Breakthrough therapy for Cystic fibrosis
26 August 2021
Cystic fibrosis is a rare, progressive, life-threatening disease, results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body.It leads to severe respiratory and digestive problems as well as other complications such as infections and diabetes. Cystic fibrosis is caused by a defective protein that results from mutations in the CFTR gene. While there are approximately 2,000 known mutations of the CFTR gene, the most common mutation is the F508del mutation.
Daily respiratory treatments are time-consuming and cumbersome, often incorporating multiple modalities such as airway clearance (e.g., chest physiotherapy or chest wall oscillating vest), nebulized mucolytic such as hypertonic saline and dornase alfa, and inhaled antibiotics. Even when the CFTR protein is not made correctly, it causes an imbalance of salt and fluids inside and outside the cells, leading to thick, sticky mucus in the lungs, pancreas and other organs. When proper chloride flow is re-established, the mucus becomes rehydrated. However, such regimens alone do not resolve disease symptoms adequately or eliminate the risk of exacerbations. Therefore, correcting the basic CF defect has long been a goal of therapeutic development.
In October 2019, The U.S. Food and Drug Administration approved Trikafta (elexacaftor/ivacaftor/tezacaftor), the first triple combination therapy available to treat patients with the most common cystic fibrosis mutation that target the defective CFTR protein. It helps the protein made by the CFTR gene mutation function more effectively. Currently available therapies that target the defective protein are treatment options for some patients with cystic fibrosis, but many patients have mutations that are ineligible for treatment. Trikafta is the first approved treatment that is effective for cystic fibrosis patients 12 years and older with at least one F508del mutation, which affects 90% of the population with cystic fibrosis or roughly 27,000 people in the United States.
It significantly improved lung function at four weeks, which was sustained through 24 weeks
Reduced lung flare-ups by 63%
Decreased the amount of salt lost through sweating
Improved patients' short-term quality of life and respiratory symptom scores
In some cases, the drug has been so effective that patients have been removed from the lung transplant list. The efficacy of Trikafta in patients with cystic fibrosis 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 who had an F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone.
The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients who had two identical F508del mutations.
In each trial, the primary analysis looked at increases in the percent predicted forced expiratory volume in one second, known as ppFEV1, which is an established marker of cystic fibrosis lung disease progression. Trikafta increased the ppFEV1 in both trials.
Trikafta(elexacaftor/ivacaftor/tezacaftor), the combo drug in which two of the drugs work together to stabilize the protein folding and allow the protein to reach the surface of the cell. The third helps improve protein function once everything is in place. It’s the combination of the efficiency of the drugs together that’s made TRIKAFTA such an effective CFTR modulator for this patient population.
Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta were rash and influenza (flu) events. The most common adverse drug reactions included headaches, upper respiratory tract infections, abdominal pains, diarrhoea, rashes, increased liver enzymes (alanine aminotransferase and aspartate aminotransferase), nasal congestion, increased blood creatine phosphokinase (an enzyme that can be associated with muscle damage), rhinorrhoea (mucus in the nasal cavity), rhinitis (swelling of the mucous membrane of the nose), influenza, sinusitis and increased blood bilirubin (may be caused by problems involving the liver, gallbladder or red blood cells).
While not a true cure, this therapy is a major breakthrough in the treatment of CF and gives new hope to affected children and their families.