can cause various defects in CFTR function (see CFTR mutations) and require diverse therapeutic approaches. CFTR modulators could help in various ways – bypass premature ending of protein synthesis, help the protein to form properly, get to the cell membrane, keep the channel open for ion passage or increase the protein stability in the membrane. These steps require multiple CFTR modulators. Personalized treatment of CF is key to targeting the underlying problems of specific mutations.
If there is no template for CFTR (e.g., a big part of the template is missing, CFTR mutations class IA), no CFTR modulator could help – because there is no defective protein to be helped. These types of CFTR mutations would benefit from genetic therapy (see Blog). If the protein is degraded too soon because of a premature stop signal, a translational read-through agent can help “skip” the faulty stop signal and finish the protein. CFTR correctors help the defective protein to fold and get to the cell surface. CFTR potentiators keep the ion channel open. When only a few proteins are produced, amplifiers could help increase the number of synthesized proteins. Stabilizers can anchor unstable CFTR proteins in the cell membrane3.
Translational read-through agents promote skipping the premature termination signal, which allows protein synthesis to continue until the proper stop signal. These compounds could help class IB CFTR mutations. There are no approved translational read-through agents yet. Aminoglycoside antibiotics, such as gentamicin or geneticin, have the read-through potential but are very toxic3. Another compound – ataluren – looked very promising. However, when tested in clinical studies, it provided contradictory results and its clinical development has been stopped4 The search for an effective and safe translational read-through compound is ongoing. A potential treatment ELX-02 has just received financial support from the Cystic Fibrosis Foundation for further clinical trials5.
CFTR correctors help defective CFTR proteins to fold properly and get to the cell membrane. CFTR trafficking mutations should benefit from this type of modulator, but these (including the most common F508del mutation) display additional defects after being corrected. Hence, a corrector on its own is simply not enough. While combining correctors with CFTR potentiators is advantageous for multiple CFTR mutation classes (for class II; in combination with other modulators also for class V and class VI), it can also be dangerous due to drug interaction. To avoid this, it would be interesting to explore dual compounds able to act both as correctors and potentiators6. So far three CFTR correctors – lumacaftor, tezacaftor and elexacaftor – are approved by the FDA and are available to CF patients with specific mutations2 (see Available CFTR modulator drugs). Many more compounds with CFTR correcting potential have been identified and are currently being studied3.
CFTR potentiators improve CFTR channel gating defects by keeping the channel open so that the chloride ions can pass through. Potentiators are effective for class III and class IV mutations, and in combination with other modulators, they can also benefit class II, class V and class VI mutations. One potentiator – ivacaftor – is approved by the FDA and available to CF patients with specific mutations2 (see Available CFTR modulator drugs). Many other compounds with potentiator ability are being studied, including various natural substances like flavonoids or curcumin4.
Amplifiers can stimulate CFTR protein production that has been decreased by class V mutations. In combination with correctors and potentiators, amplifiers could be beneficial for other mutations, too. The research for possible CFTR amplifiers is ongoing. So far, there are no amplifiers available for CF patients3.
Stabilizers can help CFTR proteins that are unstable in the cell membrane (class VI or corrected class II mutations). These proteins would be degraded faster than normal and stabilizers can anchor them in the membrane for longer. Some compounds have shown CFTR-anchoring activity, but the research is in the early stages and no stabilizers are approved at this time3.
Mutation-specific treatment strategies are focused on the fundamental CF defects and are revolutionizing the treatment of CF patients. Only a few modulators are currently available to patients and many more require extensive research7. Supporting the research of novel, more effective CFTR modulators is key in contributing to better life prospects of people with CF.
Available CFTR Modulator Drugs
At this time, three different CFTR modulator drugs are available for people with CF, marketed as Kalydeco®, Orkambi® and Symdeko®. A fourth one has just been approved by the FDA, named TrikaftaTM.
The first CFTR modulator drug that was approved by the FDA is Kalydeco®. Kalydeco® contains only one CFTR modulator – the potentiator ivacaftor. Kalydeco® was first approved in 2012 for people with the G551D mutation8. With time and more research, the list of responsive mutations expanded and now includes the following mutations9:
Based on preclinical data, even more CFTR mutations should respond to Kalydeco®9. For more information on Kalydeco®, visit https://www.kalydeco.com.
The second CFTR modulator drug approved by the FDA was Orkambi®. Orkambi® is the combination of the potentiator ivacaftor and the corrector lumacaftor10. Since its approval in 2015, it has been prescribed only to patients with two copies of the most common mutation – F508del11. For more information on Orkambi®, visit https://www.orkambi.com.
The next FDA-approved CFTR modulator drug is Symdeko® (marketed as Symkevi® in Europe). Symdeko® was first approved in 2018 and is the combination of the potentiator ivacaftor and the corrector tezacaftor12. Nowadays, Symdeko® is indicated for people with two copies of F508del, or with at least one of the following13:
For more information on Symdeko®, visit https://www.symdeko.com.
These available drugs are now joined by the triple combination drug TrikaftaTM containing ivacaftor, tezacaftor, and a novel corrector elexacaftor, which was approved by the FDA in October 2019. Based on the clinical trials, this novel drug should benefit CF patients who have at least one F508del mutation, which represents about 90% of the people with CF14. For more information on TrikaftaTM, visit https://www.trikafta.com/.
While the benefits of these drugs do outweigh the risks (otherwise they would not be approved), taking them can cause some serious side effects. These include liver problems, eye cataracts, chest pain, headache, nausea, sinus congestion or dizziness15,16,17. The relative gravity of the side effects taken together with a limited improvement of CF symptoms calls for further relentless research into CF treatment options. It is also important to note that for some classes of CFTR mutations, there is still no approved CFTR modulator drug.
- 1 - J. S. Elborn, “Cystic fibrosis - J Stewart Efborn,” Lancet, vol. 388, pp. 2519–2531, 2016.
- 2 - https://www.cff.org/Research/About-Our-Research/Research-Milestones/
- 3 - I. Pranke, A. Golec, A. Hinzpeter, A. Edelman, and I. Sermet-Gaudelus, “Emerging therapeutic approaches for cystic fibrosis. From gene editing to personalized medicine,” Frontiers in Pharmacology, vol. 10, no. FEB. Frontiers Media S.A., 2019.
- 4 - https://www.cff.org/Trials/pipeline/details/47/Ataluren
- 5 - https://investors.eloxxpharma.com/news-releases/news-release-details/eloxx-pharmaceuticals-announces-cystic-fibrosis-foundation-cf
- 6 - M. C. Dechecchi, A. Tamanini, and G. Cabrini, “Molecular basis of cystic fibrosis: from bench to bedside,” Ann. Transl. Med., vol. 6, no. 17, pp. 334–334, Sep. 2018.
- 7 - https://www.cff.org/trials/pipeline
- 8 - https://investors.vrtx.com/news-releases/news-release-details/fda-approves-kalydecotm-ivac
- 9 - https://www.kalydeco.com/
- 10 - https://www.orkambi.com/
- 11 - https://investors.vrtx.com/news-releases/news-release-details/fda-approves-orkambitm-lumacaftorivacaftor-first-medicine-treat
- 12 - https://www.vrtx.com/story/fda-approves-symdeko
- 13 - https://www.symdeko.com/
- 14 - https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis?utm_campaign=102119_PR_FDA%20approves%20new%20breakthrough%20therapy%20for%20cystic%20fibrosis&utm_medium=email&utm_source=Eloqua
- 15 - https://www.kalydeco.com/safety-side-effects
- 16 - https://www.orkambi.com/safety-side-effects
- 17 - https://www.symdeko.com/side-effects