Since 1938 when cystic fibrosis was first described, research has been underway to study the basics of the disease and how to treat its many clinical manifestations. While some efforts focus on the basic defect in cystic fibrosis (CFTR dysfunction) others are aimed at specific complications. In particular, research efforts can be divided into areas including those focused on restoring CFTR function, improving mucociliary clearance, anti-inflammatory or anti-infective treatments as well as therapies focused on improving nutritional health. While all are important and improve the health of patients with cystic fibrosis, perhaps the most exciting at this time is the expanding list of CFTR modulators.
There are greater than 1700 known mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein causing various degrees of CFTR dysfunction. This defective CFTR channel results in faulty chloride flow through this channel. Current research has focused on correcting this CFTR dysfunction and therefore improving multiple downstream effects. This work has resulted in the development of CFTR modulators, drugs which target this defect in the (CFTR) protein. There are three different kinds of modulator drugs including potentiators, correctors and amplifiers.
A potentiator drug will allow improved chloride flow through the CFTR protein channel, an example of which is ivacaftor (Kalydeco). CF patients with specific gating and conducting mutations as well as patients with residual function and splice mutations may be aided by this medication. A second type of modulator therapy would include a corrector medication. This drug would function by allowing a faulty CFTR protein to fold to a proper shape again to improve chloride flow through the channel. The most common CFTR mutation is F508del which leads to this improperly folded chloride channel. While correctors can help to improve the number of CFTR proteins that can function in a cell, they cannot correct to normal levels. Using modulators in combination, such as a corrector with a potentiator, can lead to significantly improved CFTR function. Two initial combination medications, lumacaftor/ivacaftor (Orkambi) and tezacaftor/ivacaftor (Symdeko) are available to patients with two copies of the F508del mutation with tezacaftor/ivacaftor also being available to patients with 26 other specific mutations. While these drugs are exciting, there is still limitation in who they were offered to and their potential benefits.
The final modulator developed includes amplifiers, which can actually increase the amount of CFTR protein produced. While there are no amplifiers yet offered to patients, they are currently in development.
Combination modulator therapies continue to be developed and the newest triple combination drug includes elexacaftor and tezacaftor (correctors) in combination with ivacaftor (potentiator). This drug, sold as Trikafta, is available to CF patients with at least on copy of F508del and any other mutation and is therefore available to a much greater number of patients. This combination therapy has shown great efficacy in improving lung function and decreasing the number of pulmonary exacerbations.
While these modulator therapies are great advances in caring for patients with cystic fibrosis, they are not a cure. More work must be done and the scientific community will continue to partner with CF patients and their families to improve outcomes for our patients with cystic fibrosis. The American Thoracic Society will support these advances in CF care alongside clinicians, scientists and our patient and family partners.
Debra Boyer, MD, MHPE
Associate Chief, Division of Pulmonary Medicine
Associate Professor of Pediatrics
Harvard Medical School
Quick Facts About Cystic Fibrosis |
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