Cystic Fibrosis (CF) is a life-threatening genetic disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR). The CFTR gene is located on chromosome 7 and encodes the CFTR protein. This protein functions as an ion channel on the surface of cells of a wide variety of organs such as sweat glands, respiratory tract, pancreas, liver, gut, and reproductive tract. The CFTR protein regulates chloride and water transport across the epithelial membrane. Mutations in the CFTR gene lead to defective CFTR protein or its abnormal function and result in a buildup of sticky and thick secretions in affected organs. Chronic respiratory infection and lung damage, maldigestion with growth failure, chronic liver disease, infertility, and chronic salt loss are the main clinical consequences of the CFTR gene mutation. Mutations are classified into 6 classes and described as pathogenic or disease-causing, variants of varying clinical consequence, non-CF-causing, and variants of unknown significance. A total of 485 variants are annotated on the CFTR2 database (April 29, 2022). F508del is the most prevalent CF-causing mutation worldwide. The clinical significance of rare variants is still challenging.
Historically, CF patients’ treatment has been limited by symptom management and slowing disease progression. Since the discovery of the CFTR gene in 1983, tremendous efforts have been made to develop therapies to correct the genetic defect and dysfunctions caused by CFTR mutations. The development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics.
As it was mentioned above, a normal CFTR gene sends instructions for making the CFTR protein. The normal CFTR protein has a tunnel shape with a ‘’gate’’. When the gene is defective, CFTR proteins do not form in the right shape, or ‘’gate’’ works improperly. CFTR modulators attempt to stabilize the CFTR protein and correct its shape (correctors) or increase the protein’s ability to hold the gate open long enough so the chloride can flow through (potentiators). Correctors work better when taken in combination with a potentiator (ivacaftor).
To date, four CFTR modulators have been approved by the US Food and Drug Administration (FDA) and reached the market. The first highly effective modulator Kalydeco (ivacaftor), was approved by the FDA in 2012 for about 4% of people with specific mutations in the CFTR gene, called gating mutations. 97 mutations are responsive to Kalydeco. Others-Orkambi (lumacaftor/ivacaftor), Symdeco (tezacaftor/ivacaftor), and Trikafta ()elexcaftor/tezacaftor/ivacaftor/, have been approved since, expanding the eligible CF populations for modulators.
Clinical trials and systemic review data show that CFTR modulators cause dramatic improvements in lung function (increased or stabilized FEV1 on spirometry) and nutritional status (improvement of BMI).
Orkambi is designed for people with CF ages 2 years and older with two copies of the F508del mutation.
Symdeco (tezacaftor/ivacaftor) is dedicated to the treatment of CF patients ages 6 years and older with two copies of F508 del and also for patients with a single copy of one of 154 mutations. Symdeco has been shown to have fewer side effects, such as chest tightness and drug interaction.
The last modulator was Trikafta. This modulator has already proved to be a life-changing medication. Patients call this medication a ‘’game changer’’. Recognizing the significant clinical effect of modulators, the Institute for Clinical and Economic Review (ICER) awarded Trikafta an ‘’A’’, which is a high grade for clinical effectiveness and highlighted the ‘’high certainty that treatment delivers substantial health benefits’’.
Trikafta is approved for patients ages 6 years and older with at least one mutation that is responsive to a modulator (177 mutations) or at least one F508del mutation. According to CF Foundation patient Registry data, there is a dramatic decrease in pulmonary exacerbations rate following the approval of Trikafta. Precautions should be taken in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment.
The effects of CFTR modulators last for as long as the patient is taking medication. One aspect that remains to be determined and that is a concern of parents and patients is the impact on pancreatic exocrine function and the need for PERT. A pediatric study of 28 children has shown a significant reduction in PERT consumption after 1 year of ivacaftor treatment, but further data is currently lacking. Pancreatic Enzyme Replacement Therapy (PERT) is essential for everyone with cystic fibrosis (CF) who is pancreatic insufficient. PERT helps the body digest and absorb nutrients from foods and fluids. Without PERT, children are at high risk of poor nutrient absorption leading to poor growth and slow weight gain.
Patients may experience side effects and should talk to the CF care team about:
- Any potential side effect
- Duration of side effects and how these reactions interfere with daily activity and quality of life
- Potential drug interactions
Side effects of CFTR modulators vary, but nausea and sinus congestion are common to all types of therapies. Information for patients is given in educational brochures on medication’s web pages.
CFTR modulators have brought hope for CF patients, but they are expensive, however, and equity of access to them worldwide remains an issue.
Hope this helps!
Satenik Harutyunyan, MD, Yerevan State Medical University, Department of Pediatrics # 1
Muratsan HC, Cystic Fibrosis Center