Research and Cystic Fibrosis: 2022 Update

Dr. Christelle Bergeron and Dr. André Cantin

Pulmonology department

Cystic Fibrosis Clinic (adult) Sherbrooke University Hospital Center

The main advances in cystic fibrosis research over the past year are undeniably linked to new modulators of CFTR function. Over the past two years, the arrival of triple therapy (elexacaftor, tezacaftor and ivacaftor, a trio called ETI) has transformed the lives of the majority of people with CF. We are experiencing a real revolution in the treatment of CF. These changes, which have been long overdue for so long, encourage us enormously. However, solutions of similar effectiveness remain to be found for all people with CF, including the 10% whose defective CFTR does not respond to ETI. Moreover, as is often the case, the new ETI treatment also brings new challenges that we will discuss.

Approximately 90% of people with CF have at least one F508del mutation and are therefore qualified for ETI treatment. For these people, the beneficial effects are remarkable. The chloride concentration in sweat is a marker of the fundamental defect associated with defective CFTR. The results of the sweat test of people taking ETI approach the values observed in people with a mild form of the disease. Respiratory function improves by about 14% in the majority of people treated with ETI, and globally, the number of people with CF waiting for a lung transplant has declined significantly. The number of respiratory exacerbations, the main cause of hospitalization and deterioration of respiratory functions, has decreased by at least 50% as a result of the new treatment. Bronchial images obtained by CT scan of the chest after one year of ETI treatment demonstrate a dramatic disappearance of excess mucus normally visualized in the airways of people with CF. Similar observations are also reported for sinus imaging. The beneficial effects of ETI also affect the digestive system with significant weight gain and an improvement in the serum vitamin profile. Diabetes also seems to be improving in several individuals taking ETI.

ETI medication is generally well tolerated. Some side effects, including occasional headaches, skin rash, and sometimes a feeling of respiratory congestion, are observed, especially in the first weeks of treatment, and improve thereafter. Taking ETI also requires regular medical follow-up with the determination of serum markers of liver function and with modification of doses according to the interactions of ETI with other drugs. Despite taking ETI, people with CF should continue with the many other treatments for CF unless otherwise advised by their medical team.

Several challenges remain in the treatment of CF, the most pressing of which is the discovery of effective therapies for all people, regardless of their type of CFTR gene mutation. The majority of people with CF who do not meet the eligibility criteria for ETI treatment have one or two class 1 mutations. These mutations cause an error in reading the genetic code that controls the production of the CFTR protein. The result is an absence of CFTR protein, which explains the ineffectiveness of ETI in these people. Fortunately, there are molecules that can erase this reading error in cells examined in the laboratory. As a result of these scientific observations, researchers collaborated with the pharmaceutical industry and clinicians to develop clinical studies that will determine the safety and clinical effectiveness of ELX-02 combined with ivacaftor. The preliminary results of this work failed to achieve the desired effectiveness, and researchers are examining the data to determine whether the lack of effectiveness is related to an insufficient amount of the drug reaching the target cells. Several groups of researchers continue to work on other approaches, including gene editing using molecular scissors such as CRISPR and the transfection of the healthy CFTR gene to bronchial cells. This work is the priority of many foundations working in FK.

The biggest challenge associated with the arrival of ETI is still access to this expensive medication. Fortunately, in Quebec, ETI treatment is now reimbursed for the majority of people with CF and who have at least one F508del mutation. Recently, reimbursement has now been extended to people aged six and over, regardless of respiratory function (FEV1). It is expected that the earlier in life the defective CFTR is corrected, the less likely people with CF will have the sequelae of this condition.

The arrival of ETI treatment is also associated with emerging medical situations that we will need to learn to recognize and manage. In some people, especially those with residual pancreatic function, the introduction of ETI therapy helps to remove the obstruction of the pancreatic and bile ducts. A possible consequence of this effect is that pancreatic tissue is at risk of being exposed to an abundance of pancreatic enzymes, which could lead to pancreatitis. Pancreatitis causing severe abdominal pain has been reported in some people taking ETI whose pancreatic function was preserved. We also observed that ETI treatment is often associated with an increase in the absorption capacity of vitamins A and E as well as a decrease in serum glucose in people with diabetes. It is therefore important to ensure medical and nutritional follow-up after the start of taking this medication in order to adjust vitamin supplements and hypoglycemic treatments. Finally, taking ETI can cause drug interactions, which is why it is recommended to always check with your medical team before starting a new medication.

With the benefits of ETI in FK, it is expected that we will see a marked improvement in life expectancy, which is great. This change will also bring new medical considerations, including the control of risk factors for cardiovascular disease in CF. The improved absorption associated with taking ETI brings weight gain and we are already beginning to see people with CF who are overweight and sometimes obese. In addition, we have always recommended that our patients eat a diet that is high in fat, calories, and salt. These recommendations for people taking ETI could lead to an increased risk of obesity, dyslipidemia, diabetes and high blood pressure, all factors involved in the onset of arteriosclerosis. The nutritional recommendations should be adjusted according to the situation of each person. Finally, in the past, numerous bronchitis, shortness of breath, abdominal pain, difficulties in maintaining adequate muscle mass and the therapeutic burden associated with CF are all factors that favoured a sedentary lifestyle. It will be important for people on ETI to aim for a more sustained level of physical activity to ensure better health in the long term.

The adjustments made by ETI treatments represent great challenges, because they most often come with a marked improvement in the quality of life. However, much work remains to be done to ensure that everyone benefits from the significant advances in CF research made in recent years. The best way to do this is to continue our teamwork with researchers, health professionals, and people living with CF. Together we can defeat CF.

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