Cystic Fibrosis Research 2014

Cystic fibrosis is a hereditary disease that mainly affects organs in which mucus is produced. The most affected tissues are the airways, the sinuses, the pancreas, the pancreas, the bile ducts of the liver, the intestine and the vas deferens duct in humans. The main cause of morbidity and premature death in people with cystic fibrosis is lung damage in the form of severe and chronic airway infections. The cause of cystic fibrosis is an absence of the function of a protein known as the Cystic Fibrosis Transmembrane Conductance Regulator, or CFTR. An absence of CFTR function occurs when an individual inherits two mutations, one from the father and one from the mother, in the CFTR gene. This year marks the 25th anniversary of the discovery of the identity of the gene responsible for cystic fibrosis. At the North American Cystic Fibrosis Congress held in Atlanta, Georgia, in October 2014, researchers took stock of the progress made over the past 25 years and especially the challenges that remain in order for this disease to be treated effectively.

After the discovery of the faulty gene, the researchers identified five major classes of CFTR protein defects (Figure 1). Identifying these classes allows researchers to target their research according to the specific genetic defect of each individual. The first major success reported two years ago included a defect in the CFTR class III. This defect ensures that the CFTR protein has a normal structure and fits properly into the membranes of the cells lining the mucous membranes. On the other hand, during a class III mutation, the CFTR is unable to open to allow chloride and bicarbonate to pass through. The absence of chloride secretion produces a deficit of salt secretion in the mucus and makes the mucus much too viscous. A new drug, ivacaftor (trade name Kalydeco®), has been put on the market by Vertex. This medication restores normal function to the mutant CFTR class III. Patients with class III mutations on one of their two CFTR genes have a very marked improvement in their respiratory and digestive health. Moreover, the studies presented at the recent conference confirmed that there is also a significant improvement in the quality of life of these individuals. The researchers found that ivacaftor is effective for all class III mutations and may also have some effectiveness for certain types of class IV mutations such as R117H. Although all of these mutations are only found in about 2 to 3% of patients, the significant improvement in their health confirms that even a partial correction of CFTR function can have a major impact on the quality of life of people with cystic fibrosis.

Several presentations at the conference focused on an update of studies to correct CFTR in patients with class I mutations. In the class I mutation, the transcription of the genetic message does not happen because of a defect in the genetic code that tells the cell to stop the synthesis of the CFTR protein before it is well formed. The result is a complete absence of the CFTR protein in the membranes of the cells lining the mucosa of various tissues. This defect results in cystic fibrosis with severe symptoms. For several years, we have known that it is possible to thwart this class of mutations by using certain products from the aminoglycoside antibiotic class. On the other hand, the dose of aminoglycosides needed to correct this defect in patients is too high to be safe. There has therefore been the development of a small, less toxic molecule known as Ataluren® from PTC Therapeutics and which has been the subject of several clinical studies in cystic fibrosis. The initial clinical studies were very promising, but they were small studies in a population of patients with gene mutations.
particular ticks. A larger study has been done in North America and the results show some benefit on several parameters, but the results are much less convincing than in previous studies. When a sub-analysis of patients was done to exclude those taking aminoglycoside medications, the group treated with Ataluren® showed a marked improvement compared to the placebo group. Researchers believe that there could be better results if Ataluren® was compared to a placebo in a population of patients who do not take any aminoglycosides. These studies are still ongoing and Ataluren® remains a promising drug for people with CFTR class I mutation cystic fibrosis. However, there is significant development to be done before this medication can be approved by Health Canada for the treatment of cystic fibrosis.

Finally, 89% of people with cystic fibrosis have at least one class II mutation and half of all patients with cystic fibrosis in Quebec have two CFTR gene mutations in class II. Class II mutations (e.g. F508del) cause the CFTR to not maintain a normal structure and the protein is rapidly degraded before it can reach the cell membrane to allow the hydration of the mucus. It is therefore necessary to administer a drug that can allow CFTR class II to be transported to the membrane and a second drug that will ensure its opening. Fortunately, we already have the second drug, ivacaftor. Research efforts are therefore concentrated on the discovery of new molecules that can prevent the degradation of CFTR class II and allow it to access the cell membrane. Two major studies have been done on nearly 1,000 patients with cystic fibrosis with class II mutations. In summary, it is clear that the combination of a drug that allows the transport of CFTR (corrector, e.g. VX-809) and a drug that can allow the opening of CFTR (potentiator, e.g. ivacaftor) is an effective strategy. There is a statistically significant improvement in respiratory function and sweat test in patients treated with this combination of medications. On the other hand, the improvement was only observed in the group of patients with two class II mutations. Moreover, the improvement was modest with an improvement in respiratory function (FEV1) varying from 2.6 to 4.0% and a decrease in the number of respiratory infectious exacerbations of approximately 30 to 39%. These differences were clearly significant. In addition, there were very few side effects in the group taking active medication. Because of clinical improvements in this population, Vertex is moving forward to obtain the approval of regulatory bodies such as Health Canada for this new therapy. This combination of drugs is not yet approved by Health Canada. In addition, Vertex is continuing studies with a second combination of correctors and potentiators, VX-661 with ivacaftor, for people with cystic fibrosis who have class II mutations. Some preliminary data in a small number of patients and in short studies demonstrate promising results. Moreover, this new combination is also well tolerated.

So we learned at the 2014 North American Cystic Fibrosis Congress that 25 years after the discovery of the gene involved in cystic fibrosis, it is possible to correct, at least partially, the defective function of this protein. More importantly, we learned that correcting the CFTR defect is associated with improvements in patients' quality of life as well as a decrease in the number of episodes of respiratory exacerbations. Much clinical research work remains to be done in order to confirm the results in most of the cystic fibrosis patient population, but the advances are encouraging for all patients. We are at the beginning of a new era, that of effective cystic fibrosis therapy, which involves correcting the fundamental defect in CFTR. It is expected that the effectiveness of these new molecules will continue to improve over the next few years and that we will see these drugs appear in our pharmacies within five years. However, it will be important to continue research in order to improve the effectiveness of each of these products. For now, it remains essential for each person with cystic fibrosis to do everything possible to maintain their health so that they can benefit from these new therapies as soon as they are available. This is a great challenge that requires excellent collaboration between patients, their families and the professionals in their cystic fibrosis clinics. Together, we will be able to reach our common goal of transforming the quality of life for people living with cystic fibrosis.

Dr Andre Cantin

Pulmonologist Full Professor
Department of Pulmonology Sherbrooke University Hospital Center
Sherbrooke (Quebec) Canada

‍