Passing a hereditary disease to a child is one of a parent’s worst fears. Virtually uncontrollable, there are a variety of inherited conditions that affect children the minute they’re born. For the one in every 35 Americans who carry a defective cystic fibrosis (CF) gene, this concept of inheritance is a grim reality.
People with CF have inherited two copies – one from each parent – of the defective CF gene, containing a slight abnormality called a mutation. Though most genetic tests screen for defective CF gene mutations, there are approximately 2,000 known of the disease, and tests often miss those more obscure DNA alterations. Thus, the disease can be passed unknowingly in any number of the approximate 1,000 new cases of CF diagnosed each year. Today, more than 30,000 people in the US are living with CF, with more than 75% of cases confirmed by age two.
With CF, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the CFTR protein to become dysfunctional. When the CFTR protein is not working correctly, it’s unable to help move chloride to the surface of cells in the body. Without the chloride to attract water to the surface, the mucus in various organs becomes thick and sticky.
In the lungs, the mucus clogs the airways and traps germs, leading to infections, inflammation, respiratory failure, and other complications. In the pancreas, the buildup of mucus prevents the release of digestive enzymes that help the body absorb food and key nutrients, resulting in malnutrition and poor growth. In the liver, the thick mucus can block the bile duct, causing liver disease. Each day, people with CF complete a combination of treatments including airway clearance to help loosen and get rid of thick mucus, inhaled medications to fight infections and keep the airways clean, pancreatic enzyme supplement capsules to improve absorption of vital nutrients, and CFTR modulators.
CFTR modulators are a class of drugs designed to correct the malfunctioning protein made by the CFTR gene. There are several CFTR modulators on the market. Still, the medications developed prior to last year had only been effective in people with highly specific mutations, rendering a great amount of individuals ineligible for treatment. In October 2019, the FDA approved the first triple combination therapy to treat patients with the most common CF mutation – F508del.
Elexacaftor/tezacaftor/ivacaftor is a fixed-dose combination medication of CFTR modulators and chloride channel openers approved for use in those patients with CF who have at least one F508del mutation in the CFTR gene. F508del is estimated to represent 90% of individuals living with CF in the U.S.
The new combination drug helps the CFTR protein function more effectively – thinning the mucus in the affected organs. The efficacy of the new drug in patients with CF aged 12 years and older was demonstrated in two trials. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients with an F508del mutation and a second minimal function mutation that results in little or no chloride channel activity. The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients with two F508del mutations. In each trial, primary analysis explored increases in the percent predicted forced expiratory volume in one second (ppFEV1) – an established marker of cystic fibrosis lung disease progression. The newly approved medication increased ppFEV1 in both trials – 13.8% and 10%, respectively.
Tremendous advancements in specialized CF care have added years and quality of life to the lives of people with the condition. There have been dramatic improvements from the first half of the 20th century when a child with CF rarely lived long enough to attend elementary school. Today, many are realizing their dreams of attending college, pursuing careers, getting married, and/or having kids. Pipelines remain full of potential treatments, including RNA therapies, for people with rare and nonsense mutations or those for whom current medicines show no improvement. There’s undoubtedly more CF innovation to come, riding on the coattails of elexacaftor/tezacaftor/ivacaftor approval.