Cystic fibrosis is one of the most common genetic disorders among whites in the United States, affecting approximately 30,000 children and adults. A milestone in the analysis and treatment of cystic fibrosis occurred in 1989 when the gene responsible for this condition was discovered. Since then, our understanding of the anatomy and pathophysiology of the disease has increased dramatically, as have our diagnostic and treatment modalities.
Edward A. Bell
The predicted survival age for infants diagnosed with cystic fibrosis (CF) now approaches 40 years, and nearly one-half of the current CF population in the U.S. is aged 18 years or older. Earlier diagnoses resulting from newborn screening and newer pharmacotherapies have largely contributed to this increased survival. Within the past several years, another significant advancement in the treatment of CF has occurred with the application of new classes of medications that target the underlying abnormal protein.
The gene responsible for CF morbidity and mortality codes for a protein described as the cystic fibrosis transmembrane conductance regulator (CFTR), a protein kinase A-activated chloride and bicarbonate ion channel located in epithelial cell membranes in various organ systems. These include the respiratory, gastrointestinal and reproductive systems. When activated, or opened (ie, open gating), this channel allows salt and water transport across apical membranes of epithelial cells lining these organ systems.
The complex physiologic events that result from normal CFTR function include maintenance of organ system mucous hydration and flow, acidification of mucous layers and natural antibacterial defenses. Alteration of these functions results in thickened mucus, abnormal and obstructed respiratory function, obstruction of pancreatic and biliary ducts — with resultant malabsorption and liver dysfunction — and reduced antibacterial defenses with increased infection and inflammation. Current pharmacotherapeutic treatments target these abnormalities; antibacterial and anti-inflammatory agents, and medications to decrease airway obstruction and improve airflow.
The gene encoding for CFTR is autosomal recessive, and thus two copies of the gene mutation are required for clinical disease. Greater than 2,000 different mutations have been identified. Individuals with CF can have genetic analysis performed through the Cystic Fibrosis Foundation’s Mutation Analysis Program, which allows application of more targeted pharmacotherapies for some mutations. The most common CF genotype is p.Phe508del (previously known as F508del), resulting in deletion of phenylalanine at position 508 of the CFTR protein.
Approximately 70% of individuals with CF have at least one copy of the p.Phe508del mutation. As one may recall from fundamental biology courses, cellular production and processing of functional proteins is a complex process. Mutations or abnormalities in production and processing of the CFTR protein may occur at various stages, and these functional abnormalities have been described as several types for classification (Table).
Although these classifications can be helpful to understand the various CF mutations, however, not all mutations can be easily classified. Most mutations have not been well-defined, and we are not yet able to classify their abnormal functionality. Other mutations may share abnormal functional characteristics of at least >1 class. The numerous mutations identified vary with respect to clinical manifestations. Some mutations are associated with pancreatic insufficiency or significant lung disease, while others are associated with mild disease, or no apparent clinical symptomology.
An exciting new treatment class
An exciting advancement in the pharmacotherapy of CF within the past several years has been the introduction of medications that specifically target CFTR protein abnormalities. Current drug therapies for CF target the pathophysiologic abnormalities that result from CFTR malfunction. The first of these new agents, termed CFTR modulators, was introduced in 2012 as Kalydeco (ivacaftor, Vertex Pharmaceuticals). The second modulator, Orkambi (lumacaftor/ivacaftor, Vertex Pharmaceuticals), was labeled for use by the FDA this year. Ivacaftor is described as a potentiator, as it potentiates, or improves, CFTR channel opening or gating, and chloride transport. Lumacaftor, described as a corrector, functions to promote CFTR protein-folding and transport to the cell surface.
Ivacaftor is labeled for use in individuals aged 2 years and older with CF who have one of the following 10 CFTR mutations: p.Gly551Asp, p.Gly178Arg, p.Ser549Asn, p.Ser549Arg, p.Gly551Ser, p.Gly1244Glu, p.Ser1251Asn, p.Ser1255 Pro, p.Gly1349Asp, or p.Arg117His.
In clinical studies that led to ivacaftor’s labeling, study patients demonstrated improvements in FEV1 (forced expiratory volume in 1 second) of approximately 10% (absolute change), reduced pulmonary exacerbations, and improvement in weight and quality of life measures. Ivacaftor does not have efficacy for individuals who are homozygous for the p.Phe508del mutation. Ivacaftor is hepatically metabolized by the CYP450 enzyme 3A subfamily, and thus may adversely interact with other drugs that induce or inhibit 3A activity, including rifampin, phenobarbital, phenytoin, or azole antifungal agents, Ketek (telithromycin, Sanofi Aventis), and clarithromycin, respectively.
Conversely, ivacaftor may also alter the hepatic metabolism of other medications. Thus, appropriate monitoring for drug-drug interactions is important with ivacaftor use. Lumacaftor/ivacaftor is labeled for use in individuals aged 12 years or older who are homozygous for the p.Phe508del mutation. Clinical trials of lumacaftor/ivacaftor have similarly demonstrated improvements in FEV1, weight gain, and quality of life measures. Lumacaftor is a potent inducer of the 3A enzymes, and may adversely interact with other medications metabolized by this enzyme family. Appropriate monitoring for drug-drug interactions is necessary with lumacaftor/ivacaftor use.
While ivacaftor and lumacaftor/ivacaftor represent significant advancements in the pharmacotherapy of CF, limitations of their use exist. Fully restoring the functional capacity of mutant CFTR is extremely difficult, and as many different mutations of CFTR protein production and function exist, different pharmacotherapies will be needed. Additional CFTR modulators are currently in phase 1, 2 and 3 trials, and if demonstrated to be effective and safe, they will provide more treatment options and hope for the CF community.
Bell SC, et al. Pharmacol Ther. 2015;doi:10.1016/j.pharmthera.2014.06.005.
Mall MA, et al. J Cyst Fibros. 2015;doi:10.1016/j.jcf.2015.06.002.
Solomon GM, et al. Pediatr Pulmonol. 2015;doi:10.1002/ppul.23240.
- For more information:
Edward A. Bell, PharmD, BCPS, is professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics, Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at email@example.com.
Disclosure: Bell reports no relevant financial disclosures.